Gene conversion homogenizes the CMT1A paralogous repeats

Hurles, Matthew E.

doi:10.1186/1471-2164-2-11

Cited by 35 publications

(18 citation statements)

References 30 publications

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“…These estimates are in good agreement with previous calculations of the IGC rate in the human genome [10], [62], [68], but several orders of magnitude higher than per site rates of non-allelic crossing over [69], [70]. Our analysis surveyed 38.9 Mb (19.45 Mb duplicated sequence), suggesting that ∼60 sites are converted via gene conversion per individual per generation.…”

Section: Resultssupporting

confidence: 91%

Signals of Historical Interlocus Gene Conversion in Human Segmental Duplications

Dumont

Eichler

2013

PLoS ONE

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Standard methods of DNA sequence analysis assume that sequences evolve independently, yet this assumption may not be appropriate for segmental duplications that exchange variants via interlocus gene conversion (IGC). Here, we use high quality multiple sequence alignments from well-annotated segmental duplications to systematically identify IGC signals in the human reference genome. Our analysis combines two complementary methods: (i) a paralog quartet method that uses DNA sequence simulations to identify a statistical excess of sites consistent with inter-paralog exchange, and (ii) the alignment-based method implemented in the GENECONV program. One-quarter (25.4%) of the paralog families in our analysis harbor clear IGC signals by the quartet approach. Using GENECONV, we identify 1477 gene conversion tracks that cumulatively span 1.54 Mb of the genome. Our analyses confirm the previously reported high rates of IGC in subtelomeric regions and Y-chromosome palindromes, and identify multiple novel IGC hotspots, including the pregnancy specific glycoproteins and the neuroblastoma breakpoint gene families. Although the duplication history of a paralog family is described by a single tree, we show that IGC has introduced incredible site-to-site variation in the evolutionary relationships among paralogs in the human genome. Our findings indicate that IGC has left significant footprints in patterns of sequence diversity across segmental duplications in the human genome, out-pacing the contributions of single base mutation by orders of magnitude. Collectively, the IGC signals we report comprise a catalog that will provide a critical reference for interpreting observed patterns of DNA sequence variation across duplicated genomic regions, including targets of recent adaptive evolution in humans.

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Section: Resultssupporting

confidence: 91%

Signals of Historical Interlocus Gene Conversion in Human Segmental Duplications

Dumont

Eichler

2013

PLoS ONE

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“…First, segmental duplications are known to be associated with SVs genome-wide 42 , and second, duplications have been shown specifically to facilitate structural variation in IGH 7 . Segmental duplications and tandem repeats also mediate sequence exchange either through gene conversion or recombination, that can either result in the homogenization of paralogous sequences 29,30,43 , or in an increase in genetic diversity 44,45 . Illustrating the latter of these two scenarios, we found that for IGHV, SNP density was highest in regions including segmental duplications, particularly those with >95% sequence identity with their paralogs; similar trends were not noted for SNP density estimates calculated within non-SD repeat regions (Table 2).…”

Section: Resultsmentioning

confidence: 99%

Sequencing of the human IG light chain loci from a hydatidiform mole BAC library reveals locus-specific signatures of genetic diversity

Watson

Steinberg

Graves-Lindsay

et al. 2014

Preprint

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Germline variation at immunoglobulin (IG) loci is critical for pathogen-mediated immunity, but establishing complete haplotype sequences in these regions has been problematic because of complex sequence architecture and diploid source DNA. We sequenced BAC clones from the effectively haploid human hydatidiform mole cell line, CHM1htert, across the light chain IG loci, kappa (IGK) and lambda (IGL), creating single haplotype representations of these regions. The IGL haplotype generated here is 1.25 Mb of contiguous sequence, including four novel V alleles and one novel C allele and an 11.9 kb insertion. The CH17 IGK haplotype consists of two 644 kb proximal and 466 kb distal contigs separated by a large gap of unknown size; these assemblies added 49 kb of unique sequence extending into this gap. Our analysis also resulted in the characterization of seven novel IGKV alleles and a 16.7 kb region exhibiting signatures of interlocus sequence exchange between distal and proximal IGKV gene clusters. Genetic diversity in IGK/IGL was compared to that of the IG heavy chain (IGH) locus within the same haploid genome, revealing 3-fold (IGK) and 6-fold (IGL) higher diversity in the IGH locus, potentially associated with increased levels of segmental duplication and the telomeric location of IGH.

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“…A gene conversion event, on the other hand, inherently homogenizes a region or a ''tract'' of duplicate genes because a tract of a ''donor'' gene overwrites a homologous region of an ''acceptor'' gene. This generally results in a ''patchy'' pattern of regional phylogenetic signals where short tracts of type II informative sites are dispersed in the background of type I informative sites (Kawamura et al 1992;Kitano and Saitou 1999;Hurles 2001;Winter and Ponting 2005; fig. 7B).…”

Section: Human-macaquementioning

confidence: 99%

Evolutionary Pattern of Gene Homogenization between Primate-Specific Paralogs after Human and Macaque Speciation Using the 4-2-4 Method

Ezawa¹,

Ikeo²,

Gojobori³

et al. 2010

Molecular Biology and Evolution

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Homogenization of duplicated genes is an important factor for gene family evolution. In the previous study, we developed a method, named 4-2-4 here, to detect partial homogenization with high sensitivity and high specificity using quartets. A quartet is a set of four genes generated by a duplication event and the subsequent speciation of two closely related species. We searched the human and macaque genomes and found 430 nonredundant quartets, which correspond to primate-specific paralogs. The prevalence of homogenization in these quartets was 10.0% (43/430), which was ca. one-third of that (29.8% = 206/691) in the rodent-specific nonredundant quartets obtained through comparison of mouse and rat genomes. Part of this difference comes from the fact that primate paralogs tend to be more remotely located to each other than rodent paralogs, and the remainder may be explained by the inherent difference in the neutral evolutionary rate between the primate and rodent lineages. A statistical analysis taking account of the effects of false negatives uncovered negative correlations between sequence divergence and homogenization prevalence both in primates and rodents. Further statistical analyses controlling for false-negative rates and sequence divergences revealed two characteristics shared by the primate and rodent paralogs; 1) significant negative correlations of the homogenization prevalence with physical distances, and 2) no significant correlation between the prevalence and relative transcriptional orientations. Patterns of the homogenization in the genomic alignments of human-macaque quartets indicate that gene conversion, rather than unequal crossing-over, is the major cause of the homogenization.

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Gene conversion homogenizes the CMT1A paralogous repeats

Cited by 35 publications

References 30 publications

Signals of Historical Interlocus Gene Conversion in Human Segmental Duplications

Signals of Historical Interlocus Gene Conversion in Human Segmental Duplications

Sequencing of the human IG light chain loci from a hydatidiform mole BAC library reveals locus-specific signatures of genetic diversity

Evolutionary Pattern of Gene Homogenization between Primate-Specific Paralogs after Human and Macaque Speciation Using the 4-2-4 Method

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