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Evolutionary Theories of Huntington's Disease

Relaxed Selection

In 1908, geneticist Reginald Punnett confirmed Huntington's Disease’s dominant mode of inheritance, an idea originally published by George Huntington in his influential paper “On Chorea.” Although the dominant disease allele cannot benefit from heterozygote advantage, HD has persisted throughout history. This led researchers in the 20th century to investigate evolutionary mechanisms that maintained Huntington's Disease in populations. In 1941, Geneticist J.B.S Haldane proposed that deleterious alleles, such as the ones which result in HD, escape natural selection because disease symptoms only manifest after childbearing years. In this theory, natural selection's pressure on HD is significantly "relaxed," as HD does not impact an individual's reproductive years. With support from Nobel Prize winning immunologist Peter Medawar in 1946, this theory revolutionized the perspective of aging as a phenomena in which harmful genes accumulate due to relaxed selection, rather than any physiological causes.

Age of Onset

In a study by Wexler et al., researchers demonstrated an inverse relationship between number of CAG trinucleotide repeats and the age of onset. The trend indicates that greater numbers of CAG repeats led to earlier onset of HD symptoms in individuals. The likelihood of developing symptoms before the age of 20 increased in people with the largest number of repeats, which is characteristic of juvenile or early onset HD. These effects do not appear to discriminate between genders. Wexler and colleagues also suggested that while CAG repeats contribute significantly to the age of onset, other inherited genetic factors and family environmental effects also play a role; the extent of their influence provides a potential area of further research.

Founder Effect

The founder effect, an idea proposed by Ernst Mayr in 1969, impacted the spread of HD throughout history. As populations with the HD gene migrated, established new isolated colonies, and reproduced, they passed on the dominant disease allele. This migration of small subsets of people with the HD allele spread to certain parts of the world. For example, the unusually high prevalence of HD in parts of South Africa can be traced back to a Dutch founder that migrated with the founding population, who subsequently passed on the disease genes to most of the descendents with HD in that area. In another part of the world, Nancy Wexler and her research team investigated the high prevalence of HD in Lake Maracaibo, Venezuela in the early 1980’s. Her team found that the causal gene again traces back to a single founder, Maria Concepcion, who passed on her disease allele to a majority of the people afflicted with HD in that area.