The effects of natural selection on human Y chromosome amplicons

Abstract

The Y chromosome is unique among the mammalian chromosomes: it determines sex, and is therefore normally present in a single copy, unlike all other chromosomes that can recombine with an identical homolog. These two facts have had profound effects on the fate of the Y chromosome, subjecting it to unique evolutionary pressures that caused the loss of most of its genes. Because of this lack of functional genes, speculation abounded that natural selection is ineffective on a chromosome that lacks a homolog with which to recombine, and that the Y chromosome is doomed to eventually fade away. In recent years, evidence has been building that the Y chromosome is indeed shaped by evolutionary forces acting to maintain its functional genes. However, these studies bypassed the amplicons-large, highly identical segmental duplications-which are a prominent feature of mammalian Y chromosomes and contain many genes crucial for spermatogenesis. In this thesis, we present evidence that natural selection acts on the ampliconic regions of the human Y chromosome. We first develop computational tools to detect amplicon copy number changes from whole genome sequencing data of 1216 men, and find that many men have such changes. By projecting those changes onto a phylogenetic tree of the analyzed Y chromosomes, we find that the reference copy number of each amplicon is ancestral to all modern human Y chromosomes. We then use simulations and novel analytical methods to demonstrate that the ancestral copy number of each amplicon is maintained by selection within diverse human lineages, even in the face of extremely high rates of mutation. Finally, we find that deleted amplicons are preferentially restored to their previous copy number by subsequent duplications. These results are another step forward in the ongoing reframing the history of the mammalian Y chromosome: the Y chromosome is not the victim of random neutral processes, but is the carefully calibrated result of complex interplay between various selective forces.