Cutthroat competition in the testes might explain the unexpected prevalence of a mutation that halts skull growth and fuses fingers and toes. The genetic glitch seems to give some sperm precursors an advantage by speeding their division, a new study suggests.
Apert syndrome afflicts one in every 70,000 children who are born with fused bones in their heads, hands, and feet. That incidence, although low, is 100 to 1000 times higher than the average mutation rate. The fault occurs at one spot on a single gene on chromosome 10 and is linked to the father's age. Researchers first theorized that the site might be susceptible to genetic errors, a mutation "hotspot." More recent studies posited that the mutation might instead confer some advantage to germline cells--sperm progenitors--in natural selection.
Computational biologist Peter Calabrese of the University of Southern California (USC) in Los Angeles developed mathematical simulations of how the mutations might arise and develop in each scenario. If the hotspot model held true, the mutant cells would appear evenly distributed throughout the testes. If the selection model proved right, mutants would appear in clusters, with few mutated cells in between. To test the scenarios, USC molecular geneticist Norman Arnheim and colleagues dissected testes from two deceased organ donors in their 50s and 60s–when men are 10 times as likely to carry and pass along the mutation as men under 30. The team compared the distribution of mutated germline cells with Calabrese's simulations. They found the mutants clustered together, just as in the selection model. The results, published online this week in PLoS Biology, suggest that the mutation makes these cells better at cloning themselves or surviving than are nonmutant germline cells. The accumulation of these mutant cells explains why the risk of Apert syndrome is higher than expected and increases with the father's age.
Arnheim hopes that the results will change the way geneticists think about human mutations. "You can have a mutation that causes a serious, detrimental condition," he says, "and yet the mutation has a selective advantage."
The findings offer the first answer to the century-old puzzle of genetic conditions linked to older fathers, like Apert syndrome and achondroplasia dwarfism, says James Crow, a geneticist at the University of Wisconsin, Madison. "It's nice to have that cleared up," he says. "And it's a beautiful idea … new and striking and remarkably interesting."
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