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David C. Page

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David C. Page, MD, is a professor of biology at the Massachusetts Institute of Technology (MIT) and the director of the Whitehead Institute, and is best known for his work on mapping the Y-chromosome and on its evolution in mammals and expression during development.

Education and Career

Page was born in Harrisburg, PA in 1956 and grew up in the rural outskirts of Pennsylvania Dutch country.[1][2][3] The first of his family to go to college, Page attended Swarthmore College, where he graduated with a BA with highest honors in chemistry in 1978.[2][4] During his final year at Swarthmore, Page attended class just one day a week and spent the rest of his time researched chromatin structure in the laboratory of molecular biologist Robert Simpson at the National Institutes of Health.[2][4] In 1978, Page enrolled at Harvard Medical School and the Harvard-MIT Health Sciences Program, where he worked in the laboratories of David Botstein at MIT and Raymond White at the University of Massachusetts Medical School.[4] In White’s lab, Page worked on a project to develop a genetic linkage map of the human genome that would become a precursor to the Human Genome Project.[1] The work relied on locating restriction fragment length polymorphisms (RFLP). The first RFLP that Page found was from a site of homology between the X chromosome and Y chromosome, a coincidence that would set the direction of his subsequent career.[1]

When Page finished his MD degree in the spring of 1984, he started his own lab as the first Whitehead Fellow at the Whitehead Institute for Biomedical Research researching the genetics of XX male syndrome, or de la Chapelle Syndrome.[1][4] After Page won the MacArthur “Genius Grant” in 1986, Page was promoted to the faculty of the Whitehead Institute and the MIT Department of Biology in 1988.[4][5] In 1990, Page was named a Howard Hughes Medical Institute Investigator, and in 2005 he was named as director of the Whitehead Institute.[4]

Research

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.[1][6][7]

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.[1][8] 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.[1][8][9]

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,[10] and went on to develop comprehensive clone-based physical maps of the chromosome in 1992[11][12] and systematic catalogs of Y-linked genes in 1997.[13] 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.[14] 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.[2] The development of SHIMS allowed Page to identify long palindromic sequences on the long arm of the Y chromosome, which he would go on to show made the Y chromosome vulnerable to the deletions that cause spermatogenic failure (an inability to produce sperm).[15] In 2012, Page characterized the most common genetic cause of spermatogenic failure, the deletion of the AZFc region of the Y chromosome.[16][17] 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.[16]

Evolution of the Y Chromosome

With the development of more detailed maps of the Y chromosome, in the mid-1990s Page began to find genetic evidence confirming the theory that both the X and Y chromosomes had evolved from autosomes, beginning with the 1996 discovery that a family of genes called DAZ (deleted in azoospermia) had been transposed from an autosome to the Y chromosome.[2][18] 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.[19] Later cross-species comparisons would show that while ancestral genes on the Y chromosome initially underwent rapid decay,[14][20] the remaining genes have remained stable for the last 25 million years,[21] overturning the long-held view that the Y chromosome was going extinct.[2] In a 2014 study, Page concluded that the conserved genes on the Y chromosome played an important role in male viability, since they were dosage-dependent genes with similar but not identical counterparts on the X chromosome that all have regulatory roles in transcription, translation, and protein stability. Because these genes are expressed throughout the body, Page further concluded that these genes give rise to differences in the biochemistry of male and female tissues.[22]

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.[23] 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.[24]

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.[25][26][27] 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.[28][29]

