Polymorphism, shared functions and convergent evolution of genes with sequences coding for polyalanine domains

Abstract

Mutations causing expansions of polyalanine domains are responsible for nine hereditary diseases. Other GC-rich sequences coding for some polyalanine domains were found to be polymorphic in human. These observations prompted us to identify all sequences in the human genome coding for polyalanine stretches longer than four alanines and establish their degree of polymorphism. We identified 494 annotated human proteins containing 604 polyalanine domains. Thirty-two percent (31/98) of tested sequences coding for more than seven alanines were polymorphic. The length of the polyalanine-coding sequence and its GCG or GCC repeat content are the major predictors of polymorphism. GCG codons are over-represented in human polyalanine coding sequences. Our data suggest that GCG and GCC codons play a key role in polyalanine-coding sequence appearance and polymorphism. The grouping by shared function of polyalanine-containing proteins in Homo sapiens, Drosophila melanogaster and Caenorhabditis elegans shows that the majority are involved in transcriptional regulation. Phylogenetic analyses of HOX, GATA and EVX protein families demonstrate that polyalanine domains arose independently in different members of these families, suggesting that convergent molecular evolution may have played a role. Finally polyalanine domains in vertebrates are conserved between mammals and are rarer and shorter in Gallus gallus and Danio rerio. Together our results show that the polymorphic nature of sequences coding for polyalanine domains makes them prime candidates for mutations in hereditary diseases and suggests that they have appeared in many different protein families through convergent evolution.

A Genomic Basis for the Evolution of Vertebrate Transcription Factors Containing Amino Acid Runs

“…The latter were included as they basically lack runs. This characteristic is not specific to Hox proteins Lavoie et al 2003) and could be driven by forces acting on the genome and not on the protein structure itself at first place. The human HOX set included 20 ORFs containing AGPH runs while 13 lacked any run.…”

“…Comparative genomics of amino acid runs in Hox evolution: To illustrate our previous conclusions about the genomic impact on polyAla generation, we focused on homeobox proteins since they constitute the largest single functional group of polyAla proteins in humans (49/494; Lavoie et al 2003). In addition, this family is involved in major developmental processes.…”

“…In addition, this family is involved in major developmental processes. Human Hoxs are distributed in four paralogous clusters (A-D; Ruddle et al 1994;Gehring et al 1994; Finnerty and Martindale 1998) and carry polyAla (and other repeats) that have appeared independently in various paralogs (Lavoie et al 2003). The appearance of a polyAla domain may underlie changes in Hox activity.…”

“…In 2B, and MSH3; Lavoie et al 2003). However, we have recently shown that imperfect repeats can also arise as the case of humans, the most frequently encouna result of polymerase slippage in regions of strong tered amino acids in homopolymeric tracts are glutasecondary structure (De Baere et al 2002, 2003.…”

Evolutionary appearance of mononucleotide repeats in the coding sequences of four genes in primates

“…The driving force of the expansion of homopolymeric runs might be the polymerase slippage process. It has been proposed that slipped strand replication is a major force in the evolution of genes and genomes (Dechering et al 1998), and it has been implicated in a large number of human genetic diseases (Lavoie et al 2003).…”