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A systematic approach to mapping recessive disease genes in individuals from outbred populations

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Item Type:Article
Title:A systematic approach to mapping recessive disease genes in individuals from outbred populations
Creators Name:Hildebrandt, F. and Heeringa, S.F. and Rueschendorf, F. and Attanasio, M. and Nuernberg, G. and Becker, C. and Seelow, D. and Huebner, N. and Chernin, G. and Vlangos, C.N. and Zhou, W. and O'Toole, J.F. and Hoskins, B.E. and Wolf, M.T. and Hinkes, B.G. and Chaib, H. and Ashraf, S. and Allen, S.J. and Vega-Warner, V. and Wise, E. and Harville, H.M. and Lyons, R.H. and Washburn, J. and Macdonald, J. and Nuernberg, P. and Otto, E.A.
Abstract:The identification of recessive disease-causing genes by homozygosity mapping is often restricted by lack of suitable consanguineous families. To overcome these limitations, we apply homozygosity mapping to single affected individuals from outbred populations. In 72 individuals of 54 kindred ascertained worldwide with known homozygous mutations in 13 different recessive disease genes, we performed total genome homozygosity mapping using 250,000 SNP arrays. Likelihood ratio Z-scores (ZLR) were plotted across the genome to detect ZLR peaks that reflect segments of homozygosity by descent, which may harbor the mutated gene. In 93% of cases, the causative gene was positioned within a consistent ZLR peak of homozygosity. The number of peaks reflected the degree of inbreeding. We demonstrate that disease-causing homozygous mutations can be detected in single cases from outbred populations within a single ZLR peak of homozygosity as short as 2 Mb, containing an average of only 16 candidate genes. As many specialty clinics have access to cohorts of individuals from outbred populations, and as our approach will result in smaller genetic candidate regions, the new strategy of homozygosity mapping in single outbred individuals will strongly accelerate the discovery of novel recessive disease genes.
Keywords:DNA Mutational Analysis, False Positive Reactions, Family Health, Recessive Genes, Genetic Markers, Population Genetics, Homozygote, Cystic Kidney Diseases, Genetic Models, Nephrotic Syndrome, Pedigree, Steroids
Source:PLoS Genetics
ISSN:1553-7390
Publisher:Public Library of Science (U.S.A.)
Volume:5
Number:1
Page Range:e1000353
Date:23 January 2009
Official Publication:https://doi.org/10.1371/journal.pgen.1000353
PubMed:View item in PubMed

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