The evolution of the mammalian X and Y sex-determining chromosomes from ancestral chromosomes is thought to have occurred through a rapid loss of genes from the Y chromosome. This idea of rapid degeneration1 has been bolstered by observations made during the emergence of new Y chromosomes or Y chromosome segments in fruit flies2. In this issue, Bellott et al.3 (page 494) and Cortez et al.4 (page 488) present extensive accounts of gene evolution on the Y chromosome. They show that, although there was a period of rapid degeneration and gene loss during its early evolution, the genes that are conserved across the Y chromosomes of extant mammals (and the sex-determining W chromosomes of birds) have since been remarkably stable. The researchers' data also provide a detailed picture of the evolutionary forces acting on the sex chromosomes, and offer a plausible explanation for the functional coherence of Y-linked genes across these species.
The Y chromosome is notoriously challenging to study, in terms of both genetics and molecular biology. Despite the fact that male genomes were included in early whole-genome sequencing projects, the Y chromosome was largely ignored owing to the challenge of obtaining useful data from the chromosome, which is rich in repetitive and palindromic sequences. Bellott et al. adopted a previously described approach5 — cloning regions of the DNA of interest into bacterial artificial chromosomes — to obtain and assemble DNA sequences from the Y chromosomes of four placental mammals (rat, mouse, bull and marmoset) and the marsupial opossum. They compared these with existing sequences for another three placentals (rhesus macaque, chimpanzee and human). Of the 184 genes that the authors infer to have been on the ancestral sex chromosomes some 300 million years ago, they find that only 3% survive on the Y chromosome of one or more of these mammals (Fig. 1).
Consistent with previous reports, this means that massive degeneration and gene loss did occur early in the history of the mammalian Y chromosome. However, once the genes had run this gauntlet, those that remained enjoyed remarkable stability on the Y chromosome. The authors also find that the 36 genes that are present on both the X and the Y chromosomes of all eight species they examined have maintained a stable presence for the past 25 million years. Ten genes were found to be shared across the Y chromosomes of the tammar wallaby, the Tasmanian devil and the opossum, indicating a stable Y-chromosome presence for the 78 million years of the marsupial lineage. These findings have important implications for our understanding of how natural selection acts to retain active functioning of specific subsets of genes on the Y chromosome.
Cortez et al. took a faster survey approach, in which they sought RNA molecules that are expressed in males but not females and then verified that the genes encoding these RNAs are found only in male genomic DNA. This allowed them to identify 134 genes transcribed from the Y chromosome across 10 mammals and to follow their evolutionary fates. By including the chicken (in which males have two Z chromosomes and females have one Z and one W chromosome) and the platypus (a monotreme that has a bizarre array of five X and five Y chromosomes), the authors were able to paint a broader picture of sex-chromosome evolution. Most noteworthy is their observation that the sex chromosomes of placental mammals, birds and monotremes had essentially independent origins, which means that patterns of gene loss and of specific retention of classes of genes on their Y (or W) chromosomes can be compared.
These data add depth and confidence to the model of evolutionary 'strata' on the sex chromosomes6 that mark the time points at which X and Y sequences ceased recombining and subsequently diverged. Intriguingly, despite their independent origins, the authors find that the oldest strata in placental mammals, monotremes and birds are remarkably similar in age, estimated to have occurred 181 million, 175 million and 137 million years ago, respectively.
Another key aspect of genes on sex chromosomes is dosage sensitivity. Dosage-insensitive genes are those that function perfectly well when present as a single copy, and these are especially likely to become X- or Y-specific. By contrast, two copies of dosage-sensitive genes are required for normal health, and such genes are likely to be retained on both the X and the Y chromosome7. Genes involved in regulating gene transcription — such as those that encode transcription factors — commonly function inadequately in only a single dose, providing a hypothesis for why the Y chromosome has retained genes involved in transcription regulation.
Because the Y chromosome is enriched with transcription-regulating genes, this means that it is far from being solely a male-determining switch that is flipped early in development. Instead, the Y chromosome has an impact on gene regulation across the genome in males, potentially influencing biological functions throughout life and in every tissue. It is fair to say that we are only beginning to understand the full extent of the differences in the molecular biology of males and females, and unanswered questions abound. For example, to what extent are male–female differences driven by specific interactions with Y-chromosomal factors?
In humans, the level of variation between individuals is considerably lower on the Y chromosome than on other chromosomes. However, Y-linked sequence changes can cause changes in gene expression across the genome, which could result in amplified differences among males. Despite the relative stability of the gene content on mature Y chromosomes, it is well known that DNA sequences evolve faster on the Y chromosome than on the X. Although this is generally perceived to be the result of the arrest of genetic recombination on the Y chromosome leading to reduced effectiveness of natural selection8, it seems that the Y chromosome also has the potential to mediate remarkably rapid adaptive evolutionary change.