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  • 51.
    Ayllon, Fernando
    et al.
    Inst Marine Res, N-5024 Bergen, Norway..
    Kjaerner-Semb, Erik
    Inst Marine Res, N-5024 Bergen, Norway.;Univ Bergen, Dept Biol, Bergen, Norway..
    Furmanek, Tomasz
    Inst Marine Res, N-5024 Bergen, Norway..
    Wennevik, Vidar
    Inst Marine Res, N-5024 Bergen, Norway..
    Solberg, Monica F.
    Inst Marine Res, N-5024 Bergen, Norway..
    Dahle, Geir
    Inst Marine Res, N-5024 Bergen, Norway..
    Taranger, Geir Lasse
    Inst Marine Res, N-5024 Bergen, Norway..
    Glover, Kevin A.
    Inst Marine Res, N-5024 Bergen, Norway.;Univ Bergen, Dept Biol, Bergen, Norway..
    Almén, Markus Sällman
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Edvardsen, Rolf B.
    Inst Marine Res, N-5024 Bergen, Norway..
    Wargelius, Anna
    Inst Marine Res, N-5024 Bergen, Norway..
    The vgll3 Locus Controls Age at Maturity in Wild and Domesticated Atlantic Salmon (Salmo salar L.) Males2015In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 11, no 11, e1005628Article in journal (Refereed)
    Abstract [en]

    Wild and domesticated Atlantic salmon males display large variation for sea age at sexual maturation, which varies between 1-5 years. Previous studies have uncovered a genetic predisposition for variation of age at maturity with moderate heritability, thus suggesting a polygenic or complex nature of this trait. The aim of this study was to identify associated genetic loci, genes and ultimately specific sequence variants conferring sea age at maturity in salmon. We performed a genome wide association study (GWAS) using a pool sequencing approach (20 individuals per river and phenotype) of male salmon returning to rivers as sexually mature either after one sea winter (2009) or three sea winters (2011) in six rivers in Norway. The study revealed one major selective sweep, which covered 76 significant SNPs in which 74 were found in a 370 kb region of chromosome 25. Genotyping other smolt year classes of wild and domesticated salmon confirmed this finding. Genotyping domesticated fish narrowed the haplotype region to four SNPs covering 2386 bp, containing the vgll3 gene, including two missense mutations explaining 33-36% phenotypic variation. A single locus was found to have a highly significant role in governing sea age at maturation in this species. The SNPs identified may be both used as markers to guide breeding for late maturity in salmon aquaculture and in monitoring programs of wild salmon. Interestingly, a SNP in proximity of the VGLL3 gene in humans (Homo sapiens), has previously been linked to age at puberty suggesting a conserved mechanism for timing of puberty in vertebrates.

  • 52.
    Backström, Niclas
    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.
    Ceplitis, Helene
    Berlin, Sofia
    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, Hans
    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.
    Gene conversion drives the evolution of HINTW, an ampliconic gene on the female-specific avian W chromosome.2005In: Mol Biol Evol, ISSN 0737-4038, Vol. 22, no 10, 1992-9 p.Article in journal (Refereed)
    Abstract [en]

    The HINTW gene on the female-specific W chromosome of chicken and other birds is amplified and present in numerous copies. Moreover, as HINTW is distinctly different from its homolog on the Z chromosome (HINTZ), is a candidate gene in avian sex determination, and evolves rapidly under positive selection, it shows several common features to ampliconic and testis-specific genes on the mammalian Y chromosome. A phylogenetic analysis within galliform birds (chicken, turkey, quail, and pheasant) shows that individual HINTW copies within each species are more similar to each other than to gene copies of related species. Such convergent evolution is most easily explained by recurrent events of gene conversion, the rate of which we estimated at 10(-6)-10(-5) per site and generation. A significantly higher GC content of HINTW than of other W-linked genes is consistent with biased gene conversion increasing the fixation probability of mutations involving G and C nucleotides. Furthermore, and as a likely consequence, the neutral substitution rate is almost twice as high in HINTW as in other W-linked genes. The region on W encompassing the HINTW gene cluster is not covered in the initial assembly of the chicken genome, but analysis of raw sequence reads indicates that gene copy number is significantly higher than a previous estimate of 40. While sexual selection is one of several factors that potentially affect the evolution of ampliconic, male-specific genes on the mammalian Y chromosome, data from HINTW provide evidence that gene amplification followed by gene conversion can evolve in female-specific chromosomes in the absence of sexual selection. The presence of multiple and highly similar copies of HINTW may be related to protein function, but, more generally, amplification and conversion offers a means to the avoidance of accumulation of deleterious mutations in nonrecombining chromosomes.

  • 53.
    Backström, Niclas
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Forstmeier, Wolfgang
    Schielzeth, Holger
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Mellenius, Harriet
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Nam, Kiwoong
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Bolund, Elisabeth
    Webster, Matthew T.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
    Öst, Torbjörn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Schneider, Melanie
    Kempenaers, Bart
    Ellegren, Hans
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    The recombination landscape of the zebra finch Taeniopygia guttata genome2010In: Genome Research, ISSN 1088-9051, E-ISSN 1549-5469, Vol. 20, no 4, 485-495 p.Article in journal (Refereed)
    Abstract [en]

    Understanding the causes and consequences of variation in the rate of recombination is essential since this parameter is considered to affect levels of genetic variability, the efficacy of selection, and the design of association and linkage mapping studies. However, there is limited knowledge about the factors governing recombination rate variation. We genotyped 1920 single nucleotide polymorphisms in a multigeneration pedigree of more than 1000 zebra finches (Taeniopygia guttata) to develop a genetic linkage map, and then we used these map data together with the recently available draft genome sequence of the zebra finch to estimate recombination rates in 1 Mb intervals across the genome. The average zebra finch recombination rate (1.5 cM/Mb) is higher than in humans, but significantly lower than in chicken. The local rates of recombination in chicken and zebra finch were only weakly correlated, demonstrating evolutionary turnover of the recombination landscape in birds. The distribution of recombination events was heavily biased toward ends of chromosomes, with a stronger telomere effect than so far seen in any organism. In fact, the recombination rate was as low as 0.1 cM/Mb in intervals up to 100 Mb long in the middle of the larger chromosomes. We found a positive correlation between recombination rate and GC content, as well as GC-rich sequence motifs. Levels of linkage disequilibrium (LD) were significantly higher in regions of low recombination, showing that heterogeneity in recombination rates have left a footprint on the genomic landscape of LD in zebra finch populations.

  • 54.
    Bahrampour, Shahrzad
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Genetic mechanisms regulating proliferation and cell specification in the Drosophila embryonic CNS2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The central nervous system (CNS) consists of an enormous number of cells, and large cellular variance, integrated into an elaborate network. The CNS is the most complex animal organ, and therefore its establishment must be controlled by many different genetic programs. Considering the high level of complexity in the human CNS, addressing issues related to human neurodevelopment represents a major challenge. Since comparative studies have revealed that neurodevelopmental programs are well conserved through evolution, on both the genetic and functional levels, studies on invertebrate neurodevelopmental programs are often translatable to vertebrates. Indeed, the basis of our current knowledge about vertebrate CNS development has been greatly aided by studies on invertebrates, and in particular on the Drosophila melanogaster (fruit fly) model system.

    This thesis attempted to identify novel genes regulating neural cell specification and proliferation in the CNS, using the Drosophila model system. Moreover, I aimed to address how those genes govern neural progenitor cells (neuroblasts; NBs) to obtain/maintain their stemness identity and proliferation capacity, and how they drive NBs through temporal windows and series of programmed asymmetric division, which gradually reduces their stemness identity in favor of neural differentiation, resulting in appropriate lineage progression. In the first project, we conducted a forward genetic screen in Drosophila embryos, aimed at isolating genes involved in regulation of neural proliferation and specification, at the single cell resolution. By taking advantage of the restricted expression of the neuropeptide FMRFa in the last-born cell of the NB lineage 5-6T, the Ap4 neuron, we could monitor the entire lineage progression. This screen succeeded in identifying 43 novel genes controlling different aspects of CNS development. One of the genes isolated, Ctr9, displayed extra Ap4/FMRFa neurons. Ctr9 encodes a component of the RNA polymerase II complex Paf1, which is involved in a number of transcriptional processes. The Paf1C, including Ctr9, is highly conserved from yeast to human, and in the past couple of years, its importance for transcription has become increasingly appreciated. However, studies in the Drosophila system have been limited. In the screen, we isolated the first mutant of Drosophila Ctr9 and conducted the first detailed phenotypic study on its function in the Drosophila embryonic CNS. Loss of function of Ctr9 leads to extra NB numbers, higher proliferation ratio and lower expression of neuropeptides. Gene expression analysis identified several other genes regulated by Ctr9, which may explain the Ctr9 mutant phenotypes. In summary, we identified Ctr9 as an essential gene for proper CNS development in Drosophila, and this provides a platform for future study on the Drosophila Paf1C. Another interesting gene isolated in the screen was worniou (wor), a member of the Snail family of transcription factors. In contrast to Ctr9, whichdisplayed additional Ap4/FMRFa neurons, wor mutants displayed a loss of these neurons. Previous studies in our group have identified many genes acting to stop NB lineage progression, but how NBs are pushed to proliferate and generate their lineages was not well known. Since wor may constitute a “driver” of proliferation, we decided to study it further. Also, we identified five other transcription factors acting together with Wor as pro-proliferative in both NBs and their daughter cells. These “drivers” are gradually replaced by the previously identified late-acting “stoppers.” Early and late factors regulate each other and the cell cycle, and thereby orchestrate proper neural lineage progression.

