The genomes of male and female organisms behave differently, and this may have important influences on sex differences in disease, according to David Page, M.D., director of the Whitehead Institute. Page, who is also a Howard Hughes Medical Institute researcher at the Massachusetts Institute of Technology, was the latest speaker in the NIEHS Distinguished Lecture Seminar Series, on March 30.
Humphrey Hung-Chang Yao, Ph.D., who heads the NIEHS Reproductive and Developmental Biology Group, hosted the seminar. "His research has a profound impact on the understanding of the fundamental biology of sexual differences,” Yao said. “It also provides potential clues on why certain diseases occur more prevalently in one sex than the other.”
Innovations in evolution of sexual reproduction
Key innovations in the evolution of sexual reproduction include the pairing of genes and the exchange of hereditary information via sexual recombination. Page emphasized that development of sex chromosomes, like the X and Y chromosomes in humans, happened late in the evolution of sexual reproduction.
Page used the example of the turtle to illustrate how organisms lived before sex chromosomes developed. “Turtles don’t have any sex chromosomes,” said Page. “The male and female are genetically identical, which is to say that the existence of two sexes is purely epigenetic.” This means that the underlying genome is the same, and sex differences result from which genes are turned on and off.
Sex chromosomes evolved independently
Sex chromosomes have evolved independently many different times from autosomal chromosomes, or nonsex chromosomes, Page said. Mammals evolved to have X and Y sex chromosomes. In contrast to mammals, male birds have two matching chromosomes, and the female has two different chromosomes.
Page and colleagues decided to reconstruct the autosomal ancestor of these sex chromosomes in birds and mammals. “We thought we might understand the sex chromosomes even better if we were to reconstruct these ancestral autosomes,” he said.
They found that the human X chromosome and the chicken Z chromosome each retain 600-700 ancestral genes. By contrast, the human Y chromosome and chicken W chromosome evolved to be much smaller, retaining only about 20-30 ancestral genes. Page described these striking parallels between bird and mammal sex chromosome evolution as independent but concurrent experiments in nature.
The decaying Y chromosome?
A key question in studying the Y chromosome is how did the Y become so much smaller than the X? Page used an economics analogy to explain the mechanism of how the Y chromosome shrunk over time by suppressing genetic recombination with the X chromosome. “The Y chromosome stopped engaging in commerce with the X chromosome, to the point of an absolute shutdown of business with the X,” he explained.
Page also calmed fears that the Y chromosome will continue losing genes until it eventually disappears. By comparing the human Y chromosome with the chimp and rhesus monkey counterparts, Page showed that the Y chromosome is no longer losing genes. “Gene loss in the Y basically ended before we parted company with the ancestors of the rhesus monkey, 25 million years ago,” he said.
Sex chromosomes influence disease
Sex differences have been observed with many diseases. According to Page, women are more likely than men to be diagnosed with lupus. By contrast, men with dilated cardiomyopathy die on average 10 years earlier than women with the same disease.
However, despite these clear indications of their significance, the sex chromosomes have been excluded from 90 percent of genome-wide association studies, which look for genetic causes for diseases. Page emphasized the crucial need for studying sex differences.
“Until we arrive at an understanding of how male and female genomes differ and of how males and females read their genomes differently, we will continue to be surprised every time we encounter a sex difference in disease incidence, severity, or response to therapy.”
(Samantha Hall is a postbaccalaureate Cancer Research Training Award fellow in the National Cancer Institute Center for Cancer Research Laboratory of Toxicology and Toxicokinetics, housed at NIEHS.)