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Human Molecular Genetics, 2001, Vol. 10, No. 26 2961-2972
© 2001 Oxford University Press

Dissecting a population genome for targeted screening of disease mutations

Tomi Pastinen1, Markus Perola1,2, Jaakko Ignatius3,4, Chiara Sabatti2, Päivi Tainola1, Minna Levander1, Ann-Christine Syvänen1,5 and Leena Peltonen1,2,4,+

1Department of Molecular Medicine, National Public Health Institute, Biomedicum, 00250 Helsinki, Finland, 2Department of Human Genetics, University of California, Los Angeles, CA 90095-7088, USA, 3Department of Clinical Neurophysiology, Helsinki University Hospital (Jorvi Hospital), 02740 Espoo, Finland, 4Department of Medical Genetics, University of Helsinki, 00250 Helsinki, Finland and 5Molecular Medicine, Department of Medical Sciences, S-751 85 Uppsala, Sweden

Compared to mixed populations, population isolates such as Finland show distinct differences in the prevalence of disease mutations. However, little information exists of the differences on the prevalence of different disease alleles in regional populations with different history of multiple bottlenecks. We constructed a DNA-array and monitored the prevalence of 31 rare and common disease mutations underlying 27 clinical phenotypes in a large population-based study sample. Over 64 000 genotypes were assigned in 2151 samples from four geographical areas representing early and late settlement regions of Finland. Each sample was analyzed in duplicate and a total of 142 000 array-derived genotyping calls were made. On average one in three individuals was found to be a carrier of one of the 31 monitored mutations. This should remove fears of the stigmatizing effect of a carrier-screening program monitoring multiple diseases. Regional differences were found in the prevalence of mutations, providing molecular evidence for the deviating population histories of regional subisolates. The mutations introduced early into the population revealed relatively even distribution in different subregions. More recently introduced rare mutations showed local clustering of disease alleles, indicating the persistence of population subisolates and the effect of multiple bottlenecks in molding the population gene pool. Regional differences were observed also for common disease alleles. Such precise information of the carrier frequencies could form the basis for targeted genetic screens in this population. Our approach describes a general paradigm for large-scale carrier-screening programs also in other populations.

+ To whom correspondence should be addressed at: UCLA Department of Human Genetics, Gonda Neuroscience and Genetics Research Center, Room 6506, 695 Charles E. Young Drive South, Box 708822, Los Angeles, CA 90095-7088, USA. Tel: +1 310 794 5631; Fax: +1 310 794 5446; Email: lpeltonen@mednet.ucla.edu Present address: Tomi Pastinen, Montreal Genome Centre, Montreal, H3G 1A4 Quebec, Canada


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