Developmental Biology, Genetics
Whitehead Institute for Biomedical Research
Dr. Page is also a professor of biology at the Massachusetts Institute of Technology and director of the Whitehead Institute for Biomedical Research.
Sex Chromosomes and Sex Differences
David Page is investigating the genetic differences between males and females. His studies explore how those differences arose through evolution, their biological consequences within and beyond the reproductive tract, and how they affect health and disease.
Page’s lab group pioneered a method of DNA sequencing that overcomes a major challenge in studying sex chromosomes: Because the X and Y chromosomes in mammals contain many repetitive sequences, their DNA cannot be fully sequenced using conventional approaches. Page’s team used a super-resolution sequencing method – single-haplotype iterative mapping and sequencing – to compare the Y chromosomes of humans and rhesus macaques, and overturned a long-standing view that the Y chromosome is headed for extinction. Instead, their findings suggest, the Y chromosome has remained stable for 25 million years.
Another key finding from Page’s lab came from the super-resolution sequencing of mouse sex chromosomes. Those sequences revealed that many genes active in mouse germ cells have been massively and independently amplified on both the X and Y chromosomes – evidence of a selfishly motivated battle between the two chromosomes for transmission to the next generation, a phenomenon known as sex-linked meiotic drive.
In a comparative analysis that included eight species of mammals, Page’s team discovered that as Y chromosomes evolved, they retained a set of genes that help regulate the activity of many other genes in cells throughout the body. These Y-chromosome genes have related but nonidentical counterparts on the X chromosome. Both the X and Y versions of these genetic regulators are expressed in males, whereas only the X versions are expressed in females – a distinction that likely affects all aspects of human biology.
Page is also unraveling the origins and development of mammalian germ cells, the cells that give rise to sperm and oocytes – the most fundamental expression of sex differences.
Super-resolution Sequence of the Mouse Y Chromosome. Triangular dot plot of DNA sequence identity within the 90-megabase mouse Y chromosome. Each dot represents 100% intrachromosomal identity within a 200-bp window. Direct repeats appear as horizontal lines, inverted repeats as vertical lines. Below plot, schematic representation of chromosome is shown.
Soh, Y.Q.S., Alföldi, J., Pyntikova, T., Brown, L.G., Graves, T., Minx, P.J., Fulton, R.S., Kremitzki, C., Koutseva, N., Mueller, J.L., Rozen, S., Hughes, J.F., Owens, E., Womack, J.E., Murphy, W.J., Cao, Q., de Jong, P., Warren, W.C., Wilson, R.K., Skaletsky, H., Page, D.C. 2014 Cell 159:800-13.
A grant from the National Human Genome Research Institute provides partial support for genomic studies of mammalian sex chromosomes.
For a puny little scrap of genetic material, the Y chromosome packs a real biological wallop: it sets in motion the development of everything needed to make a male. David Page has spent his career examining this compact chromosome: tracing its evolution, determining its nucleotide sequence, and unraveling the mechanism that allows the Y chromosome to fix its genes. His work has led to an appreciation of the complexity of the Y chromosome and to a better understanding of male infertility.
Page got his first taste of research as an undergraduate, when he landed a summer job at the National Institutes of Health. There, Page learned how to design experiments to answer scientific questions. “I became obsessed,” he recalls. “I was finally coming to grips with the fact that scientists are the first people in the world to know things. And I found it absolutely intoxicating.”
Page first encountered the Y chromosome as a medical student at Harvard and MIT. While working on a genome mapping project, he found a genetic probe that could be used to distinguish the Y chromosome from the X chromosome. He applied this probe, and others like it, to study XX males. These sex-reversed individuals have the chromosome complement of a female, but they develop as males. Page and his collaborators discovered that many XX males actually harbor a tiny piece of the Y chromosome – a finding that helped researchers narrow the search for the part of the Y chromosome that makes a male phenotype.
When he joined the Whitehead Institute, Page broadened his study of how genes on the Y chromosome influence male development and fertility to include how these genes found their home on the Y over the course of evolution. He cloned and sequenced the Y, in the process discovering that the DNA of this sex chromosome is rife with palindromes – sequences that read the same forward and backward. This genetic hall of mirrors, Page believes, allows the Y chromosome to preserve its important genes. All other human chromosomes come in pairs, including the X’s in female cells. This doubling up allows chromosomes to swap out bits of their DNA, a mechanism that permits repair of damaged genes. By being able to bend and pair with itself, the Y chromosome could use an error-free gene to overwrite errors in a defective version.
Page also identified a gene that accounts for the most common form of male infertility, a finding that has interesting ramifications for human reproduction. Using a procedure called ICSI, or intracytoplasmic sperm injection, doctors can often obtain a few isolated sperm cells from an otherwise infertile man and then inject them directly into a woman’s oocyte to achieve fertilization. However, as Page points out, any sons conceived by this method will also possess the defective Y chromosome, making them infertile as well, unless they opt to undergo a similar procedure when they decide to raise a family.