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David Haussler, speaking at the first Ó³»­´«Ã½ Annual Distinguished Lecture in Computational Biology on May 15
Photo by Maria Nemchuk

Whether important or inconsequential, each morsel of human DNA has a history and, perhaps, a purpose. Determining the purpose of every building block, or "base," of the human genome — some 3 billion in total — is one of the monumental tasks now facing scientists. In the first Ó³»­´«Ã½ Annual Distinguished Lecture in Computational Biology on May 15, David Haussler chronicled his team's recent efforts to accomplish this task.

Ó³»­´«Ã½ director Eric Lander introduced Haussler, a professor at the University of California at Santa Cruz (UCSC) and a Howard Hughes Medical Institute investigator who has pioneered the use of mathematical and computational methods for exploring genomes. In particular, Lander noted Haussler's early fondness for science that transcends the laboratory bench. That fondness has translated into a scientific career punctuated by several groundbreaking contributions. As part of the Human Genome Project, Haussler helped to assemble a working draft of the genome sequence that could be easily accessed and navigated by other researchers. His group also developed the UCSC genome browser, a key web-based tool for visualizing genomic data from humans and a variety of other organisms, which is now a veritable fixture in laboratories worldwide.

Now, in the years following the completion of the human genome, scientists, including Haussler, are wrestling with the next big challenge: to dissect the biological function of the human genetic code, down to the last base. In his talk, "Reconstructing 100 million years of human evolution," Haussler described ongoing efforts in his laboratory in collaboration with others to search the evidence contained in other animal genomes. As one animal species gradually evolves into another, important DNA sequences are typically shielded from genetic mutations — an evolutionary process known as negative selection — and tend to remain unchanged. Therefore, genetic preservation across several species can be a sign of a region's functional significance.

Haussler's group is currently working to detect and analyze these signs within the human genome. Sporadic mutations, which somehow escape evolution's negative influence, are particularly noticeable against the backdrop of DNA sequence conservation. These differences often spell out significant changes in gene function and therefore, can provide clues about the inner workings of the human genome. To shed light on the genetic underpinnings of human evolution, Haussler's group is also searching for such genetic changes, particularly those that have accumulated exclusively in humans relative to other animal lineages. To bolster these and other efforts, Haussler and his team are reconstructing the genome sequences of several ancient animal species that no longer walk the earth. These ancestors sit at major branch points in the evolutionary tree and are more closely related to species alive today, which lie at the ends of the tree's branches, than other existing species.

As part of this large-scale project — "DNA paleontology," according to Haussler — scientists at the Ó³»­´«Ã½, as well as other genome research centers, are sequencing the genomes of several different mammalian species. In rising to meet the "grand challenge of human molecular evolution," Haussler noted that we are gaining deep insights into how the genome works. We are also finding that much remains to be learned from its unsolved evolutionary mysteries.