title: 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.
authors.affiliation: Department of Respiratory Medicine, Saitama Medical University, Moroyama, Saitama, Japan. hagiwark@saitama-med.ac.jp
authors.forename: Koichi
authors.initials: K
authors.lastname: Hagiwara
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Morino
authors.forename: Jun
authors.initials: J
authors.lastname: Shiihara
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Tanaka
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Miyazawa
authors.forename: Tomoko
authors.initials: T
authors.lastname: Suzuki
authors.forename: Masakazu
authors.initials: M
authors.lastname: Kohda
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Okazaki
authors.forename: Kuniaki
authors.initials: K
authors.lastname: Seyama
authors.forename: Hideshi
authors.initials: H
authors.lastname: Kawakami
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D002874:Chromosome Mapping; D003241:Consanguinity; D005808:Genes, Recessive; D006239:Haplotypes / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D055815:Young Adult; D019896:alpha 1-Antitrypsin Deficiency / Q000235:genetics*