  • 55.
    Bahrampour, Shahrzad
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Thor, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Ctr9, a Key Component of the Paf1 Complex, Affects Proliferation and Terminal Differentiation in the Developing Drosophila Nervous System2016In: G3: Genes, Genomes, Genetics, ISSN 2160-1836, E-ISSN 2160-1836, Vol. 6, no 10, 3229-3239 p.Article in journal (Refereed)
    Abstract [en]

    The Paf1 protein complex (Paf1C) is increasingly recognized as a highly conserved and broadly utilized regulator of a variety of transcriptional processes. These include the promotion of H3K4 and H3K36 trimethylation, H2BK123 ubiquitination, RNA Pol II transcriptional termination, and also RNA-mediated gene silencing. Paf1C contains five canonical protein components, including Paf1 and Ctr9, which are critical for overall complex integrity, as well as Rtf1, Leo1, and Cdc73/Parafibromin(Hrpt2)/Hyrax. In spite of a growing appreciation for the importance of Paf1C from yeast and mammalian studies, there has only been limited work in Drosophila. Here, we provide the first detailed phenotypic study of Ctr9 function in Drosophila. We found that Ctr9 mutants die at late embryogenesis or early larval life, but can be partly rescued by nervous system reexpression of Ctr9. We observed a number of phenotypes in Ctr9 mutants, including increased neuroblast numbers, increased nervous system proliferation, as well as downregulation of many neuropeptide genes. Analysis of cell cycle and regulatory gene expression revealed upregulation of the E2f1 cell cycle factor, as well as changes in Antennapedia and Grainy head expression. We also found reduction of H3K4me3 modification in the embryonic nervous system. Genome-wide transcriptome analysis points to additional downstream genes that may underlie these Ctr9 phenotypes, revealing gene expression changes in Notch pathway target genes, cell cycle genes, and neuropeptide genes. In addition, we find significant effects on the gene expression of metabolic genes. These findings reveal that Ctr9 is an essential gene that is necessary at multiple stages of nervous system development, and provides a starting point for future studies of the Paf1C in Drosophila.

  • 56. Bailey-Wilson, Joan E
    et al.
    Childs, Erica J
    Cropp, Cheryl D
    Schaid, Daniel J
    Xu, Jianfeng
    Camp, Nicola J
    Cannon-Albright, Lisa A
    Farnham, James M
    George, Asha
    Powell, Isaac
    Carpten, John D
    Giles, Graham G
    Hopper, John L
    Severi, Gianluca
    English, Dallas R
    Foulkes, William D
    Maehle, Lovise
    Moller, Pal
    Eeles, Rosalind
    Easton, Douglas
    Guy, Michelle
    Edwards, Steve
    Badzioch, Michael D
    Whittemore, Alice S
    Oakley-Girvan, Ingrid
    Hsieh, Chih-Lin
    Dimitrov, Latchezar
    Stanford, Janet L
    Karyadi, Danielle M
    Deutsch, Kerry
    McIntosh, Laura
    Ostrander, Elaine A
    Wiley, Kathleen E
    Isaacs, Sarah D
    Walsh, Patrick C
    Thibodeau, Stephen N
    McDonnell, Shannon K
    Hebbring, Scott
    Lange, Ethan M
    Cooney, Kathleen A
    Tammela, Teuvo LJ
    Schleutker, Johanna
    Maier, Christiane
    Bochum, Sylvia
    Hoegel, Josef
    Gronberg, Henrik
    Wiklund, Fredrik
    Emanuelsson, Monica
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Cancel-Tassin, Geraldine
    Valeri, Antoine
    Cussenot, Olivier
    Isaacs, William B
    Analysis of Xq27-28 linkage in the international consortium for prostate cancer genetics (ICPCG) families2012In: BMC Medical Genetics, ISSN 1471-2350, E-ISSN 1471-2350, Vol. 13, 46- p.Article in journal (Refereed)
    Abstract [en]

    Background: Genetic variants are likely to contribute to a portion of prostate cancer risk. Full elucidation of the genetic etiology of prostate cancer is difficult because of incomplete penetrance and genetic and phenotypic heterogeneity. Current evidence suggests that genetic linkage to prostate cancer has been found on several chromosomes including the X; however, identification of causative genes has been elusive.

    Methods: Parametric and non-parametric linkage analyses were performed using 26 microsatellite markers in each of 11 groups of multiple-case prostate cancer families from the International Consortium for Prostate Cancer Genetics (ICPCG). Meta-analyses of the resultant family-specific linkage statistics across the entire 1,323 families and in several predefined subsets were then performed.

    Results: Meta-analyses of linkage statistics resulted in a maximum parametric heterogeneity lod score (HLOD) of 1.28, and an allele-sharing lod score (LOD) of 2.0 in favor of linkage to Xq27-q28 at 138 cM. In subset analyses, families with average age at onset less than 65 years exhibited a maximum HLOD of 1.8 (at 138 cM) versus a maximum regional HLOD of only 0.32 in families with average age at onset of 65 years or older. Surprisingly, the subset of families with only 2-3 affected men and some evidence of male-to-male transmission of prostate cancer gave the strongest evidence of linkage to the region (HLOD = 3.24, 134 cM). For this subset, the HLOD was slightly increased (HLOD = 3.47 at 134 cM) when families used in the original published report of linkage to Xq27-28 were excluded.

    Conclusions: Although there was not strong support for linkage to the Xq27-28 region in the complete set of families, the subset of families with earlier age at onset exhibited more evidence of linkage than families with later onset of disease. A subset of families with 2-3 affected individuals and with some evidence of male to male disease transmission showed stronger linkage signals. Our results suggest that the genetic basis for prostate cancer in our families is much more complex than a single susceptibility locus on the X chromosome, and that future explorations of the Xq27-28 region should focus on the subset of families identified here with the strongest evidence of linkage to this region.

  • 57.
    Bajinskis, Ainars
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Natarajan, Adayapalam T.
    Erixon, Klaus
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Harms-Ringdahl, Mats
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    DNA double strand breaks induced by the indirect effect of radiation are more efficiently repaired by non-homologous end joining compared to homologous recombination repair2013In: Mutation research. Genetic toxicology and environmental mutagenesis, ISSN 1383-5718, E-ISSN 1879-3592, Vol. 756, no 1-2, 21-29 p.Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to investigate the relative involvement of three major DNA repair pathways, i.e., non-homologous end joining (NHEJ), homologous recombination (HRR) and base excision (BER) in repair of DNA lesions of different complexity induced by low- or high-LET radiation with emphasis on the contribution of the indirect effect of radiation for these radiation qualities. A panel of DNA repair-deficient CHO cell lines was irradiated by Cs-137 gamma-rays or radon progeny alpha-particles. Irradiation was also performed in the presence of 2 M DMSO to reduce the indirect effect of radiation and the complexity of the DNA damage formed. Clonogenic survival and micronucleus assays were used to estimate efficiencies of the different repair pathways for DNA damages produced by direct and indirect effects. Removal of the indirect effect of low-LET radiation by DMSO increased clonogenic survival and decreased MN formation for all cell lines investigated. A direct contribution of the indirect effect of radiation to DNA base damage was suggested by the significant protection by DMSO seen for the BER deficient cell line. Lesions formed by the indirect effect are more readily repaired by the NHEJ pathway than by HRR after irradiation with gamma-rays or alpha-particles as evaluated by cell survival and the yields of MN. The results obtained with BER- and NHEJ-deficient cells suggest that the indirect effect of radiation contributes significantly to the formation of repair substrates for these pathways.

  • 58.
    Baker, Laura
    et al.
    Department of Psychology (SGM 501), University of Southern California, Los Angeles, United States.
    Tuvblad, Catherine
    Department of Psychology (SGM 501), University of Southern California, Los Angeles, United States.
    Wang, Pan
    Department of Psychology (SGM 501), University of Southern California, Los Angeles, United States.
    Gomez, Karina
    Department of Psychology (SGM 501), University of Southern California, Los Angeles, United States.
    Bezdjian, Serena
    Department of Psychology (SGM 501), University of Southern California, Los Angeles, United States.
    Niv, Sharon
    Department of Psychology (SGM 501), University of Southern California, Los Angeles, United States.
    Raine, Adrian
    Departments of Criminology and Psychiatry, University of Pennsylvania, Philadelphia, PA, United States .
    The southern california twin register at the University of Southern California: III2013In: Twin Research and Human Genetics, ISSN 1832-4274, E-ISSN 1839-2628, Vol. 16, no 1, 336-343 p.Article in journal (Refereed)
  • 59.
    Baker, Maggie
    et al.
    NIAAA, USA.
    Lindell, Stephen G.
    NIAAA, USA.
    Driscoll, Carlos A.
    NIAAA, USA.
    Zhou, Zhifeng
    NIAAA, USA.
    Yuan, Qiaoping
    NIAAA, USA.
    Schwandt, Melanie L.
    NIAAA, USA.
    Miller-Crews, Isaac
    NIAAA, USA.
    Simpson, Elizabeth A.
    Eunice Shriver Kennedy National Institute Child Health and Huma, MD 20837 USA.
    Paukner, Annika
    Eunice Shriver Kennedy National Institute Child Health and Huma, MD 20837 USA.
    Francesco Ferrari, Pier
    University of Claude Bernard Lyon, France.
    Kumar Sindhu, Ravi
    NIAAA, MD 20852 USA.
    Razaqyar, Muslima
    NIAAA, USA.
    Sommer, Wolfgang H.
    Heidelberg University, Germany; Heidelberg University, Germany.
    Lopez, Juan F.
    University of Michigan, MI 48109 USA.
    Thompson, Robert C.
    University of Michigan, MI 48109 USA.
    Goldman, David
    NIAAA, USA.
    Heilig, Markus
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Dee Higley, J.
    Brigham Young University, UT 84602 USA.
    Suomi, Stephen J.
    Eunice Shriver Kennedy National Institute Child Health and Huma, MD 20837 USA.
    Barr, Christina S.
    NIAAA, USA.
    Early rearing history influences oxytocin receptor epigenetic regulation in rhesus macaques2017In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 114, no 44, 11769-11774 p.Article in journal (Refereed)
    Abstract [en]

