PolyQ length co-evolution in neural proteins

Abstract

Intermolecular co-evolution optimizes physiological performance in functionally related proteins, ultimately increasing molecular co-adaptation and evolutionary fitness. Polyglutamine (polyQ) repeats, which are over-represented in nervous system-related proteins, are increasingly recognized as length-dependent regulators of protein function and interactions, and their length variation contributes to intraspecific phenotypic variability and interspecific divergence. However, it is unclear whether polyQ repeat lengths evolve independently in each protein or rather co-evolve across functionally related protein pairs and networks, as in an integrated regulatory system. To address this issue, we investigated here the length evolution and co-evolution of polyQ repeats in clusters of functionally related and physically interacting neural proteins in Primates. We observed function-/disease-related polyQ repeat enrichment and evolutionary hypervariability in specific neural protein clusters, particularly in the neurocognitive and neuropsychiatric domains. Notably, these analyses detected extensive patterns of intermolecular polyQ length co-evolution in pairs and clusters of functionally related, physically interacting proteins. Moreover, they revealed both direct and inverse polyQ length co-variation in protein pairs, together with complex patterns of coordinated repeat variation in entire polyQ protein sets. These findings uncover a whole system of co-evolving polyQ repeats in neural proteins with direct implications for understanding polyQ-dependent phenotypic variability, neurocognitive evolution and neuropsychiatric disease pathogenesis.

PolyQ length-based molecular encoding of vocalization frequency in FOXP2

“…PolyQ repeats are enriched in human proteins with speech- and language-related roles like FOXP2, 41 suggesting a potential effect of polyQ length variation on vocalization-/speech-related molecular and organismal phenotypes, consistent with initial observations of FOXP2 polyQ length variants in humans and other primates. 42 , 43 However, the full range of evolutionary polyQ length variation in FOXP2, and its possible structural and functional impact, are not yet defined.…”

“…A growing body of evidence indicates that polyQ repeats are enriched in neural proteins, displaying complex evolutionary dynamics throughout phylogenesis. 36 , 40 , 41 , 111 The evidence of convergent evolution adds a novel element to our appreciation of the complex evolutionary history of polyQ repeats.…”

“… 32 , 36 , 37 , 38 , 39 , 40 Thus, quantitative analyses of amino acid repeats, in terms of occurrence rate, length, and length ratios, can help characterize molecular evolution processes. 36 , 39 , 40 , 41 …”

Structure–function relationships in protein homorepeats

“…Computational analysis of their sequence context in proteins and some experimental evidence suggest that polyQ have a function in extending the conformation of an adjacent N-terminal coiled coil region upon its interaction with the coiled coil of another protein [19,46]. This would explain why genetic mutations changing the length of the polyQ could affect their interactome resulting in pathogenic interactions and aggregates [30,47]. Indeed, nine inherited human diseases have been lined to aberrant expansion of polyQ and subsequent amyloid formation [17].…”