September 27, 2002

Genetics Symposium highlights new approach to gene discovery

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Dr. Steven Gabbe officially started this year’s JDRF Walk. (photo by Peyton Hogue)

Genetics Symposium highlights new approach to gene discovery

There was talk last week at the Third Annual Vanderbilt/Meharry Genetics Symposium of an important international effort coming down the pike as a follow-up to the Human Genome Project. The aim of the new project, which will be announced formally later this month, is to help scientists learn how blocks of DNA, called haplotypes, are passed along within families and across generations. Genetic variability within these blocks might hold the key to understanding an individual’s response to drugs or susceptibility to genetic disease.

Haplotype mapping, which was the theme of this year’s symposium, involves identifying long stretches, or blocks, of DNA sequence that carry single letter changes, known as SNPs, which can be used as tools to discover genes associated with complex genetic disorders. It’s estimated that there are between 3 million and 10 million SNPs in the human genome.

“The problem with SNPs is that there are too many of them,” said Dr. Ellen Wright Clayton, Rosalind E. Franklin Professor of Genetics and Health Policy at Vanderbilt. “The point of the haplotype is that if you can identify these blocks, then you don’t have to look at every single SNP.”

Mark Daly, Whitehead/Pfizer fellow in computational biology at the Massachusetts Institute of Technology, explained how this indirect approach might be more successful than the traditional, direct approach of looking for candidate genes. Traditional methods require testing up to a million SNPs, a tedious, time-consuming, and expensive prospect. Using haplotype mapping, in many fewer steps one can look for mutations in haplotype blocks of DNA from ancestral founder chromosomes that have been passed to successive generations through population expansion with little genetic recombination.

Evidence supporting how genetic diversity stems from such founder chromosomes in Africa was presented by Sarah Tishkoff, Ph.D., assistant professor of Biology at the University of Maryland, College Park. Tishkoff uses haplotyping to study the genetic basis of resistance and susceptibility to infectious organisms, such as malaria, and to study predisposition to diseases that disproportionately affect those of African ancestry.

According to Tishkoff, Africans are remarkable in the level of variability seen in their DNA, most likely due to the fact that older civilizations have had more time for genetic recombination to occur. The evolutionary question arises: Are complex diseases in Africa due to modern linkage disequilibrium or to older genes that originated long ago?

Both Tishkoff and Vivian Ota Wang, Ph.D., who recently moved from Arizona State University to join Vanderbilt’s faculty in the Genetics and Health Policy Center, gave insight into the intricacies involved in establishing rapport within communities participating in genetic studies. Wang has worked extensively to facilitate studies within Chinese communities in Denver, Colo. and in Beijing. Cultural and social barriers can be formidable and must be addressed with sensitivity to successfully build trust and ensure informed consent.

The symposium highlighted the work of a number of Vanderbilt and Meharry researchers who make use of haplotyping in their studies of unique populations. Dr. John A. Phillips, III, David T. Karzon Professor of Pediatrics and professor of Biochemistry at Vanderbilt, presented his studies in a population from a village in Brazil where diminutive size is prevalent. Through haplotyping, Phillips was able to identify a single base pair change in the sequence of a gene encoding human growth hormone that was responsible for the villagers’ short stature.

Shirley Russell, Ph.D., chair and professor of Microbiology at Meharry, gave an overview and progress report on investigations into the role of genetics in keloid formation, which is an overhealing response that occurs disproportionately in those of African and Asian ancestry. Preliminary haplotyping suggests association with a region on chromosome 14, though larger studies are needed to confirm the results.

The use of computer modeling in identifying how multiple genes interact in arterial thrombosis was discussed by Jason Moore, Ph.D., assistant professor of Molecular Physiology and Biophysics at Vanderbilt. Moore is working with Dr. Doug Vaughan and Dr. Nancy Brown to investigate how epistatic interaction of the genes for PAI-1 and plasma t-PA affect plasma protein levels in a study of 8,500 Caucasians from The Netherlands and 2,000 Africans from Ghana. The effect of age, body mass index, and other covariants will also be considered in the study.

Alan Thomas, a post-doctoral fellow in pulmonary medicine working in Dr. Jim Lloyd’s lab at Vanderbilt, presented results defining the role of a surfactant protein (SP-C) in the lung disease known as Familial Interstitial Pulmonitis. The nearly two-year study identified a single base change in the SP-C gene that causes a defect in the protein that coats the alveolar sacs in the lung. The study provides a clue that alveolar epithelium defects may be key to a number of pulmonary lung diseases.

A poster session featuring other research findings was available for perusal during the lunch break. The symposium, which was held at Vanderbilt University’s Sarratt Student Center and in Light Hall, concluded with a round table discussion among speakers and attendees.