    Adaptations to stress can occur through epigenetic processes and may be a conduit for informing offspring of environmental challenge. We employed ChIP-sequencing for H3K4me3 to examine effects of early maternal deprivation (peer-rearing, PR) in archived rhesus macaque hippocampal samples (male, n = 13). Focusing on genes with roles in stress response and behavior, we assessed the effects of rearing on H3K4me3 binding by ANOVA. We found decreased H3K4me3 binding at genes critical to behavioral stress response, the most robust being the oxytocin receptor gene OXTR, for which we observed a corresponding decrease in RNA expression. Based on this finding, we performed behavioral analyses to deter mine whether a gain-of-function nonsynonymous OXTR SNP inter acted with early stress to influence relevant behavioral stress reactivity phenotypes (n = 194), revealing that this SNP partially rescued the PR phenotype. PR infants exhibited higher levels of separation anxiety and arousal in response to social separation, but infants carrying the alternative OXTR allele did not exhibit as great a separation response. These data indicate that the oxytocin system is involved in social-separation response and suggest that epigenetic down-modulation of OXTR could contribute to behavior al differences observed in PR animals. Epigenetic changes at OXTR may represent predictive adaptive responses that could impart readiness to respond to environmental challenge or maintain proximity to a caregiver but also contribute to behavioral pathology. Our data also demonstrate that OXTR polymorphism can permit animals to partially overcome the detrimental effects of early maternal deprivation, which could have translational implications for human psychiatric disorders.

  • 60.
    Balciuniene, J
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
    Emilsson, L
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
    Oreland, L
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
    Pettersson, U
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
    Jazin, Elena
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
    Investigation of the functional effect of monoamine oxidase polymorphisms in human brain2002In: Human Genetics, ISSN 0340-6717, E-ISSN 1432-1203, Vol. 110, no 1, 1-7 p.Article in journal (Refereed)
  • 61. Balciuniene, J
    et al.
    Syvänen, A-C
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
    McLeod, H L
    Pettersson, U
    Jazin, E E
    Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Department of Evolution, Genomics and Systematics, Evolutionary Biology. Evolutionsbiologi.
    The geographic distribution of monoamine oxidase haplotypes supports a bottleneck during the dispersion of modern humans from Africa.2001In: J Mol Evol, ISSN 0022-2844, Vol. 52, no 2, 157-63 p.Article in journal (Other scientific)
  • 62.
    Banerji, Shantanu
    et al.
    Manitoba Institute of Cell Biology, Winnipeg, Manitoba, Canada .
    Los, Marek Jan
    Manitoba Institute of Cell Biology, Cancer Care Manitoba; Manitoba Institute of Child Health; Department of Biochemistry and Medical Genetics; Department of Human Anatomy and Cell Science, University Manitoba, Winnipeg, Canada.
    Important differences between topoisomerase-I and -II targeting agents2006In: Cancer Biology & Therapy, ISSN 1538-4047, E-ISSN 1555-8576, Vol. 5, no 8, 965-966 p.Article in journal (Other academic)
    Abstract [en]

    Commentary to: Activation of ATM and Histone H2AX Phosphorylation Induced by Mitoxantrone But Not by Topotecan is Prevented by the Antioxidant N-acetyl-L-Cysteine Xuan Huang, Akira Kurose, Toshiki Tanaka, Frank Traganos, Wei Dai and Zbigniew Darzynkiewicz

     

  • 63. Barnett, Ross
    et al.
    Barnes, Ian
    Phillips, Matthew J
    Martin, Larry D
    Harington, C Richard
    Leonard, Jennifer A
    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.
    Cooper, Alan
    Evolution of the extinct Sabretooths and the American cheetah-like cat.2005In: Curr Biol, ISSN 0960-9822, Vol. 15, no 15, R589-90 p.Article in journal (Other scientific)
  • 64.
    Beier, Frank
    et al.
    Institut für Experimentelle Medizin, Universität Erlangen-Nürnberg, Erlangen, Germany; Department of Medical Biochemistry, University of Calgary, Calgary, Canada.
    Vornehm, Silvia
    Institut für Experimentelle Medizin, Universität Erlangen-Nürnberg, Erlangen, Germany.
    Pöschl, Ernst
    Institut für Experimentelle Medizin, Universität Erlangen-Nürnberg, Erlangen, Germany.
    von der Mark, Klaus
    Institut für Experimentelle Medizin, Universität Erlangen-Nürnberg, Erlangen, Germany.
    Lammi, Mikko
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Localization of silencer and enhancer elements in the human type X collagen gene.1997In: Journal of Cellular Biochemistry, ISSN 0730-2312, E-ISSN 1097-4644, Vol. 66, no 2, 210-218 p., 9213222Article in journal (Refereed)
    Abstract [en]

    Collagen type X is a short, network-forming collagen expressed temporally and spatially tightly controlled in hypertrophic chondrocytes during endochondral ossification. Studies on chicken chondrocytes indicate that the regulation of type X collagen gene expression is regulated at the transcriptional level. In this study, we have analyzed the regulatory elements of the human type X collagen (Col10a1) by reporter gene constructs and transient transfections in chondrogenic and nonchondrogenic cells. Four different promoter fragments covering up to 2,864 bp of 5'-flanking sequences, either including or lacking the first intron, were linked to luciferase reporter gene and transfected into 3T3 fibroblasts, HT1080 fibrosarcoma cells, prehypertrophic chondrocytes from the resting zone, hypertrophic chondrocytes, and chondrogenic cell lines. The results indicated the presence of three regulatory elements in the human Col10a1 gene besides the proximal promoter. First, a negative regulatory element located between 2.4 and 2.8 kb upstream of the transcription initiation site was active in all nonchondrogenic cells and in prehypertrophic chondrocytes. Second, a positive, but also non-tissue-specific positive regulatory element was present in the first intron. Third, a cell-type-specific enhancer element active only in hypertrophic chondrocytes was located between -2.4 and -0.9 kb confirming a previous report by Thomas et al. [(1995): Gene 160:291-296]. The enhancing effect, however, was observed only when calcium phosphate was either used for transfection or included in the culture medium after lipofection. These findings demonstrate that the rigid control of human Col10a1 gene expression is achieved by both positive and negative regulatory elements in the gene and provide the basis for the identification of factors binding to those elements.

  • 65. Belle, Elise M S
    et al.
    Webster, Matthew T
    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.
    Eyre-Walker, Adam
    Why are young and old repetitive elements distributed differently in the human genome?2005In: J Mol Evol, ISSN 0022-2844, Vol. 60, no 3, 290-6 p.Article in journal (Refereed)
    Abstract [en]

    Alu elements are not distributed homogeneously throughout the human genome: old elements are preferentially found in the GC-rich parts of the genome, while young Alus are more often found in the GC-poor parts of the genome. The process giving rise to this differential distribution remains poorly understood. Here we investigate whether this pattern could be due to a preferential degradation of Alu elements integrated in GC-poor regions by small indel mutations. We aligned 5.1 Mb of human and chimpanzee sequences and examined whether the rate of insertion and deletion inside Alu elements differed according to the base composition surrounding them. We found that Alu elements are not preferentially degraded in GC-poor regions by indel events. We also looked at whether very young L1 elements show the same change in distribution compared to older ones. This analysis indicated that L1 elements also show a shift in their distribution, although we could not assess it as precisely as for Alu elements. We propose that the differential distribution of Alu elements is likely to be due to a change in their pattern of insertion or their probability of fixation through evolutionary time.

