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  • 151.
    Cederlöf, Martin
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Pettersson, Erik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Sariaslan, Amir
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Östberg, Per
    Division of Speech and Language Pathology, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden; Department of Speech and Language Pathology, Karolinska University Hospital, Stockholm, Sweden.
    Kelleher, Ian
    Department of Psychiatry, Royal College of Surgeons in Ireland, Dublin, Ireland.
    Långström, Niklas
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Swedish Prison and Probation Service, R&D unit, Stockholm, Sweden.
    Gumpert, Clara Hellner
    Centre for Psychiatry Research & Education, Department of Clinical Neuroscience, Karolinska Institutet & Stockholm County Council, Stockholm, Sweden.
    Lundström, Sebastian
    Centre for Ethics, Law and Mental Health (CELAM), University of Gothenburg, Gothenburg, Sweden; Gillberg Neuropsychiatry Centre, University of Gothenburg, Gothenburg, Sweden.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    The association between childhood autistic traits and adolescent psychotic experiences is explained by general neuropsychiatric problems.2016In: American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, ISSN 1552-4841, E-ISSN 1552-485X, Vol. 171, no 2, 153-159 p.Article in journal (Refereed)
    Abstract [en]

    Studies suggest associations between childhood autistic traits and adolescent psychotic experiences. However, recent research suggests that a general neuropsychiatric problems factor predicts adverse outcomes better than specific diagnostic entities. To examine if the alleged association between autistic traits and psychotic experiences could rather be explained by a general neuropsychiatric problems factor comprising symptoms of ADHD, tic disorder, developmental coordination disorder, and learning disorder, we conducted a prospective cohort study based on the Child and Adolescent Twin Study in Sweden. In addition, we examined the genetic and environmental influences on the associations. A total of 9,282 twins with data on childhood autistic traits and other neuropsychiatric problems, and follow-up data on psychotic experiences at ages 15 and/or 18 years were included. First, psychotic experiences were regressed on autistic traits and second, the general neuropsychiatric problems factor was added to the model. Auditory hallucinations were analyzed separately from the other psychotic experiences. Finally, twin analyses were employed to disentangle genetic from environmental influences in the observed associations. Replicating prior research, significant associations were found between autistic traits in childhood and auditory hallucinations at ages 15 and 18. However, after controlling for the general neuropsychiatric problems factor, the associations between autistic traits and auditory hallucinations disappeared, whereas the association between the general neuropsychiatric problems factor and auditory hallucinations persisted after controlling for autistic traits. Twin analyses revealed that the association between the general neuropsychiatric problems factor and auditory hallucinations was driven by shared genetic influences. .

  • 152.
    Celorio-Mancera, Maria de la Paz
    et al.
    Stockholm University, Faculty of Science, Department of Zoology.
    Ahn, Seung-Joon
    Vogel, Heiko
    Heckel, David G.
    Transcriptional responses underlying the hormetic and detrimental effects of the plant secondary metabolite gossypol on the generalist herbivore Helicoverpa armigera2011In: BMC Genomics, ISSN 1471-2164, Vol. 12, 575- p.Article in journal (Refereed)
    Abstract [en]

    Background: Hormesis is a biphasic biological response characterized by the stimulatory effect at relatively low amounts of chemical compounds which are otherwise detrimental at higher concentrations. A hormetic response in larval growth rates has been observed in cotton-feeding insects in response to increasing concentrations of gossypol, a toxic metabolite found in the pigment glands of some plants in the family Malvaceae. We investigated the developmental effect of gossypol in the cotton bollworm, Helicoverpa armigera, an important heliothine pest species, by exposing larvae to different doses of this metabolite in their diet. In addition, we sought to determine the underlying transcriptional responses to different gossypol doses. Results: Larval weight gain, pupal weight and larval development time were measured in feeding experiments and a hormetic response was seen for the first two characters. On the basis of net larval weight gain responses to gossypol, three concentrations (0%, 0.016% and 0.16%) were selected for transcript profiling in the gut and the rest of the body in a two-color double reference design microarray experiment. Hormesis could be observed at the transcript level, since at the low gossypol dose, genes involved in energy acquisition such as beta-fructofuranosidases were up-regulated in the gut, and genes involved in cell adhesion were down-regulated in the body. Genes with products predicted to be integral to the membrane or associated with the proteasome core complex were significantly affected by the detrimental dose treatment in the body. Oxidoreductase activity-related genes were observed to be significantly altered in both tissues at the highest gossypol dose. Conclusions: This study represents the first transcriptional profiling approach investigating the effects of different concentrations of gossypol in a lepidopteran species. H. armigera's transcriptional response to gossypol feeding is tissue-and dose-dependent and involves diverse detoxifying mechanisms not only to alleviate direct effects of gossypol but also indirect damage such as pH disturbance and oxygen radical formation. Genes discovered through this transcriptional approach may be additional candidates for understanding gossypol detoxification and coping with gossypol-induced stress. In a generalist herbivore that has evolved transcriptionally-regulated responses to a variety of different plant compounds, hormesis may be due to a lower induction threshold of growth-promoting, stress-coping responses and a higher induction threshold of detoxification pathways that are costly and cause collateral damage to the cell.

  • 153.
    Ceplitis, H.
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Department of Evolution, Genomics and Systematics. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Department of Evolution, Genomics and Systematics, Evolutionary Biology. Evolutionsbiologi.
    Ellegren, H.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Department of Evolution, Genomics and Systematics. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Department of Evolution, Genomics and Systematics, Evolutionary Biology. Evolutionsbiologi.
    Adaptive molecula evolution in HINTW, a female-specific gene in birds.2004In: Molecular Biology and Evolution, no 21, 249-254 p.Article in journal (Refereed)
  • 154.
    Charpentier, Emmanuelle
    et al.
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Department of Regulation in Infection Biology, Max Planck Institute for Infection Biology.
    Hess, Wolfgang R
    Editorial: RNA in bacteria2015In: FEMS Microbiology Reviews, ISSN 0168-6445, E-ISSN 1574-6976, Vol. 39, no 3, 277-279 p.Article in journal (Refereed)
  • 155.
    Chen, Changchun
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Huang, Bo
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Anderson, James T
    Byström, Anders S
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Unexpected accumulation of ncm5U and ncm5s2U in a trm9 mutant suggests an additional step in the synthesis of mcm5U and mcm5s2U.2011In: PLoS ONE, ISSN 1932-6203, Vol. 6, no 6, e20783- p.Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Transfer RNAs are synthesized as a primary transcript that is processed to produce a mature tRNA. As part of the maturation process, a subset of the nucleosides are modified. Modifications in the anticodon region often modulate the decoding ability of the tRNA. At position 34, the majority of yeast cytosolic tRNA species that have a uridine are modified to 5-carbamoylmethyluridine (ncm(5)U), 5-carbamoylmethyl-2'-O-methyluridine (ncm(5)Um), 5-methoxycarbonylmethyl-uridine (mcm(5)U) or 5-methoxycarbonylmethyl-2-thiouridine (mcm(5)s(2)U). The formation of mcm(5) and ncm(5) side chains involves a complex pathway, where the last step in formation of mcm(5) is a methyl esterification of cm(5) dependent on the Trm9 and Trm112 proteins.

    METHODOLOGY AND PRINCIPAL FINDINGS: Both Trm9 and Trm112 are required for the last step in formation of mcm(5) side chains at wobble uridines. By co-expressing a histidine-tagged Trm9p together with a native Trm112p in E. coli, these two proteins purified as a complex. The presence of Trm112p dramatically improves the methyltransferase activity of Trm9p in vitro. Single tRNA species that normally contain mcm(5)U or mcm(5)s(2)U nucleosides were isolated from trm9Δ or trm112Δ mutants and the presence of modified nucleosides was analyzed by HPLC. In both mutants, mcm(5)U and mcm(5)s(2)U nucleosides are absent in tRNAs and the major intermediates accumulating were ncm(5)U and ncm(5)s(2)U, not the expected cm(5)U and cm(5)s(2)U.

    CONCLUSIONS: Trm9p and Trm112p function together at the final step in formation of mcm(5)U in tRNA by using the intermediate cm(5)U as a substrate. In tRNA isolated from trm9Δ and trm112Δ strains, ncm(5)U and ncm(5)s(2)U nucleosides accumulate, questioning the order of nucleoside intermediate formation of the mcm(5) side chain. We propose two alternative explanations for this observation. One is that the intermediate cm(5)U is generated from ncm(5)U by a yet unknown mechanism and the other is that cm(5)U is formed before ncm(5)U and mcm(5)U.

  • 156.
    Chen, Changchun
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Huang, Bo
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Eliasson, Mattias
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Rydén, Patrik
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics.
    Byström, Anders S
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Elongator Complex Influences Telomeric Gene Silencing and DNA Damage Response by Its Role in Wobble Uridine tRNA Modification2011In: PLoS genetics, ISSN 1553-7404, Vol. 7, no 9, e1002258- p.Article in journal (Refereed)
    Abstract [en]

    Elongator complex is required for formation of the side chains at position 5 of modified nucleosides 5-carbamoylmethyluridine (ncm(5)U(34)), 5-methoxycarbonylmethyluridine (mcm(5)U(34)), and 5-methoxycarbonylmethyl-2-thiouridine (mcm(5)s(2)U(34)) at wobble position in tRNA. These modified nucleosides are important for efficient decoding during translation. In a recent publication, Elongator complex was implicated to participate in telomeric gene silencing and DNA damage response by interacting with proliferating cell nuclear antigen (PCNA). Here we show that elevated levels of tRNA(Lys) (s(2) ) (UUU), tRNA(Gln) (s(2) ) (UUG), and tRNA(Glu) (s(2) ) (UUC), which in a wild-type background contain the mcm(5)s(2)U nucleoside at position 34, suppress the defects in telomeric gene silencing and DNA damage response observed in the Elongator mutants. We also found that the reported differences in telomeric gene silencing and DNA damage response of various elp3 alleles correlated with the levels of modified nucleosides at U(34). Defects in telomeric gene silencing and DNA damage response are also observed in strains with the tuc2Δ mutation, which abolish the formation of the 2-thio group of the mcm(5)s(2)U nucleoside in tRNA(Lys) (mcm(5) (s(2) ) (UUU) ), tRNA(Gln) (mcm(5) (s(2) ) (UUG) ), and tRNA(Glu) (mcm(5) (s(2) ) (UUC) ). These observations show that Elongator complex does not directly participate in telomeric gene silencing and DNA damage response, but rather that modified nucleosides at U(34) are important for efficient expression of gene products involved in these processes. Consistent with this notion, we found that expression of Sir4, a silent information regulator required for assembly of silent chromatin at telomeres, was decreased in the elp3Δ mutants.

  • 157.
    Chen, Jun
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Plant Ecology and Evolution.
    Conifer Evolution, from Demography and Local Adaptation to Evolutionary Rates: Examples from the Picea genus2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Evolutionary process can be inferred at three different levels: the species level, the population level and the molecular level. In this thesis, I applied approaches at these three levels and aimed to get a comprehensive picture of conifer evolution, from speciation and demography to geographic variation and local adaptation, and then to the molecular evolution of proteins and small regulatory RNAs.

    Spruce species have been observed to possess a large number of trans-species shared polymorphisms. Using an “Isolation with migration” model, we found that the large effective population size of spruce retained these shared polymorphisms, inheriting them from the common ancestor. Post-divergence gene flow only existed between Picea abies and P. glauca, and between P. wilsonii and P. schrenkiana. The combination of Tajima’s D and Fay & Wu’s H at most of loci suggested an ancient and severe bottleneck for most species except P. breweriana.

    Furthermore, I investigated the effect of local selection in two parallel clines, which is one of the major forces that can cause divergence or even speciation. The timing of bud set and growth cessation was found correlated with latitude in populations of P. abies and P. obovata. Using allele frequency spectrum analyses we identified three genes under local selection in both species including two circadian-clock genes GI and PRR7, and one photoperiodic gene FTL2. This indicated that parallel evolution could occur through groups of genes within related pathways. Clinal variation at expression level provided stronger evidence of selection in FTL2, which has previously been associated with bud set in P. abies.

    Finally we focused on the molecular evolution of mRNA and small regulatory RNAs in P. abies. With the help of Next-Generation sequencing, we have achieved in spruce the first de novel assembly of the needle transcriptome and a preliminary characterization of sRNA populations. Along with features common in plants, spruce also exhibited novelties in many aspects including lower substitution rate and protein evolutionary rate, dominance of 21-nt sRNA, and a large proportion of TIR-NBS-LRR genes as sRNA sources and targets.

  • 158.
    Chen, Jun
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Plant Ecology and Evolution.
    Källman, Thomas
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Plant Ecology and Evolution.
    Ma, Xiaofei
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Plant Ecology and Evolution.
    Gyllenstrand, Niclas
    Zaina, Giusi
    Morgante, Michele
    Bousquet, Jean
    Eckert, Andrew
    Wegrzyn, Jill
    Neale, David
    Lagercrantz, Ulf
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Plant Ecology and Evolution.
    Lascoux, Martin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Plant Ecology and Evolution.
    Disentangling the Roles of History and Local Selection in Shaping Clinal Variation of Allele Frequencies and Gene Expression in Norway Spruce (Picea abies)2012In: Genetics, ISSN 0016-6731, E-ISSN 1943-2631, Vol. 191, no 3, 865-881 p.Article in journal (Refereed)
    Abstract [en]

    Understanding the genetic basis of local adaptation is challenging due to the subtle balance among conflicting evolutionary forces that are involved in its establishment and maintenance. One system with which to tease apart these difficulties is clines in adaptive characters. Here we analyzed genetic and phenotypic variation in bud set, a highly heritable and adaptive trait, among 18 populations of Norway spruce (Picea abies), arrayed along a latitudinal gradient ranging from 47°N to 68°N. We confirmed that variation in bud set is strongly clinal, using a subset of five populations. Genotypes for 137 single-nucleotide polymorphisms (SNPs) chosen from 18 candidate genes putatively affecting bud set and 308 control SNPs chosen from 264 random genes were analyzed for patterns of genetic structure and correlation to environment. Population genetic structure was low (F(ST) = 0.05), but latitudinal patterns were apparent among Scandinavian populations. Hence, part of the observed clinal variation should be attributable to population demography. Conditional on patterns of genetic structure, there was enrichment of SNPs within candidate genes for correlations with latitude. Twenty-nine SNPs were also outliers with respect to F(ST). The enrichment for clinal variation at SNPs within candidate genes (i.e., SNPs in PaGI, PaPhyP, PaPhyN, PaPRR7, and PaFTL2) indicated that local selection in the 18 populations, and/or selection in the ancestral populations from which they were recently derived, shaped the observed cline. Validation of these genes using expression studies also revealed that PaFTL2 expression is significantly associated with latitude, thereby confirming the central role played by this gene in the control of phenology in plants.

