RCPdb: An evolutionary classification and codon usage database for repeat-containing proteins

Abstract

Over 3% of human proteins contain single amino acid repeats (repeat-containing proteins, RCPs). Many repeats (homopeptides) localize to important proteins involved in transcription, and the expansion of certain repeats, in particular poly-Q and poly-A tracts, can also lead to the development of neurological diseases. Previous studies have suggested that the homopeptide makeup is a result of the presence of G+C-rich tracts in the encoding genes and that expansion occurs via replication slippage. Here, we have performed a large-scale genomic analysis of the variation of the genes encoding RCPs in 13 species and present these data in an online database (http://repeats.med.monash.edu.au/genetic_analysis/). This resource allows rapid comparison and analysis of RCPs, homopeptides, and their underlying genetic tracts across the eukaryotic species considered. We report three major findings. First, there is a bias for a small subset of codons being reiterated within homopeptides, and there is no G+C or A+T bias relative to the organism’s transcriptome. Second, single base pair transversions from the homocodon are unusually common and may represent a mechanism of reducing the rate of homopeptide mutations. Third, homopeptides that are conserved across different species lie within regions that are under stronger purifying selection in contrast to nonconserved homopeptides.

The EDGE hypothesis: Epigenetically directed genetic errors in repeat-containing proteins (RCPs) involved in evolution, neuroendocrine signaling, and cancer

“…Comparison of the rank order of the biological process and the functional classifications between groups A and B did not reveal any such bias. [70] A key prediction of Fondon and Garner's model for rapid morphological evolution is that transcription factors and other developmental genes must have trinucleotide repeats in the coding regions for them to be highly evolvable [31]. A recent paper by Faux and colleagues, quoted above, presented evidence that they conclude does not support Fondon and Garner's hypothesis [70].…”

“…As quoted in the lead to this section, their analyses "did not reveal any such bias" [70]. The reason we argue that Fondon and Garner's hypothesis predicts that Group A would show a higher bias for the GO category "development" than Group B is that expansions and contractions of a "conserved" repeat (i.e., the homopeptide is in the same location across all three species) would drive morphological evolution.…”

“…Faux et al argued that one way to test Fondon and Garner's hypothesis that expansions and contractions are particularly important in developmental genes is to determine whether there is any bias in the rank order of GO categories in Group A (conserved RCPs) compared with Group B (non-conserved RCPs) in humans, mice, and rats [70]. As quoted in the lead to this section, their analyses "did not reveal any such bias" [70].…”

“…[70] A key prediction of Fondon and Garner's model for rapid morphological evolution is that transcription factors and other developmental genes must have trinucleotide repeats in the coding regions for them to be highly evolvable [31]. A recent paper by Faux and colleagues, quoted above, presented evidence that they conclude does not support Fondon and Garner's hypothesis [70]. However, we argue that reinterpretation of their data and more extensive clustering analyses presented below do, in fact, support the hypothesis.…”

“…[70] Faux et al determined that the primary GO categories of RCPs in Group A were in: 1) "physiological processes" (35%), 2) "regulation of biological process" (26%), 3) "development" (15%), 4) "cellular process" (14%), 5) "biological process unknown" (5%), 6) "response to stimulus" (2%), and 7) "growth" (2%) [70]. The primary GO categories of RCPs in Group B were in:1) "physiological processes" (34%), 2) "regulation of biological process" (22%), 3) "cellular process" (15%), 4) "biological process unknown" (14%), 5) "development" (9%), and 6) "response to stimulus" (3%) [70]. All of the other GO categories were represented in less than 1% of the RCPs.…”