Progress, and Applications
of the Human Genome Project
Sponsored by the U.S. Department of Energy Human Genome Program
Human Genome News Archive Edition
Human Genome News, Nov. 1994; 6(4):1
See also Growth of Mapping Data and What Are Genetic Maps?
An international team of researchers has constructed the most detailed comprehensive human genetic map yet published, with 5840 loci spaced at a mean interval of 0.7 cM. The new high-density map is a compilation of linkage data generated during the past decade by groups led by Jeffrey Murray [Cooperative Human Linkage Center (CHLC)], Jean Weissenbach (Genethon), Ray White (University of Utah), David Ward (Yale University); and over 100 Centre d'Etude du Polymorphisme Humain collaborators.
This achievement represents the fulfillment of a Human Genome Project goal, first established at the project's inception in 1990 and restated in last year's revised goals, to achieve a 2- to 5-cM linkage map by 1995 [HGN 5(4), 1-3, 5 (November 1993)]. An article describing the maps appears in the special genome issue of Science [265, 2049-54 (September 30, 1994)]. [Chart available electronically.]
The rapid saturation of the genetic map was propelled by the discovery of a new type of DNA-based marker discovered in the late 1980s. The new markers belong to a class of short (1- to 5-bp) DNA sequences first reported by Jim Weber of the Marshfield Medical Research Foundation for the dinucleotide CA. These variants are repeated up to thousands of times throughout the genome. In a few cases, repeats of trinucleotides can hyperexpand, leading to such inherited disorders as Fragile X syndrome, Huntington's disease, or myotonic dystrophy. Because the number of repeats can vary greatly among individuals, these short tandem repeat polymorphisms (short tandem repeat polymorphisms) have become one of the most useful tools for genetic mappers.
The abundance and even distribution of short tandem repeat polymorphisms throughout the genome and their ability to be assayed by polymerase chain reaction have enabled researchers to generate efficiently and rapidly the markers needed to saturate the genetic map. The new maps incorporate over 3600 short tandem repeat polymorphisms, in addition to over 400 genes and nearly 1800 other markers such as RFLPs and anonymous DNA segments. These maps describe human genetic diversity at a mean resolution of 0.7 cM. Of the three largest groups collaborating on the new linkage map, the Genethon group contributed markers containing dinucleotide repeats, the most common type of short tandem repeat polymorphism [see HGN 6(3), 5 (September 1994) for announcement of map based on these markers]. CHLC and the Utah group generated primarily tri- and tetranucleotide repeats, which are easier to genotype but less frequent. The Yale University group provided cytogenetic anchor points for a subset of the linkage markers (using fluorescence in situ hybridization of yeast artificial chromosomes).
Using Genetic Maps
Genetic maps are used for starting gene hunts, and their usefulness increases with marker density and quality. A variety of strategies can be applied using polymorphic markers, including linkage, association, allele-sharing, and loss-of-heterozygosity studies. In Science, Lender and Schork discuss which strategy to apply in a particular situation [265, 2037-48 (Sept. 30, 1994)]. Once the gene is localized to a particular area, researchers turn to physical maps (ordered clone sets) to retrieve flanking DNA segments for further detailed study. In 1986, the gene for the immune disorder chronic granulomatous disease was the first to be isolated by using linkage maps with a procedure now known as positional cloning. Genetic maps have been used since to help localize about 40 genes, including those for cystic fibrosis, Fragile X syndrome, myotonic dystrophy, and types of colon and breast cancer.
Other uses for the new high-density maps are to study candidate genes by substituting an informative short tandem repeat polymorphism as a surrogate for a less-informative gene and to explore complex, multifactorial, or polygenic disorders. Because their construction is based on sequence tagged sites, high-resolution genetic linkage maps featuring polymerase chain reaction-based markers also serve as a framework for constructing physical maps and integrating genetic, cytogenetic, and physical maps.
Although the short-term genetic mapping goal has been achieved, the maps still have gaps and lack anchor points at chromosomal telomeres and centromeres. Investigators believe that maximally useful genetic maps will require increased marker density, next at the level of 1 marker per 100 kb. A complete description of human genetic varation might require a marker every 100 to 1000 bp.
Denise Casey, HGMIS
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