  • 159.
    Chen, Jun
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Plant Ecology and Evolution.
    Källman, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ma, Xiao-Fei
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Plant Ecology and Evolution. Chinese Acad Sci, Key Lab Stress Physiol & Ecol Cold & Arid Reg, Lanzhou, Peoples R China..
    Zaina, Giusi
    Univ Udine, Dept Agr Food Environm & Anim Sci, I-33100 Udine, Italy..
    Morgante, Michele
    Univ Udine, Dept Agr Food Environm & Anim Sci, I-33100 Udine, Italy..
    Lascoux, Martin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Plant Ecology and Evolution.
    Identifying Genetic Signatures of Natural Selection Using Pooled Population Sequencing in Picea abies2016In: G3: Genes, Genomes, Genetics, ISSN 2160-1836, E-ISSN 2160-1836, Vol. 6, no 7, 1979-1989 p.Article in journal (Refereed)
    Abstract [en]

    The joint inference of selection and past demography remain a costly and demanding task. We used next generation sequencing of two pools of 48 Norway spruce mother trees, one corresponding to the Fennoscandian domain, and the other to the Alpine domain, to assess nucleotide polymorphism at 88 nuclear genes. These genes are candidate genes for phenological traits, and most belong to the photoperiod pathway. Estimates of population genetic summary statistics from the pooled data are similar to previous estimates, suggesting that pooled sequencing is reliable. The nonsynonymous SNPs tended to have both lower frequency differences and lower F-ST values between the two domains than silent ones. These results suggest the presence of purifying selection. The divergence between the two domains based on synonymous changes was around 5 million yr, a time similar to a recent phylogenetic estimate of 6 million yr, but much larger than earlier estimates based on isozymes. Two approaches, one of them novel and that considers both F-ST and difference in allele frequencies between the two domains, were used to identify SNPs potentially under diversifying selection. SNPs from around 20 genes were detected, including genes previously identified as main target for selection, such as PaPRR3 and PaGI.

  • 160.
    Chen, Jun
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Plant Ecology and Evolution.
    Tsuda, Yoshiaki
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Plant Ecology and Evolution.
    Stocks, Michael
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Plant Ecology and Evolution.
    Kallman, Thomas
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Plant Ecology and Evolution.
    Xu, Nannan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Plant Ecology and Evolution.
    Karkkainen, Katri
    Huotari, Tea
    Semerikov, Vladimir L.
    Vendramin, Giovanni G.
    Lascoux, Martin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Plant Ecology and Evolution.
    Clinal Variation at Phenology-Related Genes in Spruce: Parallel Evolution in FTL2 and Gigantea?2014In: Genetics, ISSN 0016-6731, E-ISSN 1943-2631, Vol. 197, no 3, 1025-1038 p.Article in journal (Refereed)
    Abstract [en]

    Parallel clines in different species, or in different geographical regions of the same species, are an important source of information on the genetic basis of local adaptation. We recently detected latitudinal clines in SNPs frequencies and gene expression of candidate genes for growth cessation in Scandinavian populations of Norway spruce (Picea abies). Here we test whether the same clines are also present in Siberian spruce (P. obovata), a close relative of Norway spruce with a different Quaternary history. We sequenced nine candidate genes and 27 control loci and genotyped 14 SSR loci in six populations of P. obovata located along the Yenisei river from latitude 56 N to latitude 67 N. In contrast to Scandinavian Norway spruce that both departs from the standard neutral model (SNM) and shows a clear population structure, Siberian spruce populations along the Yenisei do not depart from the SNM and are genetically unstructured. Nonetheless, as in Norway spruce, growth cessation is significantly clinal. Polymorphisms in photoperiodic (FTL2) and circadian clock (Gigantea, GI, PRR3) genes also show significant clinal variation and/or evidence of local selection. In GI, one of the variants is the same as in Norway spruce. Finally, a strong cline in gene expression is observed for FTL2, but not for GI. These results, together with recent physiological studies, confirm the key role played by FTL2 and circadian clock genes in the control of growth cessation in spruce species and suggest the presence of parallel adaptation in these two species.

  • 161.
    Chen, Jun
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Plant Ecology and Evolution.
    Tsuda, Yoshiaki
    CNR, Plant Genetics Institute, Sesto Fiorentino, Firenze, Italy.
    Stocks, Michael
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Plant Ecology and Evolution.
    Källman, Thomas
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Plant Ecology and Evolution.
    Semerikov, Vladimir
    Institute of Plant and Animal Ecology, Ural Division of the Russian Academy of Sciences.
    Vendramin, Giovanni
    CNR, Plant Genetics Institute, Sesto Fiorentino, Firenze, Italy.
    Lascoux, Martin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Plant Ecology and Evolution.
    Clinal variation in allele frequency at photoperiodic genes in Siberian spruce: an example of convergent evolution?Manuscript (preprint) (Other academic)
  • 162.
    Chen, Jun
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Plant Ecology and Evolution.
    Tsuda, Yoshiaki
    CNR, Plant Genetics Institute, Sesto Fiorentino, Firenze, Italy.
    Stocks, Michael
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Plant Ecology and Evolution.
    Källman, Thomas
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Plant Ecology and Evolution.
    Xu, Nannan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Plant Ecology and Evolution.
    Semerikov, Vladimir
    Institute of Plant and Animal Ecology, Ural Division of the Russian Academy of Sciences.
    Vendramin, Giovanni
    CNR, Plant Genetics Institute, Sesto Fiorentino, Firenze, Italy.
    Lascoux, Martin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Plant Ecology and Evolution.
    Clinal variation in allele frequency and gene expression at photoperiodic and circadian genes in Siberian spruce: an example of parallel evolution?Manuscript (preprint) (Other academic)
  • 163.
    Chen, Jun
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Plant Ecology and Evolution.
    Uebbing, Severin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Gyllenstrand, Niclas
    Department of Plant Biology and Forest Genetics, Swedish University of Agriculture Science.
    Lagercrantz, Ulf
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Plant Ecology and Evolution.
    Lascoux, Martin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Plant Ecology and Evolution.
    Källman, Thomas
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Plant Ecology and Evolution.
    Sequencing of the needle transcriptome from Norway spruce (Picea abies Karst L.) reveals lower substitution rates, but similar selective constraints in gymnosperms compared to angiosperms2012In: BMC Genomics, ISSN 1471-2164, Vol. 13, 589- p.Article in journal (Other academic)
    Abstract [en]

    Background: A detailed knowledge about which genes are expressed in which tissues and at which developmental stage is important for understanding both the function of genes and their evolution. For the vast majority of species, transcriptomes are still largely uncharacterized and even in those where substantial information is available it is often in the form of partially sequenced transcriptomes. With the development of next generation sequencing, a single experiment can now give both a snap-shot of the transcribed part of a species genome and simultaneously estimate levels of gene expression.

    Results: mRNA from actively growing needles of Norway spruce (Picea abies) was sequenced using next generation sequencing technology. In total, close to 70 million fragments with a length of 76 bp were sequenced resulting in 5 Gbp of raw data. A de novo assembly of these reads were, together with publicly available expressed sequence tag (EST) data from Norway spruce, used to create a reference transcriptome. Of the 38,419 PUTs (putative unique transcripts) longer than 150 bp in this reference assembly, 59% show similarity to ESTs from other spruce species and of the remaining PUTs, 3,704 show similarity to protein sequences from other plant species, leaving 4,167 PUTs with limited similarity to currently available plant proteins. By predicting coding frames and comparing not only the Norway spruce PUTs, but also PUTs from the close relatives Picea glauca and Picea sitchensis to both Pinus taeda and Taxus mairei, we obtained estimates of synonymous and non-synonymous divergence among conifer species. In addition, we detected close to 15,000 SNPs of high quality and estimated gene expression difference between samples collected during dark and light conditions.

    Conclusions: Our study yielded a large number of single nucleotide polymorphisms as well as estimates of gene expression on transcriptome scale. In agreement with a recent study we find that the synonymous substitution rate per year (0.6 × 10-09 and 1.1 × 10-09) is an order of magnitude smaller than values reported for angiosperm herbs, but if one takes generation time in to account, most of this difference disappear. The estimates of the non-synonymous over the synonymous divergence (dN/dS ratio) reported here is in general much lower than 1 and only a few genes showed a ratio larger than 1.

  • 164.
    Chen, Junfeng
    et al.
    Texas A&M Univ, Coll Vet Med, Dept Vet Pathobiol, College Stn, TX 77843 USA..
    Huddleston, John
    Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA.;Univ Washington, Howard Hughes Med Inst, Seattle, WA 98195 USA..
    Buckley, Reuben M.
    Univ Adelaide, Sch Biol Sci, Adelaide, SA 5005, Australia..
    Malig, Maika
    Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA..
    Lawhon, Sara D.
    Texas A&M Univ, Coll Vet Med, Dept Vet Pathobiol, College Stn, TX 77843 USA..
    Skow, Loren C.
    Texas A&M Univ, Coll Vet Med, Dept Vet Integrat Biosci, College Stn, TX 77843 USA..
    Lee, Mi Ok
    Texas A&M Univ, Coll Vet Med, Dept Vet Pathobiol, College Stn, TX 77843 USA..
    Eichler, Evan E.
    Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA.;Univ Washington, Howard Hughes Med Inst, Seattle, WA 98195 USA..
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Texas A&M Univ, Coll Vet Med, Dept Vet Integrat Biosci, College Stn, TX 77843 USA.;Swedish Univ Agr Sci, Dept Anim Breeding & Genet, SE-75007 Uppsala, Sweden..
    Womack, James E.
    Texas A&M Univ, Coll Vet Med, Dept Vet Pathobiol, College Stn, TX 77843 USA..
    Bovine NK-lysin: Copy number variation and functional diversification2015In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 112, no 52, E7223-E7229 p.Article in journal (Refereed)
    Abstract [en]

    NK-lysin is an antimicrobial peptide and effector protein in the host innate immune system. It is coded by a single gene in humans and most other mammalian species. In this study, we provide evidence for the existence of four NK-lysin genes in a repetitive region on cattle chromosome 11. The NK2A, NK2B, and NK2C genes are tandemly arrayed as three copies in similar to 30-35-kb segments, located 41.8 kb upstream of NK1. All four genes are functional, albeit with differential tissue expression. NK1, NK2A, and NK2B exhibited the highest expression in intestine Peyer's patch, whereas NK2C was expressed almost exclusively in lung. The four peptide products were synthesized ex vivo, and their antimicrobial effects against both Gram-positive and Gram-negative bacteria were confirmed with a bacteria-killing assay. Transmission electron microcopy indicated that bovine NK-lysins exhibited their antimicrobial activities by lytic action in the cell membranes. In summary, the single NK-lysin gene in other mammals has expanded to a four-member gene family by tandem duplications in cattle; all four genes are transcribed, and the synthetic peptides corresponding to the core regions are biologically active and likely contribute to innate immunity in ruminants.

  • 165.
    Chen, Lei
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University.
    Björkesten, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Wu, Di
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Mathot, Lucy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    liebs, Sandra
    Haybaeck, Johannes
    Sjöblom, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Landegren, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    A molecular approach for single molecule counting and rare mutation detection in blood plasmaManuscript (preprint) (Other academic)
    Abstract [en]

    Problems in biology and medicine frequently require the ability to observe, evaluate, and count even extremely rare macromolecules directly in biological samples. Examples include the detection of mutant DNA or RNA molecules in plasma or distributed in tissues in tumor patients, and highly precise, digital enumeration of proteins and other molecules of interest in clinical specimens. We describe herein a general means to magnify detection signals from individual molecules to easily recorded levels via a highly specific process - super rolling circle amplification (sRCA). We demonstrate the ability of this technique to vastly enhance in situ detection, to count individual molecules by flow cytometry or using a mobile phone camera, and to enumerate tumor-specific sequence variants in plasma from patients at very high efficiency, with specificity adequate to detect single nucleotide mutant sequences among 100,000 copies of the normal sequence. 

  • 166. Chen, Nansheng
    et al.
    Mah, Allan
    Blacque, Oliver E.
    Chu, Jeffrey
    Phgora, Kiran
    Bakhoum, Mathieu W.
    Newbury, C. Rebecca Hunt
    Khattra, Jaswinder
    Chan, Susanna
    Go, Anne
    Efimenko, Evgeni
    Södertörn University, School of Life Sciences. Karolinska Institute.
    Johnsen, Robert
    Phirke, Prasad
    Södertörn University, School of Life Sciences. Karolinska Institute.
    Swoboda, Peter
    Södertörn University, School of Life Sciences. Karolinska Institute.
    Marra, Marco
    Moerman, Donald G.
    Leroux, Michel R.
    Baillie, David L.
    Stein, Lincoln D.
    Identification of ciliary and ciliopathy genes in Caenorhabditis elegans through comparative genomics2006In: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 7, no 12, R126- p.Article in journal (Refereed)
    Abstract [en]

    Background: The recent availability of genome sequences of multiple related Caenorhabditis species has made it possible to identify, using comparative genomics, similarly transcribed genes in Caenorhabditis elegans and its sister species. Taking this approach, we have identified numerous novel ciliary genes in C. elegans, some of which may be orthologs of unidentified human ciliopathy genes. Results: By screening for genes possessing canonical X-box sequences in promoters of three Caenorhabditis species, namely C. elegans, C. briggsae and C. remanei, we identified 93 genes ( including known X-box regulated genes) that encode putative components of ciliated neurons in C. elegans and are subject to the same regulatory control. For many of these genes, restricted anatomical expression in ciliated cells was confirmed, and control of transcription by the ciliogenic DAF-19 RFX transcription factor was demonstrated by comparative transcriptional profiling of different tissue types and of daf-19(+) and daf-19(-) animals. Finally, we demonstrate that the dye-filling defect of dyf-5( mn400) animals, which is indicative of compromised exposure of cilia to the environment, is caused by a nonsense mutation in the serine/threonine protein kinase gene M04C9.5. Conclusion: Our comparative genomics-based predictions may be useful for identifying genes involved in human ciliopathies, including Bardet-Biedl Syndrome ( BBS), since the C. elegans orthologs of known human BBS genes contain X-box motifs and are required for normal dye filling in C. elegans ciliated neurons.

  • 167. Chen, Peng
    et al.
    Jäger, Gunilla
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Zheng, Bo
    Transfer RNA modifications and genes for modifying enzymes in Arabidopsis thaliana2010In: BMC Plant Biology, ISSN 1471-2229, Vol. 10, 201Article in journal (Refereed)
    Abstract [en]

    Background: In all domains of life, transfer RNA (tRNA) molecules contain modified nucleosides. Modifications to tRNAs affect their coding capacity and influence codon-anticodon interactions. Nucleoside modification deficiencies have a diverse range of effects, from decreased virulence in bacteria, neural system disease in human, and gene expression and stress response changes in plants. The purpose of this study was to identify genes involved in tRNA modification in the model plant Arabidopsis thaliana, to understand the function of nucleoside modifications in plant growth and development. Results: In this study, we established a method for analyzing modified nucleosides in tRNAs from the model plant species, Arabidopsis thaliana and hybrid aspen (Populus tremula x tremuloides). 21 modified nucleosides in tRNAs were identified in both species. To identify the genes responsible for the plant tRNA modifications, we performed global analysis of the Arabidopsis genome for candidate genes. Based on the conserved domains of homologs in Sacccharomyces cerevisiae and Escherichia coli, more than 90 genes were predicted to encode tRNA modifying enzymes in the Arabidopsis genome. Transcript accumulation patterns for the genes in Arabidopsis and the phylogenetic distribution of the genes among different plant species were investigated. Transcripts for the majority of the Arabidopsis candidate genes were found to be most abundant in rosette leaves and shoot apices. Whereas most of the tRNA modifying gene families identified in the Arabidopsis genome was found to be present in other plant species, there was a big variation in the number of genes present for each family. Through a loss of function mutagenesis study, we identified five tRNA modification genes (AtTRM10, AtTRM11, AtTRM82, AtKTI12 and AtELP1) responsible for four specific modified nucleosides (m1G, m2G, m7G and ncm5U), respectively (two genes: AtKTI12 and AtELP1 identified for ncm5U modification). The AtTRM11 mutant exhibited an early-flowering phenotype, and the AtELP1 mutant had narrow leaves, reduced root growth, an aberrant silique shape and defects in the generation of secondary shoots. Conclusions: Using a reverse genetics approach, we successfully isolated and identified five tRNA modification genes in Arabidopsis thaliana. We conclude that the method established in this study will facilitate the identification of tRNA modification genes in a wide variety of plant species.

