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Investigation of Mechanics of Mutation and Selection by Comparative Sequencing
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The process of evolution is of both scientific and medical interest. This thesis presents several studies using complete genomic reference sequences, comparative genomic data, and intraspecific diversity data to study the two key processes of evolution: mutation and selection.

Large duplications, deletions, inversions, and translocations of DNA contribute to genomic variation both between and within species. Human chromosomes 15 and 17 contain a high percentage of dispersed, recently duplicated sequences. Examination of the relationships between these sequences showed that the majority of all duplications within each chromosome could be linked through core sequences that are prone to duplication. Comparison to orthologous sequences in other mammals allowed a reconstruction of the ancestral state of the human chromosomes, revealing that regions of rearrangement specific to the human lineage are highly enriched in chromosome-specific duplications. Comparison to copy number variation data from other studies also shows that these regions are enriched in current human structural variation. One specific region, the MAPT locus at 17q21.31, known to contain an inversion polymorphism in Europeans, was resequenced completely across both human orientation haplotypes and in chimpanzee and orangutan, revealing complex duplication structures at the inversion breakpoints, with the human region being more complex than chimpanzee or orangutan. Fluorescent in-situ hybridization analysis of human, chimpanzee, and orangutan chromosomes showed inversion polymorphisms of independent origin in all three species, demonstrating that this region has been a hotspot of genomic rearrangement for at least twelve million years. These results reveal a mechanistic relationship between sequence duplication and rearrangement in the great apes.

We also generated a draft sequence of the chimpanzee genome and compared it to that of the human. Among other findings, this showed that CpG dinucleotides contribute 25% of all single base mutations, with a rate of mutation ~10-fold that of other bases, and that the male mutation rate in great apes is ~5-6 times the female rate, a higher ratio than had been observed in comparisons of primates and rodents. We detected six regions of probable recent positive selection in humans with a statistical method relying on chimpanzee sequence to control for regional variation in mutation rates.

Finally, resequencing of several lines of domestic chicken and comparison to the reference chicken genome identified a number of gene deletions fixed in domestic lines and also several potential selective sweeps. Of particular interest are a missense mutation in TSHR nearly fixed in all domestic chickens and a partial deletion of SH3RF2 fixed in a high growth line. The TSHR mutation may play a role in relaxation of seasonal reproduction. A high-resolution QTL mapping experiment showed that the SH3RF2 deletion is significantly associated with increased growth.

This work provides important new insights into the mechanics of evolutionary change at both the single nucleotide and structural level and identifies potential targets of natural and artificial selection in humans and chickens.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2009. , 63 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 482
Keyword [en]
chicken, chimpanzee, human, evolution, segmental duplication, structural variation, chromosomal rearrangement, comparative genomics, positive selection, selective sweep
National Category
Genetics
Research subject
Genetics
Identifiers
URN: urn:nbn:se:uu:diva-108266ISBN: 978-91-554-7604-5 (print)OAI: oai:DiVA.org:uu-108266DiVA: diva2:234816
Public defence
2009-10-23, C8:305, BMC, Husargatan 3, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2009-10-01 Created: 2009-09-10 Last updated: 2009-10-01
List of papers
1. Analysis of the DNA sequence and duplication history of human chromosome 15
Open this publication in new window or tab >>Analysis of the DNA sequence and duplication history of human chromosome 15
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2006 (English)In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 440, no 7084, 671-675 p.Article in journal (Refereed) Published
Abstract [en]

Here we present a finished sequence of human chromosome 15, together with a high-quality gene catalogue. As chromosome 15 is one of seven human chromosomes with a high rate of segmental duplication, we have carried out a detailed analysis of the duplication structure of the chromosome. Segmental duplication in chromosome 15 are largely clustered in two regions, on proximal and distal 15q; the proximal region is notable because recombination among the segmental duplications can result in deletions causing Prader-Willi and Angelman syndromes. Sequence analysis shows that the proximal and distal regions of 15q share extensive ancient similarity. Using a simple approach, we have been able to reconstruct many of the events by which the current duplication structure arose. We find that most of the intrachromosomal duplications seem to share a common ancestry. Finally, we demonstrate that some remaining gaps in the genome sequence are probably due to structural polymorphisms between haplotypes; this may explain a significant fraction of the gaps remaining in the human genome.

National Category
Genetics
Research subject
Genetics
Identifiers
urn:nbn:se:uu:diva-108245 (URN)10.1038/nature04601 (DOI)
Available from: 2009-09-10 Created: 2009-09-09 Last updated: 2017-12-13Bibliographically approved
2. DNA sequence of human chromosome 17 and analysis of rearrangement in the human lineage
Open this publication in new window or tab >>DNA sequence of human chromosome 17 and analysis of rearrangement in the human lineage
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2006 (English)In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 440, no 7087, 1045-1049 p.Article in journal (Refereed) Published
Abstract [en]

Chromosome 17 is unusual among the human chromosomes in many respects. It is the largest human autosome with orthology to only a single mouse chromosome, mapping entirely to the distal half of mouse chromosome 11. Chromosome 17 is rich in protein-coding genes, having the second highest gene density in the genome. It is also enriched in segmental duplications, ranking third in density among the autosomes. Here we report a finished sequence for human chromosome 17, as well as a structural comparison with the finished sequence for mouse chromosome 11, the first finished mouse chromosome. Comparison of the orthologous regions reveals striking differences. In contrast to the typical pattern seen in mammalian evolution, the human sequence has undergone extensive intrachromosomal rearrangement, whereas the mouse sequence has been remarkably stable. Moreover, although the human sequence has a high density of segmental duplication, the mouse sequence has a very low density. Notably, these segmental duplications correspond closely to the sites of structural rearrangement, demonstrating a link between duplication and rearrangement. Examination of the main classes of duplicated segments provides insight into the dynamics underlying expansion of chromosome-specific, low-copy repeats in the human genome.