Awards and Honors

References

  1. ^ a b c d e f g Trivedi, Bijal (2006-02-21). "Profile of David C. Page". Proceedings of the National Academy of Sciences of the United States of America. 103 (8): 2471–2473. doi:10.1073/pnas.0600615103. ISSN 0027-8424. PMC 1413862. PMID 16481618.
  2. ^ a b c d e f "Why, Oh Y? | The Scientist Magazine®". The Scientist. Retrieved 2016-02-04.
  3. ^ Jagetia, Riya; Berg, Elizabeth; Kim, Jae Hyun; Jones, Brianna (Spring 2015). "MURJ Spotlight: Professor David C. Page, Director of the Whitehead Institute" (PDF). MIT Undergraduate Research Journal. Retrieved 4 February 2016.
  4. ^ a b c d e f g "DAVID PAGE LABORATORY". pagelab.wi.mit.edu. Retrieved 2016-02-04.
  5. ^ Cruzan Morton, Carol (September 1999). "Save the males: David Page '78 reveals the evolutionary roots of sex and gender" (PDF). Swarthmore Bulletin. Retrieved 4 February 2016.
  6. ^ Page, D. C.; de la Chapelle, A.; Weissenbach, J. (1985-05-16). "Chromosome Y-specific DNA in related human XX males". Nature. 315 (6016): 224–226. ISSN 0028-0836. PMID 2987697.
  7. ^ Andersson, M.; Page, D. C.; de la Chapelle, A. (1986-08-15). "Chromosome Y-specific DNA is transferred to the short arm of X chromosome in human XX males". Science (New York, N.Y.). 233 (4765): 786–788. ISSN 0036-8075. PMID 3738510.
  8. ^ a b Page, D. C.; Mosher, R.; Simpson, E. M.; Fisher, E. M.; Mardon, G.; Pollack, J.; McGillivray, B.; de la Chapelle, A.; Brown, L. G. (1987-12-24). "The sex-determining region of the human Y chromosome encodes a finger protein". Cell. 51 (6): 1091–1104. ISSN 0092-8674. PMID 3690661.
  9. ^ Sinclair, A. H.; Berta, P.; Palmer, M. S.; Hawkins, J. R.; Griffiths, B. L.; Smith, M. J.; Foster, J. W.; Frischauf, A. M.; Lovell-Badge, R. (1990-07-19). "A gene from the human sex-determining region encodes a protein with homology to a conserved DNA-binding motif". Nature. 346 (6281): 240–244. doi:10.1038/346240a0. ISSN 0028-0836. PMID 1695712.
  10. ^ Vergnaud, G; Page, D C; Simmler, M C; Brown, L; Rouyer, F; Noel, B; Botstein, D; de la Chapelle, A; Weissenbach, J (1986-02-01). "A deletion map of the human Y chromosome based on DNA hybridization". American Journal of Human Genetics. 38 (2): 109–124. ISSN 0002-9297. PMC 1684749. PMID 3004206.
  11. ^ Vollrath, Douglas; Foote, Simon; Hilton, Adrienne; Brown, Laura G.; Beer-Romero, Peggy; Bogan, Jonathan; Page, David C. (2 October 1992). "The Human Y Chromosome: A 43-Interval Map Based on Naturally Occurring Deletions" (PDF). Science. 258 (5079): 52–59. Retrieved 4 February 2016.
  12. ^ Foote, Simon; Vollrath, Douglas; Hilton, Adrienne; Page, David C. (2 October 1992). "The Human Y Chromosome: Spanning the Euchromatic Region" (PDF). Science. 258 (5079): 60–66. Retrieved 4 February 2016.
  13. ^ Lahn, Bruce; Page, David C. (24 October 1997). "Functional Coherence of the Human Y Chromosome" (PDF). Science. 278 (5338): 675–680. Retrieved 4 February 2016.
