The National Heart, Lung, and Blood Institute (NHLBI) is committed to a broad-ranging program of research that builds on past achievements and capitalizes on the most promising new approaches and technologies. Molecular genetics constitutes an area of particular interest because it has potential to directly enhance our mastery over cardiovascular, lung, and blood diseases. Moreover, an understanding of the molecular genetics of disease will provide vital new information to extend further the considerable contributions that have come from more traditional disciplines.
To guide its efforts in this emerging area, the Institute called upon an Expert Panel on Genetic Strategies for Heart, Lung, and Blood Diseases to formulate a Master Plan for the implementation of major research opportunities and strategies (see December 1993 Circulation). In this column, we highlight the development of two major initiatives recommended in the Master Plan: “Mammalian Genotyping Service” and “Genetic Map and Large Insert Library for the Rat Genome.”
Mammalian Genotyping Service
The Master Plan identified the need for an efficient, rapid genotyping service to support projects that exploit genetic linkage analyses, association studies, and mutational analysis in an effort to identify the genetic determinants of cardiovascular, lung, and blood diseases. One of the requirements of such studies is large-scale genotyping of populations and pedigrees. At the present time, genotypes typically are determined by investigators in their own laboratories by manual techniques. This work is costly and, because of its repetitive nature, often lacking in quality control. Moreover, robust software for the documentation of genotypes is rarely used, so corruption of data is not uncommon. Such limitations could seriously impede timely application of genetics to common human disorders, particularly as more ambitious genetic strategies are developed.
Competition for the NHLBI Mammalian Genotyping Service was announced in February 1994, and a contract was recently negotiated with the Center for Medical Genetics, Marshfield Medical Research Foundation. We believe that the existence of this facility will allow large populations and pedigrees to be analyzed reliably, with many genetic markers, at reduced cost. In addition, it is expected to significantly expedite current and future genetic studies of diseases whose pathogenesis involves more than one gene. As a final point, this service will provide greater access to cutting-edge technology.
As readers of Circulation may have observed, the Mammalian Genotyping Service has widely published a call for applications in relevant scientific journals. Genotyping with microsatellite DNA polymorphisms will begin in July 1995 at an initial minimal rate of 300 000 genotypes per year. For the first 2 years of operation, no fee will be charged for projects that fall within the domain of the NHLBI; beginning in 1997, a fee of approximately $1 per genotype will go into effect as the Service gradually becomes self-supporting. The facility will be monitored by an expert panel, which will also determine the priority of competing projects if demand exceeds capacity. Further information may be obtained from Beth Buescher, Center for Medical Genetics, Marshfield Medical Research Foundation, 1000 N Oak Ave, Marshfield, WI 54449 (phone, 715-389-3525; fax, 715-389-3808).
Genetic Map and Large Insert Library for the Rat Genome
This new research program was announced in December 1994 as a collaborative effort of the NHLBI and 11 other NIH entities, including the National Center for Human Genome Research. Its goal is to construct a high-resolution genetic map of the rat genome. In addition, a large insert DNA library of the rat genome will be developed to facilitate the cloning and analysis of disease genes that have been mapped genetically. This program will construct the vital mapping resources needed to make full use of the rat as a model to study human disease. Timely plans to share and distribute data and resources generated by these efforts will be an essential element of this program.
The rat is an important experimental model for studying human diseases such as hypertension, cancer, behavioral disorders, diabetes, drug abuse, alcoholism, and obesity. Because of its large size in comparison with the mouse, the rat is also widely used in studies of anatomy, pharmacology of the chemical senses, and neuronal pathways in the brain. The rat offers many advantages because a large body of knowledge about physiological mechanisms already exists, models that mimic human diseases are available, breeding is easy, and inbred congenic rat strains can be generated.
Nonetheless, research efforts to identify genetic factors involved in disease processes have been hampered in the rat by the lack of high-resolution genetic and physical maps of the rat genome. Currently, investigators using rats to map disease genes must resort to the laborious task of identifying new genetic markers and mapping large chromosomal regions of the genome before they can attempt to locate the gene of interest, thereby substantially slowing their progress.
The NIH currently supports projects aimed at mapping the human and mouse genomes as well as selected nonmammalian genomes. These efforts have led to substantial technological and methodological advances that are reducing the time and cost to construct genomic maps. However, because of a lack of sequence identity and specificity, only 5% to 10% of mouse and human genetic markers can be used to screen the rat genome. Therefore, these tools must be generated specifically for the rat if we wish efforts to map disease genes in rat models to be continued.
This new program can be expected to expedite the timely and cost-effective development of critical mapping resources necessary to develop the full potential of the rat as an experimental model. Because rats are used extensively to study normal and disease processes, we believe that the program will provide a valuable resource that spans the diverse interests of the research community.
- Copyright © 1995 by American Heart Association