MUTYH-associated polyposis (MAP): evidence for the origin of the common European mutations p.Tyr179Cys and p.Gly396Asp by founder events.
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.
Institute of Human Genetics, University Hospital of Bonn, Bonn, Germany.
Stefan
S
Aretz
Department of Clinical Pathophysiology, University of Florence, Medical Genetics Unit, Florence, Italy.
Rossella
R
Tricarico
Department of Clinical Pathophysiology, University of Florence, Medical Genetics Unit, Florence, Italy.
Laura
L
Papi
Institute of Human Genetics, University Hospital of Bonn, Bonn, Germany.
Isabel
I
Spier
Experimental Oncology 1, Centro di Riferimento Oncologico IRCCS, Aviano, Italy.
Elisa
E
Pin
Institute of Human Genetics, University Hospital of Bonn, Bonn, Germany.
Sukanya
S
Horpaopan
Institute of Medical Genetics, Catholic University, Rome, Italy.
Emanuela Lucci
EL
Cordisco
Department of Diagnostic and Clinical Medicine and Public Health, University of Modena and Reggio Emilia, Modena, Italy.
Monica
M
Pedroni
Institute of Human Genetics, University Hospital of Bonn, Bonn, Germany.
Dietlinde
D
Stienen
Department and Laboratory of Gastroenterology, Scientific Institute and Regional General Hospital, San Giovanni Rotondo, Italy.
Annamaria
A
Gentile
Department and Laboratory of Gastroenterology, Scientific Institute and Regional General Hospital, San Giovanni Rotondo, Italy.
Anna
A
Panza
Department and Laboratory of Gastroenterology, Scientific Institute and Regional General Hospital, San Giovanni Rotondo, Italy.
Ada
A
Piepoli
Department of Diagnostic and Clinical Medicine and Public Health, University of Modena and Reggio Emilia, Modena, Italy.
Maurizio Ponz
MP
de Leon
Institute of Human Genetics, University Hospital of Bonn, Bonn, Germany.
Waltraut
W
Friedl
Experimental Oncology 1, Centro di Riferimento Oncologico IRCCS, Aviano, Italy.
Alessandra
A
Viel
1] Department of Clinical Pathophysiology, University of Florence, Medical Genetics Unit, Florence, Italy [2] Fiorgen Foundation for Pharmacogenomics, Sesto Fiorentino, Italy.
Maurizio
M
Genuardi
D011125:Adenomatous Polyposis Coli / Q000235:genetics*; D000483:Alleles; D000818:Animals; D045647:DNA Glycosylases / Q000235:genetics*; D005260:Female; D018703:Founder Effect; D005787:Gene Frequency; D005858:Germany; D006801:Humans; D007558:Italy; D008297:Male; D020125:Mutation, Missense
D045647:DNA Glycosylases; C061738:mutY adenine glycosylase