Multiple local and recent founder effects of TGM1 in spanish families

Abstract

ackground:Mutations in theTGM1gene encoding transglutaminase 1 are a major cause of autosomal recessivecongenital ichthyosis. In the Galician (NW Spain) population, three mutations, c.2278C.T, c.1223_1227delACAC andc.984+1G.A, were observed at high frequency, representing,46%,,21% and,13% of allTGM1gene mutations,respectively. Moreover, these mutations were reported only once outside of Galicia, pointing to the existence of historicalepisodes of local severe genetic drift in this region.Methodology/Principal Findings:In order to determine whether these mutations were inherited from a common ancestorin the Galician population, and to estimate the number of generations since their initial appearance, we carried out ahaplotype-based analysis by way of genotyping 21 SNPs within and flanking theTGM1gene and 10 flanking polymorphicmicrosatellite markers spanning a region of 12 Mb. Two linkage disequilibrium based methods were used to estimate thetime to the most recent common ancestor (TMRCA), while a Bayesian-based procedure was used to estimate the age of thetwo mutations. Haplotype reconstruction from unphased genotypes of all members of the affected pedigrees indicated thatall carriers for each of the two mutations harbored the same haplotypes, indicating common ancestry.Conclusions/Significance:In good agreement with the documentation record and the census, both mutations arosebetween 2,800–2,900 years ago (y.a.), but their TMRCA was in the range 600–1,290 y.a., pointing to the existence ofhistorical bottlenecks in the region followed by population growth. This demographic scenario finds further support on aBayesian Coalescent Analysis based onTGM1haplotypes that allowed estimating the occurrence of a dramatic reduction ofeffective population size around 900–4,500 y.a. (95% highest posterior density) followed by exponential growth.