Abstract
BackgroundNon-allelic homologous recombination between paralogous repeats is increasingly being recognized as a major mechanism causing both pathogenic microdeletions and duplications, and structural polymorphism in the human genome. It has recently been shown empirically that gene conversion can homogenize such repeats, resulting in longer stretches of absolute identity that may increase the rate of non-allelic homologous recombination.ResultsHere, a statistical test to detect gene conversion between pairs of non-coding sequences is presented. It is shown that the 24 kb Charcot-Marie-Tooth type 1A paralogous repeats (CMT1A-REPs) exhibit the imprint of gene conversion processes whilst control orthologous sequences do not. In addition, Monte Carlo simulations of the evolutionary divergence of the CMT1A-REPs, incorporating two alternative models for gene conversion, generate repeats that are statistically indistinguishable from the observed repeats. Bounds are placed on the rate of these conversion processes, with central values of 1.3 × 10-4 and 5.1 × 10-5 per generation for the alternative models.ConclusionsThis evidence presented here suggests that gene conversion may have played an important role in the evolution of the CMT1A-REP paralogous repeats. The rates of these processes are such that it is probable that homogenized CMT1A-REPs are polymorphic within modern populations. Gene conversion processes are similarly likely to play an important role in the evolution of other segmental duplications and may influence the rate of non-allelic homologous recombination between them.
Highlights
Non-allelic homologous recombination between paralogous repeats is increasingly being recognized as a major mechanism causing both pathogenic microdeletions and duplications, and structural polymorphism in the human genome
This study demonstrated that gene conversion events between these paralogous repeats (~94% homology) have homogenized them at least twice during recent human evolution, and that the presence of homogenized tracts within these repeats is polymorphic in modern populations
The authors argued that the majority of such products resulted from single crossovers on the basis that the rate determined in small-pool PCR of ~1.5 × 10-5 was similar to estimates of Charcot-Marie-Tooth disease type 1A (CMT1A) duplication frequencies based on patient prevalence (0.98–6.5 × 10-5) [24]
Summary
Non-allelic homologous recombination between paralogous repeats is increasingly being recognized as a major mechanism causing both pathogenic microdeletions and duplications, and structural polymorphism in the human genome. There is a rapidly growing literature describing pathogenic rearrangements caused by illegitimate recombination between non-allelic homologous sequences [1,2,3]. These paralogous repeats can cause inversions which disrupt coding sequences, and microdeletions and microduplications that result in pathogenic changes in the copy number of intervening genes. The peripheral neuropathy Charcot-Marie-Tooth disease type 1A (CMT1A) is caused by a microduplication of a 1.5 Mb region on chromosome 17 that lies between 24 kb paralogous direct repeats known as CMT1A-REPs [4]. The SMS-REP direct paralogous repeats on chromosome 17 cause both pathogenic microdeletions (causing Smith-Magenis Syndrome) and microduplications [6]. Inverted paralogous repeats are responsible for the inversion of a portion of the factor VIII gene that causes hemophilia [7]
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