Positional Cloning of Disease Genes: Advantages of Genetic IsolatesPeltonen L.
Department of Human Genetics, UCLA School of Medicine, Los Angeles, Calif., USA, and Department of Medical Genetics, University of Helsinki and National Public Health Institute, Helsinki, Finland
Genetic isolates with a history of a small founder population, long-lasting isolation and population bottlenecks represent exceptional resources in the identification of disease genes. Specific rare, monogenic diseases become enriched, and families with multiple affected individuals occur frequently enough to be used in linkage analyses for locus identification. Further, the vast majority of cases are caused by the same mutation, and disease alleles reveal linkage disequilibrium (LD) with markers over significant genetic intervals; this facilitates disease locus identification by similarity search for a shared genotype or haplotype in small study samples consisting of few affected individuals. LD observed in disease alleles adds power to linkage analyses and helps to define the exact location of disease loci on the genetic map. Typically, based on the linkage disequilibrium and the ancient haplotype, the critical DNA region can be defined from the original 1- to 2-cM resolution obtained in linkage analysis to 50–200 kb, greatly facilitating the targeting of physical cloning and sequencing efforts. These advantages have been well demonstrated in the positional cloning of several rare monogenic diseases enriched in population isolates like the example of Finland used here. How useful genetic isolates will prove to be in the identification of complex disease genes is dependent on the genealogical history of the isolate, including the size of the founding population and the expansion rate during the history of the population.
Leena Peltonen, MD, PhD
Chair and Professor, Department of Human Genetics, UCLA School of Medicine
Gonda Neuroscience and Genetics Research Center, 695 Charles E. Young Drive South
Box 708822, Los Angeles, CA 90095-7088 (USA)
Tel. +1 310 794 5631, Fax +1 310 794 5446, E-Mail firstname.lastname@example.org
Received: Received: April 28, 1999
Revision received: June 4, 1999
Accepted: June 4, 1999
Number of Print Pages : 10
Number of Figures : 1, Number of Tables : 2, Number of References : 76
Human Heredity (International Journal of Human and Medical Genetics)
Founded 1950 as Acta Genetica et Statistica Medica by Gunnar Dahlberg; Continued by M. Hauge (1965–1983)
Vol. 50, No. 1, Year 2000 (Cover Date: January-February 2000 (Released September 1999))
Journal Editor: J. Ott, New York, N.Y.
ISSN: 0001–5652 (print), 1423–0062 (Online)
For additional information: http://www.karger.ch/journals/hhe