A Systematic Approach to Mapping Recessive Disease Genes in Individuals from Outbred Populations
نویسندگان
چکیده
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.
منابع مشابه
CALL FOR PAPERS Updates on Mapping Quantitative Trait Loci QTL mapping in outbred populations: successes and challenges
Solberg Woods LC. QTL mapping in outbred populations: successes and challenges. Physiol Genomics 46: 81–90, 2014. First published December 10, 2013; doi:10.1152/physiolgenomics.00127.2013.—Quantitative trait locus (QTL) mapping in animal populations has been a successful strategy for identifying genomic regions that play a role in complex diseases and traits. When conducted in an F2 intercross ...
متن کاملQTL mapping in outbred populations: successes and challenges.
Quantitative trait locus (QTL) mapping in animal populations has been a successful strategy for identifying genomic regions that play a role in complex diseases and traits. When conducted in an F2 intercross or backcross population, the resulting QTL is frequently large, often encompassing 30 Mb or more and containing hundreds of genes. To narrow the locus and identify candidate genes, addition...
متن کاملUsing dominance relationship coefficients based on linkage disequilibrium and linkage with a general complex pedigree to increase mapping resolution.
Dominance (intralocus allelic interactions) plays often an important role in quantitative trait variation. However, few studies about dominance in QTL mapping have been reported in outbred animal or human populations. This is because common dominance effects can be predicted mainly for many full sibs, which do not often occur in outbred or natural populations with a general pedigree. Moreover, ...
متن کاملApproaches to the detection of recessive effects using next generation sequencing data from outbred populations
Conventional methods to analyze genome-wide association studies and whole exome or whole genome sequencing studies would be prone to overlook variants which might exert a recessive effect on risk of disease, either as homozygotes or compound heterozygotes. It is plausible that such effects may be common even in outbred populations. An approach is described which is based on identifying a set of...
متن کاملHomozygosity Mapping on Homozygosity Haplotype Analysis to Detect Recessive Disease-Causing Genes from a Small Number of Unrelated, Outbred Patients
Genes involved in disease that are not common are often difficult to identify; a method that pinpoints them from a small number of unrelated patients will be of great help. In order to establish such a method that detects recessive genes identical-by-descent, we modified homozygosity mapping (HM) so that it is constructed on the basis of homozygosity haplotype (HM on HH) analysis. An analysis u...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید
ثبت ناماگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید
ورودعنوان ژورنال:
- PLoS Genetics
دوره 5 شماره
صفحات -
تاریخ انتشار 2009