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Detecting positive selection within genomes: the problem of biased gene conversion
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
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2010 (English)In: Philosophical Transactions of the Royal Society of London. Biological Sciences, ISSN 0962-8436, Vol. 365, no 1552, 2571-2580 p.Article in journal (Refereed) Published
Abstract [en]

The identification of loci influenced by positive selection is a major goal of evolutionary genetics. A popular approach is to perform scans of alignments on a genome-wide scale in order to find regions evolving at accelerated rates on a particular branch of a phylogenetic tree. However, positive selection is not the only process that can lead to accelerated evolution. Notably, GC-biased gene conversion (gBGC) is a recombination-associated process that results in the biased fixation of G and C nucleotides. This process can potentially generate bursts of nucleotide substitutions within hotspots of meiotic recombination. Here, we analyse the results of a scan for positive selection on genes on branches across the primate phylogeny. We show that genes identified as targets of positive selection have a significant tendency to exhibit the genomic signature of gBGC. Using a maximum-likelihood framework, we estimate that more than 20 per cent of cases of significantly elevated non-synonymous to synonymous substitution rates ratio (d(N)/d(S)), particularly in shorter branches, could be due to gBGC. We demonstrate that in some cases, gBGC can lead to very high d(N)/d(S) (more than 2). Our results indicate that gBGC significantly affects the evolution of coding sequences in primates, often leading to patterns of evolution that can be mistaken for positive selection.

Place, publisher, year, edition, pages
2010. Vol. 365, no 1552, 2571-2580 p.
Keyword [en]
biased gene conversion, selection, recombination
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-135631DOI: 10.1098/rstb.2010.0007ISI: 000280097000017PubMedID: 20643747OAI: oai:DiVA.org:uu-135631DiVA: diva2:375269
Available from: 2010-12-07 Created: 2010-12-07 Last updated: 2015-01-23Bibliographically approved
In thesis
1. Meiotic Recombination in Human and Dog: Targets, Consequences and Implications for Genome Evolution
Open this publication in new window or tab >>Meiotic Recombination in Human and Dog: Targets, Consequences and Implications for Genome Evolution
2014 (English)Doctoral 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.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2014. 43 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1038
recombination, biased gene conversion, CpG island, copy number variation, substitutions, methylation
National Category
Genetics Evolutionary Biology
Research subject
Bioinformatics; Biology with specialization in Evolutionary Genetics; Biology with specialization in Molecular Evolution; Molecular Genetics
urn:nbn:se:uu:diva-233195 (URN)978-91-554-9057-7 (ISBN)
Public defence
2014-11-20, B41, BMC, Husargatan 3, Uppsala, 13:15 (English)
Available from: 2014-10-30 Created: 2014-09-30 Last updated: 2015-01-23

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Webster, Matthew T.
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