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Initial sequence of the chimpanzee genome and comparison with the human genome
Broad Institute.
Washington University School of Medicine, Genome Sequencing Center.
University of Washington, Department of Genome Sciences.
Broad Institute.
Show others and affiliations
2005 (English)In: Nature, ISSN 0028-0836, 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.

Place, publisher, year, edition, pages
2005. Vol. 437, no 7055, 69-87 p.
National Category
Genetics
Research subject
Genetics
Identifiers
URN: urn:nbn:se:uu:diva-108258DOI: 10.1038/nature04072OAI: oai:DiVA.org:uu-108258DiVA: diva2:234778
Available from: 2009-09-10 Created: 2009-09-10 Last updated: 2013-08-01Bibliographically approved
In thesis
1. Investigation of Mechanics of Mutation and Selection by Comparative Sequencing
Open this publication in new window or tab >>Investigation of Mechanics of Mutation and Selection by Comparative Sequencing
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
chicken, chimpanzee, human, evolution, segmental duplication, structural variation, chromosomal rearrangement, comparative genomics, positive selection, selective sweep
National Category
Genetics
Research subject
Genetics
Identifiers
urn:nbn:se:uu:diva-108266 (URN)978-91-554-7604-5 (ISBN)
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

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