  14. ^ a b Skaletsky, H.; Kuroda-Kawaguchi, T.; Minx, P. J.; Cordum, H. S.; Hillier, L.; Brown, L. G.; Repping, S.; Pyntikova, T.; Ali, J.; Bieri, T.; Chinwalla, A.; Delehaunty, A.; Delehaunty, K.; Du, H.; Fewell, G.; Fulton, L.; Fulton, R.; Graves, T.; Hou, S. F.; Latrielle, P.; Leonard, S.; Mardis, E.; Maupin, R.; McPherson, J.; Miner, T.; Nash, W.; Nguyen, C.; Ozersky, P.; Pepin, K.; Rock, S. (2003). "The male-specific region of the human Y chromosome is a mosaic of discrete sequence classes". Nature. 423 (6942): 825–837. doi:10.1038/nature01722. PMID 12815422.
  15. ^ Repping, Sjoerd; Skaletsky, Helen; Lange, Julian; Silber, Sherman; Van Der Veen, Fulco; Oates, Robert D.; Page, David C.; Rozen, Steve (2002-10-01). "Recombination between palindromes P5 and P1 on the human Y chromosome causes massive deletions and spermatogenic failure". American Journal of Human Genetics. 71 (4): 906–922. doi:10.1086/342928. ISSN 0002-9297. PMC 419997. PMID 12297986.
  16. ^ a b Whitehead Institute Faculty Page
  17. ^ Rozen, Steven G.; Marszalek, Janet D.; Irenze, Kathryn; Skaletsky, Helen; Brown, Laura G.; Oates, Robert D.; Silber, Sherman J.; Ardlie, Kristin; Page, David C. (2012-11-02). "AZFc deletions and spermatogenic failure: a population-based survey of 20,000 Y chromosomes". American Journal of Human Genetics. 91 (5): 890–896. doi:10.1016/j.ajhg.2012.09.003. ISSN 1537-6605. PMC 3487143. PMID 23103232.
  18. ^ Saxena, R.; Brown, L. G.; Hawkins, T.; Alagappan, R. K.; Skaletsky, H.; Reeve, M. P.; Reijo, R.; Rozen, S.; Dinulos, M. B. (1996-11-01). "The DAZ gene cluster on the human Y chromosome arose from an autosomal gene that was transposed, repeatedly amplified and pruned". Nature Genetics. 14 (3): 292–299. doi:10.1038/ng1196-292. ISSN 1061-4036. PMID 8896558.
  19. ^ Lahn, B. T.; Page, D. C. (1999-10-29). "Four evolutionary strata on the human X chromosome". Science (New York, N.Y.). 286 (5441): 964–967. ISSN 0036-8075. PMID 10542153.
  20. ^ Bellott, Daniel W.; Skaletsky, Helen; Pyntikova, Tatyana; Mardis, Elaine R.; Graves, Tina; Kremitzki, Colin; Brown, Laura G.; Rozen, Steve; Warren, Wesley C. (2010-07-29). "Convergent evolution of chicken Z and human X chromosomes by expansion and gene acquisition". Nature. 466 (7306): 612–616. doi:10.1038/nature09172. ISSN 1476-4687. PMC 2943333. PMID 20622855.
  21. ^ Hughes, Jennifer F.; Skaletsky, Helen; Brown, Laura G.; Pyntikova, Tatyana; Graves, Tina; Fulton, Robert S.; Dugan, Shannon; Ding, Yan; Buhay, Christian J. (2012-03-01). "Strict evolutionary conservation followed rapid gene loss on human and rhesus Y chromosomes". Nature. 483 (7387): 82–86. doi:10.1038/nature10843. ISSN 0028-0836. PMC 3292678. PMID 22367542.
  22. ^ Bellott, Daniel W.; Hughes, Jennifer F.; Skaletsky, Helen; Brown, Laura G.; Pyntikova, Tatyana; Cho, Ting-Jan; Koutseva, Natalia; Zaghlul, Sara; Graves, Tina (2014-04-24). "Mammalian Y chromosomes retain widely expressed dosage-sensitive regulators". Nature. 508 (7497): 494–499. doi:10.1038/nature13206. ISSN 0028-0836. PMC 4139287. PMID 24759411.
  23. ^ Mueller, Jacob L.; Skaletsky, Helen; Brown, Laura G.; Zaghlul, Sara; Rock, Susan; Graves, Tina; Auger, Katherine; Warren, Wesley C.; Wilson, Richard K. (2013-09-01). "Independent specialization of the human and mouse X chromosomes for the male germ line". Nature Genetics. 45 (9): 1083–1087. doi:10.1038/ng.2705. ISSN 1061-4036. PMC 3758364. PMID 23872635.
