David C. Page (born 1956) is an American biologist who is a professor at the Massachusetts Institute of Technology (MIT). He was the director of the Whitehead Institute and a Howard Hughes Medical Institute (HHMI) investigator. He is best known for his work on mapping the Y-chromosome and on its evolution in mammals and expression during development.
Education and early life
Page was born in Harrisburg, Pennsylvania, in 1956 and grew up in the rural outskirts of Pennsylvania Dutch country. The first of his family to go to college, Page attended Swarthmore College, where he graduated with a B.A. with highest honors in chemistry in 1978. During his final year at Swarthmore, Page attended class just one day a week and spent the rest of his time researching chromatin structure in the laboratory of molecular biologist Robert Simpson at the National Institutes of Health. In 1990, Page was named a Howard Hughes Medical Institute Investigator, and in 2005 he was named as director of the Whitehead Institute.
Mapping the Y chromosome
In his work on de la Chapelle Syndrome in 1986, Page collaborated with the geneticist who originally identified the first XX male, Albert de la Chapelle, and geneticist Jean Weissenbach to show that XX males carry a small piece of the Y chromosome.
In the following year, he reported that the gene ZFY induced the development of the testes, a finding which received a great deal of media attention since it putatively resolving a decade-long search for the sex-determining gene. In 1989, a British team of scientists led by Peter Goodfellow and Robin Lovell-Badge began to report that the testis-determining gene was not ZFY, which led Page to review his data. Page found that he had misinterpreted his data because one of the XY females in his study had a second deletion at the site which proved to be the location of the real sex-determining gene. Launching a second round of media attention, Nature published his findings together with a paper from the British group that identified the sex-determining gene, which they termed SRY.
Despite a belief among geneticists that the Y chromosome contained few genes other than the sex-determining gene, Page continued to map the Y chromosome. He had already published DNA-based deletion maps of the Y chromosome in 1986, and went on to develop comprehensive clone-based physical maps of the chromosome in 1992 and systematic catalogs of Y-linked genes in 1997. Page collaborated with a team at the Genome Institute at Washington University to make a complete map of the Y chromosome, which they achieved in 2003. To do so, Page and his colleagues developed a new sequencing technique, single-haplotype iterative mapping and sequencing (SHIMS), since mammalian sex chromosomes contain too many repetitive sequences to be sequenced by conventional approaches. In 2012, Page characterized the most common genetic cause of spermatogenic failure, the deletion of the AZFc region of the Y 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 Turner syndrome. In 1999, Page and his then-graduate student Bruce Lahn showed that the X and Y chromosomes had diverged in four steps, beginning 200-300 million years ago. Later cross-species comparisons would show that while ancestral genes on the Y chromosome initially underwent rapid decay, the remaining genes have remained stable for the last 25 million years, overturning the long-held view that the Y chromosome was going extinct.
In super-resolution studies of the sex chromosomes, Page has found evidence of an evolutionary "arms race" between the X and Y chromosomes for transmission to the next generation. In one study, Page found that human X and mouse Y chromosomes have converged, independently acquiring and amplifying gene families expressed in testicular germ cells. Another study found that the mouse Y chromosome had acquired and massively amplified genes homologous to the testis-expressed gene families on the mouse X chromosome.
The genetics of germ cells
Page used the mouse as a model to study the genetics of meiotic initiation, showing that retinoic acid (RA) is the key factor which induces meiosis, as well as identifying several important genes crucial to the meiotic initiation pathway, including Stra8 and DAZL. Page further discovered that the differentiation germ cells into gametocytes (oocytes in females or spermatocytes in males) does not depend on meiotic initiation, as commonly thought, showing that germ cells deficient in Stra8, a gene that activates the meiotic pathway, are still capable of growth and differentiation.
Awards and honors
His honors and awards include:
- 1986 MacArthur Prize Fellowship
- 1989 Searle Scholar Award
- 1997 Francis Amory Prize, American Academy of Arts and Sciences (for genetic studies of mammalian sex determination; prize shared with Peter Goodfellow and Robin Lovell-Badge)
- 2003 Curt Stern Award, American Society of Human Genetics (for outstanding scientific achievement in human genetics)
- 2005 Member, National Academy of Sciences
- 2011 Fellow, American Academy of Arts and Sciences (Class Speaker, Biological Sciences)