  • 66.
    Belotserkovsky, Jaroslav
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Studies on the functional interaction of translation initiation factor IF1 with ribosomal RNA2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Translation initiation factor IF1 is a small, essential and ubiquitous protein factor encoded by a single infA gene in bacteria. Although several important functions have been attributed to IF1, the precise reason for its indispensability is yet to be defined. It is known that IF1 binds to the ribosomal A-site during initiation, where it primarily contacts ribosomal RNA (rRNA) and induces large scale conformational changes in the small ribosomal subunit. To shed more light on the function of IF1 and its interaction with the ribosome, we have employed a genetic approach to elucidate structure-function interactions between IF1 and rRNA. A selection has been used to isolate second site suppressor mutations in rRNA that restore the growth of a cold sensitive mutant IF1 with an arginine to leucine substitution in position 69 (R69L).  This yielded two classes of suppressors – one class that mapped to the processing stem of 23S rRNA – a transient structure important for proper maturation of 23S rRNA; and the other class to the functional sequence of 16S rRNA. Suppressor mutations in the processing stem of 23S rRNA were shown to disrupt efficient processing of 23S rRNA. In addition, we report that at least one of the manifestations of cold sensitivity associated with the mutant IF1 is at the level of ribosomal subunit association. These results led to a model whereby the cold sensitive R69L mutant IF1 results in aberrant ribosomal subunit association properties, while the 23S processing stem mutations indirectly suppress this effect by decreasing the pool of mature 50S subunits available for association.  Spontaneous suppressor mutations in 16S rRNA were diverse in position and phenotypic properties, but all mutations affected ribosomal subunit association, in most cases by directly decreasing the affinity of the 30S for 50S subunits. Site directed mutagenesis of select positions in 16S rRNA yielded additional suppressor mutations that were localized to the mRNA and streptomycin binding sites on the small ribosomal subunit. We suggest that the 16S rRNA suppressors occur in positions that affect the conformational dynamics brought about by IF1. Taken together, this work indicates that the major function of IF1 is the modulation of ribosomal subunit association brought about through conformational changes of the 30S subunit.

  • 67.
    Belotserkovsky, Jaroslav
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Isaksson, Leif
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Mutations in the streptomycin and mRNA binding sites on 16S rRNA suppress a cold sensitive initiation factor IF1Manuscript (preprint) (Other academic)
  • 68.
    Belotserkovsky, Jaroslav M.
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Dabbs, Eric R.
    Isaksson, Leif A.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Mutations in 16S rRNA that suppress cold-sensitive initiation factor 1 affect ribosomal subunit association2011In: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 278, no 18, 3508-3517 p.Article in journal (Refereed)
    Abstract [en]

    A mutation in the infA gene encoding initiation factor 1 (IF1) gives rise to a cold-sensitive phenotype. An Escherichia coli strain with this mutation was used as a tool to select for second-site suppressors that compensate for the cold sensitivity and map specifically to rRNA. Several suppressor mutants with altered 16S rRNA that partially restore growth of an IF1 mutant strain in the cold were isolated and characterized. Suppressor mutations were found in helix (h) 18, h32, h34 and h41 in 16S rRNA. These mutations are not clustered to any particular region in 16S rRNA and none overlap previously reported sites of interaction with IF1. While the isolated suppressors are structurally diverse, they are functionally related because all affect ribosomal subunit association in vivo. Furthermore, in vitro subunit-association experiments indicate that most of the suppressor mutations directly influence ribosomal subunit association even though none of these are confined to any of the known intersubunit bridges. These results are consistent with the model that IF1 is an rRNA chaperone that induces large-scale conformational changes in the small ribosomal subunit, and as a consequence modulates initiation of translation by affecting subunit association.

  • 69.
    Belotserkovsky, Jaroslav M.
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Isak, Georgina I.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Isaksson, Leif A.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Suppression of a cold-sensitive mutant initiation factor 1 by alterations in the 23S rRNA maturation region2011In: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 278, no 10, 1745-1756 p.Article in journal (Refereed)
    Abstract [en]

    Genetic selection has been used to isolate second-site suppressors of a defective cold-sensitive initiation factor I (IF1) R69L mutant of Escherichia coli. The suppressor mutants specifically map to a single rRNA operon on a plasmid in a strain with all chromosomal rRNA operons deleted. Here, we describe a set of suppressor mutations that are located in the processing stem of precursor 23S rRNA. These mutations interfere with processing of the 23S rRNA termini. A lesion of RNase III also suppresses the cold sensitivity. Our results suggest that the mutant IF1 strain is perturbed at the level of ribosomal subunit association, and the suppressor mutations partially compensate for this defect by disrupting rRNA maturation. These results support the notion that IF1 is an RNA chaperone and that translation initiation is coupled to ribosomal maturation.

  • 70.
    Benedict, Catherine
    et al.
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Skinner, J. S.
    Meng, R.
    Chang, Y.
    Bhalerao, R.
    Finn, C.
    Chen, T. H. H.
    Umeå University, Faculty of Science and Technology.
    Hurry, Vaughan
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Umeå University, Faculty of Science and Technology, Department of Plant Physiology.
    The Role of the CBF-dependent Signalling Pathway in Woody Perennials2006In: Cold Hardiness in Plants: Molecular Genetics, Cell Biology and Physiology / [ed] T Chen, M Uemura, S Fujikawa, Wallingford: CABI Publishing, 2006, 167-180 p.Chapter in book (Other academic)
  • 71.
    Benetkiewicz, Magdalena
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Development and Application of Human Chromosome 22 Genomic Microarray: Chromosome 22-Associated Disorders Analyzed by Array-Based Comparative Genomic Hybridization2006Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The array-based form of comparative genomic hybridization (array-CGH) is a new methodology that has shown to be of significant importance. This thesis focuses on the development of array-CGH with the aim to define candidate regions/genes on chromosome 22 in a wide spectrum of cancer-related conditions. In paper I, we developed and applied the first comprehensive genomic microarray, representing human chromosome 22, for analysis of DNA copy number. Using this array-based approach, we identified gene copy number alterations, including heterozygous/homozygous deletions, amplifications, IGLV/IGLC locus instability and the breakpoints of imbalanced translocation, in several 22q-associated disorders. In paper II, we applied the same array to perform DNA copy number profiling of a series of ovarian carcinoma. cDNA arrays were also used in this study to correlate gene expression levels with DNA-copy number. In the course of this analysis, we determined a small 3.5 Mb candidate 22q telomeric region and suggested a number of specific candidate genes. Paper III described the comprehensive and high-resolution analysis of chromosome 22 in a large set of various stage breast cancers. Multiple distinct patterns of genetic aberrations were observed. The smallest identified candidate locus was 220 kb in size and mapped to a gene-rich region in the vicinity of telomere of 22q. Intriguing result of this study was the detection of high frequency (26.6%) of intra-tumoral clonal variation in gene copy number profiles, which should be viewed as a high number, considering that we study in detail only a single human chromosome. In paper IV, we profiled a series of 28 Wilms tumor samples using 22q-array in order to assess specific regions affected with DNA dosage-alterations. The distribution of aberrations defined a complex amplifier genotype and delimited two tumor suppressor/oncogene candidate loci. These results open up for several avenues for continued research of these tumor forms. These findings also demonstrate the power of array-CGH in the precise determination of minute DNA copy number alterations and strengthen the notion that further studies, preferentially in the context of the entire human genome, are needed.

  • 72. Berg, Ingrid
    Instability of the human minisatellite MS1 in yeast and man2003Doctoral thesis, comprehensive summary (Other academic)
  • 73.
    Berger, David
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal ecology.
    Postma, Erik
    Biased Estimates of Diminishing-Returns Epistasis?: Empirical Evidence Revisited2014In: Genetics, ISSN 0016-6731, E-ISSN 1943-2631, Vol. 198, no 4, 1417-1420 p.Article in journal (Refereed)
    Abstract [en]

    Empirical evidence for diminishing fitness returns of beneficial mutations supports Fisher's geometric model. We show that a similar pattern emerges through the phenomenon of regression to the mean and that few studies correct for it. Although biases are often small, regression to the mean has overemphasized diminishing returns and will hamper cross-study comparisons unless corrected for.

  • 74. Berger, Juerg
    et al.
    Senti, Kirsten-Andre
    Senti, Gabriele
    Södertörn University, School of Life Sciences. Karolinska Institute.
    Newsome, Timothy P.
    Åsling, Bengt
    Dickson, Barry J.
    Suzuki, Takashi
    Systematic identification of genes that regulate neuronal wiring in the Drosophila visual system2008In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 4, no 5, Online- p.Article in journal (Refereed)
    Abstract [en]

    Forward genetic screens in model organisms are an attractive means to identify those genes involved in any complex biological process, including neural circuit assembly. Although mutagenesis screens are readily performed to saturation, gene identification rarely is, being limited by the considerable effort generally required for positional cloning. Here, we apply a systematic positional cloning strategy to identify many of the genes required for neuronal wiring in the Drosophila visual system. From a large-scale forward genetic screen selecting for visual system wiring defects with a normal retinal pattern, we recovered 122 mutations in 42 genetic loci. For 6 of these loci, the underlying genetic lesions were previously identified using traditional methods. Using SNP-based mapping approaches, we have now identified 30 additional genes. Neuronal phenotypes have not previously been reported for 20 of these genes, and no mutant phenotype has been previously described for 5 genes. The genes encode a variety of proteins implicated in cellular processes such as gene regulation, cytoskeletal dynamics, axonal transport, and cell signalling. We conducted a comprehensive phenotypic analysis of 35 genes, scoring wiring defects according to 33 criteria. This work demonstrates the feasibility of combining large-scale gene identification with large-scale mutagenesis in Drosophila, and provides a comprehensive overview of the molecular mechanisms that regulate visual system wiring.

