Highlights of 2010: What does it mean to be human?

by Erin Wayman
Thursday, January 5, 2012

The sequencing of the Neanderthal genome in 2010 helps scientists answer the age-old question

Calling someone a “Neanderthal” in the heat of an argument may not be such an insult after all. Last May, scientists announced they had completed a draft sequence of the Neanderthal genome, and found evidence that Neanderthals and modern humans interbred, likely sometime 80,000 to 50,000 years ago when modern humans left Africa and ventured into Eurasia — Neanderthal territory. Those encounters left a mark in the modern gene pool: As much as 4 percent of the DNA in people with European or Asian ancestry may be Neanderthal DNA, the researchers reported in Science.

The discovery of our intimate history with Neanderthals received tremendous press last spring, but another implication of the sequencing of the Neanderthal genome also deserves attention, says the study’s lead author, Richard Green, a genome biologist now at the University of California at Santa Cruz. “The hope is to be able to use the Neanderthal [genome] to shine a flashlight on recent evolution in humans,” he says.

Until now, scientists had been limited to comparing human DNA to the DNA of our closest living relative, the chimpanzee. It was impossible to know, however, when any detected difference arose in our evolutionary history: Did it occur right after the split with the chimp lineage (sometime about 8 million years ago), in australopithecines, in other now-extinct species in the genus Homo? Or is it a change only found in Homo sapiens? By comparing our genome to that of Neanderthals, researchers can now look for the genetic changes that make modern humans unique among all hominins.

Genomics 101

Three Neanderthals “volunteered” their DNA for genome sequencing. Green and colleagues, including geneticist Svante Pääbo of the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany, extracted the genetic material from three bone fragments dating to more than 38,000 years ago that were found in Croatia’s Vindija Cave. Because the bones were buried in a cool, dry environment, minute amounts of DNA were preserved, Green says.

After collecting the DNA and separating the Neanderthal DNA from microbial DNA that had accumulated in the bones over time, the researchers had to “read” the DNA sequence. DNA is made up of smaller subunits called nucleotides. Each nucleotide has a different chemical base: adenine (A), guanine (G), cytosine (C) or thymine (T). Reading DNA means figuring out which chemical base occurs at each nucleotide location. The sequence of chemical bases is important because different sequences of bases, called genes, code for different proteins in the body, such as collagen in skin or hemoglobin in blood.

The Neanderthal genome consists of roughly 3 billion nucleotides. It took the team three years to identify all those A’s, G’s, C’s and T’s. The feat was made possible by advances in techniques that allow for faster, more efficient sequencing, Green says. The technology has come so far in the past few years, he says, that if the team were to begin the genome project today, it would probably only take a matter of months.

Reading the Neanderthal’s genetic blueprints was only half the battle. The next crucial step was to compare the extinct hominin’s genetic code to that of modern humans and chimpanzees.

What makes us different?

Humans and chimpanzees share many of the same genes. But over the past 8 million years, genetic mutations have cropped up, changing how these genes function. For example, consider a hypothetical gene that codes for hairiness. At some point in human evolution, a mutation — say, an “A” replaced a “C” — altered that gene, causing humans to be less hairy than chimpanzees.

One task in the Neanderthal genome project was to look for such changes. In some instances, for a gene in which humans are different from chimpanzees, Neanderthals have the human version of the gene. Scientists assume that such gene variants must have evolved in the hominin lineage sometime after the split with the chimp lineage — but when those changes happened in hominin evolution can’t be inferred, Green says.

In other instances, chimpanzees and Neanderthals share the same version of a gene and modern humans are different. In these cases, scientists think the gene must have stayed the same throughout most of hominin evolution until modern humans split from Neanderthals (our closest hominin relative) sometime between 440,000 and 270,000 years ago, according to the team’s estimates. After the split, humans evolved the new version of the gene. Such changes are what make modern humans unique.

In all of their searching, the team found very few differences between humans and Neanderthals, Green says. Only 73 human genes have mutations that probably make the genes function differently from genes shared by Neanderthals and chimpanzees. Some of these differences, for example, occur in genes that code for characteristics related to skin, such as wound healing. But exactly how these changes affect the function or appearance of skin among the species is unknown.

“That’s a little bit frustrating,” Green says. “It’s very suggestive that maybe there would be some phenotypic difference, but we don’t know right now what that difference would be.” But the researchers do have a hunch on why these things changed: genetic drift — random evolutionary changes not directed by natural selection. “Mostly when you look at things that are different it’s just random background [changes],” he says, “which happen all the time.”

Other parts of the genome, however, point to regions that were shaped by natural selection. To look for such areas, the researchers studied parts of the genome that vary between modern people — spots, perhaps, where you might have a “T” but your neighbor has a “G.” Then they looked at these areas in Neanderthals to see if they also varied in these positions. The idea is that modern humans and Neanderthals both acquired certain genetically variable areas from their common ancestor. But some of this shared variation may have been “wiped clean” if a beneficial mutation arose in humans, such as a change that helped us to develop language or engage in complex social interactions, Green says. Over many generations, this particular genetic change would “sweep” through humans, erasing any genetic variability we had in this particular section of the genome. This is an example of natural selection in action. Then over time, new genetic variation would pop up in humans due to random changes; this genetic variability, however, would not be shared with Neanderthals, he says. This non-shared variation, therefore, marks areas previously affected by natural selection.

The team found 212 regions in the modern human genome that may have been shaped by natural selection. Some of these regions appear to be related to cognition and metabolism, Green says. In genetic studies of modern people, genetic changes to these regions have been associated with cognitive and metabolic abnormalities, such as autism, schizophrenia and diabetes. Therefore, some geneticists think these parts of the genome must somehow relate to cognition and metabolism because when something “goes wrong” in these areas, these abilities are affected.

But it may be premature to link these 212 regions to any particular function, notes Erik Trinkaus, an anthropologist at Washington University in St. Louis, Mo. “The reality is, with few exceptions … [the correlation between certain] genetic variants and medical issues [like autism] are just statistical associations,” he says — it’s not clear how those genetic variants are related to the abnormalities or how they actually work. Before scientists can figure out what genetic differences between modern humans and Neanderthals mean, he says, they need to better understand how the modern human genome itself works.

Another issue with identifying instances of natural selection is that it’s hard to find evidence for it in complex genetic traits, says Tim Weaver, a paleoanthropologist at the University of California at Davis. For example, some traits such as height are influenced by many parts of the genome, each having a small effect. “Selection may not strongly influence any single [part of the genome], and hence would not leave a detectable signature,” he says. Therefore, he says, the researchers' list of 212 regions affected by natural selection is likely an underestimate.

Despite all of the challenges that lie ahead, many researchers are excited about the prospects of working with Neanderthal DNA. “It’s the beginning stages of this,” says John Hawks, a paleoanthropologist at the University of Wisconsin at Madison. “It gives us the opportunity to look … at components of our biology that we had no ability to investigate before.” Weaver agrees. “The most interesting genetic studies of human uniqueness are those that address aspects … for which we have no direct fossil or archaeological evidence,” he says. Now researchers can investigate the evolution of human physiological systems, language and even cognition in new ways.

Perhaps the next step is to bring together the range of scientists who study human evolution — paleoanthropologists, archaeologists and geneticists — so the various lines of evidence can be integrated. “There needs to be a synthesis of what [paleoanthropologists and archaeologists] have done and what [geneticists] have done,” Green says. “We know in broad strokes what has happened in Neanderthal history, from what bones were found, where and from what time. The genetics now adds a wrinkle to this, and putting it together is something that needs to be done.”

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