Mutational bias provides a model for the evolution of Huntington's disease and predicts a general increase in disease prevalence

Abstract

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.

Haplotype analysis of the CAG and CCG repeats in 21 Brazilian families with Huntington’s disease

“…29 The allelic diversity of CCG repeats is much lower than that of CAG repeats, indicating a lower overall mutation rate. 30 An intergenerational Brazilian study 14 found that five CAG alleles had a greater number of repeats (new expansions) and were inherited paternally, and two new expansions were inherited from the mother. On the other hand, only one CAG allele had fewer repeats (new contraction) and was inherited maternally.…”

“…33,34 The mutational bias model for the evolution of HD predicts an ever-increasing incidence of HD. 30 This model says that the allele frequency distributions we see today are not endpoints but a snapshot in an on-going process of gradual expansion. According to the model, the incidence of HD will accelerate because mutation towards detrimental repeat lengths happens over the course of several generations.…”

“…According to the model, the incidence of HD will accelerate because mutation towards detrimental repeat lengths happens over the course of several generations. 30 Rubinsztein et al 30 have speculated that single repeat units are gained and lost with equal frequency but that larger blocks are more likely to be gained rather than lost. This would provide a possible mechanism to link mutational bias, mutation rate and length dependency.…”

“…This would provide a possible mechanism to link mutational bias, mutation rate and length dependency. 30 Haplotype analysis demonstrated that certain normal chromosomes, with CAG lengths at the high range of normal, are prone to further expansion and eventually result in HD chromosomes. Analysis of normal chromosomes in different populations suggests that genetic factors contribute to CAG expansion and account for the worldwide variation in HD prevalence.…”

Huntington disease in the South African population occurs on diverse and ethnically distinct genetic haplotypes

“…15 The prevalence of HD in any population is thought to be the result of a balance between the incidence of de novo mutations and the loss of HD alleles due to negative selection of very large CAG tracts that result in juvenile-onset HD. 29 The new mutation rate has been estimated at approximately 10%. 30,31 Factors influencing the expansion of the CAG tract are therefore of crucial importance for determining HD prevalence rates.…”