  • 75.
    Berggren Bremdal, Karin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
    Evolution of MHC Genes and MHC Gene Expression2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Polymorphism in coding regions and regions controlling gene expression is the major determinant of adaptive differences in natural populations. Genes of the major histocompatibility complex (MHC) possess a high level of genetic variation, which is maintained by selection over long coalescence times. MHC genes encode antigen-presenting molecules in the adaptive immune system, which protects the host from infectious diseases. However, MHC molecules may also present self-peptides and for most autoimmune diseases there is a genetic factor associated with the MHC.

    MHC genes have been used to learn about the interplay of selection and historical population events. In domestic dogs and their progenitor, the wolf, I explored factors associated with domestication and breed formation and their influence not only on MHC coding regions but also on the haplotypic structure of the class II region. Polymorphism and strong selection was demonstrated in the proximal promoters of MHC genes in dogs and wolves. Hence, genetic variation associated with MHC gene expression may have at least equal importance for a well functioning immune system. Associations between promoter sequences and particular coding alleles suggested allele-specific expression patterns. SNP haplotypes of the MHC class II region revealed ancestral as well as convergent haplotypes, in which combinations of alleles are kept by selection. Interestingly, weaker allelic associations were found between different genes and between coding regions and promoters in dogs compared to wolves. Potentially, this could cause insufficient defense against infections and predispose dogs to autoimmune diseases. For example, I identified a site in the promoter region that showed a consistent difference between haplotypes conferring susceptibility and protection to diabetes in dogs, which should be investigated further.

    Furthermore, I investigated how selection and demographic changes associated with glacial and inter-glacial periods have affected MHC variation in European hedgehogs and extended the prevailing knowledge concerning their population history.

  • 76.
    Berggren, Karin
    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.
    Hewitt, G M
    Seddon, J M
    Understanding the phylogeographic patterns of European hedgehogs, Erinaceus concolor and E. europaeus using the MHC.2005In: Heredity, ISSN 0018-067X, Vol. 95, no 1, 84-90 p.Article in journal (Refereed)
    Abstract [en]

    The genome of the European hedgehog, Erinaceus concolor and E. europaeus, shows a strong signal of cycles of restriction to glacial refugia and postglacial expansion. Patterns of expansion, however, differ for mitochondrial DNA (mtDNA) and preliminary analysis of nuclear markers. In this study, we determine phylogeographic patterns in the hedgehog using two loci of the major histocompatibility complex (MHC), isolated for the first time in hedgehogs. These genes show long persistence times and high polymorphism in many species because of the actions of balancing selection. Among 84 individuals screened for variation, only two DQA alleles were identified in each species, but 10 DQB alleles were found in E. concolor and six in E. europaeus. A strong effect of demography on patterns of DQB variability is observed, with only weak evidence of balancing selection. While data from mtDNA clearly subdivide both species into monophyletic subgroups, the MHC data delineate only E. concolor into distinct subgroups, supporting the preliminary findings of other nuclear markers. Together with differences in variability, this suggests that the refugia history and/or expansion patterns of E. concolor and E. europaeus differ.

  • 77.
    Berggren, Karin
    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, Hans
    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.
    Hewitt, G. M.
    Seddon, J. M.
    Demographic effects have been more important than selection in shaping patterns of variation at MHC genes in European hedgehogs, Erinaceus europaeus and Erinaceus concolor.2005In: Heredity, no 85, 84-90 p.Article in journal (Refereed)
  • 78.
    Berggren, Karin
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
    Seddon, Jennifer
    University of Queensland.
    Linkage disequilibrium and haplotype patterns of the MHC class II region - a comparison between wolves and dogs.Manuscript (preprint) (Other academic)
  • 79.
    Berggren, Karin T
    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.
    Seddon, Jennifer M
    MHC promoter polymorphism in grey wolves and domestic dogs.2005In: Immunogenetics, ISSN 0093-7711, Vol. 57, no 3-4, 267-72 p.Article in journal (Refereed)
    Abstract [en]

    A functional immune system requires a tight control over major histocompatibility complex (MHC) gene transcription, as the abnormal MHC expression patterns of severe immunodeficiency and autoimmune diseases demonstrate. Although the regulation of MHC expression has been well documented in humans and mice, little is known in other species. In this study, we detail the level of polymorphism in wolf and dog MHC gene promoters. The promoter regions of the DRB, DQA and DQB locus were sequenced in 90 wolves and 90 dogs. The level of polymorphism was high in the DQB promoters, with variation found within functionally relevant regions, including binding sites for transcription factors. Clear associations between DQB promoters and exon 2 alleles were noted in wolves, indicating strong linkage disequilibrium in this region. Low levels of polymorphism were found within the DRB and DQA promoter regions. However, a variable site was identified within the T box, a TNF-alpha response element, of the DQA promoter. Furthermore, we identified a previously unrecognised 18-base-pair deletion within exon 1 of the DQB locus.

  • 80.
    Berglund, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Meiotic Recombination in Human and Dog: Targets, Consequences and Implications for Genome Evolution2014Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Understanding the mechanism of recombination has important implications for genome evolution and genomic variability. The work presented in this thesis studies the properties of recombination by investigating the effects it has on genome evolution in humans and dogs.

    Using alignments of human genes with chimpanzee and macaque orthologues we studied substitution patterns along the human lineage and scanned for evidence of positive selection. The properties mirror the situation in human non-coding sequences with the fixation bias ‘GC-biased gene conversion’ (gBGC) as a driving force in the most rapidly evolving regions. By assigning candidate genes to distinct classes of evolutionary forces we quantified the extent of those genes affected by gBGC to 20%. This suggests that human-specific characters can be prompted by the fixation bias of gBGC, which can be mistaken for selection.

    The gene PRDM9 controls recombination in most mammals, but is lacking in dogs. Using whole-genome alignments of dog with related species we examined the effects of PRDM9 inactivation. Additionally, we analyzed genomic variation in the genomes of several dog breeds. We identified that non-allelic homologous recombination (NAHR) via sequence identity, often GC-rich, creates structural variants of genomic regions. We show that these regions, which are also found in dog recombination hotspots, are a subset of unmethylated CpG-islands (CGIs). We inferred that CGIs have experienced a drastic increase in biased substitution rates, concurrent with a shift of recombination to target these regions. This enables recurrent episodes of gBGC to shape their distribution.

    The work presented in this thesis demonstrates the importance of meiotic recombination on patterns of molecular evolution and genomic variability in humans and dogs. Bioinformatic analyses identified mechanisms that regulate genome composition. gBGC is presented as an alternative to positive selection and is revealed as a major factor affecting allele configuration and the emergence of accelerated evolution on the human lineage. Characterization of recombination-induced sequence patterns highlights the potential of non-methylation and establishes unmethylated CGIs as targets of meiotic recombination in dogs. These observations describe recombination as an interesting process in genome evolution and provide further insights into the mechanisms of genomic variability.

  • 81.
    Berglund, Jonas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Quilez, Javier
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Webster, Matthew
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Germline Metyhlation Patterns Determine The Distribution Of Recombination Events In The Dog GenomeIn: Genome Biology and Evolution, ISSN 1759-6653, E-ISSN 1759-6653Article in journal (Refereed)
  • 82.
    Bergman, Ingrid-Maria
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Polymorphism in pattern recognition receptor genes in pigs2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The mammalian immune defense consists of two systems, which are interconnected and co-operate to provide host defense. The innate immune system is always active and detects and responds to non-self without delay. The adaptive immune system has a lag phase, but is more specific and has got a memory.

    The innate immune system relies on pattern recognition receptors (PRRs) to detect molecular patterns signaling microbial presence. This thesis focuses on a centrally placed family of PRRs, namely the Toll-like receptors (TLRs), and on mannan-binding lectin (MBL), a PRR which initiates the lectin activation pathway of complement. TLRs are expressed on the cell surface and in intracellular compartments, while MBL is a soluble protein present in most body fluids.

    Polymorphism – literally ’many forms’ – refers to variation between individuals, at DNA level as well as in traits. A single nucleotide polymorphism (SNP) implicates that alternative nucleotides are present at a particular position in the genome. Mutations, together with phenomena like gene duplication and whole genome duplication, are the ultimate source of variation in nature and the fuel for evolution. Through natural selection and breeding, i.e. artificial selection, species are shaped and change over time.

    Domestic animals are well suited for genetic studies, since they enable comparisons of populations exposed to different selection criteria and environmental challenges. Also, in the case of pigs, comparisons to the wild ancestor – i.e. the wild boar – can shed light on the evolutionary process. Moreover, pigs are large animal models for humans.

    Paper I reports the refinement of previously identified quantitative trait loci for immune-related traits on pig chromosome 8.

    Papers II and III report differences in polymorphic patterns between wild boars and domestic pigs in the TLR1, TLR2, TLR6, and TLR10 genes. In TLR1 and TLR2, more SNPs were present in the domestic pigs than in the wild boars. In TLR6, SNP numbers were similar in both animal groups, but the level of heterozygosity was higher in the domestic pigs than in the wild boars. In TLR10, again, more SNPs were present in the domestic pigs, and a higher number of non-synonymous SNPs was detected in TLR10 compared to the other genes. This might suggest redundancy for TLR10 in pigs.

    Paper IV reports the presence of an SNP, previously detected in domestic pigs and assumed to affect MBL concentrations in serum, in European wild boars. Also, the connection between the presumed low-producing allele and low MBL concentration in serum was confirmed. Moreover, a novel SNP, with potential to be functionally important, was detected.

