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Science 12 December 2003:
Vol. 302. no. 5652, pp. 1960 - 1963
DOI: 10.1126/science.1088821
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Reports

Inferring Nonneutral Evolution from Human-Chimp-Mouse Orthologous Gene Trios

Andrew G. Clark,1 Stephen Glanowski,3 Rasmus Nielsen,2 Paul D. Thomas,4 Anish Kejariwal,4 Melissa A. Todd,2 David M. Tanenbaum,5 Daniel Civello,6 Fu Lu,5 Brian Murphy,3 Steve Ferriera,3 Gary Wang,3 Xianqgun Zheng,5 Thomas J. White,6 John J. Sninsky,6 Mark D. Adams,5* Michele Cargill6{dagger}

Even though human and chimpanzee gene sequences are nearly 99% identical, sequence comparisons can nevertheless be highly informative in identifying biologically important changes that have occurred since our ancestral lineages diverged. We analyzed alignments of 7645 chimpanzee gene sequences to their human and mouse orthologs. These three-species sequence alignments allowed us to identify genes undergoing natural selection along the human and chimp lineage by fitting models that include parameters specifying rates of synonymous and nonsynonymous nucleotide substitution. This evolutionary approach revealed an informative set of genes with significantly different patterns of substitution on the human lineage compared with the chimpanzee and mouse lineages. Partitions of genes into inferred biological classes identified accelerated evolution in several functional classes, including olfaction and nuclear transport. In addition to suggesting adaptive physiological differences between chimps and humans, human-accelerated genes are significantly more likely to underlie major known Mendelian disorders.

1 Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853, USA.
2 Biological Statistics and Computational Biology, Cornell University, Ithaca, NY 14853, USA.
3 Applied Biosystems, 45 West Gude Drive, Rockville, MD 20850, USA.
4 Protein Informatics, Celera Genomics, 850 Lincoln Centre Drive, Foster City, CA 94404, USA.
5 Celera Genomics, 45 West Gude Drive, Rockville, MD20850, USA.
6 Celera Diagnostics, 1401 Harbor Bay Parkway, Alameda, CA 94502, USA.


* Present address: Department of Genetics, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, USA.

{dagger} To whom correspondence should be addressed. E-mail: michele_cargill{at}celeradiagnostics.com

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