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UCSF's Jeff Wall Uses New Computational Methods to Search for Neanderthal Legacy & Disease Genes

By Jeffrey Norris

Jeff Wall

Each year, Jurassic Park seems less like science fiction. Scientists are decoding woolly mammoth DNA. They also are decoding DNA from an extinct species much closer to us in genetic makeup - the Neanderthal. Neanderthals generally are regarded as a distinct species within our own genus, Homo. The first fellow-hominid fossil discovery in 1856 in Germany's Neander Valley helped revolutionize scientific thinking about human origins and evolution. Today, new Neanderthal studies might again upend thinking about who we are and where we came from. It turns out that the Neanderthals might not be extinct, after all. Some Neanderthal genes may live on within us. That's to say, long ago, ancestors of modern Homo sapiens might have mated with Homo neanderthalensis.

Sexual Adventurers of the Paleolithic

Neanderthals and Homo sapiens evolved into separate species from a common ancestor roughly half a million years ago. Neanderthals moved to Europe early on, but vanished from the continent almost 30,000 years ago. Homo sapiens did not settle in Europe until perhaps 45,000 years ago. Thus far, few Neanderthal remains show signs of DNA. The fossils found to have DNA only have small amounts, in molecular bits and pieces. There is more DNA contamination than true Neanderthal DNA in the fossils. Much of the contamination dates to the first decaying of the remains. "There's contamination in the fossilized bone from bacteria, pollen and other environmental DNA," says mathematician and evolutionary geneticist Jeff Wall, PhD, of UCSF's Institute for Human Genetics. Additional contamination is due to more recent exposure and fossil handling by modern-day discoverers, researchers and curators, he adds. But by using recent technical advances, scientists now can decipher genetic code from the meager bits of DNA that can be extracted from fossils. The work requires careful handling of the archaic material, as well as sensitive lab techniques. But in addition, scientists with a mathematical bent, like Wall, have worked to develop necessary computational methods. These methods can help correct for contamination and decay and allow for detailed comparisons of DNA between individuals and species. This past October, Wall and UCSF postdoctoral fellow Sung Kim, PhD, shed new light on the first two major research reports on Neanderthal genes. Researchers are hoping those studies of DNA from cell chromosomes will lay the groundwork for more ambitious studies of the Neanderthal genome. But there was an early glitch. "One group presented results that were consistent with what we thought we knew before," Wall says. "At the same time, the other group presented results that suggested that Neanderthal DNA looked very similar to modern human DNA - much more similar than we would have expected, based on every previous genetic, anthropological and archaeological study that had been done." The unexpected findings were presented by a team led by Svante Pääbo, PhD, of the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany. Edward M. Rubin, MD, PhD, of the US Department of Energy Joint Genome Institute, in Walnut Creek, led the other research team. Both groups spelled out a very fragmentary genetic code of a Neanderthal, starting with samples from the same bone. One interpretation of Pääbo's data was that the two species exchanged genes in Europe. However, Wall's careful study concluded that the more provocative data were instead the result of a failure to detect and account for new contamination of the sample. Despite the false alarm, Wall would not be surprised at all if H. neanderthalensis and H. sapiens did in fact interbreed. And it would not take much interbreeding for Neanderthals to sow a significant impact on the modern human genome, he says. "It only takes a few migrants in each generation to keep the gene pools of two populations tied to each other. Interbreeding rates on the order of one in 1,000 or less can still cause a substantial amount of genetic exchange."

Neanderthals and Homo Sapiens Adapted via Different Genes

Despite common biases, it is not clear that our Homo sapiens ancestors - who arrived in Europe with more advanced tools - were simply superior to Neanderthals, Wall suggests. "We do know that Neanderthals' brains on average were as large as, or larger than, modern human brains. We know they were able to live in a very harsh climate for a very long time, probably a result of genetic adaptations conducive to living in cold weather." If the two hominid groups did interbreed, advantageous genes could have flowed both ways, and could still be present in modern humans, Wall says. But distinguishing Neanderthal DNA from modern human DNA may be tough, even when today's human handlers do not add more DNA contamination to fossil DNA. Fortunately, Wall is not reliant on ancient DNA for most of his research. Wall and others are exploring new mathematical techniques for tracking and analyzing ancestry and genetic variability through the course of evolution. Wall compares and analyzes data from the genomes of living humans and closely related primates, as well as the newly available data from ancient genes. "It's possible to look at DNA of the people alive today and to look indirectly for signs their ancestors may have interbred with Neanderthals many years ago," Wall says. "Part of what I do is to try to develop those indirect methods. But it's easier when you have actual Neanderthal fossils from which you can get good DNA and analyze it." Even if a compelling statistical case for interbreeding emerges from DNA study, it does not necessarily mean that researchers will be able to identify the specific genes in living human populations that were contributed by Neanderthals, Wall says.

Genetics of Eye Disease Among Mexican Americans

Wall is developing computational methods that he will apply to data from the genomes of humans and apes. He will explore ideas about human evolution, and about how migrations and changes in population size and changes in specific genes arose over time among different living and extinct populations. In separate research, Wall is exploring the use of similar methods to better track disease susceptibility in genetically distinct, living populations. For his most recent study, he is trying to identify genes associated with risk for eye diseases, such as age-related macular degeneration and diabetic retinopathy. He is focusing on a Mexican American population in Los Angeles. The structures of the genomes of distinct populations have characteristics that can be exploited in searches for risk genes, Wall believes. For instance, most Mexican Americans have Native American as well as European ancestors. It was not until the arrival of the Spanish that these very distinct populations began to mix for the first time. "When we look at their genomes, most are going to be like mosaics," Wall says. "There will be chunks of ancestry inherited from native populations, and chunks inherited from Europeans. Many of these chunks are pretty large. "By starting with the knowledge that this is how genetic variability is structured within this population, it may make it easier to track down genetic factors that contribute to disease."

Related Links:

Inconsistencies in Neanderthal Genomic DNA Sequences Jeffrey Wall and Sung Kim, PloS Genetics Neanderthal Genome Svante Paabo, Nature Neanderthal Genome Edward Rubin, Science UCSF Institute for Human Genetics