David C. Page
Director, Whitehead Institute
Professor of Biology, MIT
Investigator of the Howard Hughes Medical Institute
Whitehead Institute Director David C. Page studies the genetic differences between males and females. In particular, the Page lab is focused on understanding the biology and evolution of sex chromosomes (X and Y), the role that the X and Y chromosomes play in fundamental sex differences beyond the reproductive tract, and the origins and development of germ cells – the precursors of eggs and sperm.
The Page lab’s enduring interest in the foundations of mammalian reproduction stems from early studies of the human Y chromosome. Page’s lab first reported DNA-based deletion maps of the Y chromosome in 1986, comprehensive clone-based physical maps of the chromosome in 1992, and systematic catalogs of Y-linked genes in 1997. In 2003, his lab completed the sequencing of the human Y chromosome in conjunction with the Genome Institute at Washington University.
These genomic studies have led to unanticipated biological insights. The Page lab discovered that the mammalian X and Y chromosomes evolved from an ordinary pair of autosomes. The lab also uncovered the evolutionary mechanisms by which the Y chromosome became functionally specialized in male germ-cell development and spermatogenesis. The lab characterized the most common genetic cause of spermatogenic failure in humans – the deletion of the AZFc region of the Y chromosome. The lab discovered that most of the Y chromosome’s testis genes exist as mirror-image pairs on massive palindromes. They determined that these palindromes are sites of frequent gene conversion and, thus, that the male-specific chromosome is intensely recombinogenic despite the absence of conventional crossing over with a partner chromosome. The lab also found that aberrant crossing over within the Y chromosome’s palindromes underlies a wide range of disorders of sexual differentiation, including sex reversal and Turner syndrome.
As part of a long-term project to reconstruct sex chromosome evolution over hundreds of millions of years, Page and colleagues completed the sequence of the chimpanzee, rhesus macaque, and mouse Y chromosomes, the repetitive regions of the human X chromosome, and the chicken Z chromosome. Additional mammalian sex chromosome sequencing projects are underway. The Page lab developed an innovative sequencing approach – SHIMS, or single-haplotype iterative mapping and sequencing – to accurately assemble sex chromosomes, which are the most challenging sequencing targets in their respective genomes.
Through a systematic and exhaustive comparison of the Y-chromosome gene contents of eight mammals, the lab found that Y-chromosome genes with counterparts on the X chromosome are enriched for broadly expressed, global regulators of cellular processes. The X and Y (male-specific) versions of these genes encode distinct proteins throughout the body. Therefore, fundamental sexual dimorphism exists at the cellular level, which has important implications for understanding the differences between males and females in health and disease.
Another long-term goal of the Page lab is to understand the developmental regulation of germ cells and how they acquire a female or male identity (ultimately eggs or sperm). Starting in the late 1990’s, the lab has used the mouse as an experimental model to genetically dissect the process of meiotic initiation, which is a critical juncture in mammalian development. One of the Page lab’s key findings overturned the long-held view that germ-cell sex determination is dependent on the timing of meiotic initiation. The lab also discovered and characterized an epigenetic mechanism that might explain the unique ability of germ cells to undergo dramatic specialization while retaining the potential to create a new, fully formed organism. The lab uses the latest genomic technologies to uncover the regulatory network of meiotic initiation and epigenetic regulation in germ cells.
Page is Director of the Whitehead Institute, Professor of Biology at the Massachusetts Institute of Technology, and Investigator at the Howard Hughes Medical Institute. In 1992, he founded the Whitehead Task Force on Genetics and Public Policy. Page serves on the Selection Committees of the March of Dimes Prize in Developmental Biology, the National Academy of Sciences Award in Molecular Biology, and the Taubman Prize in Translational Medical Science. He is a member of the advisory boards of Harvard Medical School/Harvard School of Dental Medicine, the Searle Scholar Program, and the Board of Directors of PepsiCo. Page trained in the laboratory of David Botstein, at MIT, while earning an M.D. magna cum laude from Harvard Medical School and the Harvard-MIT Health Sciences and Technology Program.
- Mapping and cloning the human Y chromosome
- Publishing the complete sequence of the human Y chromosome
- MacArthur Foundation Prize Fellowship (1986)
- Searle Scholar’s Award (1989)
- Science magazine’s Top 10 Scientific Advances of the Year (1992, 2003)
- Amory Prize from the American Academy of Arts and Sciences (1997)
- Curt Stern Award from the American Society of Human Genetics (2003
- Elected to the National Academy of Sciences (2005)
- Elected to the Institute of Medicine (2010)
- March of Dimes Prize in Developmental Biology (2011)