  • 168.
    Chen, Sa
    Umeå University, Faculty of Science and Technology, Molecular Biology (Faculty of Science and Technology).
    Expression and function of Suppressor of zeste 12 in Drosophila melanogaster2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The development of animals and plants needs a higher order of regulation of gene expression to maintain proper cell state. The mechanisms that control what, when and where a gene should (or should not) be expressed are essential for correct organism development. The Polycomb group (PcG) is a family of genes responsible for maintaining gene silencing and Suppressor of zeste 12 (Su(z)12) is one of the core components in the PcG. The gene is highly conserved in organisms ranging from plants to humans, however, the specific function is not well known. The main tasks of this thesis was to investigate the function of Su(z)12 and its expression at different stages of Drosophila development.

    In polytene chromosomes of larval salivary glands, Su(z)12 binds to about 90 specific euchromatic sites. The binding along the chromosome arms is mostly in interbands, which are the most DNA de-condensed regions. The binding sites of Su(z)12 in polytene chromosomes correlate precisely with those of the Enhancer-of-zeste (E(z)) protein, indicating that Su(z)12 mainly exists within the Polycomb Repressive Complex 2 (PRC2). However, the binding pattern does not overlap well with Histone 3 lysine 27 tri-methylations (H3K27me3), the specific chromatin mark created by PRC2. The Su(z)12 binding to chromatin is dynamically regulated during mitotic and meiotic cell division. The two different Su(z)12 isoforms: Su(z)12-A and Su(z)12-B (resulting from alternative RNA splicing), have very different expression patterns during development. Functional analyses indicate that they also have different functions he Su(z)12-B form is the main mediator of silencing. Furthermore, a neuron specific localization pattern in larval brain and a giant larval phenotype in transgenic lines reveal a potential function of Su(z)12-A in neuron development.  In some aspects the isoforms seem to be able to substitute for each other.

    The histone methyltransferase activity of PRC2 is due to the E(z) protein. However, Su(z)12 is also necessary for H3K27me3 methylation in vivo, and it is thus a core component of PRC2. Clonal over-expression of Su(z)12 in imaginal wing discs results in an increased H3K27me3 activity, indicating that Su(z)12 is a limiting factor for silencing. When PcG function is lost, target genes normally become de-repressed. The segment polarity gene engrailed, encoding a transcription factor, is a target for PRC2 silencing. However, we found that it was not activated when PRC2 function was deleted. We show that the Ultrabithorax protein, encoded by another PcG target gene, also acts as an inhibitor of engrailed and that de-regulation of this gene causes a continued repression of engrailed. The conclusion is that a gene can have several negative regulators working in parallel and that secondary effects have to be taken into consideration, when analyzing effects of mutants.

    PcG silencing affects very many cellular processes and a large quantity of knowledge is gathered on the overall mechanisms of PcG regulation. However, little is known about how individual genes are silenced and how cells “remember” their fate through cell generations.

  • 169.
    Chen, Tian-Jiao
    et al.
    Institute of Child and Adolescent Health, School of Public Health, Health Science Center, Peking University, Beijing, China.
    Ji, Cheng-Ye
    Institute of Child and Adolescent Health, School of Public Health, Health Science Center, Peking University, Beijing, China.
    Wang, Shang-Shang
    Institute of Child and Adolescent Health, School of Public Health, Health Science Center, Peking University, Beijing, China.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Chang, Zheng
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Genetic and environmental influences on the relationship between ADHD symptoms and internalizing problems: A Chinese twin study2016In: American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, ISSN 1552-4841, E-ISSN 1552-485X, Vol. 171, no 7, 931-937 p.Article in journal (Refereed)
    Abstract [en]

    Several twin studies have investigated the overlap between attention deficit hyperactivity disorder (ADHD) and externalizing problems; however, limited information is known regarding the genetic and environmental contribution to the overlap between ADHD and internalizing problems. This study examined the genetic and environmental influences on the variation in and covariation between ADHD symptoms and internalizing problems by using the Child Behavior Checklist (CBCL). We investigated 1,316 child and adolescent twins, including 780 monozygotic twins and 536 dizygotic twins, aged 6 years to 18 years from the Chinese Child and Adolescent Twin Registry. ADHD symptoms and internalizing problems were quantified through parent rating by using the Attention Problems Scale and other three scales, which include Anxious/Depressed, Withdrawn, and Somatic Complaints of CBCL. Genetic and environmental susceptibilities common to ADHD symptoms and internalizing problems were examined through bivariate twin modeling. Results showed that genetic factors substantially influenced the ADHD symptoms with a heritability of 72%. Modest genetic influences and substantial shared environmental influences (20-77%) were observed in the three internalizing problem scales. Common genetic and shared environmental influences were essential for the overlap between ADHD and the three internalizing problems respectively. Approximately one-fifth of the genetic variance of ADHD symptoms was shared with anxiety/depression. In conclusion, substantial genetic and shared environmental influences on ADHD symptoms and internalizing problems were observed in Chinese children and adolescents. Our finding supports a common etiology between ADHD and internalizing problems. This finding can also help explain the co-existence of these behavior problems. © 2015 Wiley Periodicals, Inc.

  • 170. Chen, Xinyu
    et al.
    Yuan, Huwei
    Hu, Xiange
    Meng, Jingxiang
    Zhou, Xianqing
    Wang, Xiao-Ru
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences. National Engineering Laboratory for Forest Tree Breeding, Key Laboratory of Genetic and Breeding in Forest Trees and Ornamental Plants of Ministry of Education, College of Biological Sciences and Technology, Beijing Forestry University, Beijing, People’s Republic of China.
    Li, Yue
    Variations in electrical impedance and phase angle among seedlings of Pinus densata and parental species in Pinus tabuliformis habitat environment2015In: Journal of Forestry Research, ISSN 1007-662X, E-ISSN 1993-0607, Vol. 26, no 3, 777-783 p.Article in journal (Refereed)
    Abstract [en]

    Electrical impedance (EI) and phase angle (PHI) parameters in AC impedance spectroscopy are important electrical parameters in the study of medical pathology. However, little is known about their application in variation and genetic relationship studies of forest trees. In order to test whether impedance parameters could be used in genetic relationship analysis among conifer species, EI and PHI were measured in a seedling experiment test composed of Pinus tabuliformis, Pinus yunnanensis, and Pinus densata in a habitat of Pinus tabuliformis. The results showed that variations in both EI and PHI among species were significant in different electric frequencies, and the EI and PHI values measured in the two populations of P. densata were between the two parental species, P. yunnanensis and P. tabuliformis. These results show that these two impedance parameters could reflect the genetic relationship among pine species. This was the first time using the two AC impedance spectroscopy parameters to test the genetic relationship analysis between tree species, and would be a hopeful novel reference methodology for future studies in evolution and genetic variation of tree species.

  • 171.
    Cherif, E.
    et al.
    Ctr IRD, UMR DIADE, IRD CIRAD Palm Grp F2F, 911 Ave Agropolis, F-34394 Montpellier, France.;Univ Tunis El Manar, Fac Sci Tunis, Lab Genet Mol Immunol & Biotechnol, El Manar, Tunisia..
    Zehdi-Azouzi, S.
    Univ Tunis El Manar, Fac Sci Tunis, Lab Genet Mol Immunol & Biotechnol, El Manar, Tunisia..
    Crabos, A.
    Ctr IRD, UMR DIADE, IRD CIRAD Palm Grp F2F, 911 Ave Agropolis, F-34394 Montpellier, France..
    Castillo, K.
    Ctr IRD, UMR DIADE, IRD CIRAD Palm Grp F2F, 911 Ave Agropolis, F-34394 Montpellier, France..
    Chabrillange, N.
    Ctr IRD, UMR DIADE, IRD CIRAD Palm Grp F2F, 911 Ave Agropolis, F-34394 Montpellier, France..
    Pintaud, J. -C
    Salhi-Hannachi, A.
    Univ Tunis El Manar, Fac Sci Tunis, Lab Genet Mol Immunol & Biotechnol, El Manar, Tunisia..
    Glemin, Sylvain
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Plant Ecology and Evolution. Unite Mixte Rech 5554 Univ Montpellier CNRS IRD E, Inst Sci Evolut Montpellier, Montpellier, France..
    Aberlenc-Bertossi, F.
    Ctr IRD, UMR DIADE, IRD CIRAD Palm Grp F2F, 911 Ave Agropolis, F-34394 Montpellier, France..
    Evolution of sex chromosomes prior to speciation in the dioecious Phoenix species2016In: Journal of Evolutionary Biology, ISSN 1010-061X, E-ISSN 1420-9101, Vol. 29, no 8, 1513-1522 p.Article in journal (Refereed)
    Abstract [en]

    Understanding the driving forces and molecular processes underlying dioecy and sex chromosome evolution, leading from hermaphroditism to the occurrence of male and female individuals, is of considerable interest in fundamental and applied research. The genus Phoenix, belonging to the Arecaceae family, consists uniquely of dioecious species. Phylogenetic data suggest that the genus Phoenix has diverged from a hermaphroditic ancestor which is also shared with its closest relatives. We have investigated the cessation of recombination in the sex-determination region within the genus Phoenix as a whole by extending the analysis of P.dactylifera SSR sex-related loci to eight other species within the genus. Phylogenetic analysis of a date palm sex-linked PdMYB1 gene in these species has revealed that sex-linked alleles have not clustered in a species-dependent way but rather in X and Y-allele clusters. Our data show that sex chromosomes evolved from a common autosomal origin before the diversification of the extant dioecious species.

