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James Noonan |
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| Assistant Professor |
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B.S. State University of New York, Binghamton, 1997
Ph.D. Stanford University, 2004
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| Research Interests: | |
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Human Evolution
Evolutionary Dynamics of Gene Regulation
Synthetic Biology
Applications of Ultra-High Throughput Sequencing Technologies
Comparative and Functional Genomics in Vertebrates
Our laboratory studies the genetic mechanisms that underlie the profound phenotypic divergence of humans from other primates. We use a combination of computational and experimental approaches to identify and characterize functional sequences with possible human-specific adaptive sequence changes, focusing on gene regulatory elements.
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| Current Research: | |
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| All uniquely human traits, including our talents for language and abstract reasoning, are ultimately due to changes in our genome that occurred in the ~6 million years since the human-chimpanzee divergence. Most of these changes have yet to be discovered. It has long been thought that differences in gene regulation, rather than in structural genes, contribute to many biological differences between humans and the great apes. Comparative genomic analyses, by revealing hundreds of thousands of conserved sequences in the human genome that do not appear to encode proteins, have provided the means to test this hypothesis. Results from many efforts to functionally characterize these conserved noncoding sequences suggest that they are rich in gene regulatory elements. We are building on these insights to investigate how human-specific evolutionary modifications in such elements influence human biology and disease.
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| We recently identified 992 conserved noncoding sequences that are evolving rapidly on the human lineage. The elements we discovered are disproportionately associated with genes involved in neuronal migration, adhesion, axon guidance and synapse formation, suggesting that cis-regulatory changes in human evolution may have contributed to changes in brain development and function. We have also identified several loci with a significant excess of rapidly evolving noncoding sequences. These loci may have been hotspots of positive selection throughout human evolution.
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| We are currently using in vitro quantitative approaches and in vivo mouse transgenic assays to examine particular elements in our dataset for human-specific gene regulatory functions by comparison to chimpanzee and rhesus orthologs. We have shown that several of the most rapidly evolving noncoding sequences in the human genome function as developmental enhancers in transgenic mice. These experiments have also provided evidence of functional differences between human and chimpanzee orthologs. We are dissecting a number of elements in detail using a synthetic approach, in which subsets of the human-specific sequence changes in each element are transferred into the chimpanzee enhancer sequence. This will allow us to precisely identify the sequence changes conferring the novel human function, and will provide insight into how adaptive processes can alter cis-regulatory codes. Our long-term goal is to model the phenotypic effect of human-specific sequence change in selected elements by generating “humanized” mice, using homologous recombination to replace endogenous mouse elements with their human orthologs. We anticipate that these studies will contribute to our understanding of how uniquely human traits arose and how they are encoded in the genome.
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| Representative Publications: | |
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Noonan JP, Coop G, Kudaravalli S, Smith D, Krause J, Alessi J, Chen F, Platt D, Pääbo
S, Pritchard JK, Rubin EM. Sequencing and analysis of Neanderthal genomic
DNA. Science 314: 1113-1118 (2006).
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Prabhakar S*, Noonan JP*, Pääbo S, Rubin EM. Accelerated evolution of
conserved noncoding sequences in humans. Science 314: 786 (2006).
*Equal contribution
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Noonan JP, Hofreiter M, Smith D, Priest JR, Rohland N, Rabeder G, Krause J, Detter
JC, Pääbo S, Rubin EM. Genomic sequencing of Pleistocene cave bears. Science
309: 597-599 (2005).
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Noonan JP, Grimwood J, Danke J, Schmutz J, Dickson M, Amemiya CT, Myers RM.
Coelacanth genome sequence reveals the evolutionary history of vertebrate genes.
Genome Res. 14: 2397-2405 (2004).
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Noonan JP, Grimwood J, Schmutz J, Dickson M, Myers RM. Gene conversion
and the evolution of protocadherin gene cluster diversity. Genome Res. 14: 354-366 (2004).
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Noonan JP, Li J, Nguyen L, Caoile C, Dickson M, Grimwood J, Schmutz J, Feldman
MW, Myers RM. Extensive linkage disequilibrium, a common 16.7-kilobase
deletion, and evidence of balancing selection in the human protocadherin ? cluster.
Am J Hum Genet. 72: 621-635 (2003).
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