Scientists Publish First Dense SNP Map of the Human Genome; SNP Total Exceeds 1.2 Million

CAMBRIDGE, Mass. — Researchers at the Whitehead Institute and The Sanger Centre report their contributions to the methodology and progress of The SNP Consortium, an international effort to assemble and release the first high-resolution map of common variations in human DNA called single nucleotide polymorphisms, or SNPs. SNPs are the bedrock of human genetics: they can be used to track inheritance of any gene, contribute to the traits that make us unique, and underlie our susceptibilities to common diseases such as cancer, diabetes, and heart disease. It is also believed that SNPs help explain why individuals respond differently to drugs.

In the September 28 issue of Nature, the Whitehead researchers report a novel method, called reduced representation shotgun sequencing, that increases the efficiency and accuracy of SNP discovery for genetic mapping. These tools are being used by The SNP Consortium (TSC), a unique collaboration of academic centers, pharmaceutical companies and a private foundation established with the goal of discovering 300,000 SNPs by April 2001. Already, 300,000 of SNPs have been mapped to the draft sequence of the human genome and are freely available at the TSC website. Progress in SNP discovery promises to far outstrip this original goal.

In fact, the pace of SNP discovery has moved more quickly than the writing and publication of the manuscripts. During the editorial process this spring, the SNP total grew from 60,000 to 150,000; by the time page proofs were ready, it was necessary to add a note in proof describing a total of 300,000 SNPs. Since then, the number of SNPs discovered has more than doubled to approximately 800,000; these are being mapped and will be released to the public within the next 4-6 weeks. During the same time, the Human Genome Project's sequencing effort has yielded a bumper crop of at least 400,000 SNPs, bringing the total number of SNPs now available in the public domain to more than 1.2 million.

This number far exceeds the goal set by the TSC last year to discover and release to the public at least 300,000 human SNPs by April 2001. The TSC was formed in April 1999 when in an unprecedented move, several industry giants and academic institutions joined hands and pooled their resources to discover and map SNPs, so high was their promise to humankind. Then, in July 2000, The SNP Consortium and the Human Genome Project announced a collaborative effort to generate 250,000 additional SNPs. The Consortium has already exceeded these goals.

"This is a clear example of how industry and academic scientists can join hands successfully and efficiently toward meeting a common goal. A high-resolution SNP map that is accurate, reliable, and freely available to medical researchers worldwide will greatly accelerate the discovery of the genetic underpinnings of the most common diseases that affect human populations," says Eric Lander, Director of the Whitehead Institute Center for Genome Research.

"SNP maps will also enhance our understanding of disease processes, help us predict susceptibility, and improve diagnosis and treatment of common diseases. Ultimately, SNP technology may lead to the development of customized medicine in which disease prevention strategies and treatments are closely tailored to an individual's genetic profile," says David Altshuler, first author on the study and a research scientist at the Whitehead Institute Center for Genome Research.

The Whitehead method re-samples specific subsets of the genome from several individuals, and compares the resulting sequences using a highly accurate SNP detection algorithm. The technical advantage of the method is that it can be performed without prior knowledge of genome sequence, and avoids the expense and labor of traditional PCR-based resequencing methods. However, the approach has become much more efficient with the Human Genome sequence, says Altshuler. Aligning the SNPs to available genome sequence has increased the yield of SNPs and allowed researchers to locate the position of the SNPs in the genome map. More broadly, the Whitehead Institute method facilitates the rapid, inexpensive construction of SNP maps in biomedically and agriculturally important species.

The SNP map represents an essential companion to the "Book of Life"—the 3 billion letter genetic blueprint announced this summer. Because any two humans are 99.9 percent similar, the human genome sequence serves a valuable reference of a typical human's DNA terrain. But to gain insights into human history and to uncover the causes of diseases, researchers need a map of the 0.1 percent difference in our DNA that determines our unique traits and helps to explain why some of us are more susceptible to certain diseases than others.

Scientists have long known that diseases caused by single genes and inherited according to the laws of Mendel are actually rare. Most common diseases, like diabetes and heart disease, which affect large numbers of the population, are caused by the interaction of several genes. But finding these genes has proven a difficult task. Recently, there has been tremendous focus on the idea that the risk of contracting these diseases can be traced by using tiny genetic variations in our genetic code, single letter substitutions in DNA—i.e. SNPs.

By comparing the SNP patterns in affected and non-affected individuals—patients with diabetes and healthy controls, for example—scientists can catalog the specific DNA variations that underlie risk or susceptibility for a given disease and individual differences in responses to treatment.

A few years ago, Lander and others suggested that a dense map of SNPs (containing 30,000 to 500,000 SNPs) would allow them to scan the genome and detect the underlying causes of common diseases. But until the progress in The SNP Consortium and Human Genome Project this year, there were simply too few SNPs available to test out and implement this idea.

The SNP Consortium is organized as a non-profit entity whose goal is to create and make publicly available a high-quality SNP map of the human genome. The Consortium's members include the Wellcome Trust, the world's largest biomedical research charity; 10 pharmaceutical companies including AstraZeneca PLC, Aventis Pharma, Bayer AG, Bristol-Myers Squibb Company, F. Hoffman-La Roche, Glaxo Wellcome PLC, Novartis Pharmaceuticals, Pfizer Inc, Searle (now part of Pharmacia), and SmithKline Beecham PLC; and Motorola, Inc., IBM, and Amersham Pharmacia Biotech. Academic centers including the Whitehead Institute for Biomedical Research, Washington University School of Medicine in St. Louis, the Wellcome Trust's Sanger Centre, Stanford Human Genome Center, and Cold Spring Harbor Laboratory, are involved in SNP identification and analysis.