Origin and structural evolution of the complex genomic regions of human Y chromosome

The human Y chromosome comprises mosaic classes of complex male-specific sequences that remain unclear for their evolution origins, structural variations and pathogenic roles. To address these, we present population-scale analyses of high-quality Y chromosomal sequences of 206 human individuals vs. six ape species, including 160 near complete sequences from the East Asian population, 85 of which are gapless. We uncovered an extensive cryptic diversity of the largest heterochromatin of the human genome on the Y chromosome Yq12, and traced its dual-origin from ancestral centromeric satellites respectively on the Y chromosome and acrocentric autosomes shared with other apes. We showed that such diversity is attributed to the variable and layered expansion of DYZ satellites in the internal array of Yq12, while the Yq12 boundary is marked by conserved inverted arrays. Similarly, the largest Y-linked gene family TSPY can be divided into a highly variable tandem array whose copy number was found to be associated with prostate cancer risks, and an invariable TSPY2 under stronger functional constraints. Within the largest amplicon region AMPL7, we annotated the orientation and copy number per individual of the highly similar amplicons in palindromes, and characterized their recurrent inversion togglings and subsequent microdeletions impacting the male fertility. We further identified population-stratified structural variants in disease-associated genes, including some fixed mutations in TSPY2 and the promoter of DDX3Y in the prevalent Asian haplogroups O1a that are probably associated with elevated prostate cancer risks. Together, our study revealed the mosaic internal structures and evolutionary history of respective complex regions of the human Y chromosome, and provided a foundation for understanding its functional role beyond male determination.