  24. ^ Soh, Y. Q. Shirleen; Alföldi, Jessica; Pyntikova, Tatyana; Brown, Laura G.; Graves, Tina; Minx, Patrick J.; Fulton, Robert S.; Kremitzki, Colin; Koutseva, Natalia (2014-11-06). "Sequencing the mouse Y chromosome reveals convergent gene acquisition and amplification on both sex chromosomes". Cell. 159 (4): 800–813. doi:10.1016/j.cell.2014.09.052. ISSN 1097-4172. PMC 4260969. PMID 25417157.
  25. ^ Baltus, Andrew E.; Menke, Douglas B.; Hu, Yueh-Chiang; Goodheart, Mary L.; Carpenter, Anne E.; de Rooij, Dirk G.; Page, David C. (2006-12-01). "In germ cells of mouse embryonic ovaries, the decision to enter meiosis precedes premeiotic DNA replication". Nature Genetics. 38 (12): 1430–1434. doi:10.1038/ng1919. ISSN 1061-4036. PMID 17115059.
  26. ^ Lin, Yanfeng; Gill, Mark E.; Koubova, Jana; Page, David C. (2008-12-12). "Germ Cell-Intrinsic and -Extrinsic Factors Govern Meiotic Initiation in Mouse Embryos". Science. 322 (5908): 1685–1687. doi:10.1126/science.1166340. ISSN 0036-8075. PMID 19074348.
  27. ^ Koubova, Jana; Menke, Douglas B.; Zhou, Qing; Capel, Blanche; Griswold, Michael D.; Page, David C. (2006-02-21). "Retinoic acid regulates sex-specific timing of meiotic initiation in mice". Proceedings of the National Academy of Sciences of the United States of America. 103 (8): 2474–2479. doi:10.1073/pnas.0510813103. ISSN 0027-8424. PMC 1413806. PMID 16461896.
  28. ^ Endo, Tsutomu; Romer, Katherine A.; Anderson, Ericka L.; Baltus, Andrew E.; de Rooij, Dirk G.; Page, David C. (2015-05-05). "Periodic retinoic acid-STRA8 signaling intersects with periodic germ-cell competencies to regulate spermatogenesis". Proceedings of the National Academy of Sciences of the United States of America. 112 (18): E2347–2356. doi:10.1073/pnas.1505683112. ISSN 1091-6490. PMC 4426408. PMID 25902548.
  29. ^ Dokshin, Gregoriy A.; Baltus, Andrew E.; Eppig, John J.; Page, David C. (2013-08-01). "Oocyte differentiation is genetically dissociable from meiosis in mice". Nature Genetics. 45 (8): 877–883. doi:10.1038/ng.2672. ISSN 1061-4036. PMC 3747777. PMID 23770609.
  30. ^ "David C. Page — MacArthur Foundation". www.macfound.org. Retrieved 2016-02-04.
  31. ^ "Searle Scholars Program : David C. Page (1989)". www.searlescholars.net. Retrieved 2016-02-04.
  32. ^ Page, David C. (2004-03-01). "On Low Expectations Exceeded; or, The Genomic Salvation of the Y Chromosome". American Journal of Human Genetics. 74 (3): 399–402. ISSN 0002-9297. PMC 1182254. PMID 15053010.
  33. ^ Trivedi, B. (2006). "Profile of David C. Page". Proceedings of the National Academy of Sciences. 103 (8): 2471–2473. doi:10.1073/pnas.0600615103. PMC 1413862. PMID 16481618.
  34. ^ "MIT Office of the Provost, Institutional Research". web.mit.edu. Retrieved 2016-02-04.
  35. ^ "Press Releases - American Academy of Arts & Sciences". www.amacad.org. Retrieved 2016-02-04.
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