    Owing to the domestication process and differences in selection pressure, differences in polymorphic patterns between wild boars and domestic pigs are not surprising. However, since breeding means choosing among genotypes, the opposite pattern – more SNPs in wild boars than in domestic pigs – would have been expected. However, the result confirms other studies, which have shown that European wild boars went through a bottle neck before domestication started. The higher number of SNPs in domestic pigs may be due to relaxed purifying selection during the domestication process.

  • 83.
    Bergman, Ingrid-Maria
    et al.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Edman, Kjell
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences. Uppsala University.
    Rosengren, K. Johan
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences. The University of Queensland, Australia.
    Edfors, Inger
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Extensive polymorphism in the porcine Toll-like receptor 10 gene2012In: International Journal of Immunogenetics, ISSN 1744-3121, E-ISSN 1744-313X, Vol. 39, no 1, 68-76 p.Article in journal (Refereed)
    Abstract [en]

    The great importance of the Toll-like receptors (TLRs) in innate immunity is well established, but one family member – TLR10 – remains elusive. TLR10 is expressed in various tissues in several species, but its ligand is not known and its function is still poorly understood. The open reading frame of TLR10 was sequenced in 15 wild boars, representing three populations, and in 15 unrelated domestic pigs of Hampshire, Landrace and Large White origin. Amino acid positions corresponding to detected nonsynonymous single nucleotide polymorphisms (SNPs) were analysed in the crystal structures determined for the human TLR1–TLR2–lipopeptide complex and the human TLR10 Toll/Interleukin 1 receptor (TIR) dimer. SNP occurrence in wild boars and domestic pigs was compared, and haplotypes for the TLR10 gene and the TLR6-1-10 gene cluster were reconstructed. Despite the limited number of animals sequenced in the present study (N = 30), a larger number of SNPs were found in TLR10 than recently reported for TLR1, TLR6 and TLR2. Thirty-three SNPs were detected, of which 20 were nonsynonymous. The relative frequency of nonsynonymous (dN) and synonymous (dS) SNPs between wild boars and domestic pigs was higher in TLR10 than recently reported for TLR1, TLR6 and TLR2. However, the polymorphism reported in the present study seems to leave the function of the TLR10 molecule unaffected. Furthermore, no nonsynonymous SNPs were detected in the part of the gene corresponding to the hinge region of the receptor, probably reflecting rigorously acting functional constraint. The total number of SNPs and the number of nonsynonymous SNPs were significantly lower (< 0.05) in the wild boars than in the domestic pigs, and fewer TLR10 haplotypes were present in the wild boars. The majority of the TLR6-1-10 haplotypes were specific for either wild boars or domestic pigs, probably reflecting differences in microbial environment and population history.

  • 84.
    Bergman, Ingrid-Maria
    et al.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Edman, Kjell
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Rosengren, K. Johan
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Edfors, Inger
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    European wild boars and domestic pigs display different polymorphic patterns in the Toll-like receptor (TLR)1, TLR2, TLR6, and TLR10 genes.2010In: International Symposium on Animal Genomics for Animal Health Paris, France, 31 May – 2 June 2010: The AGAH 2010 Abstract Book, 2010, 35- p.Conference paper (Other academic)
    Abstract [en]

    The Toll-like receptors (TLR) are vitally important pattern recognition receptors linking innate and adaptive immunity. Several single nucleotide polymorphisms (SNP) in human TLR genes have been associated with disease. There are few studies on associations between polymorphisms in TLR genes and disease in pigs, but the TLR2/TLR6 heterodimer is activated by Mycoplasma hyopneumoniae, and the expression of TLR2, TLR4, and TLR9 is modulated in the presence of different Salmonella serovars. Porcine TLR1, TLR6, and TLR10 are located in a cluster on the p arm of chromosome 8, while TLR2 resides on the q arm. Previously, we identified quantitative trait loci (QTL) for immune-related traits on pig chromosome 8, close to the KIT gene and the microsatellite S0225, respectively. In order to explore polymorphism in some TLR genes in European wild boars and domestic pigs, TLR1, TLR2, and TLR6 were sequenced in 25 wild boars, representing three populations, and in 15 domestic pigs of Hampshire, Landrace, and Large White origin. Similarly, TLR10 was sequenced in 15 wild boars and 15 domestic pigs. In TLR1 and TLR2, more SNP were present in the domestic pigs than in the wild boars. In TLR6, SNP numbers were similar in both animal groups, but the level of heterozygosity was higher in the domestic pigs than in the wild boars. In TLR10, again, more SNP were present in the domestic pigs, and a higher number of nonsynonymous SNP were detected in TLR10 compared to the other genes. This may suggest redundancy for TLR10 in pigs. 

  • 85.
    Bergman, Ingrid-Maria
    et al.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Johansson, Amelie
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Wattrang, Eva
    Fossum, Caroline
    Andersson, Leif
    Edfors, Inger
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Refined analysis of quantitative trait loci (QTLs) for immune capacity related traits on pig chromosome 8Manuscript (preprint) (Other academic)
  • 86.
    Bergman, Ingrid-Maria
    et al.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Rosengren, K. Johan
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Edman, Kjell
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Edfors, Inger
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    European wild boars and domestic pigs display different polymorphic patterns in the Toll-like receptor (TLR) 1, TLR2, and TLR6 genes2010In: Immunogenetics, ISSN 0093-7711, E-ISSN 1432-1211, Vol. 62, no 1, 49-58 p.Article in journal (Refereed)
    Abstract [en]

    During the last decade, the Toll-like receptors (TLRs) have been extensively studied and their immense importance in innate immunity is now being unveiled. Here, we report pronounced differences – probably reflecting the domestication process and differences in selective pressure – between wild boars and domestic pigs regarding single nucleotide polymorphisms (SNPs) in TLR genes. The open reading frames of TLR1, TLR2, and TLR6 were sequenced in 25 wild boars, representing three populations, and in 15 unrelated domestic pigs of Hampshire, Landrace, and Large White origin. In total, 20, 27, and 26 SNPs were detected in TLR1, TLR2, and TLR6, respectively. In TLR1 and TLR2, the numbers of SNPs detected were significantly lower (P ≤ 0.05, P ≤ 0.01) in the wild boars than in the domestic pigs. In the wild boars, one major high frequency haplotype was found in all three genes, while the same pattern was exhibited only by TLR2 in the domestic pigs. The relative frequency of non-synonymous (dN) and synonymous (dS) SNPs was lower for the wild boars than for the domestic pigs in all three genes. In addition, differences in diversity between the genes were revealed: the mean heterozygosity at the polymorphic positions was markedly lower in TLR2 than in TLR1 and TLR6. Because of its localization – in proximity of the bound ligand – one of the non-synonymous SNPs detected in TLR6 may represent species-specific function on the protein level. Furthermore, the codon usage pattern in the genes studied deviated from the general codon usage pattern in Sus scrofa.

  • 87.
    Bergman, Ingrid-Maria
    et al.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Sandholm, Kerstin
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Juul-Madsen, Helle R.
    Heegaard, Peter M.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Edfors, Inger
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    MBL-A concentrations and MBL1 genotypes in European wild boars, Large White pigs, and wild boar/Large White crossbreds2010In: 8th European Colloquium on Acute Phase Proteins in Helsinki, 2010.08.25-2010.08.27, 2010, 25-26 p.Conference paper (Refereed)
  • 88.
    Bergman, Ingrid-Maria
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Sandholm, Kerstin
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Okumura, Naohiko
    Institute of Society for Techno-innovation of Agriculture, Forestry and Fisheries, Tsukuba, Japan.
    Uenishi, Hirohide
    National Institute of Agrobiological Sciences, Tsukuba, Japan.
    Guldbrandtsen, Bernt
    Aarhus University, Tjele, Denmark.
    Essler, Sabine
    Univ of Veterinary Medicine, Vienna.
    Knoll, Ales
    Mendel University, Brno, Czech Republic.
    Heegaard, Peter
    Technical University of Denmark, Kgs Lyngby.
    Edfors, Inger
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Juul-Madsen, Helle
    Aarhus University, Tjele, Denmark.
    MBL1 genotypes in wild boar populations from Sweden, Austria, the Czech Republic and Japan2013In: International Journal of Immunogenetics, ISSN 1744-3121, E-ISSN 1744-313X, Vol. 40, no 2, 131-139 p.Article in journal (Refereed)
    Abstract [en]

    The single nucleotide polymorphism (SNP) G949T in the mannose-binding lectin (MBL) 1 gene has been associated with low MBL-A concentration in serum and detected at different frequencies in various European pig populations. However, the origin of this SNP is not known. Part of the MBL1 gene was sequenced in 12 wild boar/Large White crossbred pigs from the second backcross (BC 2) generation in a family material originating from two wild boar x Large White intercrosses. Also, MBL-A serum concentration was measured in the entire BC 2 generation (n = 45). Furthermore, the genotypes of 68 wild boars from Sweden, Austria, the Czech Republic, and Japan were determined in regard to five previously described SNPs in MBL1. The T allele of G949T was present among the BC 2 animals. MBL-A serum concentration in the BC 2 animals showed a bimodal distribution, with one-third of the animals at levels between 0.7 and 1.6 μg mL−1 and the remaining pigs at levels around 13 μg mL−1. There was a co-variation between the presence of the T allele and low MBL-A concentration in serum. The genotyping of the wild boars revealed differences between populations. The T allele of G949T was not detected in the Austrian and Japanese samples and is thus unlikely to be an original feature of wild boars. In contrast, it was present at high frequency (0.35) among the Swedish wild boars, probably representing a founder effect. Five MBL1 haplotypes were resolved. Only two of these were present among the Japanese wild boars compared to four in each of the European populations. This difference may reflect differences in selection pressure and population history.

