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

Abstract

The human Y chromosome provides a fertile ground for structural rearrangements owing to its haploidy and high content of repeated sequences. The methodologies used for copy number variation (CNV) studies have developed over the years. Low-throughput techniques based on direct observation of rearrangements were developed early on, and are still used, often to complement array-based or sequencing approaches which have limited power in regions with high repeat content and specifically in the presence of long, identical repeats, such as those found in human sex chromosomes. Some specific rearrangements have been investigated for decades; because of their effects on fertility, or their outstanding evolutionary features, the interest in these has not diminished. However, following the flourishing of large-scale genomics, several studies have investigated CNVs across the whole chromosome. These studies sometimes employ data generated within large genomic projects such as the DDD study or the 1000 Genomes Project, and often survey large samples of healthy individuals without any prior selection. Novel technologies based on sequencing long molecules and combinations of technologies, promise to stimulate the study of Y-CNVs in the immediate future.

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

“…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.…”

The Role of Number of Copies, Structure, Behavior and Copy Number Variations (CNV) of the Y Chromosome in Male Infertility

“…Therefore, several scientists investigated MSY role in traits and diseases, such as sex determination and reversal, spermatogenesis and male infertility, urogenital malignancies, such as prostate cancer, sex-specific effects on the brain and behavior, male viability and graft-versus-host disease [20,113,119]; in some cases, these genes also show a dosage-dependent function with their X-linked counterparts [20]. Most recently, MSY has also been studied with high-throughput techniques [120,121]. Despite the lack of homology between the X chromosome and the MSY region, recent evidence demonstrates that a specialized form of recombination, namely gene conversion [122], may take place in human MSY [123][124][125][126], and that these events occur (i) within the Y chromosome (intrachromosomal recombination by gene conversion or other mechanisms), (ii) between the Y and X chromosomes, and also, although to a lesser extent, (iii) between the Y chromosome and some autosomal sequences [127].…”

A systematic review on the genetics of male infertility in the era of next-generation sequencing

“…Thus, given the current challenges of CNV assignment, it is no surprise that most NGS studies altogether ignore the Y-chromosome [54] . Whilst recent efforts have begun to patch together Y-chromosome structural rearrangements using NGS, there have been no studies targeting infertile men to date.…”