Homozygosity Mapping on Homozygosity Haplotype Analysis to Detect Recessive Disease-Causing Genes from a Small Number of Unrelated, Outbred Patients

Abstract

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 using 6 unrelated patients with Siiyama-type α1-antitrypsin deficiency, a disease caused by a founder gene, the correct gene locus was pinpointed from data of any 2 patients (length: 1.2–21.8 centimorgans, median: 1.6 centimorgans). For a test population in which these 6 patients and 54 healthy subjects were scrambled, the approach accurately identified these 6 patients and pinpointed the locus to a 1.4-centimorgan fragment. Analyses using synthetic data revealed that the analysis works well for IBD fragment derived from a most recent common ancestor (MRCA) who existed less than 60 generations ago. The analysis is unsuitable for the genes with a frequency in general population more than 0.1. Thus, HM on HH analysis is a powerful technique, applicable to a small number of patients not known to be related, and will accelerate the identification of disease-causing genes for recessive conditions.

Autozygome-guided exome sequencing in retinal dystrophy patients reveals pathogenetic mutations and novel candidate disease genes

“…We and others have shown that the autozygome approach can be very effective in guiding the mutation analysis (Aldahmesh et al 2009;Pomares et al 2010). Interestingly, this approach was also used successfully in populations where consanguinity is uncommon (Hildebrandt et al 2009;Collin et al 2011;Hagiwara et al 2011;Schuurs-Hoeijmakers et al 2011). However, this approach has its limitations.…”

Genomic Patterns of Homozygosity in Worldwide Human Populations

“…13 Although homozygosity mapping has been focused primarily on inbred affected individuals, recent advances potentially provide a basis for homozygosity mapping in affected individuals who are not inbred. [14][15][16][17][18] Deleterious recessive variants in such individuals might reside in smaller ROH than in inbred individuals, but in ROH nonetheless. Increased density of genotype data has enabled the detection of increasingly smaller ROH, thereby reducing the level of inbreeding required for subjects examined in homozygosity-mapping studies.…”

“…Increased density of genotype data has enabled the detection of increasingly smaller ROH, thereby reducing the level of inbreeding required for subjects examined in homozygosity-mapping studies. [14][15][16][17][18] In these studies, however, the fact that patterns of homozygosity, including ROH patterns, are influenced not only by the locations of recessive-disease loci, but also by population history and consanguinity levels, is a major consideration.…”

Biallelic mutation of HSD17B4 induces middle age–onset spinocerebellar ataxia

“…We used homozygosity fingerprinting to obtain the identity by descent (IBD). 12 Exome sequencing was performed using 2 samples from patients, 1-IV-2 and 2-IV-1 (figure 1A), as previously described. 13 More than 100,000 variants in each sample were called.…”