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Meiotic Recombination in Human and Dog: Targets, Consequences and Implications for Genome Evolution
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
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
Keyword [en]
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: urn:nbn:se:uu:diva-233195ISBN: 978-91-554-9057-7OAI: diva2:752232
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
List of papers
1. Hotspots of biased nucleotide substitutions in human genes
Open this publication in new window or tab >>Hotspots of biased nucleotide substitutions in human genes
2009 (English)In: PLoS biology, ISSN 1544-9173, E-ISSN 1545-7885, Vol. 7, no 1, e26- p.Article in journal (Refereed) Published
Abstract [en]

Genes that have experienced accelerated evolutionary rates on the human lineage during recent evolution are candidates for involvement in human-specific adaptations. To determine the forces that cause increased evolutionary rates in certain genes, we analyzed alignments of 10,238 human genes to their orthologues in chimpanzee and macaque. Using a likelihood ratio test, we identified protein-coding sequences with an accelerated rate of base substitutions along the human lineage. Exons evolving at a fast rate in humans have a significant tendency to contain clusters of AT-to-GC (weak-to-strong) biased substitutions. This pattern is also observed in noncoding sequence flanking rapidly evolving exons. Accelerated exons occur in regions with elevated male recombination rates and exhibit an excess of nonsynonymous substitutions relative to the genomic average. We next analyzed genes with significantly elevated ratios of nonsynonymous to synonymous rates of base substitution (dN/dS) along the human lineage, and those with an excess of amino acid replacement substitutions relative to human polymorphism. These genes also show evidence of clusters of weak-to-strong biased substitutions. These findings indicate that a recombination-associated process, such as biased gene conversion (BGC), is driving fixation of GC alleles in the human genome. This process can lead to accelerated evolution in coding sequences and excess amino acid replacement substitutions, thereby generating significant results for tests of positive selection.

National Category
Medical and Health Sciences Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
urn:nbn:se:uu:diva-119520 (URN)10.1371/journal.pbio.1000026 (DOI)000262811000008 ()19175294 (PubMedID)
Available from: 2010-02-26 Created: 2010-02-26 Last updated: 2015-01-23Bibliographically approved
2. Detecting positive selection within genomes: the problem of biased gene conversion
Open this publication in new window or tab >>Detecting positive selection within genomes: the problem of biased gene conversion
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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.

biased gene conversion, selection, recombination
National Category
Medical and Health Sciences
urn:nbn:se:uu:diva-135631 (URN)10.1098/rstb.2010.0007 (DOI)000280097000017 ()20643747 (PubMedID)
Available from: 2010-12-07 Created: 2010-12-07 Last updated: 2015-01-23Bibliographically approved
3. Novel origins of copy number variation in the dog genome
Open this publication in new window or tab >>Novel origins of copy number variation in the dog genome
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2012 (English)In: Genome Biology, ISSN 1465-6906, E-ISSN 1465-6914, Vol. 13, no 8, R73- p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Copy number variants (CNVs) account for substantial variation between genomes and are a major source of normal and pathogenic phenotypic differences. The dog is an ideal model to investigate mutational mechanisms that generate CNVs as its genome lacks a functional ortholog of the PRDM9 gene implicated in recombination and CNV formation in humans. Here we comprehensively assay CNVs using high-density array comparative genomic hybridization in 50 dogs from 17 dog breeds and 3 gray wolves. RESULTS: We use a stringent new method to identify a total of 430 high-confidence CNV loci, which range in size from 9 kb to 1.6 Mb and span 26.4 Mb, or 1.08%, of the assayed dog genome, overlapping 413 annotated genes. Of CNVs observed in each breed, 98% are also observed in multiple breeds. CNVs predicted to disrupt gene function are significantly less common than expected by chance. We identify a significant overrepresentation of peaks of GC content, previously shown to be enriched in dog recombination hotspots, in the vicinity of CNV breakpoints. CONCLUSIONS: A number of the CNVs identified by this study are candidates for generating breed-specific phenotypes. Purifying selection seems to be a major factor shaping structural variation in the dog genome, suggesting that many CNVs are deleterious. Localized peaks of GC content appear to be novel sites of CNV formation in the dog genome by non-allelic homologous recombination, potentially activated by the loss of PRDM9. These sequence features may have driven genome instability and chromosomal rearrangements throughout canid evolution.

National Category
Natural Sciences
urn:nbn:se:uu:diva-194244 (URN)10.1186/gb-2012-13-8-r73 (DOI)000315867500007 ()22916802 (PubMedID)

Additional author: The LUPA Consortium (

Available from: 2013-02-11 Created: 2013-02-11 Last updated: 2015-01-23Bibliographically approved
4. Germline Metyhlation Patterns Determine The Distribution Of Recombination Events In The Dog Genome
Open this publication in new window or tab >>Germline Metyhlation Patterns Determine The Distribution Of Recombination Events In The Dog Genome
(English)In: Genome Biology and Evolution, ISSN 1759-6653Article in journal (Refereed) Submitted
National Category
urn:nbn:se:uu:diva-233190 (URN)
Available from: 2014-09-30 Created: 2014-09-30 Last updated: 2015-01-23Bibliographically approved

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