  • 172.
    Christophersen, Ingrid E.
    et al.
    Broad Inst & Harvard, Program Med & Populat Genet, Cambridge, MA USA.;Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA.;Vestre Viken Hosp Trust, Baerum Hosp, Dept Med Res, Rud, Norway..
    Rienstra, Michiel
    Univ Groningen, Dept Cardiol, Univ Med Ctr Groningen, Groningen, Netherlands..
    Roselli, Carolina
    Broad Inst & Harvard, Program Med & Populat Genet, Cambridge, MA USA.;Helmholtz Zentrum Munchen German Res Ctr Environm, Inst Genet Epidemiol, Neuherberg, Germany.;Ludwig Maximilians Univ Munchen, Genet Epidemiol, Inst Med Informat Biometry & Epidemiol, Munich, Germany..
    Yin, Xiaoyan
    NHLBI, Framingham, MA USA.;Boston Univ Framingham Heart Study, Framingham, MA USA.;Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA..
    Geelhoed, Bastiaan
    Univ Groningen, Dept Cardiol, Univ Med Ctr Groningen, Groningen, Netherlands..
    Barnard, John
    Cleveland Clin, Dept Cardiovasc Med, Cleveland, OH 44106 USA.;Cleveland Clin, Dept Cellular & Mol Med, Cleveland, OH 44106 USA.;Cleveland Clin, Dept Mol Cardiol, Cleveland, OH 44106 USA.;Cleveland Clin, Dept Quantitat Hlth Sci, Cleveland, OH 44106 USA..
    Lin, Honghuang
    NHLBI, Framingham, MA USA.;Boston Univ Framingham Heart Study, Framingham, MA USA.;Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA..
    Arking, Dan E.
    Johns Hopkins Univ Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD USA..
    Smith, Albert V.
    Iceland Heart Assoc, Kopavogur, Iceland.;Univ Iceland, Fac Med, Reykjavik, Iceland..
    Albert, Christine M.
    Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA.;Harvard Med Sch, Boston, MA USA.;Brigham & Womens Hosp, Div Cardiovasc Med, 75 Francis St, Boston, MA 02115 USA..
    Chaffin, Mark
    Broad Inst & Harvard, Program Med & Populat Genet, Cambridge, MA USA..
    Tucker, Nathan R.
    Broad Inst & Harvard, Program Med & Populat Genet, Cambridge, MA USA.;Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA..
    Li, Molong
    Klarin, Derek
    Broad Inst & Harvard, Program Med & Populat Genet, Cambridge, MA USA..
    Bihlmeyer, Nathan A.
    Johns Hopkins Univ Sch Med, McKusick Nathans Inst Genet Med, Predoctoral Training Program Human Genet, Baltimore, MD USA..
    Low, Siew-Kee
    RIKEN, Ctr Integrat Med Sci, Lab Stat Anal, Yokohama, Kanagawa, Japan..
    Weeke, Peter E.
    Vanderbilt Univ, Med Ctr, Dept Med, 221 Kirkland Hall, Nashville, TN 37235 USA.;Copenhagen Univ Hosp, Rigshosp, Dept Cardiol, Heart Ctr, Copenhagen, Denmark..
    Mueller-Nurasyid, Martina
    Helmholtz Zentrum Munchen German Res Ctr Environm, Inst Genet Epidemiol, Neuherberg, Germany.;Univ Hosp Munich, Ludwig Maximilians Univ, Dept Med 1, Munich, Germany.;DZHK German Ctr Cardiovasc Res, Munich Heart Alliance, Munich, Germany..
    Smith, J. Gustav
    Broad Inst & Harvard, Program Med & Populat Genet, Cambridge, MA USA.;Lund Univ, Clin Sci, Molecular Epidemiol & Cardiol, Lund, Sweden..
    Brody, Jennifer A.
    Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA..
    Niemeijer, Maartje N.
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands..
    Doerr, Marcus
    Univ Med Greifswald, Dept Internal Med B, Greifswald, Germany.;DZHK German Ctr Cardiovasc Res, Greifswald, Germany..
    Trompet, Stella
    Leiden Univ, Med Ctr, Dept Cardiol, Leiden, Netherlands..
    Huffman, Jennifer
    Univ Edinburgh, Inst Genet & Mol Med, MRC, Human Genet Unit, Edinburgh, Midlothian, Scotland..
    Gustafsson, Stefan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Schurmann, Claudia
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA..
    Kleber, Marcus E.
    Heidelberg Univ, Med Fac Mannheim, Dept Med 5, Heidelberg, Germany..
    Lyytikainen, Leo-Pekka
    Fimlab Labs, Dept Clin Chem, Tampere, Finland.;Univ Tampere, Sch Med, Tampere, Finland..
    Seppala, Ilkka
    Fimlab Labs, Dept Clin Chem, Tampere, Finland.;Univ Tampere, Sch Med, Tampere, Finland..
    Malik, Rainer
    Klinikum Univ Munchen, Inst Stroke & Dementia Res, Ludwig Maximilians Univ, Munich, Germany..
    Horimoto, Andrea R. V. R.
    Univ Sao Paulo, Heart Inst, Lab Genet & Mol Cardiol, Sao Paulo, Brazil..
    Perez, Marco
    Stanford Univ, Dept Cardiovasc Med, Stanford, CA 94305 USA..
    Sinisalo, Juha
    Univ Helsinki, Cent Hosp, Heart & Lung Ctr HUS, Helsinki, Finland..
    Aeschbacher, Stefanie
    Univ Basel Hosp, Dept Med, Basel, Switzerland.;Cardiovasc Res Inst Basel, Basel, Switzerland..
    Theriault, Sebastien
    Populat Hlth Res Inst, Hamilton, ON, Canada.;McMaster Univ, Dept Pathol & Mol Med, Hamilton, ON, Canada..
    Yao, Jie
    Harbor UCLA Med Ctr, LABioMed, Dept Pediat, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA..
    Radmanesh, Farid
    Broad Inst & Harvard, Program Med & Populat Genet, Cambridge, MA USA.;Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA..
    Weiss, Stefan
    DZHK German Ctr Cardiovasc Res, Greifswald, Germany.;Univ Med, Interfac Inst Genet & Funct Gen, Greifswald, Germany.;Ernst Moritz Arndt Univ Greifswald, Greifswald, Germany..
    Teumer, Alexander
    DZHK German Ctr Cardiovasc Res, Greifswald, Germany.;Univ Med Greifswald, Inst Community Med, Greifswald, Germany..
    Choi, Seung Hoan
    Broad Inst & Harvard, Program Med & Populat Genet, Cambridge, MA USA..
    Weng, Lu-Chen
    Broad Inst & Harvard, Program Med & Populat Genet, Cambridge, MA USA.;Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA..
    Clauss, Sebastian
    Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA.;Univ Hosp Munich, Ludwig Maximilians Univ, Dept Med 1, Munich, Germany.;DZHK German Ctr Cardiovasc Res, Munich Heart Alliance, Munich, Germany..
    Deo, Rajat
    Univ Penn, Perelman Sch Med, Dept Med, Div Cardiovasc Med, Philadelphia, PA 19104 USA..
    Rader, Daniel J.
    Univ Penn, Perelman Sch Med, Dept Med, Div Cardiovasc Med, Philadelphia, PA 19104 USA..
    Shah, Svati H.
    Duke Univ, Sch Med, Dept Med, Div Cardiol, Durham, NC 27706 USA..
    Sun, Albert
    Duke Univ, Sch Med, Dept Med, Div Cardiol, Durham, NC 27706 USA..
    Hopewell, Jemma C.
    Univ Oxford, CTSU Nuffield Dept Populat Hlth, Oxford, England..
    Debette, Stephanie
    Bordeaux Populat Hlth Ctr, INSERM U1219, Bordeaux, France.;Univ Bordeaux, Bordeaux, France.;Bordeaux Univ Hosp, Dept Neurol, Bordeaux, France.;Boston Univ, Sch Med, Dept Neurol, Boston, MA 02215 USA..
    Chauhan, Ganesh
    Bordeaux Populat Hlth Ctr, INSERM U1219, Bordeaux, France.;Univ Bordeaux, Bordeaux, France..
    Yang, Qiong
    Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA..
    Worrall, Bradford B.
    Univ Virginia Hlth Syst, Dept Neurol, Charlottesville, VA USA.;Univ Virginia Hlth Syst, Dept Publ Hlth Sci, Charlottesville, VA USA..
    Pare, Guillaume
    Populat Hlth Res Inst, Hamilton, ON, Canada.;McMaster Univ, Dept Pathol & Mol Med, Hamilton, ON, Canada..
    Kamatani, Yoichiro
    RIKEN, Ctr Integrat Med Sci, Lab Stat Anal, Yokohama, Kanagawa, Japan..
    Hagemeijer, Yanick P.
    Univ Groningen, Dept Cardiol, Univ Med Ctr Groningen, Groningen, Netherlands..
    Verweij, Niek
    Univ Groningen, Dept Cardiol, Univ Med Ctr Groningen, Groningen, Netherlands..
    Siland, Joylene E.
    Univ Groningen, Dept Cardiol, Univ Med Ctr Groningen, Groningen, Netherlands..
    Kubo, Michiaki
    RIKEN, Ctr Integrat Med Sci, Yokohama, Kanagawa, Japan..
    Smith, Jonathan D.
    Cleveland Clin, Dept Cardiovasc Med, Cleveland, OH 44106 USA.;Cleveland Clin, Dept Cellular & Mol Med, Cleveland, OH 44106 USA.;Cleveland Clin, Dept Mol Cardiol, Cleveland, OH 44106 USA.;Cleveland Clin, Dept Quantitat Hlth Sci, Cleveland, OH 44106 USA..
    Van Wagoner, David R.
    Cleveland Clin, Dept Cardiovasc Med, Cleveland, OH 44106 USA.;Cleveland Clin, Dept Cellular & Mol Med, Cleveland, OH 44106 USA.;Cleveland Clin, Dept Mol Cardiol, Cleveland, OH 44106 USA.;Cleveland Clin, Dept Quantitat Hlth Sci, Cleveland, OH 44106 USA..
    Bis, Joshua C.
    Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA..
    Perz, Siegfried
    Helmholtz Zentrum Munchen German Res Ctr Environm, Inst Epidemiol 2, Neuherberg, Germany..
    Psaty, Bruce M.
    Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA.;Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA.;Univ Washington, Cardiovasc Hlth Res Unit, Washington, DC USA.;Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA.;Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA..
    Ridker, Paul M.
    Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA.;Harvard Med Sch, Boston, MA USA.;Brigham & Womens Hosp, Div Cardiovasc Med, 75 Francis St, Boston, MA 02115 USA..
    Magnani, Jared W.
    NHLBI, Framingham, MA USA.;Boston Univ Framingham Heart Study, Framingham, MA USA.;Boston Univ, Sch Med, Dept Med, Boston, MA 02215 USA..
    Harris, Tamara B.
    Natl Inst Aging, Lab Epidemiol Demog & Biometry, Bethesda, MD USA..
    Launer, Lenore J.
    Natl Inst Aging, Lab Epidemiol Demog & Biometry, Bethesda, MD USA..
    Shoemaker, M. Benjamin
    Vanderbilt Univ, Med Ctr, Dept Med, 221 Kirkland Hall, Nashville, TN 37235 USA..
    Padmanabhan, Sandosh
    Univ Glasgow, BHF Glasgow Cardiovasc Res Ctr, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland..
    Haessler, Jeffrey
    Univ Washington, Fred Hutchinson Canc Res Ctr, Seattle, WA 98195 USA..
    Bartz, Traci M.
    Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA.;Univ Washington, Dept Biostat, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA..
    Waldenberger, Melanie
    DZHK German Ctr Cardiovasc Res, Munich Heart Alliance, Munich, Germany.;Helmholtz Zentrum Munchen German Res Ctr Environm, Inst Epidemiol 2, Neuherberg, Germany.;Helmholtz Zentrum Munchen German Res Ctr Environm, Res Unit Mol Epidemiol, Neuherberg, Germany..
    Lichtner, Peter
    Helmholtz Zentrum Munchen German Res Ctr Environm, Inst Human Genet, Neuherberg, Germany..
    Arendt, Marina
    Univ Hosp Essen, Inst Med Informat Biometry & Epidemiol, Essen, Germany..
    Krieger, Jose E.
    Univ Sao Paulo, Heart Inst, Lab Genet & Mol Cardiol, Sao Paulo, Brazil..
    Kahonen, Mika
    Univ Tampere, Sch Med, Tampere, Finland.;Tampere Univ Hosp, Dept Clin Physiol, Tampere, Finland..
    Risch, Lorenz
    Univ Bern, Univ Inst Clin Chem, Bern, Switzerland.;Labormed Zentrum Dr Risch, Schaan, Liechtenstein..
    Mansur, Alfredo J.
    Univ Sao Paulo, Heart Inst, Sao Paulo, Brazil..
    Peters, Annette
    DZHK German Ctr Cardiovasc Res, Munich Heart Alliance, Munich, Germany.;Helmholtz Zentrum Munchen German Res Ctr Environm, Inst Epidemiol 2, Neuherberg, Germany.;German Ctr Diabet Res, Neuherberg, Germany..
    Smith, Blair H.
    Univ Dundee, Div Populat Hlth Sci, Dundee, Scotland..
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Scott, Stuart A.
    Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA..
    Lu, Yingchang
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA..
    Bottinger, Erwin B.
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Dept Pharmacol & Syst Therapeut, New York, NY 10029 USA..
    Hernesniemi, Jussi
    Fimlab Labs, Dept Clin Chem, Tampere, Finland.;Univ Tampere, Sch Med, Tampere, Finland.;Tampere Univ Hosp, Heart Hosp, Dept Cardiol, Tampere, Finland..
    Lindgren, Cecilia M.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England..
    Wong, Jorge A.
    McMaster Univ, Div Cardiol Hamilton Hlth Sci, Hamilton, ON, Canada..
    Huang, Jie
    Boston VA Res Inst Inc, Boston, MA USA..
    Eskola, Markku
    Univ Tampere, Sch Med, Tampere, Finland.;Tampere Univ Hosp, Heart Hosp, Dept Cardiol, Tampere, Finland..
    Morris, Andrew P.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Liverpool, Dept Biostat, Liverpool, Merseyside, England..
    Ford, Ian
    Univ Glasgow, Robertson Ctr Biostat, Glasgow, Lanark, Scotland..
    Reiner, Alex P.
    Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA.;Univ Glasgow, BHF Glasgow Cardiovasc Res Ctr, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland..
    Delgado, Graciela
    Heidelberg Univ, Med Fac Mannheim, Dept Med 5, Heidelberg, Germany..
    Chen, Lin Y.
    Univ Minnesota, Dept Med, Med Sch, Cardiovasc Div, Box 736 UMHC, Minneapolis, MN 55455 USA..
    Chen, Yii-Der Ida
    Harbor UCLA Med Ctr, LABioMed, Dept Pediat, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA..
    Sandhu, Roopinder K.
    Univ Alberta, Div Cardiol, Edmonton, AB, Canada..
    Li, Man
    Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA.;Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA.;Univ Utah, Sch Med, Div Nephrol & Hypertens, Internal Med, Salt Lake City, UT USA..
    Boerwinkle, Eric
    Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA..
    Eisele, Lewin
    Univ Hosp Essen, Inst Med Informat Biometry & Epidemiol, Essen, Germany..
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Rost, Natalia
    Broad Inst & Harvard, Program Med & Populat Genet, Cambridge, MA USA.;Massachusetts Gen Hosp, Acute Stroke Serv, Boston, MA 02114 USA..
    Anderson, Christopher D.
    Broad Inst & Harvard, Program Med & Populat Genet, Cambridge, MA USA.;Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA..
    Taylor, Kent D.
    Harbor UCLA Med Ctr, LABioMed, Dept Pediat, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA..
    Campbell, Archie
    Univ Edinburgh, Inst Genet & Mol Med, Ctr Genom & Expt Med, Generat Scotland, Edinburgh, Midlothian, Scotland..
    Magnusson, Patrik K.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Porteous, David
    Univ Edinburgh, Inst Genet & Mol Med, Ctr Genom & Expt Med, Generat Scotland, Edinburgh, Midlothian, Scotland..
    Hocking, Lynne J.
    Univ Aberdeen, Div Appl Med, Musculoskeletal Res Programme, Aberdeen, Scotland..
    Vlachopoulou, Efthymia
    Univ Helsinki, Medicum, Transplantat Lab, Helsinki, Finland..
    Pedersen, Nancy L.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Nikus, Kjell
    Univ Tampere, Sch Med, Tampere, Finland.;Tampere Univ Hosp, Heart Hosp, Dept Cardiol, Tampere, Finland..
    Orho-Melander, Marju
    Lund Univ, Dept Clin Sci, Malmo, Sweden..
    Hamsten, Anders
    Karolinska Inst, Dept Med Solna, Atherosclerosis Res Unit, Cardiovasc Genet & Genom Grp, Stockholm, Sweden..
    Heeringa, Jan
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands..
    Denny, Joshua C.
    Vanderbilt Univ, Med Ctr, Dept Med, 221 Kirkland Hall, Nashville, TN 37235 USA..
    Kriebel, Jennifer
    Helmholtz Zentrum Munchen German Res Ctr Environm, Inst Epidemiol 2, Neuherberg, Germany.;Helmholtz Zentrum Munchen German Res Ctr Environm, Res Unit Mol Epidemiol, Neuherberg, Germany.;German Ctr Diabet Res, Neuherberg, Germany..
    Darbar, Dawood
    Univ Illinois, Dept Med & Pharmacol, Chicago, IL USA..
    Newton-Cheh, Christopher
    Broad Inst & Harvard, Program Med & Populat Genet, Cambridge, MA USA.;Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA..
    Shaffer, Christian
    Vanderbilt Univ, Med Ctr, Dept Med, 221 Kirkland Hall, Nashville, TN 37235 USA..
    Macfarlane, Peter W.
    Univ Glasgow, Coll Med Vet & Sci, Inst Hlth & Wellbeing, Glasgow, Lanark, Scotland..
    Heilmann-Heimbach, Stefanie
    Univ Bonn, Inst Human Genet, Bonn, Germany.;Univ Bonn, Life & Brain Res Ctr, Dept Gen, Bonn, Germany..
    Almgren, Peter
    Lund Univ, Dept Clin Sci, Malmo, Sweden..
    Huang, Paul L.
    Broad Inst & Harvard, Program Med & Populat Genet, Cambridge, MA USA..
    Sotoodehnia, Nona
    Univ Washington, Cardiovasc Hlth Res Unit, Washington, DC USA..
    Soliman, Elsayed Z.
    Wake Forest Sch Med, Epidemiol Cardiol Res Ctr EPICARE, Winston Salem, NC USA..
    Uitterlinden, Andre G.
    Erasmus MC, Dept Epidemiol & Internal Med, Rotterdam, Netherlands..
    Hofman, Albert
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands..
    Franco, Oscar H.
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands..
    Voelker, Uwe
    DZHK German Ctr Cardiovasc Res, Greifswald, Germany.;Univ Med, Interfac Inst Genet & Funct Gen, Greifswald, Germany.;Ernst Moritz Arndt Univ Greifswald, Greifswald, Germany..
    Joeckel, Karl-Heinz
    Univ Hosp Essen, Inst Med Informat Biometry & Epidemiol, Essen, Germany..
    Sinner, Moritz F.
    Univ Hosp Munich, Ludwig Maximilians Univ, Dept Med 1, Munich, Germany.;DZHK German Ctr Cardiovasc Res, Munich Heart Alliance, Munich, Germany..
    Lin, Henry J.
    Harbor UCLA Med Ctr, LABioMed, Dept Pediat, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA..
    Guo, Xiuqing
    Harbor UCLA Med Ctr, LABioMed, Dept Pediat, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA..
    Dichgans, Martin
    Klinikum Univ Munchen, Inst Stroke & Dementia Res, Ludwig Maximilians Univ, Munich, Germany.;Munich Cluster Syst Neurol SyNergy, Munich, Germany.;German Ctr Neurodegenerat Dis DZNE, Munich, Germany..
    Ingelsson, Erik
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Kooperberg, Charles
    Univ Washington, Fred Hutchinson Canc Res Ctr, Seattle, WA 98195 USA..
    Melander, Olle
    Lund Univ, Clin Sci, Dept Internal Med, Malmo, Sweden..
    Loos, Ruth J. F.
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA..
    Laurikka, Jari
    Univ Tampere, Sch Med, Tampere, Finland.;Tampere Univ Hosp, Heart Hosp, Dept Cardio Thorac Surg, Tampere, Finland..
    Conen, David
    Univ Basel Hosp, Dept Med, Basel, Switzerland.;Cardiovasc Res Inst Basel, Basel, Switzerland..
    Rosand, Jonathan
    Broad Inst & Harvard, Program Med & Populat Genet, Cambridge, MA USA.;Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA..
    van der Harst, Pim
    Univ Groningen, Dept Cardiol, Univ Med Ctr Groningen, Groningen, Netherlands..
    Lokki, Marja-Liisa
    Univ Helsinki, Medicum, Transplantat Lab, Helsinki, Finland..
    Kathiresan, Sekar
    Broad Inst & Harvard, Program Med & Populat Genet, Cambridge, MA USA..
    Pereira, Alexandre
    Univ Sao Paulo, Heart Inst, Lab Genet & Mol Cardiol, Sao Paulo, Brazil.;Harvard Med Sch, Dept Genet, Boston, MA USA..
    Jukema, J. Wouter
    Leiden Univ, Med Ctr, Dept Cardiol, Leiden, Netherlands.;Durrer Ctr Cardiogenet Res, Amsterdam, Netherlands.;Interuniv Cardiol Inst Netherlands, Utrecht, Netherlands..
    Hayward, Caroline
    Univ Edinburgh, Inst Genet & Mol Med, MRC, Human Genet Unit, Edinburgh, Midlothian, Scotland..
    Rotter, Jerome I.
    Harbor UCLA Med Ctr, LABioMed, Dept Pediat, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA.;Harbor UCLA Med Ctr, LABioMed, Dept Med, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA..
    Maerz, Winfried
    Med Univ Graz, Inst Clin Med, Graz, Austria.;Med Univ Graz, Chem Lab Diagnost, Graz, Austria.;Synlab Holding Deutschland GmbH, Synlab Acad, Mannheim, Germany.;Synlab Holding Deutschland GmbH, Synlab Acad, Augsburg, Germany..
    Lehtimaki, Terho
    Fimlab Labs, Dept Clin Chem, Tampere, Finland.;Univ Tampere, Sch Med, Tampere, Finland..
    Stricker, Bruno H.
    Erasmus MC, Dept Epidemiol & Internal Med, Rotterdam, Netherlands.;Inspectorate Hlth Care, Utrecht, Netherlands..
    Chung, Mina K.
    Cleveland Clin, Dept Cardiovasc Med, Cleveland, OH 44106 USA.;Cleveland Clin, Dept Cellular & Mol Med, Cleveland, OH 44106 USA.;Cleveland Clin, Dept Mol Cardiol, Cleveland, OH 44106 USA.;Cleveland Clin, Dept Quantitat Hlth Sci, Cleveland, OH 44106 USA..
    Felix, Stephan B.
    Univ Med Greifswald, Dept Internal Med B, Greifswald, Germany.;DZHK German Ctr Cardiovasc Res, Greifswald, Germany..
    Gudnason, Vilmundur
    Iceland Heart Assoc, Kopavogur, Iceland.;Univ Iceland, Fac Med, Reykjavik, Iceland..
    Alonso, Alvaro
    Emory Univ, Rollins Sch Publ Hlth, Dept Epidemiol, Atlanta, GA 30322 USA..
    Roden, Dan M.
    Vanderbilt Univ, Med Ctr, Dept Med, 221 Kirkland Hall, Nashville, TN 37235 USA..
    Kaeaeb, Stefan
    Univ Hosp Munich, Ludwig Maximilians Univ, Dept Med 1, Munich, Germany.;DZHK German Ctr Cardiovasc Res, Munich Heart Alliance, Munich, Germany..
    Chasman, Daniel I.
    Broad Inst & Harvard, Program Med & Populat Genet, Cambridge, MA USA.;Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA.;Harvard Med Sch, Boston, MA USA.;Brigham & Womens Hosp, Div Genet, 75 Francis St, Boston, MA 02115 USA..
    Heckbert, Susan R.
    Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA.;Univ Washington, Cardiovasc Hlth Res Unit, Washington, DC USA.;Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA..
    Benjamin, Emelia J.
    NHLBI, Framingham, MA USA.;Boston Univ Framingham Heart Study, Framingham, MA USA.;Boston Univ, Sch Med, Dept Med, Boston, MA 02215 USA.;Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02215 USA..
    Tanaka, Toshihiro
    RIKEN, Ctr Integrat Med Sci, Lab Cardiovasc Dis, Yokohama, Kanagawa, Japan.;Tokyo Med & Dent Univ, Grad Sch Med & Dent Sci, Dept Human Genet & Dis Divers, Tokyo, Japan..
    Lunetta, Kathryn L.
    NHLBI, Framingham, MA USA.;Boston Univ Framingham Heart Study, Framingham, MA USA..
    Lubitz, Steven A.
    Broad Inst & Harvard, Program Med & Populat Genet, Cambridge, MA USA.;Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA.;Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA..
    Ellinor, Patrick T.
    Broad Inst & Harvard, Program Med & Populat Genet, Cambridge, MA USA.;Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA.;Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA..
    Large-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation2017In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 49, no 6, 946-+ p.Article in journal (Refereed)
    Abstract [en]

