Copy number variation in the human Y chromosome in the UK population

Abstract

We have assessed copy number variation (CNV) in the male-specific part of the human Y chromosome discovered by array comparative genomic hybridization (array-CGH) in 411 apparently healthy UK males, and validated the findings using SNP genotype intensity data available for 149 of them. After manual curation taking account of the complex duplicated structure of Y-chromosomal sequences, we discovered 22 curated CNV events considered validated or likely, mean 0.93 (range 0–4) per individual. 16 of these were novel. Curated CNV events ranged in size from <1 kb to >3 Mb, and in frequency from 1/411 to 107/411. Of the 24 protein-coding genes or gene families tested, nine showed CNV. These included a large duplication encompassing the AMELY and TBL1Y genes that probably has no phenotypic effect, partial deletions of the TSPY cluster and AZFc region that may influence spermatogenesis, and other variants with unknown functional implications, including abundant variation in the number of RBMY genes and/or pseudogenes, and a novel complex duplication of two segments overlapping the AZFa region and including the 3′ end of the UTY gene.Electronic supplementary materialThe online version of this article (doi:10.1007/s00439-015-1562-5) contains supplementary material, which is available to authorized users.

Selection Has Countered High Mutability to Preserve the Ancestral Copy Number of Y Chromosome Amplicons in Diverse Human Lineages

“…58 The true breadth of amplicon copy number variation has been revealed by recent surveys. [20][21][22][23] In accordance with these studies, we found that most amplicon CNVs in the general population do not fall within the small set of CNVs with confirmed phenotypes, and that duplications are more common than deletions. Our results suggest that most or all amplicon CNVs have phenotypic effects that cause selection to remove them from the population.…”

“…5,18,19 Later studies, bolstered by developing technology, described many types of CNVs in larger numbers of men. 11,[20][21][22][23][24] Amplicon CNVs have recently been discovered on the Y chromosomes of chimpanzees, macaques, gorillas, and mice. [25][26][27][28] Some amplicon CNVs have been implicated in spermatogenic failure, sex reversal, Turner syndrome, and testis cancer.…”

“…[5][6][7][8][9][10][11][12] However, the amplicon CNVs with well-described phenotypes represent only a small part of the spectrum of amplicon variation; the vast majority of amplicon CNVs that have been discovered have no known effect on spermatogenesis or any other trait. [20][21][22][23] Even though amplicon CNVs have been the subject of intense investigation, most previous studies made only nominal attempts to reconstruct the evolution of the amplicons, instead focusing on documenting amplicon variation. Here, we present a detailed reconstruction of Y chromosome amplicon evolution in humans.…”

Analysis of 62 hybrid assembled human Y chromosomes exposes rapid structural changes and high rates of gene conversion

“…Mapping of short reads to the reference genome (Next generation sequencing or NGS) has been used to survey single nucleotide variants (SNVs), small indels and copy number variants on the Y chromosome [ 13 – 15 ]. However, NGS has limited power when calling variants in highly similar regions such as the ampliconic regions or in the heterochromatic regions, indels that exceed the read length, large chromosomal rearrangements and variants with sequence not present in the reference.…”

Human Y chromosome copy number variation in the next generation sequencing era and beyond

“…In one study published in 2015, CNVs across the whole MSY were investigated in 411 apparently healthy males from the UK, using an array CGH design that had been employed in the DDD study; SNP-array data were used to validate the CNVs discovered in a subset of individuals (Wei et al 2015). After merging overlapping CNVs called in individual samples into CNV events (CNVEs) and manual curation, 22 curated CNVEs (curCNVEs) were identified.…”