CSHL’s Siepel compares Neanderthal genes to those of modern humans

CSHL’s Siepel compares Neanderthal genes to those of modern humans

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Two groups lived at about the same time. At around 40,000 years ago, one of them died off, while the other grew, changed and developed, becoming individuals who build airplanes, send text messages instantaneously over thousands of miles and harvest and replant crops that become high fructose corn syrup.

The winner was Homo sapiens, or wise man. Neanderthals, with their muscular frames, prominent brows and wide noses, came up short. Scientists on the winning team have been asking everything from how Neanderthals and Homo sapiens coexisted to why one group is still around, while the other left clues including fossils, cave drawings and genetic evidence.

Using mathematical and computational techniques to study DNA sequences, Adam Siepel, a professor at Cold Spring Harbor Laboratory, teams up with numerous collaborators to paint a clearer picture of what happened all those years ago.

“We try to reconstruct aspects of human history by comparing these sequences,” said Siepel, who joined CSHL this summer as chair of the new Simons Center for Quantitative Biology. The center, which started with a $50 million donation from the Simons Foundation, uses a combination of applied mathematics, computer science, theoretical physics and engineering to make sense of the explosion of data produced in labs on Long Island and throughout the world.

In his research, Siepel is trying to “make sense of how much gene flow” there was between Neanderthals and Homo Sapiens, he said. He is reconstructing models of ancient human demography based on a joint analysis of genome sequences from the two groups. He is currently seeing signatures of gene flow in both directions.
Scientists have been finding that the size of the Neanderthal population declined steadily over time. By using statistical models, researchers can look at patterns of genetic variation and can reconstruct the size of the population.

“There is a clear signal of the population shrinking over time, reaching precipitously low levels in anticipation of extinction,” Siepel said. This can be interpreted as signaling a steady decline, arguing against a cursory event where Neanderthals suddenly all died out.

In building these statistical models to reconstruct the Neanderthal story, scientists recognize numerous challenges. Researchers try to consider as many model violations as possible and cross check their results carefully, he added.

Siepel also conducts research into gene transcription, or the process through which DNA is copied into RNA, which is needed for a wide range of assembly and regulatory functions.

About a month ago, in conjunction with John Lis, a professor and former colleague of Siepel’s at Cornell University, Siepel published a paper in Nature Genetics in which the team showed that the first steps in transcribing genes and their regulatory elements are highly similar. This, he said, suggests that the differences between promoters and enhancers must occur downstream through mechanisms that cause an abrupt termination of transcription at enhancers.

This research and Siepel’s work on Neanderthals underscores the two major focuses of his lab: the process of transcriptional regulation and natural selection and human evolution. These disciplines “intersect in various ways,” Siepel said. He has, for example, studied the “influence of natural selection on transcription factor binding sites in the human genome.”

Siepel and his wife Amber bought a Victorian house in Huntington that has become a “fun project” for the family, which includes their 12-year-old daughter Ella and their 9-year-old son Charlie.

Siepel said he had never planned on living on Long Island, where he had a “vision of a big strip mall,” but he’s been “pleasantly surprised by Huntington” where he and the family can walk their two labradoodles along the streets by the harbor and visit nearby parks.

Siepel has enjoyed his first few months at Cold Spring Harbor Laboratory, where he said it is easy “to make changes.” The group has promoted Justin Kinney to assistant professor and Michael Schatz to associate professor. Siepel is also reviewing applications of researchers who are seeking to fill an open assistant professor job.

As for his work, Siepel said he is “fascinated by the idea of being able to reconstruct the past through the analysis
of present-day and fossil
genome sequences.”