    Atrial fibrillation affects more than 33 million people worldwide and increases the risk of stroke, heart failure, and death(1,2). Fourteen genetic loci have been associated with atrial fibrillation in European and Asian ancestry groups(3-7). To further define the genetic basis of atrial fibrillation, we performed large-scale, trans-ancestry meta-analyses of common and rare variant association studies. The genome-wide association studies (GWAS) included 17,931 individuals with atrial fibrillation and 115,142 referents; the exome-wide association studies (ExWAS) and rare variant association studies (RVAS) involved 22,346 cases and 132,086 referents. We identified 12 new genetic loci that exceeded genome-wide significance, implicating genes involved in cardiac electrical and structural remodeling. Our results nearly double the number of known genetic loci for atrial fibrillation, provide insights into the molecular basis of atrial fibrillation, and may facilitate the identification of new potential targets for drug discovery(8).

  • 173.
    Chylenski, Maciej
    et al.
    Adam Mickiewicz Univ, Fac Hist, Inst Archaeol, Umultowska 89D, PL-61614 Poznan, Poland..
    Juras, Anna
    Adam Mickiewicz Univ, Fac Biol, Inst Anthropol, Dept Human Evolutionary Biol, Umultowska 89, PL-61614 Poznan, Poland..
    Ehler, Edvard
    Adam Mickiewicz Univ, Fac Biol, Inst Anthropol, Dept Human Evolutionary Biol, Umultowska 89, PL-61614 Poznan, Poland.;Charles Univ Prague, Fac Educ, Dept Biol & Environm Studies, Magdaleny Rettigove 4, Prague 11639, Czech Republic..
    Malmström, Helena
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Evolution and Developmental Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Piontek, Janusz
    Adam Mickiewicz Univ, Fac Biol, Inst Anthropol, Dept Human Evolutionary Biol, Umultowska 89, PL-61614 Poznan, Poland..
    Jakobsson, Mattias
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Evolution and Developmental Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Marciniak, Arkadiusz
    Adam Mickiewicz Univ, Fac Hist, Inst Archaeol, Umultowska 89D, PL-61614 Poznan, Poland..
    Dabert, Miroslawa
    Adam Mickiewicz Univ, Fac Biol, Mol Biol Techn Lab, Umultowska 89, PL-61614 Poznan, Poland..
    Late Danubian mitochondrial genomes shed light into the Neolithisation of Central Europe in the 5th millennium BC2017In: BMC Evolutionary Biology, ISSN 1471-2148, E-ISSN 1471-2148, Vol. 17, 80Article in journal (Refereed)
    Abstract [en]

    Background: Recent aDNA studies are progressively focusing on various Neolithic and Hunter-Gatherer (HG) populations, providing arguments in favor of major migrations accompanying European Neolithisation. The major focus was so far on the Linear Pottery Culture (LBK), which introduced the Neolithic way of life in Central Europe in the second half of 6th millennium BC. It is widely agreed that people of this culture were genetically different from local HGs and no genetic exchange is seen between the two groups. From the other hand some degree of resurgence of HGs genetic component is seen in late Neolithic groups belonging to the complex of the Funnel Beaker Cultures (TRB). Less attention is brought to various middle Neolithic cultures belonging to Late Danubian sequence which chronologically fall in between those two abovementioned groups. We suspected that genetic influx from HG to farming communities might have happened in Late Danubian cultures since archaeologists see extensive contacts between those two communities. Results: Here we address this issue by presenting 5 complete mitochondrial genomes of various late Danubian individuals from modern-day Poland and combining it with available published data. Our data show that Late Danubian cultures are maternally closely related to Funnel Beaker groups instead of culturally similar LBK. Conclusions: We assume that it is an effect of the presence of individuals belonging to U5 haplogroup both in Late Danubians and the TRB. The U5 haplogroup is thought to be a typical for HGs of Europe and therefore we argue that it is an additional evidence of genetic exchange between farming and HG groups taking place at least as far back as in middle Neolithic, in the Late Danubian communities.

  • 174.
    Clement, Yves
    et al.
    Montpellier SupAgro, UMR AGAP, Montpellier, France.;Univ Montpellier, CNRS IRD EPHE, UMR ISEM 5554, Montpellier, France.;PSL Res Univ, Ecole Normale Super, CNRS, IBENS,INSERM, Paris, France..
    Sarah, Gautier
    INRA, UMR AGAP, Montpellier, France.;SouthGreen Platform, Montpellier, France..
    Holtz, Yan
    Montpellier SupAgro, UMR AGAP, Montpellier, France..
    Homa, Felix
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab. SouthGreen Platform, Montpellier, France..
    Pointet, Stephanie
    SouthGreen Platform, Montpellier, France.;CIRAD, UMR AGAP, Montpellier, France.;ALCEDIAG CNRS Sys2Diag FRE3690, Biol Complex Syst Modelling & Engn Diag, Montpellier, France..
    Contreras, Sandy
    SouthGreen Platform, Montpellier, France.;GenoScreen, Lille, France..
    Nabholz, Benoit
    Univ Montpellier, CNRS IRD EPHE, UMR ISEM 5554, Montpellier, France..
    Sabot, Francois
    SouthGreen Platform, Montpellier, France.;IRD, UMR DIADE, Montpellier, France..
    Saune, Laure
    INRA, CBGP UMR1062, Montferrier Sur Lez, France..
    Ardisson, Morgane
    INRA, UMR AGAP, Montpellier, France..
    Bacilieri, Roberto
    INRA, UMR AGAP, Montpellier, France..
    Besnard, Guillaume
    Univ Toulouse III, CNRS ENSFEA IRD, UMR EDB 5174, Toulouse, France..
    Berger, Angelique
    CIRAD, UMR AGAP, Montpellier, France..
    Cardi, Celine
    CIRAD, UMR AGAP, Montpellier, France..
    De Bellis, Fabien
    CIRAD, UMR AGAP, Montpellier, France..
    Fouet, Olivier
    CIRAD, UMR AGAP, Montpellier, France..
    Jourda, Cyril
    CIRAD, UMR AGAP, Montpellier, France.;CIRAD, UMR PVBMT, St Pierre, Reunion, France..
    Khadari, Bouchaib
    INRA, UMR AGAP, Montpellier, France..
    Lanaud, Claire
    CIRAD, UMR AGAP, Montpellier, France..
    Leroy, Thierry
    CIRAD, UMR AGAP, Montpellier, France..
    Pot, David
    Sauvage, Christopher
    INRA, GAFL UR1052, Montfavet, France..
    Scarcelli, Nora
    IRD, UMR DIADE, Montpellier, France..
    Tregear, James
    IRD, UMR DIADE, Montpellier, France..
    Vigouroux, Yves
    IRD, UMR DIADE, Montpellier, France..
    Yahiaoui, Nabila
    CIRAD, UMR AGAP, Montpellier, France..
    Ruiz, Manuel
    SouthGreen Platform, Montpellier, France.;CIRAD, UMR AGAP, Montpellier, France..
    Santoni, Sylvain
    INRA, UMR AGAP, Montpellier, France..
    Labouisse, Jean-Pierre
    CIRAD, UMR AGAP, Montpellier, France..
    Pham, Jean-Louis
    IRD, UMR DIADE, Montpellier, France..
    David, Jacques
    Montpellier SupAgro, UMR AGAP, Montpellier, France..
    Glemin, Sylvain
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Plant Ecology and Evolution. Univ Montpellier.
    Evolutionary forces affecting synonymous variations in plant genomes2017In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 13, no 5, e1006799Article in journal (Refereed)
    Abstract [en]

    Base composition is highly variable among and within plant genomes, especially at third codon positions, ranging from GC-poor and homogeneous species to GC-rich and highly heterogeneous ones (particularly Monocots). Consequently, synonymous codon usage is biased in most species, even when base composition is relatively homogeneous. The causes of these variations are still under debate, with three main forces being possibly involved: mutational bias, selection and GC-biased gene conversion (gBGC). So far, both selection and gBGC have been detected in some species but how their relative strength varies among and within species remains unclear. Population genetics approaches allow to jointly estimating the intensity of selection, gBGC and mutational bias. We extended a recently developed method and applied it to a large population genomic dataset based on transcriptome sequencing of 11 angiosperm species spread across the phylogeny. We found that at synonymous positions, base composition is far from mutation-drift equilibrium in most genomes and that gBGC is a widespread and stronger process than selection. gBGC could strongly contribute to base composition variation among plant species, implying that it should be taken into account in plant genome analyses, especially for GC-rich ones.

