15 Million Differences“Only one in 100 base pairs is different, which doesn’t sound like much,” says Pollard. “But when you consider that the genome is 3 billion base pairs long, that means there are 15 million human-specific letters of code that are not shared by the chimp. That’s more than anybody can look through manually.” To do a better job of finding out which of these spelling differences in DNA sequences are most important, Pollard has developed powerful computer software for comparing the complete genetic codes – or genomes. She’s analyzing not only the genomes of chimps and humans, but also the genomes of other vertebrates. She’s looking for hot spots along the genome where DNA has been evolving rapidly in humans. Already the top-scoring DNA hot spots to emerge from her number crunching have been shown by Pollard’s research team and other scientists to be important in brain development and limb formation. Other DNA differences affect the digestion of foods – not surprising when you consider how much our diets have diverged from chimp diets. When Pollard was a postdoctoral fellow at UC Santa Cruz (UCSC) she joined the Chimpanzee Genome Project. The consortium of dozens of researchers from universities around the world completed the map in 2005. Pollard was among the first scientists to begin comparing human and chimp DNA side by side. At that time only a handful of vertebrate genomes had been mapped out. Today scientists can compare genomic data from 50 different vertebrate species, Pollard says. Pollard, whose lab is all about computational ideas and experiments, collaborates with UCSF scientists who study diseases and work with biological materials. She also still collaborates closely with UCSC researchers, but now the banks of computers she relies on for analyzing massive amounts of data are housed at the UCSF Mission Bay site of the California Institute for Quantitative Biosciences (QB3).
DNA Changes Are the Ticking Clock of EvolutionTo measure advances in the ticking clock of evolutionary time, biological scientists like to count the accumulation of DNA changes. Specific DNA mutations that arise rarely in sperm and egg may sometimes over time spread among populations to become the fixed norm within a species. When these mutations become fixed in this way, most often it is by chance. In looking across the whole genome of a species over millions of years, changes are thought to accumulate at a slow and steady rate -- like the ticks marking the movement of a clock measuring evolutionary time. The greater the number of accumulated differences in DNA between human and another species, the farther back in time you have to go to find a common ancestor from which their evolutionary paths diverged. Chimps and the first hominids split about six million years ago. The much greater DNA differences among mammals suggest that the first mammals arose more than 200 million years ago. The dawn of the vertebrate era occurred more than 500 million years ago. If a specific mutation arises and becomes fixed in an unusually brief stretch of evolutionary time, it might signify that the change in DNA represents an important adaptation to a changing environment. On the other hand, Pollard says, DNA sequences with fewer changes than the rest of the genome predominate when mutations to the sequence are likely to be harmful. “Where chimp, monkey, mouse, cat, chicken and fish have the exact same letter at a certain place for hundreds of millions of years, it suggests that evolution wouldn’t let it change because it was needed for an important role in those animals,” Pollard explains.
Chimps, Neanderthals and HumansIn scouring the genomes of humans, chimps and other vertebrates, Pollard says, “Our algorithms look for regions of DNA that have been frozen throughout mammalian evolution, but where there is a relatively sudden burst of change in the human lineage.” Neanderthals are part of the human lineage, and the first Neanderthal genome was reported just a few months ago. The study of Neanderthal DNA might reveal changes in our own human ancestors that occurred even more recently. Information from the fossil record – and now from DNA -- suggests that that modern humans and Neanderthals diverged from a common ancestor roughly 600,000 years ago. The mapping of Neanderthal DNA is very exciting and important, Pollard says. Even so, she also notes that scientists don’t know much about how we differ from Neanderthals (called Neandertals by scientists). “Looking at a bone, you can’t determine if the Neandertal talked,” Pollard says. “Neandertals are our closest relatives that ever lived, as far as we know, but chimpanzees are our closest living relatives. It helps to be able to look at variations within chimps, their medical problems, and their behaviors.” Pollard starts each new research project by considering every bit of DNA equally – regardless of whether or not it’s a blueprint for a protein. Just a few years ago higher costs and the slower speeds of DNA decoding technologies and computational methods limited how much DNA researchers could compare. Scientists focused on differences in genes coding for known proteins of interest. Now researchers have learned that only about two percent of human and chimp DNA encodes genetic blueprints for proteins. They also know that most of the rest -- once referred to dismissively as “junk DNA” -- contains sequences that affect whether, where and when proteins are made – and in what combinations, a key factor in development. Pollard raises a question that scientists have been debating for decades: “Do you make a human by making different proteins or do you make one by taking the same building blocks and putting them together in a different way?” She says most scientists now believe the greatest potential for change arises from rearranging the building blocks. Some of the DNA formerly regarded as junk plays an important role in these rearrangements.
Emphasis on Rapidly Evolving DNAPollard and her collaborators are most interested in rapidly evolving bits of DNA that may play a role in determining human attributes such as language, the complexity of the brain’s cerebral cortex, hairless skin, fine motor coordination of the thumb and fingers, and the ability to easily digest certain foods we commonly eat. The top-ranking piece of human DNA to emerge form Pollard’s first comprehensive round of number-crunching differed from chimp DNA in 18 of 118 base pairs. In contrast, between chimp and chicken --a vertebrate that has evolved on a separate path from our evolutionary ancestors for about 300 million years – there were only two differences along the same DNA stretch. Pollard and colleagues named the DNA segment HAR1, for “human accelerated region.” The name refers to this DNA’s relatively fast evolution in our human ancestors. Pollard’s colleagues subsequently showed that HAR1 encodes RNA. But it’s not like the biology-textbook messenger RNA that is translated into protein. Instead the HAR1-encoded RNA has a more direct influence. There is more to learn about HAR1 RNA, but already a Belgian colleague of Pollard’s has shown that it is made in specific nerve cells within the brain’s developing cerebral cortex. The second highest-ranking DNA in Pollard’s screen, dubbed HAR2, is a switch regulating the activation of specific genes. Scientists have discovered that it plays a role in limb development. Differences between human and chimp may help explain why human can more precisely control finger and thumb movements.
Using Chimp DNA to Shed Light on Human DiseasePollard is interested in identifying differences between chimp and humans that may shed light on human diseases that do not similarly afflict chimps. These include certain infectious diseases, such as the HIV virus that causes AIDS, and heart disease. “Instead of always starting with differences in the genome and working up to identify the traits affected, we also can start with differences in anatomy, behavior or disease susceptibility and work back down to genomic differences,” she says. Students working in Pollard’s lab have begun focusing on heart disease. They are combing scientific databases and published research to identify regions of the genome that are associated with heart-disease risk. Then they will apply Pollard’s computational algorithms to the points within these larger genomic regions where chimp and human DNA differ, in order to gauge which DNA hot spots are most likely to contribute to the risk.
Related Links:Researchers Probe Links between Modern Humans and Neanderthals UCSF Science Café, September 4, 2009 UCSF's Jeff Wall Uses New Computational Methods to Search for Neanderthal Legacy & Disease Genes
UCSF Today, January 18, 2008 Gladstone Institute of Cardiovascular Disease UCSF Institute for Human Genetics California Institute for Quantitative Biosciences (QB3)