Mutational bias provides a model for the evolution of Huntington's disease and predicts a general increase in disease prevalence.
Huntington's disease (HD) correlates with abnormal expansion in a block of CAG repeats in the Huntington's disease gene. We have investigated HD evolution by typing CAG alleles in several human populations and in a variety of primates. We find that human alleles have expanded from a shorter ancestral state and exhibit unusual asymmetric length distributions. Computer simulations are used to show that the human state can be derived readily from a primate ancestor, without the need to invoke natural selection. The key element is a simple length-dependent mutational bias towards longer alleles. Our model can explain a number of empirical observations, and predicts an ever-increasing incidence of HD.
East Anglian Regional Genetics Service Molecular Genetics Laboratory, Addenbrooke's NHS Trust, Cambridge, UK.
D C
DC
Rubinsztein
W
W
Amos
J
J
Leggo
S
S
Goodburn
R S
RS
Ramesar
J
J
Old
R
R
Bontrop
R
R
McMahon
D E
DE
Barton
M A
MA
Ferguson-Smith
D000483:Alleles; D000818:Animals; D001483:Base Sequence; D005075:Biological Evolution; D003198:Computer Simulation; D017931:DNA Primers / Q000235:genetics; D005787:Gene Frequency; D006239:Haplotypes; D006801:Humans; D006816:Huntington Disease / Q000209:etiology / Q000235:genetics*; D015810:Linkage Disequilibrium; D008540:Meiosis / Q000235:genetics; D018598:Minisatellite Repeats; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009154:Mutation; D009838:Oligodeoxyribonucleotides / Q000235:genetics; D011323:Primates
D017931:DNA Primers; D009838:Oligodeoxyribonucleotides