Heading the gene study at the Feinberg School of Medicine at Northwestern University are J. Larry Jameson, M.D., Irving S. Cutter Professor and chair of medicine, and Jeffrey Weiss, research associate professor of medicine.
The study is one of four collaborative projects funded by the National Institute of Child Health and Human Development to identify mutations in mice that cause developmental and fertility defects and to characterize the mutations responsible for these defects. The research projects are part of the NIH's initiative to determine the function of mammalian genes.
To identify mutations in the sex determination genes that cause sex reversal, Jameson and Weiss will employ a technique known as genome-wide mutagenesis. The process uses a chemical called ENU (N-ethyl-N-nitrosourea) to create a broad spectrum of point mutations throughout the mouse genome that are passed on to subsequent generations. The various mutations introduced by ENU mutagenesis are then studied and, once there is evidence of a single gene mutation for a given trait, the researchers can pinpoint the gene using positional cloning.
The Northwestern investigators will screen tens of thousands of mice harboring random, chemically induced mutations for sex reversal, characterize the mutations in detail and, it is hoped, find the responsible genes. This will involve comparing phenotypic (appearance) sex to genotypic sex (presence or absence of the male-determining factor Sry) in the genome.
The mice progeny from the sex determination/sex reversal study will be made available to the scientific community for future research. Weiss believes that the Northwestern study will reveal much-needed information about how the genes regulate gonad development as well as about gonadal dysgenesis and infertility in humans.
They also will make the animals available to the scientific community for future research.
"Defects in these genes can presumably cause not only overt sex reversal – XY females and XX males – but also much milder manifestations of sex reversal disorder," Weiss said.
Thus far, Jameson and Weiss have focused on the Sry gene and another gene called DAX1 that also is believed to play an important in role in development of the testes.
The new gene research project will build on the ENU mutagenesis program developed at the NIH-funded Neurogenomics Center at Northwestern University by Joseph S. Takahashi, who cloned the first mammalian circadian gene, Clock. Takahashi, who directs the center, is professor of neurobiology and physiology and of neurology.
Collaborating with the Feinberg School researchers on these projects are leading genetic scientists from Sloan Kettering Institute for Cancer Research, New York; Brigham and Women's Hospital, Boston; and Baylor College of Medicine, Houston.
KEYWORDS: sex reversal, gonadal dysgenesis, infertility