A systematic approach to mapping recessive disease genes in individuals from outbred populations.
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.
Hildebrandt
Friedhelm
F
Department of Pediatrics, University of Michigan School of Medicine, Ann Arbor, Michigan, United States of America.
Heeringa
Saskia F
SF
Rüschendorf
Franz
F
Attanasio
Massimo
M
Nürnberg
Gudrun
G
Becker
Christian
C
Seelow
Dominik
D
Huebner
Norbert
N
Chernin
Gil
G
Vlangos
Christopher N
CN
Zhou
Weibin
W
O'Toole
John F
JF
Hoskins
Bethan E
BE
Wolf
Matthias T F
MT
Hinkes
Bernward G
BG
Chaib
Hassan
H
Ashraf
Shazia
S
Schoeb
Dominik S
DS
Ovunc
Bugsu
B
Allen
Susan J
SJ
Vega-Warner
Virginia
V
Wise
Eric
E
Harville
Heather M
HM
Lyons
Robert H
RH
Washburn
Joseph
J
Macdonald
James
J
Nürnberg
Peter
P
Otto
Edgar A
EA
D004252:DNA Mutational Analysis; D005189:False Positive Reactions; D005192:Family Health; D005260:Female; D005808:Genes, Recessive; D005819:Genetic Markers; D005828:Genetics, Population; D006720:Homozygote; D006801:Humans; D052177:Kidney Diseases, Cystic / Q000235:genetics; D008297:Male; D008957:Models, Genetic; D009404:Nephrotic Syndrome / Q000235:genetics; D010375:Pedigree; D013256:Steroids / Q000494:pharmacology
D005819:Genetic Markers; D013256:Steroids