Origin and spread of the 1278insTATC mutation causing Tay-Sachs disease in Ashkenazi Jews: genetic drift as a robust and parsimonious hypothesis

Abstract

The 1278insTATC is the most prevalent beta-hexosaminidase A ( HEXA) gene mutation causing Tay-Sachs disease (TSD), one of the four lysosomal storage diseases (LSDs) occurring at elevated frequencies among Ashkenazi Jews (AJs). To investigate the genetic history of this mutation in the AJ population, a conserved haplotype (D15S981:175-D15S131:240-D15S1050:284-D15S197:144-D15S188:418) was identified in 1278insTATC chromosomes from 55 unrelated AJ individuals (15 homozygotes and 40 heterozygotes for the TSD mutation), suggesting the occurrence of a common founder. When two methods were used for analysis of linkage disequilibrium (LD) between flanking polymorphic markers and the disease locus and for the study of the decay of LD over time, the estimated age of the insertion was found to be 40+/-12 generations (95% confidence interval: 30-50 generations), so that the most recent common ancestor of the mutation-bearing chromosomes would date to the 8th-9th century. This corresponds with the demographic expansion of AJs in central Europe, following the founding of the Ashkenaz settlement in the early Middle Ages. The results are consistent with the geographic distribution of the main TSD mutation, 1278insTATC being more common in central Europe, and with the coalescent times of mutations causing two other LSDs, Gaucher disease and mucolipidosis type IV. Evidence for the absence of a determinant positive selection (heterozygote advantage) over the mutation is provided by a comparison between the estimated age of 1278insTATC and the probability of the current AJ frequency of the mutant allele as a function of its age, calculated by use of a branching-process model. Therefore, the founder effect in a rapidly expanding population arising from a bottleneck provides a robust parsimonious hypothesis explaining the spread of 1278insTATC-linked TSD in AJ individuals.

Tay-Sachs disease preconception screening in Australia: self-knowledge of being an Ashkenazi Jew predicts carrier state better than does ancestral origin, although there is an increased risk for c.1421 + 1G > C mutation in individuals with South African heritage

“…Although it is therefore not possible to determine the ethnicity of any students who may have refused testing, given the very small number of students declining testing the potential for a negative ascertainment bias on this basis is extremely unlikely to have influenced our findings. Frisch et al (2004) identified a conserved c.1278insTATC haplotype in 55 unrelated AJ individuals, suggesting the occurrence of a common founder in Central Europe. The c.1278insTATC mutation was diagnosed in 73.2% of Australian carriers (Sydney, 69.8%; Melbourne, 81.0%), comparable to the figure of 70-82% reported in other AJ populations (Peleg et al 1994;Grebner and Tomczak 1991;Paw et al 1990;Myerowitz and Costigan 1988).…”

“…The most likely explanation for the origin of multiple HEXA mutations in AJ populations is that they arose around 1100 AD by founder effect and genetic drift (Slatkin 2004;Durst et al 2001;Risch et al 1995;Goldstein et al 1999;Niell et al 2003;Frisch et al 2004). Four independent sphingolipid storage diseases have arisen in the AJ population (TSD, Niemann-Pick disease, Gaucher disease, and mucolipidosis type IV) leading some investigators to hypothesize a heterozygote advantage (Zlotogora et al 1988;Motulsky 1995;Myrianthopoulos and Melnick 1977).…”

The mystery of the mystery of common genetic diseases

“…Significant differences in the European geographic distribution of mutation frequencies for LSDs versus non-LSDs would support the hypothesis that special selective forces have operated on the former. However, this is not the case in GD [Gaucher disease], NPD [Niemann-Pick disease], and TSD [Tay Sachs disease] (Risch et al 2003), and the lack of such geographic differences supports genetic drift as the primary determinant of disease mutations among AJs (Frisch, et al 2004). …”

“…As is laid out in the above block quote by Frisch et al (2004), the problem of phenomenon choice is a major obstacle to debate between the conflicting selectionist (HA) and stochastic (RGD/FE) camps. But the problem of phenomenon choice does not prevent all progress.…”

“…Alternative solutions cannot be constructed in the forms of ''this evolutionary model for the 1278insTATC mutation of TS predicts that…'' (Frisch et al 2004) or ''the likelihood that several lysosomal storage disorders suggests that natural selection must…'' (Diamond 1988). Statements such as these have bearing on the 'why' question at hand, but they are not candidate explanations for it.…”