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GEN News Highlights : Sep 3, 2013

It’s a Boy? Y Chromosome Presence No Guarantee

Scientists at Case Western Reserve University report that the gene responsible for determining that a developing human embryo will ultimately be a male appears to be, from an evolutionary point of view, unreliable. The team, which worked with the SRY gene, published their results in an article (“Inherited human sex reversal due to impaired nucleocytoplasmic trafficking of SRY defines a male”) in this week’s issue of the Proceedings of the National Academy of Sciences.

SRY initiates the genetic program that leads to the formation of testes and the production of fetal testosterone. To investigate this gene, Michael Weiss, M.D., Ph.D., and colleagues at the university’s school of medicine, studied families in which a daughter shares the same Y chromosome as her father. Females usually develop with an XX chromosomal pair, but, in these families, the father instead produced a daughter with an XY pair. This occurs during fetal development when the SRY gene’s master switch fails to trigger. Internal female tissues, such as the uterus and fallopian tubes, continue to develop but are dysfunctional and infertile.

“Yet the father has the same Y chromosome and the same mutation as the daughter,” noted Dr. Weiss. “And since he is a fertile male, we know that the switch must be poised right at its edge.”

The team decided to measure the biochemical environment that affects the threshold of the SRY master switch. “Our expectation was that we’d find that [a change in the biochemical environment would involve] a factor of 100 or more to alter development,” said Dr. Weiss. “But what we found was that the SRY threshold, as probed in father-daughter pairs, is only a factor of two.”

Therefore, human males actually develop near the edge of sexual ambiguity. This means that, unlike the robust genetic programs which develop other essential processes like heart function, the SRY gene master switch is particularly vulnerable to change. It only takes a slight deviation from the normal process to dramatically alter fetal sexual development.

“A general principle of developmental biology is that evolution favors reliability,” Dr. Weiss explained. “Robust switches ensure that our genetic programs give rise to a consistent body plan to ensure that babies have one heart, two arms, ten fingers, and so forth.”

Traditional viewpoints emphasize the uniformity of this process. The new research indicates that male sexual development is less stable than other genetic programs.

Given the importance of sexual reproduction to the survival of a species, why do human SRY genes function so close to the boundary of infertility? The idea of an unreliable master switch might appear paradoxical, but a growing body of research suggests that it might be an evolutionary necessity.

“We speculate that genetic variation in fetal testosterone production influenced the evolution of eutherian mammals, especially species (like humans and mice) that evolved within social groups,” wrote the researchers in PNAS. “Implicit in this view are connections between genotype, development, differentiation of the central nervous system, and complex behaviors, including empathy and other social competencies as defined in longitudinal studies of human fetal testosterone exposure.”

“We have this tenuous switch on the Y chromosome, and we anticipate that its gift to humanity is variability in the pathway of male development from its earliest stages,” added Dr. Weiss. “The essential idea is that our evolution has favored a broad range of social competencies. In prehistory, this range would have given a survival advantage to communities enriched by a diversity of gender styles.”

The implications of Dr. Weiss’s research suggest that elements of human culture, which had been assumed to be psychological or cultural, may be biological, instead. Therefore, human evolution would not have been dependent on consistency and homogeneity, but on their exact opposite.