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PLoS Genet. 2009 Jan;5(1):e1000353. doi: 10.1371/journal.pgen.1000353. Epub 2009 Jan 23.

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

Author information

1
Department of Pediatrics, University of Michigan School of Medicine, Ann Arbor, Michigan, United States of America.

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.

PMID:
19165332
PMCID:
PMC2621355
DOI:
10.1371/journal.pgen.1000353
[Indexed for MEDLINE]
Free PMC Article

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