  • 175. Collins, Emily
    et al.
    Sullivan, Alexis R.
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Gailing, Oliver
    Limited effective gene flow between two interfertile red oak species2015In: Trees, ISSN 0931-1890, E-ISSN 1432-2285, Vol. 29, no 4, 1135-1148 p.Article in journal (Refereed)
    Abstract [en]

    Highly elevated differentiation in different life stages between two interfertile oak species at a CONSTANS -like gene suggests a role of this gene in pre-zygotic isolation and adaptive divergence between species. Genome-wide differentiation patterns among oak species suggest that divergent selection can maintain species-specific adaptations and morphological integrity by reducing effective interspecific gene flow. While there is evidence for both pre- and post-zygotic isolation mechanisms in oaks (e.g., differences in flowering time, selection against hybrids), these mechanisms are rarely studied at each life stage from acorns to adult trees within the same forest. To assess the reproductive isolation mechanisms between two ecologically divergent species, we (1) quantified the number of hybrids in different life stages in Quercus rubra and Quercus ellipsoidalis, two interfertile red oaks with different adaptations to drought, and (2) assessed the timing of bud burst in both natural populations and in a seedling common garden trial. The low number of hybrids in all life stages suggested pre-zygotic isolation between species or selection in very early life stages that have not been sampled (e.g., early seed abortion). Significant differences in bud burst were found in two consecutive years between species in a common garden seedling trial but not in natural populations of the same provenance. In addition, we found evidence for divergent selection on several gene loci between species in each life stage. In particular, an SSR repeat located within the coding sequence of a CONSTANS-like gene, a locus involved in the photoperiodic regulation of flowering time and development, showed very high interspecific differentiation between species in all life stages (mean F (ST) = 0.83), compared to the average neutral differentiation of 3.7 %.

  • 176. Corander, Jukka
    et al.
    Gyllenberg, Mats
    Koski, Timo
    KTH, School of Engineering Sciences (SCI), Mathematics (Dept.), Mathematical Statistics.
    Learning Genetic Population Structures Using Minimization of Stochastic Complexity2010In: Entropy, ISSN 1099-4300, Vol. 12, no 5, 1102-1124 p.Article in journal (Refereed)
    Abstract [en]

    Considerable research efforts have been devoted to probabilistic modeling of genetic population structures within the past decade. In particular, a wide spectrum of Bayesian models have been proposed for unlinked molecular marker data from diploid organisms. Here we derive a theoretical framework for learning genetic population structure of a haploid organism from bi-allelic markers for which potential patterns of dependence are a priori unknown and to be explicitly incorporated in the model. Our framework is based on the principle of minimizing stochastic complexity of an unsupervised classification under tree augmented factorization of the predictive data distribution. We discuss a fast implementation of the learning framework using deterministic algorithms.

  • 177.
    Corcoran, Pádraic
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Neurospora tetrasperma from Natural Populations: Toward the Population Genomics of a Model Fungus2013Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The study of DNA sequence variation is a powerful approach to study genome evolution, and to reconstruct evolutionary histories of species. In this thesis, I have studied genetic variation in the fungus Neurospora tetrasperma and other closely related Neurospora species. I have focused on N. tetrasperma in my research because it has large regions of suppressed recombination on its mating-type chromosomes, had undergone a recent change in reproductive mode and is composed of multiple reproductively isolated lineages. Using DNA sequence data from a large sample set representing multiple species of Neurospora I estimated that N. tetrasperma evolved ~1 million years ago and that it is composed of at least 10 lineages. My analysis of the type of asexual spores produced using newly described N. tetrasperma populations in Britain revealed that lineages differ considerably in life history characteristics that may have consequences for their evolution. A comparative genomic analysis using three genomes of N. tetrasperma and the genome of N. crassa revealed that the mat a chromosomes in the lineages examine have been introgressed from other Neurospora species and that this introgression has reduced levels of molecular degeneration on the mating-type chromosomes. Finally, I generated a population genomic dataset composed of 92 N. tetrasperma genomes and two genomes of other Neurospora species. Analysis of these genomes revealed that all strains of N. tetrasperma have large regions of suppressed recombination on their mating-type chromosomes ranging from 69-84% of the chromosome and that the extent of divergence between mating-type chromosomes within lineages varies greatly (from 1.3 to 3.2%). I concluded that the source of this great divergence mating-type chromosome is large-scale introgression from other Neurospora species, and that these introgressed tracts have become fixed within N. tetrasperma lineages. I also discovered that genes within non-recombining introgressed regions of the mating-type chromosome have severely reduced levels of genetic variation as compared to the autosomes, and exhibit signatures of reduced molecular degeneration. My analysis of variation in coding regions revealed that positive selection on the introgressed regions has resulted in the removal of deleterious mutations and is responsible for the reductions in molecular degeneration observed.

  • 178.
    Corcoran, Pádraic
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Chen, Fen
    BGI, Hong Kong.
    Lascoux, Martin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Plant Ecology and Evolution.
    Ni, Peixang
    BGI, Hong Kong.
    Johanesson, Hanna
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Adaptive introgression slows down molecular degeneration of the mating-type chromosome in Neurospora tetraspermaManuscript (preprint) (Other academic)
  • 179.
    Cornille, Amandine
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics.
    Salcedo, A.
    Univ Toronto, Dept Ecol & Evolutionary Biol, 25 Willcocks St, Toronto, ON M6R 1M3, Canada..
    Kryvokhyzha, Dmytro
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Plant Ecology and Evolution.
    Glemin, Sylvain
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Plant Ecology and Evolution.
    Holm, Karl
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Plant Ecology and Evolution.
    Wright, S. I.
    Univ Toronto, Dept Ecol & Evolutionary Biol, 25 Willcocks St, Toronto, ON M6R 1M3, Canada..
    Lascoux, Martin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Plant Ecology and Evolution.
    Genomic signature of successful colonization of Eurasia by the allopolyploid shepherd's purse (Capsella bursa-pastoris)2016In: Molecular Ecology, ISSN 0962-1083, E-ISSN 1365-294X, Vol. 25, no 2, 616-629 p.Article in journal (Refereed)
    Abstract [en]

    Polyploidization is a dominant feature of flowering plant evolution. However, detailed genomic analyses of the interpopulation diversification of polyploids following genome duplication are still in their infancy, mainly because of methodological limits, both in terms of sequencing and computational analyses. The shepherd's purse (Capsella bursa-pastoris) is one of the most common weed species in the world. It is highly self-fertilizing, and recent genomic data indicate that it is an allopolyploid, resulting from hybridization between the ancestors of the diploid species Capsella grandiflora and Capsella orientalis. Here, we investigated the genomic diversity of C.bursa-pastoris, its population structure and demographic history, following allopolyploidization in Eurasia. To that end, we genotyped 261 C.bursa-pastoris accessions spread across Europe, the Middle East and Asia, using genotyping-by-sequencing, leading to a total of 4274 SNPs after quality control. Bayesian clustering analyses revealed three distinct genetic clusters in Eurasia: one cluster grouping samples from Western Europe and Southeastern Siberia, the second one centred on Eastern Asia and the third one in the Middle East. Approximate Bayesian computation (ABC) supported the hypothesis that C.bursa-pastoris underwent a typical colonization history involving low gene flow among colonizing populations, likely starting from the Middle East towards Europe and followed by successive human-mediated expansions into Eastern Asia. Altogether, these findings bring new insights into the recent multistage colonization history of the allotetraploid C.bursa-pastoris and highlight ABC and genotyping-by-sequencing data as promising but still challenging tools to infer demographic histories of selfing allopolyploids.

  • 180.
    Cortes, Andres J.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Plant Ecology and Evolution.
    Waeber, S.
    Lexer, C.
    Sedlacek, J.
    Wheeler, J. A.
    van Kleunen, M.
    Bossdorf, O.
    Hoch, G.
    Rixen, C.
    Wipf, S.
    Karrenberg, Sophie
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Plant Ecology and Evolution.
    Small-scale patterns in snowmelt timing affect gene flow and the distribution of genetic diversity in the alpine dwarf shrub Salix herbacea2014In: Heredity, ISSN 0018-067X, E-ISSN 1365-2540, Vol. 113, no 3, 233-239 p.Article in journal (Refereed)
    Abstract [en]

    Current threats to biodiversity, such as climate change, are thought to alter the within-species genetic diversity among microhabitats in highly heterogeneous alpine environments. Assessing the spatial organization and dynamics of genetic diversity within species can help to predict the responses of organisms to environmental change. In this study, we evaluated whether small-scale heterogeneity in snowmelt timing restricts gene flow between microhabitats in the common long-lived dwarf shrub Salix herbacea L. We surveyed 273 genets across 12 early-and late-snowmelt sites (that is, ridges and snowbeds) in the Swiss Alps for phenological variation over 2 years and for genetic variation using seven SSR markers. Phenological differentiation triggered by differences in snowmelt timing did not correlate with genetic differentiation between microhabitats. On the contrary, extensive gene flow appeared to occur between microhabitats and slightly less extensively among adjacent mountains. However, ridges exhibited significantly lower levels of genetic diversity than snowbeds, and patterns of effective population size (Ne) and migration (Nem) between microhabitats were strongly asymmetric, with ridges acting as sources and snowbeds as sinks. As no recent genetic bottlenecks were detected in the studied sites, this asymmetry is likely to reflect current metapopulation dynamics of the species dominated by gene flow via seeds rather than ancient re-colonization after the last glacial period. Overall, our results suggest that seed dispersal prevents snowmelt-driven genetic isolation, and snowbeds act as sinks of genetic diversity. We discuss the consequences of such small-scale variation in gene flow and diversity levels for population responses to climate change.

  • 181.
    Cortobius Fredriksson, Moa
    Södertörn University College, School of Life Sciences.
    ProBenefit: Implementing the Convention on Biological Diversity in the Ecuadorian Amazon2009Independent thesis Basic level (degree of Bachelor), 15 credits / 22,5 HE creditsStudent thesis
    Abstract [en]

    Legislation on benefit sharing dates back to 1992 and the commandment of the UNConvention on Biological Diversity, hence implementation still has few cases to fall back on(CBD, 1992). The case study of the project ProBenefit presented by the thesis highlights howlack of deliberation can undermine a democratic process. The objective of the thesis is thatProBenefit’s attempt to implement the standards of the CBD on access and benefit sharingwill highlight not only problems met by this specific project, but difficulties that generallymeet democratic processes in contexts of high inequality. To define if the project ProBenefitsucceeded in carrying out a deliberative process the project will be analyzed by the criteria:access to information, representation, legitimacy and involvement.The population in the project area of ProBenefit had a long history of social marginalization,which made it hard for foreign projects to gain legitimacy. The lack of independentorganizations and the late establishment of the project, which resulted in time shortage, madeit impossible to prevent the distrust of the local population. The failure of the projectcoordinators to ensure active participation of all stakeholders resulted in a late and lowinvolvement of the local participants. The absence of independent organization also madedemocratic legitimacy of the process questionable. Even if ProBenefit had a vision ofdemocratic deliberation the project was unable to break down the prevailing unequal powerdistribution which resulted in an unsustainable process and failure. The conclusion of thethesis is that the attainment of deliberation foremost depends on how a project deals with theexisting distribution of power and how it succeeds in involving all stakeholders.

  • 182. Costa, H.
    et al.
    Xu, X.
    Overbeek, G.
    Vasaikar, S.
    Pawan K. Patro, C.
    Kostopoulou, O. N.
    Jung, M.
    Shafi, G.
    Ananthaseshan, S.
    Tsipras, G.
    Davoudi, B.
    Mohammad, A. -A
    Lam, H.
    Strååt, Klas
    KTH, School of Biotechnology (BIO), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab. Karolinska Institutet, Sweden.
    Wilhelmi, V.
    Shang, M.
    Tegner, J.
    Tong, J. C.
    Wong, K. T.
    Söderberg-Naucler, C.
    Yaiw, K. -C
    Human cytomegalovirus may promote tumour progression by upregulating arginase-22016In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 30, 47221-47231 p.Article in journal (Refereed)
    Abstract [en]

    Background: Both arginase (ARG2) and human cytomegalovirus (HCMV) have been implicated in tumorigenesis. However, the role of ARG2 in the pathogenesis of glioblastoma (GBM) and the HCMV effects on ARG2 are unknown. We hypothesize that HCMV may contribute to tumorigenesis by increasing ARG2 expression. Results: ARG2 promotes tumorigenesis by increasing cellular proliferation, migration, invasion and vasculogenic mimicry in GBM cells, at least in part due to overexpression of MMP2/9. The nor-NOHA significantly reduced migration and tube formation of ARG2-overexpressing cells. HCMV immediate-early proteins (IE1/2) or its downstream pathways upregulated the expression of ARG2 in U-251 MG cells. Immunostaining of GBM tissue sections confirmed the overexpression of ARG2, consistent with data from subsets of Gene Expression Omnibus. Moreover, higher levels of ARG2 expression tended to be associated with poorer survival in GBM patient by analyzing data from TCGA. Methods: The role of ARG2 in tumorigenesis was examined by proliferation-, migration-, invasion-, wound healing- and tube formation assays using an ARG2- overexpressing cell line and ARG inhibitor, N (omega)-hydroxy-nor-L-arginine (nor-NOHA) and siRNA against ARG2 coupled with functional assays measuring MMP2/9 activity, VEGF levels and nitric oxide synthase activity. Association between HCMV and ARG2 were examined in vitro with 3 different GBM cell lines, and ex vivo with immunostaining on GBM tissue sections. The viral mechanism mediating ARG2 induction was examined by siRNA approach. Correlation between ARG2 expression and patient survival was extrapolated from bioinformatics analysis on data from The Cancer Genome Atlas (TCGA). Conclusions: ARG2 promotes tumorigenesis, and HCMV may contribute to GBM pathogenesis by upregulating ARG2.

  • 183.
    Crona, Filip
    et al.
    Stockholm University, Wenner-Gren Institute, Developmental Biology, Arrhenius laboratories E3, Stockholm SE-10691, Sweden.
    Dahlberg, Olle
    Stockholm University, Wenner-Gren Institute, Developmental Biology, Arrhenius laboratories E3, Stockholm SE-10691, Sweden.
    Lundberg, Lina E
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Larsson, Jan
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Mannervik, Mattias
    Stockholm University, Wenner-Gren Institute, Developmental Biology, Arrhenius laboratories E3, Stockholm SE-10691, Sweden.
    Gene regulation by the lysine demethylase KDM4A in Drosophila2013In: Developmental Biology, ISSN 0012-1606, E-ISSN 1095-564X, Vol. 737, no 2, 453-463 p.Article in journal (Refereed)
    Abstract [en]

    Lysine methylation of histones is associated with both transcriptionally active chromatin and with silent chromatin, depending on what residue is modified. Histone methyltransferases and demethylases ensure that histone methylations are dynamic and can vary depending on cell cycle- or developmental stage. KDM4A demethylates H3K36me3, a modification enriched in the 3' end of active genes. The genomic targets and the role of KDM4 proteins in development remain largely unknown. We therefore generated KDM4A mutant Drosophila, and identified 99 mis-regulated genes in first instar larvae. Around half of these genes were down-regulated and the other half up-regulated in dKDM4A mutants. Although heterochromatin protein 1a (HP1a) can stimulate dKDM4A demethylase activity in vitro, we find that they antagonize each other in control of dKDM4A-regulated genes. Appropriate expression levels for some dKDM4A-regulated genes rely on the demethylase activity of dKDM4A, whereas others do not. Surprisingly, although highly expressed, many demethylase-dependent and independent genes are devoid of H3K36me3 in wild-type as well as in dKDM4A mutant larvae, suggesting that some of the most strongly affected genes in dKDM4A mutant animals are not regulated by H3K36 methylation. By contrast, dKDM4A over-expression results in a global decrease in H3K36me3 levels and male lethality, which might be caused by impaired dosage compensation. Our results show that a modest increase in global H3K36me3 levels is compatible with viability, fertility, and the expression of most genes, whereas decreased H3K36me3 levels are detrimental in males.

