May 06, 2008

David Haussler, UC Santa Cruz

Evolutionary Genomics of the Human Genome

David Haussler's research lies at the interface of mathematics, computer science, and molecular biology. He develops new statistical and algorithmic methods to explore the molecular evolution of the human genome, integrating cross-species comparative and high-throughput genomics data to study gene structure, function, and regulation.

Haussler is credited with pioneering the use of mathematical computer models-hidden Markov models (HMMs), stochastic context-free grammars, and discriminative kernel methods-for analyzing DNA, RNA, and protein sequences. As a collaborator on the international Human Genome Project, his team posted the first publicly available computational assembly of the human genome sequence on the internet. Most recently, Haussler has focused on broadly exploring the functional elements of the human genome, primarily through interspecies comparisons. His findings have shed light on the possible functionality of what was once considered to be "junk" DNA, and his lab has identified and explored the function of genomic elements that have remained conserved for millions of years and then undergone rapid evolution in newer species.

Haussler received his PhD in computer science from the University of Colorado at Boulder. He is a member of the National Academy of Sciences and the American Academy of Arts and Sciences and a fellow of AAAS and AAAI. He has won a number of awards, including the 2006 Dickson Prize for Science from Carnegie Mellon University and the 2003 ACM/ AAAI Allen Newell Award.


With our ability to sequence entire genomes, we have for the first time
the opportunity to compare the genomes of present day species, and
deduce the trajectories by which they diversified from a common
ancestral genome. Starting with a small shrew-like ancestor in the
Cretaceous period approximately 100 million years ago, the different
species of placental mammals radiated outward, creating a stunning
diversity of forms from whales to armadillos to humans. From the genomes
of present-day species, it is possible to computationally reconstruct
what most of the DNA bases in the genome of the common ancestor of
placental mammals must have looked like. We can then deduce most of the
changes that lead to humans. In so doing, we discover how Darwinian
evolution has shaped us at the molecular level.

Because most random mutations to functionally important regions of DNA
reduce fitness, these changes usually disappear over time in a process
known as negative selection. From its unusually high conservation
between species, it is immediately evident that at least 5% of the human
genome has been under negative selection during most of mammalian
evolution, and is hence likely to be functionally important.
Protein-coding genes and structural RNA genes stand out among the
negatively selected regions because of their distinctive pattern of
restricted DNA base substitutions, insertions and deletions. However,
most of the DNA under negative selection in mammalian genomes, and
indeed vertebrate genomes in general, does not appear to be part of
protein-coding genes, and shares no sequence similarity with any DNA in
the genomes of invertebrates. Experimental evidence suggests that many
of these unclassified functional elements serve to regulate genes
involved in embryonic development.

Overlaid on the background of negative selection, we occasionally see a
short segment of widely conserved DNA that has rapidly changed in a
particular lineage, suggesting possible positive selection for a
modified function in that lineage. The most dramatic example of this in
the last 5 million years of human evolution occurs in a previously
unstudied RNA gene expressed in the developing cerebral cortex, known as
Human Accelerated Region 1 (HAR1). This gene is turned on only in a
select set of neurons, during the time in fetal development when these
neurons orchestrate the formation of the substantially larger cortex of
the human brain. It will be many years before the biology of such
examples is fully understood, but right now we relish the opportunity to
get a first peek at the molecular tinkering that transformed our animal
ancestors into humans.

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