SNP Potential

For this article, Jennifer Fisher Wilson interviewed Eric S. Lander, professor of biology and director of the Whitehead/Massachusetts Institute of Technology Center for Genome Research. Data from the Web of Science (ISI, Philadelphia) show that the Hot Papers are cited 50 to 100 times more often than the average paper of the same type and age. D.G. Wang, J.B. Fan, C.J. Siao, A. Berno, P. Young, R. Sapolsky, G. Ghandour, N. Perkins, E. Winchester, J. Spencer, L. Kruglyak, L. Stein, L. Hsie, T. Topaloglou, E. Hubbell, E. Robinson, M. Mittmann, M.S. Morris, N.P. Shen, D. Kilburn, J. Rioux, C. Nusbaum, S. Rozen, T.J. Hudson, R. Lipshutz, M. Chee, E.S. Lander, "Large-scale identification, mapping, and genotyping of single-nucleotide polymorphisms in the human genome," Science, 280:1077-82, 1998. (Cited in more than 205 papers since publication) It wasn't until recently that researchers realized the potential of SNPs. "We first proposed the idea of creating a comprehensive catalog of all common human genetic variations in a paper in 1995,"1 says Eric S. Lander, professor of biology and director of the Whitehead/Massachusetts Institute of Technology Center for Genome Research. "We realized that the fact that the human population rapidly expanded from a small founding population some 7,000 generations ago in Africa meant that all humans must be closely related, and that it should be possible to recognize and trace the ancestral alleles and chromosomal segments in the population. In effect, it should be possible to study the human population as if it were one very large family." In 1998, a group headed by Lander from the Whitehead Institute and Robert Lipshutz from Affymetrix Inc. of Santa Clara, Calif., published this paper, the first research demonstrating that it is possible to identify, characterize, and use the thousands of SNPs found in organisms for genetic studies. "In the wake of the paper, there has been an explosion of work on SNPs," according to Lander. Photo: Sam Ogden Eric S. Lander The paper reported about 4,000 human SNPs. Within six months, the National Institutes of Health expanded the Human Genome Project's goals to include the identification of 100,000 human SNPs by 2003. "In fact, this proved way too modest," Lander said. An industry-academia collaboration, called the SNP Consortium, formed in 1999. Principally composed of researchers at Whitehead, the Sanger Centre, and Washington University, the consortium has already identified 300,000 SNPs and expects to reach two million by next summer. What makes SNPs particularly valuable is their potential for automation. That is, SNP genotyping is "digital" (involving detection of presence or absence of a sequence) rather than "analogue" (involving length measures, as for the more informative but fussier genetic markers called microsatellites), Lander explains. "Biotechnology companies have seized on the challenge of how to genotype SNPs most efficiently, with roughly a dozen different solutions contending in the marketplace, including DNA arrays, mass spectrometry, fiber optics, high- performance liquid chromatography, direct sequencing, TaqMan, and many others," he says. Parallel, large-scale studies of SNPs in coding regions of genes have shed light on the role of selective pressures during human evolution.2,3 "SNPs include the vast majority of genetic variation responsible for disease susceptibility such as the ApoE variant in Alzheimer's disease and the factor V variant in deep venous thrombosis," Lander says. He and his group at the Whitehead Institute continue to identify, map, and genotype SNPs. Their ultimate goal is to identify every common SNP in the human population, to be able to genotype 100,000 or so SNPs at a time, and to correlate the risk of every common disease with the presence of specific SNPs. "It's a tall order, but it seems more and more possible with each passing day," Lander says. Jennifer Fisher Wilson is a freelance science writer in Philadelphia. References 1. E.S. Lander, "The new genomics: global views of biology," Science, 274:536-9, 1996. 2. M. Cargill et al., "Characterization of single-nucleotide polymorphisms in coding regions of human genes," Nature Genetics, 22:231-8, 1999. 3. M.K. Halushka et al., "Patterns of single-nucleotide polymorphisms in candidate genes for blood-pressure homeostasis," Nature Genetics, 22:239-47, 1999.

SNP Potential

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