Baylor Human Genome Sequence Center key player in mapping human genetic variation

10/24/05

A comprehensive map of human genetic variation, published today in the journal Nature, is not only a major achievement by the International HapMap Consortium, but it also opens the door to future efforts that could pinpoint the changes that actually alter the way genes work, said the Baylor College of Medicine researcher who led the local HapMap effort.

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 Dr. Richard Gibbs, director of the Baylor Human Genome Sequencing Center. "Researchers everywhere can carry out genetic studies, based on the HapMap data and disease gene discoveries will emerge from this work."

Gibbs also describes a natural next stepping stone to understanding human gene variation and its relationship to disease in a commentary in the same issue of Nature. Together with the results from HapMap, the project, this effort puts the focus back on gene changes that directly affect humans.

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.

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.

"We worked closely with Paul Hardenbol and Tom Willis at ParAllele Biosciences, to show the power of their recently developed Molecular Inversion Probe genotyping technology," said Fuli Yu, the graduate student who carried out the genotyping at Baylor. "The genotyping rate increased over the course of the project and by the end we were generating more than 250,000 genotypes in a single day."

Gibbs credits Yu and Dr. John Belmont, 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. The HapMap catalogues more than one 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 at http://genetics.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pgen.0010041.eor

The completed HapMap paves the way for further disease gene hunts at BCM.

Source: Eurekalert & others

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