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Gene activity sets humans apart from extinct hominids

Methylation differs between modern people, Neandertals and Denisovans

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2:00pm, April 17, 2014

BARE BONES  Differences between the skeletons of modern humans (back) and Neandertals (front) may stem from the way the groups use some genes involved in bone growth. Chemical modifications of DNA may have dialed down the activity of these genes in Neandertals, leading to stocky frames. 

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Extinct human cousins may have used some genes differently than modern people do, an analysis of Neandertal and Denisovan DNA reveals.

Compared with living people, Neandertals and ancient Siberians known as Denisovans had slightly different patterns of DNA methylation — a chemical modification of DNA that doesn’t change the information in genes but helps control gene activity. Evolutionary geneticist Liran Carmel of the Hebrew University of Jerusalem and colleagues found that the extinct hominids had lower levels of activity in a group of genes called the HOXD cluster, which governs limb growth. Low HOXD activity could account for Neandertals’ stocky build, the team reports April 17 in Science.

When and how strongly genes are turned on or off plays a big role in determining how an organism looks and behaves. To figure out whether modern humans use their genes differently from extinct human groups, the researchers had to find a record of gene activity in Neandertal and Denisovan DNA. The team combed previously sequenced ancient DNA for signs of methylation.

DNA methylation influences gene activity, usually by turning genes off. It is one of the most likely chemical marks to be preserved in the DNA record because it involves tacking a methyl group — a carbon atom surrounded by three hydrogen atoms — directly onto the DNA base cytosine. Over long periods of time, unmethylated cytosine spontaneously degrades into another base, uracil. But if the cytosine carries a methyl group, it transforms into thymine instead of uracil.

Carmel’s group looked for places in the ancient DNA where cytosines had morphed into thymines. The researchers then compared methylation patterns from the Neandertal and the Denisovan DNA with that of modern humans.

Overall, the three groups had similar DNA methylation patterns, the researchers found. But there were a few notable exceptions, including heavier methylation of genes in the HOXD cluster in the extinct hominids than in present-day people. Heavier methylation means those genes likely had lower activity. Low activity in this cluster has been previously linked in humans and mice to bigger bones, shorter limbs, broader elbows and knees, and more robust hands and fingers — all traits that distinguish Neandertals from modern humans.  

Denisovans had HOXD methylation patterns more similar to Neandertals’ than to modern humans’. That finding, along with Denisovans’ unique methylation characteristics, may help reveal what Denisovans looked like. Scientists have never found a complete Denisovan skeleton.

The technique for comparing methylation patterns may also help scientists learn what made modern humans successful while the other groups died out, says Sarah Tishkoff, an evolutionary geneticist at the University of Pennsylvania in Philadelphia.

“It’s an amazing technical feat,” Tishkoff says. “I’m impressed.”

She would also like to know whether Neandertal genes carried by some modern humans are methylated differently than other human versions of those genes are. If so, those changes may influence susceptibility to diseases.  

Other researchers say the work falls short of demonstrating biological relevance of the methylation patterns. “They haven’t really proven anything,” says Andrew Sharp, a genomics researcher at the Icahn School of Medicine at Mount Sinai in New York City. Scientists are still learning how chemical modifications known as epigenetic marks, such as DNA methylation, influence an organism’s development. It may be too soon to draw firm conclusions about how ancient hominids’ methylation affected their physiology, he says.

Environmental factors, such as nutrition and exercise, can also influence how genes are methylated, says Adrian Briggs, a molecular biologist at AbVitro, Inc., a biotechnology company in Boston. The gene activity difference the researchers uncovered may reflect the different lifestyle of Neandertals and Denisovans compared with that of present-day people. To find out if there is a meaningful biological difference encoded in the DNA methylation patterns, he says, scientists should conduct similar analyses on humans who lived at the same time as the Neandertals and Denisovans, some 50,000 years ago.

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