NIH Funds Comprehensive New Look at Genome

An alliance of scientists at three universities will employ an unconventional, exhaustive approach to analyze genetic variation and its connection to common chronic diseases under a grant from the National Institutes of Health.

The National Institute of General Medical Sciences has awarded $2.8 million for the first year to the University of Michigan and collaborators at The University of Texas Health Science Center at Houston and Pennsylvania State University, for a project that the investigators note will test many of the central assumptions that have governed genome research to date. Over the course of the five-year award, NIGMS anticipates spending $12.8 million.

Information from the Human Genome Project and advances in technology provide an unprecedented opportunity to track down crucial genetic variations by analyzing all variation found in the human genome.

The complexity involved in that task overwhelms present research methods, which focus on limited portions of the genome, said Dr. Eric Boerwinkle, a project investigator and director of the Center for Human Genetics at The University of Texas Institute of Molecular Medicine for the Prevention of Human Disease at Houston.

"We have the opportunity to examine the whole genome of an individual and we do not yet have the analytical methods to handle and properly analyze the large amount of data that will be generated." Dr. Boerwinkle said. "Our ability to collect data in the laboratory far outstrips our ability to make sense of it. This project will develop new methods of analysis that exhaustively document genetic variation and then connect those variations to human health."

"With the reference sequence of the human genome nearly complete, an important next step is studying the nature of genetic variation – how much there is, how it is organized and maintained, and how it is related to the genetics of human traits," said Irene Eckstrand, an NIGMS geneticist. "This is a daunting area of research, and scientists will need new tools to gain a deeper understanding. This grant brings together a strong group of scientists with novel ideas, and we are eager to see what they discover."

Project leaders are Dr. Charles Sing, professor of human genetics at the University of Michigan; Dr. Boerwinkle and UT-Houston colleague Dr. Jim Hixson, professor of biological sciences at the School of Public Health; and Dr. Andrew Clark, professor of biology at Penn State.

Susceptibility to common major illnesses such as cancer, cardiovascular disease and stroke is caused by variation involving multiple genes interacting with environmental and demographic factors. This makes isolating genetic aspects of these common diseases particularly challenging, said Dr. Boerwinkle, whose labs have discovered genetic variations that raise risk for hypertension, stroke and atherosclerosis.

Present methods of connecting genetic variation to disease fail to take into account other variation in the genome that might also be relevant. They focus only on those areas of genes that code for amino acids, which in turn join to form proteins, which perform most of a cell’s functions.

The research team proposes to exhaustively analyze all genetic variation and will pilot this approach by focusing on 60 genes, all of which are expressed in the liver, and several other large genomic portions on chromosome 19. For the first time, the project will extensively characterize DNA variation in all areas studied, including those thought to have no obvious role in creating proteins.

Dr. Hixson will begin by sequencing the DNA of 40 people – 20 African-Americans and 20 non-Hispanic whites – from a total study population of 4,146 individuals belonging to an existing project that has extensively documented their health and physical information. Every single variation in the 60 genes and other genomic areas studied will then be genotyped by Dr. Boerwinkle in all 4,146 individuals.

The team expects to analyze about 2,000 areas of variation in each person, one of the most intensive genomic documentations ever undertaken.

Dr. Clark at Penn State will then analyze every variation to determine each one’s evolutionary history – how the variation arose and in what populations.

In the final step, Drs. Sing and Boerwinkle will analyze the relationship between the genetic variations and measures of health and disease. They will employ traditional statistical methods in their analysis as well as new methods under development based on areas of artificial intelligence.

The investigators plan to use this project as a pilot study toward eventually analyzing the entire genome.

"Let’s do this on one chromosome before someone spends a couple hundred million dollars trying to do the entire genome," Dr. Boerwinkle said. "In the end, we are all unique, so we need to devise clever methods to reduce the amount of data needed in order to make statements about who is at increased risk for disease, and who is not."

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©2006 Texas Medical Center

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