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 per cent 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 nonrandom, and in two cases, convergent across placental and marsupial mammals. We conclude that the gene content of the Y chromosome 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 has unappreciated roles in Turner's syndrome and in phenotypic differences between the sexes in health and disease.

Figure 1. Y-linked genes by species and human X homolog location

Y-linked genes (filled circles) and pseuodgenes (open circles) listed in order of position of human X chromosome homolog. Added (red bar) and conserved (blue bar) regions of the sex chromosomes are indicated on the left. Human sex chromosome evolution was punctuated by formation of at least 4 evolutionary strata (light blue, green, yellow and orange); other strata formed independently in opossum (purple) and marmoset (red).

Figure 2. Regulatory annotations of X-Y pair genes

Venn diagram depicting regulatory functions predicted for selected X-Y pair genes on basis of UniProt annotations of human X-homolog. Common alternatives to official gene symbols in parentheses.

Figure 3. Reconstruction of human sex chromosome evolution

Major events in the evolution of the human sex chromsomes are labeled with approximate dates. After SRY evolved, at least 4 evolutionary strata (light blue, green, yellow and orange) formed in the lineage leading to the human Y chromosome. Each stratum expanded the MSY (male-specific region of the Y, deep blue) at the expense of the PAR (pseudoautosomal region, grey). Genetic decay eliminated most genes from MSY. A chromosomal fusion extended the PAR, generating conserved (XCR/YCR) and added (XAR/YAR) regions.

Figure 4. Decay of Y-linked genes to a baseline level

Gene numbers (on a log scale on y axis) plotted versus time (in Myr before present on × axis). Filled circles show inferred or observed gene numbers in (from left to right) Ancestral X-Y genes (before stratum formation), the MSY of common ancestor of human and opossum (176 Myr ago), bull (97 Myr ago), mouse and rat (91 Myr ago), marmoset (44 Myr ago), rhesus (30 Myr ago) and chimpanzee (6 Myr ago), and modern human MSY. Lines represent best-fit curves to data points using alternate models of decay. Exponential decay to a constant baseline provides the best fit; shaded regions represent parameters producing an equally good fit.

Figure 5. Factors in the survival of Y-linked genes

Violin plots, white bar - interquartile range, circle - median value; asterisk - significant difference in one-tailed Mann-Whitney U-test. a, Multicopy genes (n = 9) have greater longevity than single copy genes (n = 27) (P < 4.28 × 10^-5). b, X-Y pair genes (n = 32) have higher haploinsufficiency probability than other ancestral X genes (n = 478) (P < 6.59 × 10^-3). c, X-Y pair genes (n = 28) are have broader expression across human tissues than other ancestral X genes (n = 383) (P < 2.20 × 10^-3). d, XY-pair genes (n = 27) have lower dN/dS ratio than other ancestral X genes (n = 489) (P < 3.39 × 10^-4).