  • 89. Bergman, Ingvar
    et al.
    Almkvist, Ove
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    The effect of age on fluid intelligence is fully mediated by physical health2013In: Archives of gerontology and geriatrics (Print), ISSN 0167-4943, E-ISSN 1872-6976, Vol. 57, no 1, 100-109 p.Article in journal (Refereed)
    Abstract [en]

    The present study investigated the extent to which the effect of age on cognitive ability is predicted by individual differences in physical health. The sample consisted of 118 volunteer subjects who were healthy and ranging in age from 26 to 91. The examinations included a clinical investigation, magnetic resonance imaging (MRI) brain neuroimaging, and a comprehensive neuropsychological assessment. The effect of age on fluid IQ with and without visual spatial praxis and on crystallized IQ was tested whether being fully-, partially-or non-mediated by physical health. Structural equation analyses showed that the best and most parsimonious fit to the data was provided by models that were fully mediated for fluid IQ without praxis, non-mediated for crystallized IQ and partially mediated for fluid IQ with praxis. The diseases of the circulatory and nervous systems were the major mediators. It was concluded from the pattern of findings that the effect of age on fluid intelligence is fully mediated by physical health, while crystallized intelligence is non-mediated and visual spatial praxis is partially mediated, influenced mainly by direct effects of age. Our findings imply that improving health by acting against the common age-related circulatory-and nervous system diseases and risk factors will oppose the decline in fluid intelligence with age.

  • 90. Bergquist, Helen
    et al.
    Rocha, Cristina S. J.
    Alvarez-Asencio, Ruben
    KTH, School of Chemical Science and Engineering (CHE), Chemistry. Universitario de Cantoblanco, Spain.
    Nguyen, Chi-Hung
    Rutland, Mark W.
    KTH, School of Chemical Science and Engineering (CHE), Chemistry.
    Smith, C. I. Edvard
    Good, Liam
    Nielsen, Peter E.
    Zain, Rula
    Disruption of Higher Order DNA Structures in Friedreich's Ataxia (GAA)(n) Repeats by PNA or LNA Targeting2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 11, e0165788Article in journal (Refereed)
    Abstract [en]

    Expansion of (GAA)(n) repeats in the first intron of the Frataxin gene is associated with reduced mRNA and protein levels and the development of Friedreich's ataxia. (GAA)(n) expansions form non-canonical structures, including intramolecular triplex (H-DNA), and Rloops and are associated with epigenetic modifications. With the aim of interfering with higher order H-DNA (like) DNA structures within pathological (GAA)(n) expansions, we examined sequence-specific interaction of peptide nucleic acid (PNA) with (GAA)(n) repeats of different lengths (short: n= 9, medium: n= 75 or long: n= 115) by chemical probing of triple helical and single stranded regions. We found that a triplex structure (H-DNA) forms at GAA repeats of different lengths; however, single stranded regions were not detected within the medium size pathological repeat, suggesting the presence of a more complex structure. Furthermore, (GAA) 4-PNA binding of the repeat abolished all detectable triplex DNA structures, whereas (CTT) 5-PNA did not. We present evidence that (GAA) 4-PNA can invade the DNA at the repeat region by binding the DNA CTT strand, thereby preventing non-canonical-DNA formation, and that triplex invasion complexes by (CTT) 5-PNA form at the GAA repeats. Locked nucleic acid (LNA) oligonucleotides also inhibited triplex formation at GAA repeat expansions, and atomic force microscopy analysis showed significant relaxation of plasmid morphology in the presence of GAA-LNA. Thus, by inhibiting disease related higher order DNA structures in the Frataxin gene, such PNA and LNA oligomers may have potential for discovery of drugs aiming at recovering Frataxin expression.

  • 91.
    Berlin, S.
    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.
    Chicken W:: A genetically uniform chromosome in a highly variable genome.2004In: Proceedings of the National Academy of Sciences USA, no 101, 15967-15969 p.Article in journal (Refereed)
  • 92.
    Berlin, S.
    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.
    Smith, N.G.
    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.
    Do avian mitochondria recombine?2004In: Journal of Molecular Evolution, no 58, 163-167 p.Article in journal (Refereed)
  • 93.
    Berlin, Sofia
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
    The Effects of Mutation and Selection on the Rate and Pattern of Molecular Evolution in Birds2004Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    By comparing sequence diversity and divergence on sex chromosomes one can study how the rate of evolution in affected by mutation and/or selection. The rate of mutation in male biased, meaning that relatively more mutations are created in the male germ line than in the female. Since the male mutation bias (αm) most likely is a consequence of the difference in cell divisions between male and female germ lines, life history characters that affect this difference should covary with αm. Indeed, we found a positive correlation between estimates of αm and increased generation times and increased intensity of sperm competition. We have also found that estimates of αm varied significantly between gametologous introns located on the sex chromosomes. This could be a consequence of the variation in substitution rates between loci.

    Population genetics theory predicts that both positive and negative selection reduce genetic diversity around a selected locus at a distance determined by the rate of recombination. Consequently, a non-recombining chromosome, like the female specific W chromosome in birds, selection is expected to have a large impact on sequence diversity. Indeed, in a large sequence screening we found only one segregating site among 7643 base pairs sequenced in 47 chicken females. Furthermore, we also found that deleterious substitutions are fixed in a higher rate for W- than Z-linked sequences, which is in agreement with the lack of recombination and strong genetic drift due to the low effective population size.

    Rarely non-synonymous mutations are beneficial for an individual, but when it happens, the mutation is positively selected and rapidly reaches fixation in a population. We have found that positive selection has been acting on the female reproductive protein, zona pellucida c in birds. This rapid evolution is likely a mechanism to prevent hybridisation.

  • 94.
    Berlin, Sofia
    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.
    Smith, Nick G C
    Testing for adaptive evolution of the female reproductive protein ZPC in mammals, birds and fishes reveals problems with the M7-M8 likelihood ratio test.2005In: BMC Evol Biol, ISSN 1471-2148, Vol. 5, 65- p.Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Adaptive evolution appears to be a common feature of reproductive proteins across a very wide range of organisms. A promising way of addressing the evolutionary forces responsible for this general phenomenon is to test for adaptive evolution in the same gene but among groups of species, which differ in their reproductive biology. One can then test evolutionary hypotheses by asking whether the variation in adaptive evolution is consistent with the variation in reproductive biology. We have attempted to apply this approach to the study of a female reproductive protein, zona pellucida C (ZPC), which has been previously shown by the use of likelihood ratio tests (LRTs) to be under positive selection in mammals. RESULTS: We tested for evidence of adaptive evolution of ZPC in 15 mammalian species, in 11 avian species and in six fish species using three different LRTs (M1a-M2a, M7-M8, and M8a-M8). The only significant findings of adaptive evolution came from the M7-M8 test in mammals and fishes. Since LRTs of adaptive evolution may yield false positives in some situations, we examined the properties of the LRTs by several different simulation methods. When we simulated data to test the robustness of the LRTs, we found that the pattern of evolution in ZPC generates an excess of false positives for the M7-M8 LRT but not for the M1a-M2a or M8a-M8 LRTs. This bias is strong enough to have generated the significant M7-M8 results for mammals and fishes. CONCLUSION: We conclude that there is no strong evidence for adaptive evolution of ZPC in any of the vertebrate groups we studied, and that the M7-M8 LRT can be biased towards false inference of adaptive evolution by certain patterns of non-adaptive evolution.

  • 95.
    Bernhardsson, Carolina
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Molecular population genetics of inducible defense genes in Populus tremula2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Plant-herbivore interactions are among the most common of ecological interactions. It is therefore not surprising that plants have evolved multiple mechanisms to defend themselves, using both constitutive chemical and physical barriers and by induced responses which are only expressed after herbivory has occurred. Herbivores, on the other hand, respond to these plant defenses by evolving counter-adaptations which makes defenses less effective or even useless. Adaptation can occur at different geographical scales, with varying coevolutionary interactions across a spatially heterogenous landscape. By looking at the underlying genes responsible for these defensive traits and herbivore related phenotypic traits, it is possible to investigate the coevolutionary history of these plant- herbivore interactions. Here I use molecular population genetic tools to investigate the evolutionary history of several inducible defense genes in European Aspen (Populus tremula) in Sweden. Two genes, belonging to the Polyphenol oxidase gene-family (PPO1 and PPO2), show skews in their site frequency spectrum together with patterns of diversity and divergence from an outgroup which correspond to signatures of adaptive evolution (Paper II). 71 single nucleotide polymorphisms (SNPs) from seven inducible defense genes (PPO1-PPO3, TI2-TI5) show elevated levels of population differentiation compared to control genes (genes not involved in plant defense), and 10 of these defense SNPs show strong signatures of natural selection (Paper III). These 71 defense SNPs also divides a sample of Swedish P. tremula trees into three distinct geographical groups, corresponding to a Southern, Central and Northern cluster, a patterns that is not present in control SNPs (Paper III). The same geographical pattern, with a distinct Northern cluster, is also observed in several phenotypic traits related to herbivory in our common garden in Sävar (Paper IV). These phenotypic traits show patterns of apparent local maladaptation of the herbivore community to the host population which could indicate the presence of “information coevolution” between plants and herbivores (Paper IV). 15 unique defense SNPs also show significant associations to eight phenotypic traits but the causal effects of these SNP associations may be confounded by the geographic structure found in both the underlying genes and in the phenotypic traits. The co-occurrence of population structure in both defense genes and herbivore community traits may be the result from historical events during the post-glacial recolonization of Sweden.