  • 184.
    Crooks, Lucy
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Nettelblad, Carl
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Scientific Computing. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computational Science.
    Carlborg, Örjan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    An improved method for estimating chromosomal line origin in QTL analysis of crosses between outbred lines2011In: G3: Genes, Genomes, Genetics, ISSN 2160-1836, E-ISSN 2160-1836, Vol. 1, 57-64 p.Article in journal (Refereed)
  • 185.
    Dahlberg, Helena
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Has modern Swedish forestry affected genetic diversity in Norway spruce stands?2015Independent thesis Advanced level (degree of Master (Two Years)), 40 credits / 60 HE creditsStudent thesis
    Abstract [en]

    Norway spruce is one of two dominating species in Swedish forestry and the most economically important tree species in Sweden. In order to preserve the ability to adapt to a changing environment and to keep populations healthy, genetic diversity has to be preserved. When choosing a small number of individuals from a natural stand to establish a seed orchard the population size decrease. With only a small number of genetically different individuals the risk of inbreeding increase. Furthermore if many clones of the same tree are used in one seed orchard there is also an increased risk selfing. The aim of this study was therefore to investigate whether genetic diversity in Norway spruce differs between age groups and if this can be attributed to forestry practices. All sampling was done from a single location in Västerbotten, Sweden and the different age groups were chosen to represent stands not affected by the modern forest industry to recently planted forests. The chosen age groups are young (12-18 years), intermediate (30-45 years), and old (above 85 years). From each age group 150 individuals were sampled. With genomic microsatellite markers each individual was genotyped at eight simple sequence repeat (SSR) loci. Results show an overall high genetic diversity with an average expected heterozygosity (He) at 0.842 and low genetic differentiation with an average fixation index among populations (FST) of 0.003. The genetic diversity of each age group was also high (He 0.832 to 0.843) and the inbreeding coefficient ranged from 0.061 in the old group to 0.078 in the intermediate group. The pairwise FST value was highest between the old group and the young group but the differentiation was only 0.005 (P=0.001). An analysis of molecular variance also showed that only 0.34% of the total genetic variance was explained by differences among age groups. This study found little evidence for a decrease in genetic diversity due to forestry practices and revealed high genetic diversity and low differentiation between the age groups, indicating a healthy population.

  • 186.
    Damen, Wim
    et al.
    Universität zu Köln.
    Janssen, Ralf
    Uppsala University, Disciplinary Domain of Science and Technology, Earth Sciences, Department of Earth Sciences, Palaeobiology.
    Prpic, Nikola-Michael
    Universität zu Köln.
    Pair rule gene orthologs in spider segmentation2005In: Evolution & Development, ISSN 1520-541X, E-ISSN 1525-142X, Vol. 7, no 6, 618-628 p.Article in journal (Refereed)
    Abstract [en]

    The activation of pair rule genes is the first indication of the metameric organization of the Drosophila embryo and thus forms a key step in the segmentation process. There are two classes of pair rule genes in Drosophila: the primary pair rule genes that are directly activated by the maternal and gap genes and the secondary pair rule genes that rely on input from the primary pair rule genes. Here we analyze orthologs of Drosophila primary and secondary pair rule orthologs in the spider Cupiennius salei. The expression patterns of the spider pair rule gene orthologs can be subdivided in three groups: even-skipped and runt-1 expression is in stripes that start at the posterior end of the growth zone and their expression ends before the stripes reach the anterior end of the growth zone, while hairy and pairberry-3 stripes also start at the posterior end, but do not cease in the anterior growth zone. Stripes of odd-paired, odd-skipped-related-1, and sloppy paired are only found in the anterior portion of the growth zone. The various genes thus seem to be active during different phases of segment specification. It is notable that the spider orthologs of the Drosophila primary pair rule genes are active more posterior in the growth zone and thus during earlier phases of segment specification than most orthologs of Drosophila secondary pair rule genes, indicating that parts of the hierarchy might be conserved between flies and spiders. The spider ortholog of the Drosophila pair rule gene fushi tarazu is not expressed in the growth zone, but is expressed in a Hox-like fashion. The segmentation function of fushi tarazu thus appears to be a newly acquired role of the gene in the lineage of the mandibulate arthropods.

    PMID:16336415

  • 187.
    Daniel, Chammiran
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Silberberg, Gilad
    Behm, Mikaela
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Öhman, Marie
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Alu elements shape the primate transcriptome by cis-regulation of RNA editing2014In: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 15, no 2, R28Article in journal (Refereed)
    Abstract [en]

    Background: RNA editing by adenosine to inosine deamination is a widespread phenomenon, particularly frequent in the human transcriptome, largely due to the presence of inverted Alu repeats and their ability to form double-stranded structures - a requisite for ADAR editing. While several hundred thousand editing sites have been identified within these primate-specific repeats, the function of Alu-editing has yet to be elucidated. Results: We show that inverted Alu repeats, expressed in the primate brain, can induce site-selective editing in cis on sites located several hundred nucleotides from the Alu elements. Furthermore, a computational analysis, based on available RNA-seq data, finds that site-selective editing occurs significantly closer to edited Alu elements than expected. These targets are poorly edited upon deletion of the editing inducers, as well as in homologous transcripts from organisms lacking Alus. Sequences surrounding sites near edited Alus in UTRs, have been subjected to a lesser extent of evolutionary selection than those far from edited Alus, indicating that their editing generally depends on cis-acting Alus. Interestingly, we find an enrichment of primate-specific editing within encoded sequence or the UTRs of zinc finger-containing transcription factors. Conclusions: We propose a model whereby primate-specific editing is induced by adjacent Alu elements that function as recruitment elements for the ADAR editing enzymes. The enrichment of site-selective editing with potentially functional consequences on the expression of transcription factors indicates that editing contributes more profoundly to the transcriptomic regulation and repertoire in primates than previously thought.

  • 188. Das, S
    et al.
    Lagercrantz, Ulf
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Department of Evolution, Genomics and Systematics. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Department of Evolution, Genomics and Systematics, Evolutionary Functional Genomics. Evolutionär Funktionsgenomik.
    Lascoux, Martin
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Department of Evolution, Genomics and Systematics. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Department of Evolution, Genomics and Systematics, Evolutionary Functional Genomics. Evolutionär Funktionsgenomik.
    Black mustard2006In: Genome mapping and molecular breeding in plants: Oilseeds, Springer, , 2006Chapter in book (Refereed)
  • 189.
    Daskalaki, Evangelia
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Archaeological Genetics - Approaching Human History through DNA Analysis2014Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    There are a variety of archaeological questions, which are difficult to assess by traditional archaeological methods. Similarly, there are genetic and population genetic questions about human evolution and migration that are difficult to assess by studying modern day genetic variation. Archaeological genetics can directly study the archaeological remains, allowing human history to be explored by means of genetics, and genetics to be expanded into historical and pre-historical times. Examples of archaeological questions that can be resolved by genetics are determining biological sex on archaeological remains and exploring the kinship or groups buried in close proximity. Another example is one of the most important events in human prehistory – the transition from a hunter-gatherer lifestyle to farming - was driven through the diffusion of ideas or with migrating farmers. Molecular genetics has the potential to contribute in answering all these questions as well as others of similar nature. However, it is essential that the pitfalls of ancient DNA, namely fragmentation, damage and contamination are handled during data collection and data analysis.

    Analyses of ancient DNA presented in this thesis are based on both mitochondrial DNA and nuclear DNA through the study of single nuclear polymorphisms (SNPs). I used pyrosequencing assays in order to identify the biological sex of archaeological remains as well as verifying if fragmented remains were human or from animal sources. I used a clonal assay approach in order to retrieve sequences for the HVRI of a small family-like burial constellation from the Viking age. By the use of low coverage shotgun sequencing I retrieved sequence data from 13 crew members from the 17th century Swedish man-of-war Kronan. This data was used to determine the ancestry of the crew, which in some cases was speculated to be of non-Scandinavian or non-European origin. However, I demonstrate that all individuals were of European ancestry. Finally, I retrieved sequence data from a Neolithic farmer from the Iberian Peninsula, which added one more facet of information in exploring the Neolithization process of Europe. The Neolithic Iberian individual was genetically similar to Scandinavian Neolithic farmers, indicating that the genetic variation of prehistoric Europe correlated with subsistence mode rather than with geography.

  • 190.
    Daskalaki, Evangelia
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Andersson, Lars
    Stockholms läns museum.
    Wilerslev, Eske
    Statens Naturhistoriske Museum.
    Götherström, Anders
    Stockholm University.
    Mitochondrial DNA reveals a lack of kin relations in a suspected Viking age family constellation from a Swedish proto-Christian burial site.Manuscript (preprint) (Other academic)
  • 191.
    Daskalaki, Evangelia
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Skoglund, Pontus
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Einarson, Lars
    Kalmars läns museum.
    Kjellström, Anna
    Stockholm University.
    Jakobsson, Mattias
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Götherström, Anders
    Stockholm University.
    Genomic analysis of biogeographic ancestry of 15 crewmembers from the 300 year-old Swedish man-of-war KronanManuscript (preprint) (Other academic)
  • 192. Dawson, Deborah
    et al.
    Ball, Alexander
    Spurgin, Lewis
    Martin-Galvez, David
    Stewart, Ian RK
    Horsburgh, Gavin
    Potter, Jonathan
    Molina-Morales, Mercedes
    Bicknell, Anthony W J
    Preston, Stephanie A J
    Ekblom, Robert
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Slate, Jon
    Burke, Terry
    High-utility conserved avian microsatellite markers enable parentage and population studies across a wide range of species2013In: BMC Genomics, ISSN 1471-2164, Vol. 14, no 1, 176- p.Article in journal (Refereed)
    Abstract [en]

    Background: Microsatellites are widely used for many genetic studies. In contrast to single nucleotide polymorphism (SNP) and genotyping-by-sequencing methods, they are readily typed in samples of low DNA quality/concentration (e.g. museum/non-invasive samples), and enable the quick, cheap identification of species, hybrids, clones and ploidy. Microsatellites also have the highest cross-species utility of all types of markers used for genotyping, but, despite this, when isolated from a single species, only a relatively small proportion will be of utility. Marker development of any type requires skill and time. The availability of sufficient "off-the-shelf" markers that are suitable for genotypinga wide range of species would not only save resources but also uniquely enablenew comparisons of diversity among taxa at the same set of loci. No other marker types are capable of enabling this. We therefore developed a set of avianmicrosatellite markers with enhanced cross-species utility. Results: We selected highly-conserved sequences with a high number of repeat units in both of two genetically distant species. Twenty-four primer sets were designed from homologous sequences that possessed at least eight repeat units in both the zebra finch (Taeniopygia guttata) and chicken (Gallus gallus). Each primer sequence was a complete match to zebra finch and, after accounting for degenerate bases, at least 86% similar to chicken. We assessed primer-set utilityby genotyping individuals belonging to eight passerine and four non-passerinespecies. The majority of the new Conserved Avian Microsatellite (CAM) markersamplified in all 12 species tested (on average, 94% in passerines and 95% in non-passerines). This new marker set is of especially high utility in passerines, with amean 68% of loci polymorphic per species, compared with 42% in non-passerinespecies. Conclusions: When combined with previously described conserved loci, this new set of conserved markers will not only reduce the necessity and expense ofmicrosatellite isolation for a wide range of genetic studies, including avianparentage and population analyses, but will also now enable comparisons ofgenetic diversity among different species (and populations) at the same set of loci, with no or reduced bias. Finally, the approach used here can be applied to other taxa in which appropriate genome sequences are available.

  • 193.
    De Bustos, Cecilia
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Genetic and Epigenetic Variation in the Human Genome: Analysis of Phenotypically Normal Individuals and Patients Affected with Brain Tumors2006Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Genetic and epigenetic variation is a key determinant of human diversity and has an impact on disease predisposition. Single nucleotide polymorphisms (SNPs) and copy number polymorphisms (CNPs) are the main forms of genetic variation. The challenge is to distinguish normal variations from disease-associated changes. Combination of genetic and epigenetic alterations, often together with an environmental component, can cause cancer. In paper I, we investigated possible alterations affecting the transcriptional regulation of PDGFRα in patients affected with central nervous system tumors by characterizing the haplotype combinations in the PDGFRA gene promoter. A specific over-representation of one haplotype (H2δ) in primitive neuroectodermal tumors and ependymomas was observed, suggesting a functional role for the ZNF148/PDGFRα pathway in the tumor pathogenesis. In paper II, 50 glioblastomas were analyzed for DNA copy number variation with a chromosome 22 tiling genomic array. While 20% of tumors displayed monosomy 22, copy number variations affecting a portion of chromosome 22 were found in 14% of cases. This implies the presence of genes involved in glioblastoma development on 22q. Paper III described the analysis of copy number variation of 37 ependymomas using the same array. We detected monosomy in 51.5% of the samples. In addition, we identified two overlapping germline deletions of 2.2 Mb and 320 kb (the latter designated as Ep CNP). In order to investigate whether Ep CNP was a common polymorphism in the normal population or had an association with ependymoma development, we constructed a high-resolution PCR product-based microarray covering this locus (paper IV). For this purpose, we developed a program called Sequence Allocator, which automates the process of array design. This approach allowed assessment of copy number variation within regions of segmental duplications. Our results revealed that gains or deletions were identical in size and encompassed 290 kb. Therefore, papers I-IV suggest that some SNPs and CNPs can be regarded as tumor-associated polymorphisms. Finally, paper V describes variation of DNA methylation among fully differentiated tissues by using an array covering ~9% of the human genome. Major changes in the overall methylation were also found in colorectal cancer cell lines lacking one or two DNA methyltransferases.

  • 194.
    de La Torre, Amanda R
    et al.
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Birol, Inanc
    Bousquet, Jean
    Ingvarsson, Pär K
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Umeå University, Faculty of Science and Technology, Department of Plant Physiology.
    Jansson, Stefan
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Umeå University, Faculty of Science and Technology, Department of Plant Physiology.
    Jones, Steven J. M
    Keeling, Christopher I
    MacKay, John
    Nilsson, Ove
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Umeå University, Faculty of Science and Technology, Department of Plant Physiology.
    Ritland, Kermit
    Street, Nathaniel
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Umeå University, Faculty of Science and Technology, Department of Plant Physiology.
    Yanchuk, Alvin
    Zerbe, Philipp
    Bohlmann, Jörg
    Insights into conifer giga-genomes2014In: Plant Physiology, ISSN 0032-0889, E-ISSN 1532-2548, Vol. 166, no 4, 1724-1732 p.Article in journal (Refereed)
    Abstract [en]

    Insights from sequenced genomes of major land plant lineages have advanced research in almost every aspect of plant biology. Until recently, however, assembled genome sequences of gymnosperms have been missing from this picture. Conifers of the pine family (Pinaceae) are a group of gymnosperms that dominate large parts of the world's forests. Despite their ecological and economic importance, conifers seemed long out of reach for complete genome sequencing, due in part to their enormous genome size (20-30 Gb) and the highly repetitive nature of their genomes. Technological advances in genome sequencing and assembly enabled the recent publication of three conifer genomes: white spruce (Picea glauca), Norway spruce (Picea abies), and loblolly pine (Pinus taeda). These genome sequences revealed distinctive features compared with other plant genomes and may represent a window into the past of seed plant genomes. This Update highlights recent advances, remaining challenges, and opportunities in light of the publication of the first conifer and gymnosperm genomes.

