Huntington’s Disease’s Exclusivity to Humans from an Evolutionary Perspective

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by CAG repeat expansions in the huntingtin gene (HTT). Despite the evolutionary conservation of HTT across vertebrates, HD manifests almost exclusively in humans, yet the mechanisms remain poorly understood. This review aims to provide insight into why Huntington's disease is fundamentally a human affliction, despite the widespread presence of the HTT gene across species. By examining comparative aspects of huntingtin protein structure, CAG repeat stability, and expansion mechanisms between humans, our closest primate relatives, and other mammalian species, this review explores potential explanations for why only humans develop HD. Synthesis of peer-reviewed literature was conducted using Google Scholar and PubMed, supplemented by a comparative analysis of polyglutamine repeats across 10 mammalian genomes using UniProt. Collectively, the evidence suggests that humans possess a distinctly elongated and unstable CAG repeat, and that human-specific variations in DNA mismatch repair mechanisms may drive progressive somatic expansion within susceptible neurons. These findings support the hypothesis that evolutionary changes in the human HTT gene may have created an unintended susceptibility to Huntington’s disease while identifying promising directions for future research.