National Category
Genetics
Research subject
Genetics
Identifiers
urn:nbn:se:uu:diva-108247 (URN)10.1038/nature04689 (DOI)
Available from: 2009-09-10 Created: 2009-09-10 Last updated: 2017-12-13Bibliographically approved
3. Evolutionary toggling of the MAPT 17q21.31 inversion region
Open this publication in new window or tab >>Evolutionary toggling of the MAPT 17q21.31 inversion region
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2008 (English)In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 40, no 9, 1076-83 p.Article in journal (Refereed) Published
Abstract [en]

Using comparative sequencing approaches, we investigated the evolutionary history of the European-enriched 17q21.31 MAPT inversion polymorphism. We present a detailed, BAC-based sequence assembly of the inverted human H2 haplotype and compare it to the sequence structure and genetic variation of the corresponding 1.5-Mb region for the noninverted H1 human haplotype and that of chimpanzee and orangutan. We found that inversion of the MAPT region is similarly polymorphic in other great ape species, and we present evidence that the inversions occurred independently in chimpanzees and humans. In humans, the inversion breakpoints correspond to core duplications with the LRRC37 gene family. Our analysis favors the H2 configuration and sequence haplotype as the likely great ape and human ancestral state, with inversion recurrences during primate evolution. We show that the H2 architecture has evolved more extensive sequence homology, perhaps explaining its tendency to undergo microdeletion associated with mental retardation in European populations.

National Category
Biological Sciences
Identifiers
urn:nbn:se:uu:diva-100873 (URN)10.1038/ng.193 (DOI)000258761200020 ()19165922 (PubMedID)
Available from: 2009-04-09 Created: 2009-04-09 Last updated: 2017-12-13Bibliographically approved
4. Initial sequence of the chimpanzee genome and comparison with the human genome
Open this publication in new window or tab >>Initial sequence of the chimpanzee genome and comparison with the human genome
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2005 (English)In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 437, no 7055, 69-87 p.Article in journal (Refereed) Published
Abstract [en]

Here we present a draft genome sequence of the common chimpanzee (Pan troglodytes). Through comparison with the human genome, we have generated a largely complete catalogue of the genetic differences that have accumulated since the human and chimpanzee species diverged from our common ancestor, constituting approximately thirty-five million single-nucleotide changes, five million insertion/deletion events, and various chromosomal rearrangements. We use this catalogue to explore the magnitude and regional variation of mutational forces shaping these two genomes, and the strength of positive and negative selection acting on their genes. In particular, we find that the patterns of evolution in human and chimpanzee protein-coding genes are highly correlated and dominated by the fixation of neutral and slightly deleterious alleles. We also use the chimpanzee genome as an outgroup to investigate human population genetics and identify signatures of selective sweeps in recent human evolution.

National Category
Genetics
Research subject
Genetics
Identifiers
urn:nbn:se:uu:diva-108258 (URN)10.1038/nature04072 (DOI)
Available from: 2009-09-10 Created: 2009-09-10 Last updated: 2017-12-13Bibliographically approved
5. Whole genome resequencing reveals loci under selection during chicken domestication
Open this publication in new window or tab >>Whole genome resequencing reveals loci under selection during chicken domestication
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2010 (English)In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 464, no 7288, 587-591 p.Article in journal (Refereed) Published
Abstract [en]

Domestic animals are excellent models for genetic studies of phenotypic evolution. They have evolved genetic adaptations to a new environment, the farm, and have been subjected to strong human-driven selection leading to remarkable phenotypic changes in morphology, physiology and behaviour. Identifying the genetic changes underlying these developments provides new insight into general mechanisms by which genetic variation shapes phenotypic diversity. Here we describe the use of massively parallel sequencing to identify selective sweeps of favourable alleles and candidate mutations that have had a prominent role in the domestication of chickens (Gallus gallus domesticus) and their subsequent specialization into broiler (meat-producing) and layer (egg-producing) chickens. We have generated 44.5-fold coverage of the chicken genome using pools of genomic DNA representing eight different populations of domestic chickens as well as red jungle fowl (Gallus gallus), the major wild ancestor. We report more than 7,000,000 single nucleotide polymorphisms, almost 1,300 deletions and a number of putative selective sweeps. One of the most striking selective sweeps found in all domestic chickens occurred at the locus for thyroid stimulating hormone receptor (TSHR), which has a pivotal role in metabolic regulation and photoperiod control of reproduction in vertebrates. Several of the selective sweeps detected in broilers overlapped genes associated with growth, appetite and metabolic regulation. We found little evidence that selection for loss-of-function mutations had a prominent role in chicken domestication, but we detected two deletions in coding sequences that we suggest are functionally important. This study has direct application to animal breeding and enhances the importance of the domestic chicken as a model organism for biomedical research.

National Category
Genetics
Research subject
Genetics
Identifiers
urn:nbn:se:uu:diva-108259 (URN)10.1038/nature08832 (DOI)000275974200047 ()20220755 (PubMedID)
Available from: 2009-09-10 Created: 2009-09-10 Last updated: 2017-12-13

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