MUTYH-associated polyposis (MAP): evidence for the origin of the common European mutations p.Tyr179Cys and p.Gly396Asp by founder events

Abstract

MUTYH-associated polyposis (MAP) is an autosomal recessive adenomatous polyposis caused by biallelic germline mutations of the base-excision-repair gene MUTYH. In MAP patients of European origin, the combined allele frequency of the mutations p.Tyr179Cys and p.Gly396Asp ranges between 50 and 82%, while these mutations have not been identified in Far Eastern Asian populations, supporting the hypothesis that a founder effect has occurred at some point in European history. To investigate the natural history of the two common European MUTYH alleles, we genotyped six gene-flanking microsatellite markers in 80 unrelated Italian and German MAP patients segregating one or both mutations and calculated their age in generations (g) by using DMLE+2.2 software. Three distinct common haplotypes, one for p.Tyr179Cys and two for p.Gly396Asp, were identified. Estimated mutation ages were 305 g (95% CS: 271-418) for p.Tyr179Cys and 350 g (95% CS: 313-435) for p.Gly396Asp. These results provide evidence for strong founder effects and suggest that the p.Tyr179Cys and p.Gly396Asp mutations derive from ancestors who lived between 5-8 thousand years and 6-9 thousand years B.C., respectively.

Figure 1

Haplotype branching trees of p.Tyr179Cys (right) and p.Gly396Asp (left) chromosomes in Italian (top panels) and German (bottom panels) families. The markers used are shown according to their position on the physical map (UCSC Genome Browser Feb. 2009 GRCh37/h19). Boxed numbers indicate STR alleles comprised in the ancestral haplotypes; for p.Gly396Asp, the two most common haplotypes (A and B) are indicated by solid and dashed lines, respectively; non boxed numbers correspond to additional alleles detected in the study families. Family codes are indicated above or below alleles in which they have been identified; for each family, the number of chromosomes with the corresponding allele is indicated as × 1 (1 copy) or × 2 (2 copies).

Figure 2

Posterior probability distribution plots of p.Tyr179Cys and p.Gly396Asp ages (in generations), as estimated by DMLE+2.2 software using a population growth rate (^genr) of 0.034. (a) Age estimate in the Italian population for p.Tyr179Cys (fc=0.00016); (b) age estimate in the German population for p.Tyr179Cys (fc=0.00012); (c) age estimate for p.Tyr179Cys using combined data from both populations (fc=0.00014); (d) age estimate in the Italian population for p.Gly396Asp (fc=0.00004); (e) age estimate in the German population for p.Gly396Asp (fc=0.000047); (f) age estimate for p.Gly396Asp using combined data from both populations (fc=0.000043). The vertical broken lines indicate the 95% credible set values.