Compound Dynamics and Combinatorial Patterns of Amino Acid Repeats Encode a System of Evolutionary and Developmental Markers

Abstract

Homopolymeric amino acid repeats (AARs) like polyalanine (polyA) and polyglutamine (polyQ) in some developmental proteins (DPs) regulate certain aspects of organismal morphology and behavior, suggesting an evolutionary role for AARs as developmental “tuning knobs.” It is still unclear, however, whether these are occasional protein-specific phenomena or hints at the existence of a whole AAR-based regulatory system in DPs. Using novel approaches to trace their functional and evolutionary history, we find quantitative evidence supporting a generalized, combinatorial role of AARs in developmental processes with evolutionary implications. We observe nonrandom AAR distributions and combinations in HOX and other DPs, as well as in their interactomes, defining elements of a proteome-wide combinatorial functional code whereby different AARs and their combinations appear preferentially in proteins involved in the development of specific organs/systems. Such functional associations can be either static or display detectable evolutionary dynamics. These findings suggest that progressive changes in AAR occurrence/combination, by altering embryonic development, may have contributed to taxonomic divergence, leaving detectable traces in the evolutionary history of proteomes. Consistent with this hypothesis, we find that the evolutionary trajectories of the 20 AARs in eukaryotic proteomes are highly interrelated and their individual or compound dynamics can sharply mark taxonomic boundaries, or display clock-like trends, carrying overall a strong phylogenetic signal. These findings provide quantitative evidence and an interpretive framework outlining a combinatorial system of AARs whose compound dynamics mark at the same time DP functions and evolutionary transitions.

PolyQ length co-evolution in neural proteins

“…The complete proteome of Homo sapiens was downloaded from Uniprot (uniprot.org) and polyQ repeats of four or more glutamine residues were detected using a previously developed script ( 5 ). In proteins with multiple repeats, the total polyQ length was calculated as the sum of all the individual repeat lengths.…”

“…The GWAS Catalog entries were filtered to include only intragenic SNP and insertion/deletion (indel) mutations, either coding or non-coding, thus excluding intergenic mutations or non-univocal gene-phenotype/-disease associations. These lists of terms and associated genes were analyzed using ad hoc Perl scripts ( 5 ) to select terms/associations of interest based on string/keyword matching. A list of text strings and keywords of interest covering the major aspects of neural pathophysiology (e.g.…”

“…We also downloaded the gene/protein IDs of the available orthologs of human polyQ proteins in 22 primate species ( Pan troglodytes (Pan tro), Pan paniscus (Pan pan), Gorilla gorilla (Gor gor), Pongo abelii (Pon abe), Nomascus leucogenys (Nom leu), Mandrillus leucophaeus (Man leu), Cercocebus atys (Cer aty), Papio anubis (Pap anu), Macaca nemestrina (Mac nem), Macaca mulatta (Mac mul), Macaca fascicularis (Mac fas), Chlorocebus sabaeus (Chl sab), Rhinopithechus roxellana (Rhi rox), Rhinopithechus bieti (Rhi bie), Colobus angolensis (Col ang), Saimiri boliviensis (Sai bol), Cebus capucinus (Ceb cap), Callithrix jacchus (Cal jac), Aotus nancymae (Aot nan), Tarsius/Carlito syrichta (Tar syr), Propithechus coquereli (Pro coq), Otolemur garnettii (Oto gar)) belonging to the major taxonomic groups of Primates, including only orthologs coded as ‘ one-to-one ’ in the database, that we combined in a single orthology table. The primate proteomes were then analyzed to identify polyQ repeats and quantify their total length in each ortholog protein, as described above for the human proteome ( 5 ). For each polyQ protein, we also calculated the coefficient of variation of the total repeat length (CV rl ) across orthologs, counting proteins with either phylogenetically constant (i.e.…”

“…Homopolymeric amino acid repeats (AARs), such as polyglutamine (polyQ), are increasingly recognized as mediators and regulators of protein function, interactions and evolution (e.g. 1 , 2 , 3 , 4 , 5 , 6 , 7 ). AAR length variation in proteins contributes to intraspecific phenotypic variability and interspecific divergence ( 3 , 5 , 7 , 8 , 9 , 10 , 11 ).…”

“… 4 , 7 ), their functional roles in higher-order biological processes at the organismal level, and their involvement in human diseases besides expansion-related disorders ( 13 ), are still not clearly understood. PolyQ repeats occur frequently in proteins involved in the development of the nervous system ( 12 ) with some degree of regional specificity ( 5 ), suggesting that polyQ variation may have a considerable impact on neural development and evolution. However, the overall functional meaning and quantitative dynamics of the complex, proteome-wide evolutionary variation patterns of polyQ stretches remain largely obscure.…”