1000 human genomes carry widespread signatures of GC biased gene conversion

Abstract

BackgroundGC-Biased Gene Conversion (gBGC) is one of the important theories put forward to explain profound long-range non-randomness in nucleotide compositions along mammalian chromosomes. Nucleotide changes due to gBGC are hard to distinguish from regular mutations. Here, we present an algorithm for analysis of millions of known SNPs that detects a subset of so-called “SNP flip-over” events representing recent gBGC nucleotide changes, which occurred in previous generations via non-crossover meiotic recombination.ResultsThis algorithm has been applied in a large-scale analysis of 1092 sequenced human genomes. Altogether, 56,328 regions on all autosomes have been examined, which revealed 223,955 putative gBGC cases leading to SNP flip-overs. We detected a strong bias (11.7% ± 0.2% excess) in AT- > GC over GC- > AT base pair changes within the entire set of putative gBGC cases.ConclusionsOn average, a human gamete acquires 7 SNP flip-over events, in which one allele is replaced by its complementary allele during the process of meiotic non-crossover recombination. In each meiosis event, on average, gBGC results in replacement of 7 AT base pairs by GC base pairs, while only 6 GC pairs are replaced by AT pairs. Therefore, every human gamete is enriched by one GC pair. Happening over millions of years of evolution, this bias may be a noticeable force in changing the nucleotide composition landscape along chromosomes.Electronic supplementary materialThe online version of this article (10.1186/s12864-018-4593-1) contains supplementary material, which is available to authorized users.

Hotspots of Human Mutation

“…GC-biased gene conversion is an example of a mutational mechanism occuring at recombination hotspots and is a major driver of base composition heterogeneity [ 23 ]. In this process , meiotic recombination favors GC-rich alleles over AT-rich alleles and facilitates local GC-content increases [ 24 , 25 ]. During the pairing step of gene conversion, there may be G:T or C:A mismatches resolved in favor of the G or C alleles [ 24 ].…”

“…In this process , meiotic recombination favors GC-rich alleles over AT-rich alleles and facilitates local GC-content increases [ 24 , 25 ]. During the pairing step of gene conversion, there may be G:T or C:A mismatches resolved in favor of the G or C alleles [ 24 ]. After analysis of autosomes in >1000 sequenced genomes, AT to GC changes were enriched compared with GC to AT [ 24 ].…”

Adapting Biased Gene Conversion theory to account for intensive GC-content deterioration in the human genome by novel mutations

“…Let's consider the average bias in BGC mismatch reparation (S!W)/(W!S) = 56:44, as evaluated by Dutta et al This bias causes only one A:T base pair to be converted into G:C pair per gamete, according to the authors' calculations [31]. This single W!S replacement is not enough to withstand the loss of 7-14 G:C pairs by novel mutations per individual.…”

“…The impact of BGC on the increase of G:C content is proportional not only to the mismatch repair bias (W!S over S!W), but also to the total length of heteroduplexes formed during meiosis. In our calculations [31] we used the literature data for non-crossover heteroduplex average length of 75 nucleotides, which is considerably less than 1200 nucleotides for crossover heteroduplexes [34,35]. Yet the non-crossover heteroduplexes twenty times outnumber the crossover ones, so their impacts are about the same [36,37].…”

“…However, in 2015 this bias in the humans was re-evaluated, and dramatically increased to over twofold 68% vs. 32% [30]. Our lab also re-evaluated it to the 56% vs. 44% ratio based on the 1000 Genomes public dataset [31]. However, the known quantitative traits and parameters for BGC are unable to explain phenomenon of preservation of GC-composition from degradation by novel mutations.…”