High mutation rates have driven extensive structural polymorphism among human Y chromosomes

Abstract

Although much structural polymorphism in the human genome has been catalogued, the kinetics of underlying change remain largely unexplored. Because human Y chromosomes are clonally inherited, it has been possible to capture their detailed relationships in a robust, worldwide genealogical tree. Examination of structural variation across this tree opens avenues for investigating rates of underlying mutations. We selected one Y chromosome from each of 47 branches of this tree and searched for large-scale variation. Four chromosomal regions showed extensive variation resulting from numerous large-scale mutations. Within the tree encompassed by the studied chromosomes, the distal-Yq heterochromatin changed length > or = 12 times, the TSPY gene array changed length > or = 23 times, the 3.6-Mb IR3/IR3 region changed orientation > or = 12 times and the AZFc region was rearranged > or = 20 times. After determining the total time spanned by all branches of this tree (approximately 1.3 million years or 52,000 generations), we converted these mutation counts to lower bounds on rates: > or = 2.3 x 10(-4), > or = 4.4 x 10(-4), > or = 2.3 x 10(-4) and > or = 3.8 x 10(-4) large-scale mutations per father-to-son Y transmission, respectively. Thus, high mutation rates have driven extensive structural polymorphism among human Y chromosomes. At the same time, we found limited variation in the copy number of Y-linked genes, which raises the possibility of selective constraints.

Long Y chromosome is not a fetal loss risk

“…The distal end of the long arm of the Y chromosome is the heterochromatin region, one of the most variable in length in the human genome [28]. Increased length of the Y chromosome is heritable, and Yqh+ has not been associated with an abnormal phenotype [29].…”

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

“…It is notable that gene conversion events of up to 9 kb have been reported on the Y chromosome (Hallast et al 2013), exceeding the maximum size of ~ 4 kb on other chromosomes (Dumont and Eichler 2013;Trombetta and Cruciani 2017). Nevertheless, the large size of some of the events has been reported (Williams 1998;Repping et al 2006). Although recurrent, only 12 changes in orientation for this inversion have so far been identified here suggests that reconsideration of the possible involvement of double crossovers is merited.…”

“…Left: simplified Y-chromosomal phylogeny showing the branching pattern of the lineages considered in this study; branch lengths do not correspond to the number of SNPs. Subsequent columns show the numbers of samples in our data set of 1234 chromosomes with 1, 0, 2, or 3 copies of TTTY22-CNV, the number of deletion (Dels) and duplication (Dups) events inferred from the full phylogeny (total of 20) (Poznik et al 2016), and for comparison, the IR3 orientation reported for these haplogroups, where available (Repping et al 2006). The simplified haplogroups common between the two data sets were named according to the International Society of Genetic Genealogy (2013) Table S3.…”

“…However, some information about the frequencies of single crossovers is available. Single crossovers between sister chromatids would result in isodicentric or acentric chromosomes, which are both very rare (and evolutionarily lethal), but intra-chromatid single crossovers result in inversions which are unlikely to affect the phenotype and have in fact been inferred between IR3 proximal and IR3 distal within the Y-chromosomal phylogeny (Repping et al 2006). Repping et al counted 12 inversions in the phylogeny they sampled and inferred a mutation rate of ≥ 2.3 × 10 −4 per generation.…”

“…To understand the relation between the TTTY22-CNV and the IR3 inversion events (Repping et al 2006), we placed both TTTY22-CNV copy number changes and IR3 inversion events onto a simplified phylogeny as described in the main text and compared their phylogenetic locations.…”