Defending the Honor of the Y Chromosome

2015 Nirenberg Lecture with David Page

“Sex differences in incidence and severity are not the exception—they are in fact the rule,” said Whitehead Institute Director David Page at the 2015 Nirenberg Lecture held at NIH in May. “For every affected man, there are two or three women affected with rheumatoid arthritis. Flip it around and take autism spectrum disorders—for every girl diagnosed with an autism spectrum disorder, [there are] about five or six boys diagnosed.” Page’s work focuses on the evolution of the Y chromosome and its role in reading and regulating gene expression not just in the gonads, but throughout the body.

The regulation of gene activity can be similar to the conflict between a strong central government and states’ rights, Page explained. The traditional view of body politics features a “strong central gonad,” which means sex chromosomes have influence only over sex-specific regions of the body. His research points to a more widespread influence of sex chromosomes, which may underlie the variability we observe in rates and treatment success of diseases.

David Page at the podium

PHOTO BY BILL BRANSON

This research lends further support to the 2014 editorial in the journal Nature by NIH Director Francis Collins and Associate Director for Research on Women’s Health Janine Clayton: “Policy: NIH to balance sex in cell and animal studies,” which highlights the importance of including both sexes in basic and clinical studies.

Gender-determining chromosomes are a recent evolutionary trait that appeared only about 300 million years ago. Pre-chromosome alternatives to sex determination can still be observed today. For example, in turtles and other reptiles, egg-incubation temperatures determine the sex of the offspring. A special characteristic of the mammalian Y chromosome is what Page calls its “demure and diminutive” stature, which is the result of genetic deterioration that has left it with only 17 of the original 649 genes found on the ancestral autosome. These surviving 17 genes are important for reading genetic code and are widely expressed throughout the adult body. The hypothesis about why these last few genes have not deteriorated is that they play an important role in reading genetic code throughout the body, not just in sex-specific domains.

Page and colleagues also examined the homology of human Y chromosome to that of various species, including mice, monkeys, and chickens. His work suggests that mice have the least-comparable Y chromosome (with only 7 of the human’s 17), whereas the genes on the rhesus monkey Y chromosome match every gene on the human Y. These findings highlight the challenges scientists encounter when translating basic research into clinical results, which can be complicated by variability between both species and sex.

Page is the director of the Whitehead Institute for Biomedical Research (Cambridge, Mass.), a professor at Massachusetts Institute of Technology (Cambridge), and a Howard Hughes Medical Institute Investigator, but he began his career in research at NIH in the laboratory of Robert T. Simpson (1977–1978). Simpson was a lab chief in the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and studied the role of histone-DNA interactions in chromatin structures. Their studies of the chromatin structure of genes was influenced by Marshall Nirenberg’s work. Page spent the first few minutes of his presentation reminding the NIH community of Simpson’s excellent mentorship. In fact, in Page’s first publication (J Biol Chem 255:3629–3637, 1980), the postdoctoral fellow was the first author, Page was last (senior) author, and Simpson wasn’t listed at all. “Bob’s rule was that he would not list his name on a paper unless he himself had done an experiment,” said Page.

Because the Y chromosome has lost so many genes over the course of evolution, some scientists think it may eventually become unnecessary in future generations. In response to these theories Page says, “Truth be known, I’ve spent the better part of my career defending the honor of the Y chromosome in the face of insults to its character and future prospects.”

REFERENCES
• J.A. Clayton, F.S. Collins, “Policy: NIH to balance sex in cell and animal studies,” Nature 509:282–283 (2014).
• D.W. Bellott et al. “Mammalian Y chromosomes retain widely expressed dosage-sensitive regulators,” Nature 508:494–499 (2014).
• A. Stein, D. Page. “Core histone associations in solutions of high salt,” J Biol Chem 255:3629–3637 (1980).


Marshall W. Nirenberg, a Nobel Prize–winning biochemist and geneticist, served the NIH community for 48 years as head of the section of biochemical genetics at NHLBI. The Marshall Nirenberg lecture series honors this distinguished researcher and others who have made significant contributions to the study of genomics. To watch a video of Page’s lecture from May 20, “Lost in Translation: Do Males and Females Read Their Genomes Differently?” go to http://videocast.nih.gov/launch.asp?19013. Another Nirenberg lecture is scheduled for September 30, 2015, with Timothy Ley from Washington University in St. Louis.