October 31, 2002
HapMap Genetic Variation Mapping Project Begins

It is now believed that in most people genetic variations vary in groups. By looking at a relatively small number of locations in the genome it should be possible to predict (albeit with less than complete certainty) what genetic variations will be found between the tested locations (these ranges are called Haplotypes). To map out and identify the marker locations from which other locations can be predicted an ambitious 3 year $100 million dollar international project is attempting to collect analyze the DNA of several hundred humans. This project is known as the HapMap project:

Genetic information is physically inscribed in a linear molecule called deoxyribonucleic acid (DNA). DNA is composed of four chemicals, called bases, which are represented by the four letters of the genetic code: A, T, C and G. The Human Genome Project determined the order, or sequence, of the 3 billion As, Ts, Cs and Gs that make up the human genome. The order of genetic letters is as important to the proper functioning of the body as the order of letters in a word is to understanding its meaning. When a letter in a word changes, the words meaning can be lost or altered. Variation in a DNA base sequence when one genetic letter is replaced by another may similarly change the meaning.

More than 2.8 million examples of these substitutions of genetic letters called single nucleotide polymorphisms or SNPs (pronounced snips) are already known and described in a public database called dbSNP (http://www.ncbi.nlm.nih.gov/SNP/), operated by NIH. The major source of this public SNP catalog was work done by The SNP Consortium (TSC), a collaborative genomics effort of major pharmaceutical companies, the Wellcome Trust and academic centers.

The human genome is thought to contain at least 10 million SNPs, about one in every 300 bases. Theoretically, researchers could hunt for genes using a map listing all 10 million SNPs, but there are major practical drawbacks to that approach.

Instead, the HapMap will find the chunks into which the genome is organized, each of which may contain dozens of SNPs. Researchers then only need to detect a few tag SNPs to identify that unique chunk or block of genome and to know all of the SNPs associated with that one piece. This strategy works because genetic variation among individuals is organized in "DNA neighborhoods," called haplotype blocks. SNP variants that lie close to each other along the DNA molecule form a haplotype block and tend to be inherited together. SNP variants that are far from each other along the DNA molecule tend to be in different haplotype blocks and are less likely to be inherited together.

"Essentially, the HapMap is a very powerful shortcut that represents enormous long-term savings in studies of complex disease," said David Bentley, Ph.D., of the UK's Wellcome Trust Sanger Institute.

Since all humans descended from a common set of ancestors that lived in Africa about 100,000 years ago, there have been relatively few generations in human history compared to older species. As a result, the human haplotype blocks have remained largely intact and provide an unbroken thread that connects all people to a common past and to each other. Recent research indicates that about 65 to 85 percent of the human genome may be organized into haplotype blocks that are 10,000 bases or larger.

The exact pattern of SNP variants within a given haplotype block differs among individuals. Some SNP variants and haplotype patterns are found in some people in just a few populations. However, most populations share common SNP variants and haplotype patterns, most of which were inherited from the common ancestor population. Frequencies of these SNP variants and haplotype patterns may be similar or different among populations. For example, the gene for blood type is variable in all human populations, but some populations have higher frequencies of one blood type, such as O, while others have higher frequencies of another, such as AB. For this reason, the HapMap consortium needs to include samples from a few geographically separated populations to find the SNP variants that are common in any of the populations.

Charles Rotimi, Ph.D., leader of the Howard University group collecting the blood samples in Nigeria, said, "We need to be inclusive in the populations that we study to maximize the chance that all people will eventually benefit from this international research effort."

Because of the block pattern of haplotypes, it will be possible to identify just a few SNP variants in each block to uniquely mark, or tag, that haplotype. As a result, researchers will need to study only about 300,000 to 600,000 tag SNPs, out of the 10,000,000 SNPs that exist, to efficiently identify the haplotypes in the human genome. It is the haplotype blocks, and the tag SNPs that identify them, that will form the HapMap.

Share |      Randall Parker, 2002 October 31 10:38 PM  Biotech Advance Rates


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