Mapping Genetic Diseases
One small snip from man; one giant leap for the genome
October 23, 2006, ANN ARBOR, Mich.---Snips from the DNA of only 270 people from just four world locations provide a reliable map of genetic disease variations in the human genome for nearly all populations around the world.
A team of researchers, including University of Michigan scientists, will report their findings about how the HapMap is a good indicator for testing human disease genes in a paper to be published in Nature Genetics.
The team evaluated the worldwide coverage of a database of genetic markers and variations spread across the genome, called the HapMap, released one year ago by an international research consortium. The HapMap typed about 4.5 million SNPs from the genome of the small population sample from the Yoruba group in Nigeria, Chinese from Beijing, Japanese from Tokyo, and a group of European Americans.
A SNP (pronounced snip) is a site in the genome that has two different types of variations in the DNA sequence, and an individual's variations at a collection of nearby SNPs are called haplotypes.
The HapMap database of genetic markers allows researchers to select markers that will be useful to their studies and also to develop a standard set of markers to be used in studies of many diseases. However, until now, the extent to which the genetic variants in the HapMap database represented the rest of the world's populations had not been studied.
"The variants in the HapMap provide a good set of markers to use to test for diseases such as diabetes in most human populations," said Noah Rosenberg, assistant professor in the Life Sciences Institute and Bioinformatics Program and Human Genetics at the U-M Medical School, an author of the new study.
Rosenberg's U-M group studies genetic variation across populations and wanted to find the extent to which the genetic variants in the HapMap study would work in populations that were not considered. His team collected data from 927 individuals from 52 different world populations, which were much more globally distributed than the four populations studied by the HapMap, and measured the proportion of variants in these populations that were already contained in the HapMap.
"Initially we expected that there would be many parts of the world where the coverage by the HapMap was inadequate," Rosenberg said. "Instead, what we found was that the variation in the HapMap does a reasonable job of capturing the genetic variation in nearly all populations."
Therefore, researchers like Rosenberg who study disease variants in populations will be able to use the HapMap to test genetic markers spread out across the genome to investigate any differences related to that disease. Rosenberg has previously shown that the geographic distribution of haplotypes strongly reflects human history, with a loss of diversity as distance increases from the human species� ancestral range in Africa. In fact, this history explains part of the current finding.
"Except in some parts of Africa, where haplotypes are older and more distinctive, human populations have diverged recently enough that their haplotypes are fairly similar," Rosenberg said.
"These variations are of interest not only for the study of human history but also for disease-related studies," said Rosenberg. "That we can use the history of human evolution in the search for disease genes turns out to be a very powerful idea."
The paper "A worldwide survey of haplotype variation and linkage disequilibrium in the human genome" was published in the advance online version on the Nature Genetics website on October 22, 2006.
Figure above shows the coverage by the HapMap of the haplotypes in worldwide populations. The y-axis measures the fraction of a population's haplotypes that are found in the HapMap. The x-axis gives the length of the DNA sequence that forms the haplotype. For haplotypes of length 20,000 base pairs, 83% of the haplotypes common in a randomly chosen population are found in the HapMap. Except for a few groups from Sub-Saharan Africa (San, Mbuti Pygmy, Biaka Pygmy), the HapMap provides good coverage in all populations studied.
Figure above shows a picture of haplotypes in populations from around the world. Each individual's haplotypes are represented as rows, and each column corresponds to a specific position in a representative region of the genome. Haplotypes drawn in the same color at the same position in the sequence are identical. For example, in nearly all populations, there is a sizeable fraction of individuals who have the "blue" haplotype in the center of the region.
