Human Genetics

, Volume 114, Issue 4, pp 366–376 | Cite as

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

  • Amos FrischEmail author
  • Roberto ColomboEmail author
  • Elena Michaelovsky
  • Mazal Karpati
  • Boleslaw Goldman
  • Leah Peleg
Original Investigation


The 1278insTATC is the most prevalent β-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.


Linkage Disequilibrium Gauche Disease Linkage Disequilibrium Analysis Much Recent Common Ancestor Ancestral Haplotype 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



This study was supported by a grant from the CARIPLO Foundation (to R.C.). We thank Angelo A. Bignamini (Milan) for advice regarding statistical analysis.


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Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Amos Frisch
    • 1
    • 2
    Email author
  • Roberto Colombo
    • 3
    Email author
  • Elena Michaelovsky
    • 1
    • 2
  • Mazal Karpati
    • 2
    • 4
  • Boleslaw Goldman
    • 2
    • 4
  • Leah Peleg
    • 2
    • 4
  1. 1.Felsenstein Medical Research CenterRabin Medical CenterPetah Tikva Israel
  2. 2.Sackler Faculty of MedicineTel-Aviv UniversityTel-AvivIsrael
  3. 3.Laboratory of Human Molecular Biology and Genetics, Faculty of PsychologyCatholic University of the Sacred HeartMilanItaly
  4. 4.Danek Gertner Institute of Human GeneticsSheba Medical CenterTel-HashomerIsrael

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