The evolutionary history of the polyQ tract in huntingtin sheds light on its functional pro-neural activities

Abstract

Huntington’s disease is caused by a pathologically long (>35) CAG repeat located in the first exon of the Huntingtin gene (HTT). While pathologically expanded CAG repeats are the focus of extensive investigations, non-pathogenic CAG tracts in protein-coding genes are less well characterized. Here, we investigated the function and evolution of the physiological CAG tract in the HTT gene. We show that the poly-glutamine (polyQ) tract encoded by CAGs in the huntingtin protein (HTT) is under purifying selection and subjected to stronger selective pressures than CAG-encoded polyQ tracts in other proteins. For natural selection to operate, the polyQ must perform a function. By combining genome-edited mouse embryonic stem cells and cell assays, we show that small variations in HTT polyQ lengths significantly correlate with cells’ neurogenic potential and with changes in the gene transcription network governing neuronal function. We conclude that during evolution natural selection promotes the conservation and purity of the CAG-encoded polyQ tract and that small increases in its physiological length influence neural functions of HTT. We propose that these changes in HTT polyQ length contribute to evolutionary fitness including potentially to the development of a more complex nervous system.

Common huntingtin-related genetic variation is associated with neurobiological and aging traits in humans

“…Specifically, it was proposed that longer non-pathogenic CAG tracts increase neurogenic potential, alter transcription networks responsible for neuronal function and contribute to evolutionary fitness. These findings support the notion that non-pathogenic HTT plays a vital neurological role in humans [ 5 ].…”

“…CAG repeat length is variable in humans, individuals affected by HD have an expansion of 36 or more CAG repeats [ 4 ]. Therefore, we read with interest the recent study by Iennaco et al, which examined the function and evolutionary aspects of non-pathogenic HTT CAG repeats [ 5 ].…”

Multi-OMIC analysis of Huntington disease reveals a neuroprotective astrocyte state

“…Although the disease-causing mutation is present in all brain cells, the severity of the disease varies across brain regions 5, 6 . New evidence suggests that the CAG repeats in exon 1 of the Huntingtin gene ( HTT ) can expand during the lifetime of the organism, and in different cell types at different rates, which may contribute to disease progression 8–11 . Moreover, research implicates mutant HTT (mHTT) expression in cortical and striatal neurons as a necessary substrate for striatal neurodegeneration 12 .…”

Insights on Microsatellite Characteristics, Evolution, and Function From the Social Amoeba Dictyostelium discoideum

“…Because of this Dictyostelium may serve as an interesting organism to use in studying the effects of the presence and absence of polyglutamine tracts in the HTT protein. Dictyostelium may also serve as an ideal model to assess the impacts of polyglutamine tract length on protein function, a topic of interest in recent studies ( Iennaco et al, 2022 ).…”