  • 195.
    de La Torre, Amanda R.
    et al.
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences. Department of Plant Sciences, University of California–Davis, Davis, CA.
    Li, Zhen
    Van de Peer, Yves
    Ingvarsson, Pär K.
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences. Department of Plant Biology, Uppsala Biocenter, Swedish University of Agr icultural Sciences, Uppsala, Sweden.
    Contrasting Rates of Molecular Evolution and Patterns of Selection among Gymnosperms and Flowering Plants2017In: Molecular biology and evolution, ISSN 0737-4038, E-ISSN 1537-1719, Vol. 34, no 6, 1363-1377 p.Article in journal (Refereed)
    Abstract [en]

    The majority of variation in rates of molecular evolution among seed plants remains both unexplored and unexplained. Although some attention has been given to flowering plants, reports of molecular evolutionary rates for their sister plant clade (gymnosperms) are scarce, and to our knowledge differences in molecular evolution among seed plant clades have never been tested in a phylogenetic framework. Angiosperms and gymnosperms differ in a number of features, of which contrasting reproductive biology, life spans, and population sizes are the most prominent. The highly conserved morphology of gymnosperms evidenced by similarity of extant species to fossil records and the high levels of macrosynteny at the genomic level have led scientists to believe that gymnosperms are slow-evolving plants, although some studies have offered contradictory results. Here, we used 31,968 nucleotide sites obtained from orthologous genes across a wide taxonomic sampling that includes representatives of most conifers, cycads, ginkgo, and many angiosperms with a sequenced genome. Our results suggest that angiosperms and gymnosperms differ considerably in their rates of molecular evolution per unit time, with gymnosperm rates being, on average, seven times lower than angiosperm species. Longer generation times and larger genome sizes are some of the factors explaining the slow rates of molecular evolution found in gymnosperms. In contrast to their slow rates of molecular evolution, gymnosperms possess higher substitution rate ratios than angiosperm taxa. Finally, our study suggests stronger and more efficient purifying and diversifying selection in gymnosperm than in angiosperm species, probably in relation to larger effective population sizes.

  • 196.
    De La Torre, Amanda R
    et al.
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Lin, Yao-Cheng
    Van de Peer, Yves
    Ingvarsson, Pär K
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Genome-wide analysis reveals diverged patterns of codon bias, gene expression, and rates of sequence evolution in Picea gene families2015In: Genome Biology and Evolution, ISSN 1759-6653, E-ISSN 1759-6653, Vol. 7, no 4, 1002-1015 p.Article in journal (Refereed)
    Abstract [en]

    The recent sequencing of several gymnosperm genomes has greatly facilitated studying the evolution of their genes and gene families. In this study, we examine the evidence for expression-mediated selection in the first two fully sequenced representatives of the gymnosperm plant clade (Picea abies and Picea glauca). We use genome-wide estimates of gene expression (> 50,000 expressed genes) to study the relationship between gene expression, codon bias, rates of sequence divergence, protein length, and gene duplication. We found that gene expression is correlated with rates of sequence divergence and codon bias, suggesting that natural selection is acting on Picea protein-coding genes for translational efficiency. Gene expression, rates of sequence divergence, and codon bias are correlated with the size of gene families, with large multicopy gene families having, on average, a lower expression level and breadth, lower codon bias, and higher rates of sequence divergence than single-copy gene families. Tissue-specific patterns of gene expression were more common in large gene families with large gene expression divergence than in single-copy families. Recent family expansions combined with large gene expression variation in paralogs and increased rates of sequence evolution suggest that some Picea gene families are rapidly evolving to cope with biotic and abiotic stress. Our study highlights the importance of gene expression and natural selection in shaping the evolution of protein-coding genes in Picea species, and sets the ground for further studies investigating the evolution of individual gene families in gymnosperms.

  • 197. Decker, Jared E.
    et al.
    McKay, Stephanie D.
    Rolf, Megan M.
    Kim, JaeWoo
    Molina Alcala, Antonio
    Sonstegard, Tad S.
    Hanotte, Olivier
    Götherström, Anders
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Seabury, Christopher M.
    Praharani, Lisa
    Babar, Masroor Ellahi
    de Almeida Regitano, Luciana Correia
    Yildiz, Mehmet Ali
    Heaton, Michael P.
    Liu, Wan-Sheng
    Lei, Chu-Zhao
    Reecy, James M.
    Saif-Ur-Rehman, Muhammad
    Schnabel, Robert D.
    Taylor, Jeremy F.
    Worldwide Patterns of Ancestry, Divergence, and Admixture in Domesticated Cattle2014In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 10, no 3, e1004254- p.Article in journal (Refereed)
    Abstract [en]

    The domestication and development of cattle has considerably impacted human societies, but the histories of cattle breeds and populations have been poorly understood especially for African, Asian, and American breeds. Using genotypes from 43,043 autosomal single nucleotide polymorphism markers scored in 1,543 animals, we evaluate the population structure of 134 domesticated bovid breeds. Regardless of the analytical method or sample subset, the three major groups of Asian indicine, Eurasian taurine, and African taurine were consistently observed. Patterns of geographic dispersal resulting from co-migration with humans and exportation are recognizable in phylogenetic networks. All analytical methods reveal patterns of hybridization which occurred after divergence. Using 19 breeds, we map the cline of indicine introgression into Africa. We infer that African taurine possess a large portion of wild African auroch ancestry, causing their divergence from Eurasian taurine. We detect exportation patterns in Asia and identify a cline of Eurasian taurine/indicine hybridization in Asia. We also identify the influence of species other than Bos taurus taurus and B. t. indicus in the formation of Asian breeds. We detect the pronounced influence of Shorthorn cattle in the formation of European breeds. Iberian and Italian cattle possess introgression from African taurine. American Criollo cattle originate from Iberia, and not directly from Africa with African ancestry inherited via Iberian ancestors. Indicine introgression into American cattle occurred in the Americas, and not Europe. We argue that cattle migration, movement and trading followed by admixture have been important forces in shaping modern bovine genomic variation.

  • 198.
    Delgado Vega, Angélica María
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Dissecting the Genetic Basis of Systemic Lupus Erythematosus: The Pursuit of Functional Variants2013Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Systemic lupus erythematosus (SLE) is a chronic and systemic autoimmune disease that primarily affects women during the childbearing years. SLE is characterized by the production of autoantibodies against nucleic acids and their interacting proteins. The exact molecular mechanisms leading to the breakdown of self-tolerance remain to a large extent unknown, but it is well established that they are influenced by both non-genetic (i.e. environmental and hormonal) and genetic factors. SLE is a complex, polygenic disease. Several susceptibility variants have been identified in SLE. However, the functional role in disease pathogenesis for the majority of them remains largely unknown.

    This thesis includes case-control association studies where the role of the genes TNFSF4 (Paper I), STAT4 (Paper II), CD226 (Paper III), and BLK (Papers IV and V) in the susceptibility of developing SLE was investigated. The primary focus was on the identification of the functional variants underlying the association. For each of these genes, fine mapping was performed using single nucleotide polymorphisms (SNPs), the linkage disequilibrium (LD) was characterized, and the association was narrowed down to specific haplotypes by means of several different statistical genetic strategies. Candidate variants were prioritized for further functional analysis on the basis of their potential effect on the gene function, their association, and/or biological plausibility. In Paper I, the association of TNFSF4 with SLE was validated and attributed to a risk haplotype tagged by SNPs rs1234317-T and rs12039904-T. Paper II provides evidence supporting the presence of at least two independent genetic effects within the STAT4 gene represented by rs3821236-A and rs7574865-A, which correlated with increased levels of gene expression. In Paper III, a functional allele in CD226 (rs727088-C) was identified, which was responsible for decreased levels in both mRNA and protein expression. In Paper IV, two independent genetic effects in the BLK gene were demonstrated. The first one comprised multiple regulatory variants in high LD that were enriched for NFκB and IRF4 binding sites and correlated with low BLK mRNA levels. The second was a low-frequency missense substitution (Ala71Thr) that decreased the BLK protein half-life. In Paper V, a genetic epistatic interaction between BANK1 rs10516487 (GG) and BLK rs2736340 (TT+TC) was demonstrated. Additional molecular analyses established that these molecules interact physically.  

    These studies have contributed to the dissection of the genetic architecture of SLE. They highlight the allelic heterogeneity of the disease and provide functional links to the associated variants, which has significantly aided in the understanding of SLE disease pathogenesis.

  • 199.
    Demczuk, Walter H.B.
    et al.
    National Microbiology Laboratory, Winnipeg, Canada.
    Sidhu, S.
    National Microbiology Laboratory, Winnipeg, Canada.
    Unemo, Magnus
    WHO Collaborating Centre for Gonorrhoea and Other STIs, Örebro University Hospital, Örebro, Sweden; School of Medical Sciences, Örebro University, Örebro, Sweden.
    Whiley, David M.
    The University of Queensland, Centre for Clinical Research, Brisbane, Australia.
    Allen, Vanessa G. Public Health Ontario, Toronto, Canada
    Public Health Ontario Laboratories, Toronto , Canada.
    Dillon, Jeremiah R.
    Department of Microbiology and Immunology, University of Saskatchewan, Saskatoon, Canada.
    Cole, Michelle J.
    Public Health England, London, United Kingdom.
    Seah, Christine
    Public Health Ontario Laboratories, Toronto, Canada.
    Trembizki, Ella
    The University of Queensland, Centre for Clinical Research, Brisbane, Australia.
    Trees, David L.
    Centers for Disease Control and Prevention, Atlanta GA, United States.
    Kersh, Ellen N. Centers for Disease Control and Prevention, Division of Sexually Transmitted Disease Prevention, Atlanta, United States
    Centers for Disease Control and Prevention, Atlanta GA, United States.
    Abrams, A. Jeanine
    Centers for Disease Control and Prevention, Atlanta GA, United States.
    de Vries, Henry J.C.
    STI Outpatient Clinic, Department of Infectious Diseases, Public Health Service Amsterdam, Amsterdam, the Netherlands; Department of Dermatology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; Center for Infection and Immunity Amsterdam, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
    van Dam, Alje P.
    Public Health Laboratory, Public Health Service Amsterdam, Amsterdam, the NetheDepartment of Medical Microbiology, OLVG General Hospital, Amsterdam, the Netherlandsrlands; .
    Medina, I.
    Public Health Agency of Canada, National Microbiology Laboratory, Winnipeg MB, Canada.
    Bharat, Amrita
    Public Health Agency of Canada, National Microbiology Laboratory, Winnipeg MB, Canada.
    Mulvey, Michael Richard
    Public Health Agency of Canada, National Microbiology Laboratory, Winnipeg MB, Canada.
    Van Domselaar, Gary
    Public Health Agency of Canada, National Microbiology Laboratory, Winnipeg MB, Canada.
    Martin, Irene E.
    Public Health Agency of Canada, National Microbiology Laboratory, Winnipeg MB, Canada.
    Neisseria gonorrhoeae Sequence Typing for Antimicrobial Resistance: a Novel Antimicrobial Resistance Multilocus Typing Scheme for Tracking Global Dissemination of N. gonorrhoeae Strains2017In: Journal of Clinical Microbiology, ISSN 0095-1137, E-ISSN 1098-660X, Vol. 55, no 5, 1454-1468 p.Article in journal (Refereed)
    Abstract [en]

    A curated Web-based user-friendly sequence typing tool based on antimicrobial resistance determinants in Neisseria gonorrhoeae was developed and is publicly accessible (https://ngstar.canada.ca). The N. gonorrhoeae Sequence Typing for Antimicrobial Resistance (NG-STAR) molecular typing scheme uses the DNA sequences of 7 genes (penA, mtrR, porB, ponA, gyrA, parC, and 23S rRNA) associated with resistance to β-lactam antimicrobials, macrolides, or fluoroquinolones. NG-STAR uses the entire penA sequence, combining the historical nomenclature for penA types I to XXXVIII with novel nucleotide sequence designations; the full mtrR sequence and a portion of its promoter region; portions of ponA, porB, gyrA, and parC; and 23S rRNA sequences. NG-STAR grouped 768 isolates into 139 sequence types (STs) (n = 660) consisting of 29 clonal complexes (CCs) having a maximum of a single-locus variation, and 76 NG-STAR STs (n = 109) were identified as unrelated singletons. NG-STAR had a high Simpson's diversity index value of 96.5% (95% confidence interval [CI] = 0.959 to 0.969). The most common STs were NG-STAR ST-90 (n = 100; 13.0%), ST-42 and ST-91 (n = 45; 5.9%), ST-64 (n = 44; 5.72%), and ST-139 (n = 42; 5.5%). Decreased susceptibility to azithromycin was associated with NG-STAR ST-58, ST-61, ST-64, ST-79, ST-91, and ST-139 (n = 156; 92.3%); decreased susceptibility to cephalosporins was associated with NG-STAR ST-90, ST-91, and ST-97 (n = 162; 94.2%); and ciprofloxacin resistance was associated with NG-STAR ST-26, ST-90, ST-91, ST-97, ST-150, and ST-158 (n = 196; 98.0%). All isolates of NG-STAR ST-42, ST-43, ST-63, ST-81, and ST-160 (n = 106) were susceptible to all four antimicrobials. The standardization of nomenclature associated with antimicrobial resistance determinants through an internationally available database will facilitate the monitoring of the global dissemination of antimicrobial-resistant N. gonorrhoeae strains.

  • 200.
    den Tex, Robert-Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Patterns and Processes of Evolution in Sundaland2011Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Biodiversity in the tropics is disproportionately high compared to other habitats, and also under disproportionate threat from human impact. It is necessary to understand how this diversity evolved and how it is partitioned across space in order to preserve it. In this thesis I construct phylogenies of tropical forest dependent vertebrates from Southeast Asia and the islands of the Sunda shelf, a region referred to as Sundaland. I focus on the tree squirrels (genus Sundasciurus) and Asian barbets (Aves: Family Megalaimidae), two taxa with similar ecological characteristics. I use these phylogenies to test hypotheses that have been put forward to explain high levels of tropical diversity including the Pleistocene pump and museum hypotheses. I also use phylogenies to elucidate phylogeographic patterns within the region. I find no evidence for an increase in speciation in the Pleistocene, but I do find within species structure that dates to this period. Common phylogeographic patterns were identified between many forest dependent vertebrates that suggest that populations on the island of Sumatra are generally more closely related to Malay Peninsula populations than to populations on Borneo.

    From a methodological viewpoint we propose careful usage of universal primers in ancient DNA studies because of our finding of increased risk of amplifying pseudogenes of the mtDNA.

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