David Haussler

Howard Hughes Medical Institute, UC Santa Cruz

Ultraconserved elements, living fossil transposons, and rapid

bursts of change: reconstructing the uneven evolutionary history of the

human genome.

Abstract

Comparison of the human genome with the genomes of the mouse, rat,
dog, cow, and other mammals reveals that at least 5% of the human genome
is under negative selection. Negative selection occurs in important
functional segments of the genome where random (mostly deleterious)
mutations are rejected by natural selection, leaving them more similar
between species than would be expected under a neutral substitution
model. Protein coding regions account for at most 1/3 of the segments
that are under negative selection. In fact, the most conserved segments
of the human genome do not appear to code for protein. These
"ultraconserved" elements, of length from 200-800bp, are totally
unchanged between human mouse and rat, and are on average 96% identical
in chicken. The function of most is currently unknown, but we have
evidence that many may be distal enhancers controlling the expression of
genes involved in embryonic development. Other ultraconserved elements
appear to be involved in the regulation of alternative splicing.
Evolutionary analysis indicates that many of these elements date from a
period very early in the evolution of vertebrates, as they have no
orthologous counterparts in sea squirts, flies or worms. At least one
group, involving a conserved enhancer of one gene and an ultraconserved
altspliced exon of another, evolved from a novel retrotransposon family
that was active in lobe-finned fishes, and is still active today in the
"living fossil" coelacanth, the ancient link between marine and land
vertebrates.

In contrast with the slowly changing ultraconserved regions, in other
areas of the genome recent genetic innovations that are specific to
primates or specific to humans have caused relatively rapid bursts of
localized changes, possibly through positive selection. Via simulation,
we estimate that most of the DNA sequence of the common ancestor of all
placental mammals, which lived in the last part Cretaceous period about
100 million years ago, can be predicted with 98% accuracy. We recently
reconstructed and entire chromosome arm from the genome of this ancient
species, and are currently working on a full genome reconstruction.
Given this as a basis, and enough well-placed primate genomes to
reconstruct intermediate states, we should eventually be able to
document most of the genomic changes that occurred in the evolution of
the human lineage from the placental ancestor over the last 100 million
years, including innovations that arose by positive selection.

References

http://genome.ucsc.edu/goldenPath/pubs.html

Credits

UCSC Genome Bioinformatics Group and Genome Laboratory;
enhancer work is collaboration with Eddy Rubin lab at Berkeley,
reconstruction project is collaboration with Webb Miller group at Penn
State, Mathieu Blanchette at McGill, and Eric Lander group at the Broad
Institute.

Biography

Dr. Haussler is a professor of biomolecular engineering UC Santa Cruz,
where he directs the Center for Biomolecular Science & Engineering. He
is an Investigator with the Howard Hughes Medical Institute. He serves
as scientific co-director for the California Institute for Quantitative
Biomedical Research (QB3), and he is a consulting professor at both
Stanford Medical School and UC San Francisco Biopharmaceutical Sciences
Department. He is a fellow of both AAAS and AAAI. He received his B.A.
degree in mathematics from Connecticut College, an M.S. degree in
applied mathematics from California Polytechnic State University at San
Luis Obispo, and his Ph.D. degree in computer science from the
University of Colorado at Boulder.

By focusing on scientific interactions between computer scientists and
molecular biologists, Dr. Haussler has played a leading role in
developing the new field of computational biology. His work laid the
foundation for the modern probabilistic approach to detecting and
analyzing the biological components of the human genome. His
collaborations led to algorithms to assemble the first public working
draft of the human genome and posting it on the World Wide Web. After
assembling the genome, his group went on to create a web-based
"microscope" (The UCSC Genome Browser, found at www.genome.ucsc.edu)
that allows researchers to view the genome and its bioinformatic
analysis at any scale from a full chromosome down to an individual
nucleotide. Exploring the vast and often uncharted terrain of the 3
billion DNA bases of the human genome has for biomedical researchers
been akin to taking the first steps in exploring a new continent. Using
the UCSC Genome Browser as a platform, Haussler explores the molecular
evolution of the human genome.

Honors

Research and Development Magazine Scientist of the Year in 2001,
Distinguished Scientist Award from the Clinical Ligand Assay Society in
2002, Tech Award Laureate, San Jose Tech Museum of Innovation in 2003,
elected as a Fellow of the American Association for the Advancement of
Science in 2003, the Allen Newell Award from the Association for
Computing Machinery and the American Association for Artificial
Intelligence in 2004, University of Colorado Distinguished Engineering
Alumni Award in 2005, Carnegie Mellon^Òs Dickson Prize in Science in 2006.