Mammalian Y chromosomes retain widely expressed dosage-sensitive regulators

Abstract

The human X and Y chromosomes evolved from an ordinary pair of autosomes, but millions of years ago genetic decay ravaged the Y chromosome, and only three percent of its ancestral genes survived. We reconstructed the evolution of the Y chromosome across eight mammals to identify biases in gene content and the selective pressures that preserved the surviving ancestral genes. Our findings indicate that survival was non-random, and in two cases, convergent across placental and marsupial mammals. We conclude that the Y chromosome's gene content became specialized through selection to maintain the ancestral dosage of homologous X-Y gene pairs that function as broadly expressed regulators of transcription, translation and protein stability. We propose that beyond its roles in testis determination and spermatogenesis, the Y chromosome is essential for male viability, and plays unappreciated roles in Turner syndrome and in phenotypic differences between the sexes in health and disease.

Radical remodeling of the Y chromosome in a recent radiation of malaria mosquitoes

“…From studies of mammals (6,7,11,56,57) and Drosophila (58-60), it is known that the Y chromosomes in both groups have lost most of their ancestral gene repertoires and have acquired copious amounts of repetitive and ampliconic/palindromic DNA. In the ∼250 My since Drosophila and Anopheles last shared a common Dipteran ancestor, there has been parallel evolution of heteromorphic sex chromosomes from the same ancestral linkage group (61), implying that the Anopheles Y must have undergone a similar fate of massive ancestral gene loss and genomic degradation.…”

“…In animals with morphologically distinct (heterogametic) sex chromosomes, the Y has ceased crossing over with the X across some or all of its length and the nonrecombining region is transmitted clonally by males (4,5). The absence of recombination initiates progressive genetic decaygene loss and accumulation of repetitive sequences-but there is increasing recognition that even relatively old and otherwise highly degenerate Y chromosomes retain functional importance not only for sexual reproduction but for their contributions to global gene regulation, affecting health and survival (6)(7)(8)(9)(10). Notwithstanding these critical roles, the Y chromosome remains one of the most recalcitrant and poorly characterized portions of any genome more than a decade into the postgenomic era, with current knowledge resting largely on only two animal groups: mammals and Drosophila (2,11).…”

Sexual dimorphism in cancer

“…Besides the pseudoautosomal regions (PAR), which have corresponding regions of homology on the Y chromosome, other single genes escaping inactivation are spread throughout the chromosome. In particular, UTX (KDM6A) is a H3K27 demethylase expressed from both X chromosomes 110 . In men, UTX has a homolog on the Y chromosome, called UTY (KDM6C), whose catalytic activity is very low or absent 111 .…”

Extreme selective sweeps independently targeted the X chromosomes of the great apes

“…For the same reason, a male-beneficial allele may be fixed by selection even when a deleterious effect in females far exceeds the advantageous effect in males (3), making the X chromosome a potential target of sexually antagonistic genes. These unique characteristics as well as the close evolutionary links between the X and Y chromosomes (4,5) are likely to be responsible for the different gene content of the X chromosome compared with autosomes (6) and the higher nonsynonymous-to-synonymous substitution ratio in X-linked protein coding sequences compared with that of the autosomal ones (7,8).…”