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

Abstract

Although much structural polymorphism in the human genome has been catalogued^1,2,3,4,5, 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^6,7. 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 ≥12 times, the TSPY gene array changed length ≥23 times, the 3.6-Mb IR3/IR3 region changed orientation ≥12 times and the AZFc region was rearranged ≥20 times. After determining the total time spanned by all branches of this tree ( ∼ 1.3 million years or 52,000 generations), we converted these mutation counts to lower bounds on rates: ≥2.3 × 10⁻⁴, ≥4.4 × 10⁻⁴, ≥2.3 × 10⁻⁴ and ≥3.8 × 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.