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Born to Run Long Distance

10 September 2007 (All day)
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Kathryn North

Going the distance.
When alpha-actinin-3 (red staining) is missing, fast muscle fibers turn into slow ones.

Marathon running might be in some people's genes, according to a new study, which shows that a genetic mutation that boosts muscle endurance has spread widely in some human populations.

There are two types of skeletal muscle fibers. Fast fibers, which use sugars for fuel and do not require oxygen, kick in for tasks that require maximum force and quick action, such as sprinting. Slow fibers, which employ oxygen-using (or aerobic) pathways, power activities that require endurance, such as long-distance running. A protein called alpha-actinin-3 is made mostly by fast fibers and is implicated in their capacity for rapid force generation. About 18% of people of European descent do not produce the protein at all due to mutations in both their copies of the gene ACTN3, which codes for alpha-actinin-3. Previous studies have shown that endurance athletes such as long-distance runners have higher frequencies of this mutation, whereas sprinters and athletes in other sports that require quick muscle strength have lower frequencies.

Researchers led by geneticist Kathryn North of the Institute for Neuromuscular Research in Sydney, Australia, decided to investigate how ACTN3 affects muscle activity so dramatically. The team first created mice that lacked a functioning gene. The researchers found that the mice's fast fibers contained much higher levels of several enzymes associated with aerobic metabolism, suggesting that the absence of alpha-actinin-3 caused the fast fibers to work more like slow fibers. Moreover, on a treadmill, the altered mice could run about 33% farther before becoming exhausted than could control rodents, indicating that the ACTN3 mutation enhances endurance.

To trace the gene's evolutionary history in humans, the team sequenced a segment of DNA that includes ACTN3 in 96 people from Europe, Asia, or Africa. Earlier work had found that the frequency of the mutant gene varies in human populations, ranging from an average of 10% in Africans to about 50% in Europeans and Asians. North and her co-workers found that the region surrounding the mutant version of the gene showed less variability than did other parts of the genome, a sign of positive natural selection. The authors suggest that the mutation might have had an adaptive advantage for modern humans, who migrated out of Africa into Europe and Asia beginning about 60,000 years ago. The research appeared online 9 September in Nature Genetics.

Michael Nachmann, a geneticist at the University of Arizona, Tucson, says that the team's experiments are "a great test" of ACTN3's role and support the conclusion that the mutation "affects some kind of athletic ability." Marcio Pie, an evolutionary biologist at the Federal University of Paraná in Curitiba, Brazil, calls the study a "beautiful piece of work." Although North and her colleagues declined to speculate on why the frequency of the mutation differs among human groups and what its adaptive role might have been, Pie says that this question "would be interesting to explore further."

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