  • 96.
    Bernhardsson, Carolina
    et al.
    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).
    Ingvarsson, Pär
    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).
    Geographic structure and adaptive population differentiation in herbivore defence genes in European aspen (Populus tremula L., Salicaceae)2012In: Molecular Ecology, ISSN 0962-1083, E-ISSN 1365-294X, Vol. 21, no 9, 2197-2207 p.Article in journal (Refereed)
    Abstract [en]

    When a phenotypic trait is subjected to spatially variable selection and local adaptation, the underlying genes controlling the trait are also expected to show strong patterns of genetic differentiation since alternative alleles are favored in different geographical locations. Here we study 71 SNPs from seven genes associated with inducible defense responses in a sample of P. tremula collected from across Sweden. Four of these genes (PPO2, TI2, TI4 and TI5) show substantial population differentiation and a PCA conducted on the defense SNPs divides the Swedish population into three distinct clusters. Several defense SNPs show latitudinal clines, although these were not robust to multiple testing. However, five SNPs (located within TI4 and TI5) show strong longitudinal clines that remain significant after multiple test correction. Genetic geographical variation, supporting local adaptation, has earlier been confirmed in genes involved in the photoperiod pathway in P. tremula, but this is, to our knowledge, one of the first times that geographic variation has been found in genes involved in plant defense against antagonists.

  • 97.
    Bernhardsson, Carolina
    et al.
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Robinson, Kathryn M.
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology.
    Abreu, Ilka N.
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology.
    Jansson, Stefan
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology.
    Ingvarsson, Pär K.
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Albrectsen, Benedicte R.
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology.
    Population differentiation in arthropod community structure and phenotypic association with inducible defense genes in European Aspen (Populus tremula L., salicaceae)Manuscript (preprint) (Other academic)
    Abstract [en]

    Plant-herbivore interactions are known to vary across a landscape due to both variation in abiotic and biotic factors. Such spatial variation tends to promoting local adaption of plants to the prevailing herbivore regime. Here we use data from a common garden to look for patterns across populations in the abundance and diversity of herbivorous insects. We also screen for variation in the untargeted metabolome of the foliage of a subset of the same trees. We also search for phenotypic associations between genetic variation in a number of wound-induced genes and phenotypic variation in herbivore abundance, diversity and in metabolomes. We observe significant genetic variation in a number of herbivore-related traits but low correlations between traits. We do observe substantial genetic structure in both herbivore community structure and in metabolic profiles and this structure is aligned with genetic structure we have previously documented for a set of defense genes. We also identify a number of significant associations between SNPs from wound-induced defense genes and a number of the herbivore traits and metabolic profiles. However, these associations are likely not causal, but are rather caused by the underlying population structure we observe. These results highlight to the importance of historical processes and the need to better understand both the current-day geographic distribution of different herbivore species as well as the post-glacial colonization history of both plants and herbivores.

  • 98. Bertrand, Yann
    et al.
    Topel, Mats
    Elvang, Annelie
    Melik, Wessam
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Johansson, Magnus
    First Dating of a Recombination Event in Mammalian Tick-Borne Flaviviruses2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 2, e31981- p.Article in journal (Refereed)
    Abstract [en]

    The mammalian tick-borne flavivirus group (MTBFG) contains viruses associated with important human and animal diseases such as encephalitis and hemorrhagic fever. In contrast to mosquito-borne flaviviruses where recombination events are frequent, the evolutionary dynamic within the MTBFG was believed to be essentially clonal. This assumption was challenged with the recent report of several homologous recombinations within the Tick-borne encephalitis virus (TBEV). We performed a thorough analysis of publicly available genomes in this group and found no compelling evidence for the previously identified recombinations. However, our results show for the first time that demonstrable recombination (i.e., with large statistical support and strong phylogenetic evidences) has occurred in the MTBFG, more specifically within the Louping ill virus lineage. Putative parents, recombinant strains and breakpoints were further tested for statistical significance using phylogenetic methods. We investigated the time of divergence between the recombinant and parental strains in a Bayesian framework. The recombination was estimated to have occurred during a window of 282 to 76 years before the present. By unravelling the temporal setting of the event, we adduce hypotheses about the ecological conditions that could account for the observed recombination.

  • 99.
    Besnier, Francois
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    Wahlberg, Per
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Rönnegård, Lars
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    Ek, Weronica
    Swedish University of Agricultural Sciences .
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Siegel, Paul
    virginia polytechnic institute and state university.
    Carlborg, Örjan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    Fine mapping and replication of QTL in outbred chicken advanced intercross lines2011In: Genetics Selection Evolution, ISSN 0999-193X, E-ISSN 1297-9686, Vol. 43, 3- p.Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Linkage mapping is used to identify genomic regions affecting the expression of complex traits. However, when experimental crosses such as F2 populations or backcrosses are used to map regions containing a Quantitative Trait Locus (QTL), the size of the regions identified remains quite large, i.e. 10 or more Mb. Thus, other experimental strategies are needed to refine the QTL locations. Advanced Intercross Lines (AIL) are produced by repeated intercrossing of F2 animals and successive generations, which decrease linkage disequilibrium in a controlled manner. Although this approach is seen as promising, both to replicate QTL analyses and fine-map QTL, only a few AIL datasets, all originating from inbred founders, have been reported in the literature.

    METHODS: We have produced a nine-generation AIL pedigree (n = 1529) from two outbred chicken lines divergently selected for body weight at eight weeks of age. All animals were weighed at eight weeks of age and genotyped for SNP located in nine genomic regions where significant or suggestive QTL had previously been detected in the F2 population. In parallel, we have developed a novel strategy to analyse the data that uses both genotype and pedigree information of all AIL individuals to replicate the detection of and fine-map QTL affecting juvenile body weight.

    RESULTS: Five of the nine QTL detected with the original F2 population were confirmed and fine-mapped with the AIL, while for the remaining four, only suggestive evidence of their existence was obtained. All original QTL were confirmed as a single locus, except for one, which split into two linked QTL.

    CONCLUSIONS: Our results indicate that many of the QTL, which are genome-wide significant or suggestive in the analyses of large intercross populations, are true effects that can be replicated and fine-mapped using AIL. Key factors for success are the use of large populations and powerful statistical tools. Moreover, we believe that the statistical methods we have developed to efficiently study outbred AIL populations will increase the number of organisms for which in-depth complex traits can be analyzed.

     

  • 100. Besnier, Francois
    et al.
    Wahlberg, Per
    Rönnegård, Lars
    Dalarna University, School of Technology and Business Studies, Statistics.
    Ek, Weronika
    Andersson, Leif
    Siegel, Paul
    Carlborg, Örjan
    Fine mapping and replication of QTL in outbred chicken advanced intercross lines2011In: Genetics Selection Evolution, ISSN 0999-193X, E-ISSN 1297-9686, Vol. 43, 3Article in journal (Refereed)
    Abstract [en]

    Background: Linkage mapping is used to identify genomic regions affecting the expression of complex traits. However, when experimental crosses such as F2 populations or backcrosses are used to map regions containing a Quantitative Trait Locus (QTL), the size of the regions identified remains quite large, i.e. 10 or more Mb. Thus, other experimental strategies are needed to refine the QTL locations. Advanced Intercross Lines (AIL) are produced by repeated intercrossing of F2 animals and successive generations, which decrease linkage disequilibrium in a controlled manner. Although this approach is seen as promising, both to replicate QTL analyses and fine-map QTL, only a few AIL datasets, all originating from inbred founders, have been reported in the literature.

    Methods: We have produced a nine-generation AIL pedigree (n = 1529) from two outbred chicken lines divergently selected for body weight at eight weeks of age. All animals were weighed at eight weeks of age and genotyped for SNP located in nine genomic regions where significant or suggestive QTL had previously been detected in the F2 population. In parallel, we have developed a novel strategy to analyse the data that uses both genotype and pedigree information of all AIL individuals to replicate the detection of and fine-map QTL affecting juvenile body weight.

    Results: Five of the nine QTL detected with the original F2 population were confirmed and fine-mapped with the AIL, while for the remaining four, only suggestive evidence of their existence was obtained. All original QTL were confirmed as a single locus, except for one, which split into two linked QTL.

    Conclusions: Our results indicate that many of the QTL, which are genome-wide significant or suggestive in the analyses of large intercross populations, are true effects that can be replicated and fine-mapped using AIL. Key factors for success are the use of large populations and powerful statistical tools. Moreover, we believe that the statistical methods we have developed to efficiently study outbred AIL populations will increase the number of organisms for which in-depth complex traits can be analyzed.

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