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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 what research was all about 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, Page identified a genetic probe that could be used to distinguish the Y chromosome from the X. 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 which part of the Y chromosome makes a male. When he joined the Whitehead Institute, Page broadened his study of how genes on the Y chromosome influence male development and fertility—and 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 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 over and pair with itself, the Y chromosome could use the pristine gene copy to overwrite the errors in the defective version. He also identified a gene that accounts for the most common form of male infertility, a finding that has interesting ramifications for the future of human reproduction. Using a procedure called ICSI—intracytoplasmic sperm injection—doctors can often obtain a few isolated sperm cells from otherwise infertile individuals and then inject them directly into a female oocyte to achieve fertilization. Unfortunately, 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.
Dr. Page is also Professor of Biology at the Massachusetts Institute of Technology, an Associate Member of the Broad Institute, and Director of the Whitehead Institute for Biomedical Research.
RESEARCH ABSTRACT SUMMARY:
David Page studies the human sex chromosomes and genes that play critical roles in the making of sperm and eggs.
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Photo: Sam Ogden/Whitehead Institute
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