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HapMap: Looking for differences in homogeneity

by Ruth SoRelle, M.P.H.

Richard Gibbs, Ph.D.

In a world beset by differences that are political, social and religious, it is perhaps surprising to most people that the human genome is perhaps 99.9 percent homogeneous. Yet for the past three years, a host of international researchers – among them those at the Baylor College of Medicine Human Genome Sequencing Center – have been seeking to define that minute percentage of difference.

Their aim is lofty – to define those alterations that can lead to disease and even death. In a report in a recent issue of the journal Nature, they released phase 1 of their HapMap, a compilation of the findings from this study.

Richard Gibbs, Ph.D., director of the BCM Human Genome Sequencing Center and leader of the local HapMap effort, said "Researchers everywhere can carry out genetic studies based on the HapMap data and disease gene discoveries will emerge from this work."

Accelerating the search

The HapMap itself, now in Phase I, will accelerate the search for genes that contribute to common diseases such as asthma, diabetes, cancer and heart disease. "This effort epitomizes the maturation of genomics back into genetics," said Gibbs.

In a commentary in the same issue of Nature, Gibbs describes a natural next stepping stone to understand human gene variation and its relationship to disease.

Data from the HapMap, which took three years and $138 million to produce, was made available on the web as it was generated, resulting in findings that have already been published in a variety of journals and presented at scientific meetings. The map also provides information that could lead to explanations about variations in response to drugs, chemicals and factors in the environment.

International effort

More than 200 researchers from Canada, China, Japan, Nigeria, the United Kingdom and the United States forged a public-private partnership to determine the patterns of genetic variation common in the world’s populations. Gibbs and the Baylor sequencing center participated in genotyping in collaboration with a California company called ParAllele that had developed new technology in the area.

Gibbs credits graduate student Fuli Yu and John Belmont, M.D., Ph.D., BCM professor of Molecular and Human Genetics, with taking lead roles in the HapMap project. Along with Drs. David Nelson, George Weinstock and other members of the BCM faculty and staff in the sequencing center, they completed their work in less than two years.

The study finds that the less than 1 percent of genomic variation among humans is divided into "neighborhoods" called haplotypes. Haplotypes are usually inherited as intact blocks of information – including the variants in the structure of genes called single nucleotide polymorphisms (SNPs). These are single-letter changes in the DNA sequences made up of the building blocks of adenosime (A), thymine (T), guanine (G) and cytosine (C), and most do not directly affect the function of genes.

One million changes

The HapMap catalogues more than 1 million such changes found in the genetic sequences of 269 people from around the globe. Samples came from Yoruba in Ibadan, Nigeria; Japanese in Tokyo, Han Chinese in Beijing and Utah residents whose ancestry is northern and western European. The identities of the individuals who donated the samples were not recorded and are kept private for ethical reasons.

The HapMap also provides tantalizing tidbits about the evolution of the human species as well as defining sites of DNA recombination, which explains much of the diversity in our species. In most instances, all the populations studied shared the genetic variations outlined in the HapMap. However in a few cases, they found that some variations were limited to particular populations.

For example, in the course of the study, Yu identified a large chunk of DNA on chromosome 12 that was highly conserved in a European population, indicating that in that group, this DNA segment was favored by natural selection. It was located near a version of the gene that when mutated to repeat certain sequences of DNA causes a neurodegenerative disorder called spinocerebellar ataxia type 2. A report of this work appears in the latest issue of the Public Library of Science Genetics.

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