Copy number variation arising from gene conversion on the human Y chromosome

Abstract

We describe the variation in copy number of a ~ 10 kb region overlapping the long intergenic noncoding RNA (lincRNA) gene, TTTY22, within the IR3 inverted repeat on the short arm of the human Y chromosome, leading to individuals with 0-3 copies of this region in the general population. Variation of this CNV is common, with 266 individuals having 0 copies, 943 (including the reference sequence) having 1, 23 having 2 copies, and two having 3 copies, and was validated by breakpoint PCR, fibre-FISH, and 10× Genomics Chromium linked-read sequencing in subsets of 1234 individuals from the 1000 Genomes Project. Mapping the changes in copy number to the phylogeny of these Y chromosomes previously established by the Project identified at least 20 mutational events, and investigation of flanking paralogous sequence variants showed that the mutations involved flanking sequences in 18 of these, and could extend over > 30 kb of DNA. While either gene conversion or double crossover between misaligned sister chromatids could formally explain the 0-2 copy events, gene conversion is the more likely mechanism, and these events include the longest non-allelic gene conversion reported thus far. Chromosomes with three copies of this CNV have arisen just once in our data set via another mechanism: duplication of 420 kb that places the third copy 230 kb proximal to the existing proximal copy. Our results establish gene conversion as a previously under-appreciated mechanism of generating copy number changes in humans and reveal the exceptionally large size of the conversion events that can occur.

The Y‐STR landscape of coastal southeastern Han: Forensic characteristics, haplotype analyses, mutation rates, and population genetics

“…A total of 121 off‐ladders were detected at 22 Y‐STRs with 58 different genotypes, while 95 copy number variants were comprised of 24 duplications, 39 triplications, 27 quadruplications, and 5 quintuplicates, which were observed at 24 Y‐STR markers. All variant alleles, which were confirmed by re‐amplification and genotyping in this study, should be interpreted with caution to exclude DNA mixtures in forensics and may be caused by one‐step slippage replication [39,40], gene conversion [41], non‐allelic, and homologous recombination [42].…”

Copy number variation of ZNF280AY across 21 cattle breeds and its association with the reproductive traits of Holstein and Simmental bulls

“…Recently, the mechanism of intrapalindrome gene conversion was theoretically verified, and this mechanism can generate CN changes in the human Y chromosome (Trombetta and Cruciani, 2017;Shi et al, 2018). However, the driving mechanism behind the large expansion and CNV of multicopy genes on the bovine Y chromosome remains unknown.…”

Eight Y chromosome genes show copy number variations in horses

“…We suggest that other methods, such as array comparative genomic hybridization (array-CGH) (Wei et al, 2015;Shi et al, 2018) and the AccuCopy ® assay method (Yan et al, 2017) could be applied to increase the accuracy of CNVs detection of ECAY genes. More functional analyses regarding the relationship between CNVs on ECAY and fertility should be investigated in the future.…”