Bovine proteins containing poly-glutamine repeats are often polymorphic and enriched for components of transcriptional regulatory complexes

Abstract

BackgroundAbout forty human diseases are caused by repeat instability mutations. A distinct subset of these diseases is the result of extreme expansions of polymorphic trinucleotide repeats; typically CAG repeats encoding poly-glutamine (poly-Q) tracts in proteins. Polymorphic repeat length variation is also apparent in human poly-Q encoding genes from normal individuals. As these coding sequence repeats are subject to selection in mammals, it has been suggested that normal variations in some of these typically highly conserved genes are implicated in morphological differences between species and phenotypic variations within species. At present, poly-Q encoding genes in non-human mammalian species are poorly documented, as are their functions and propensities for polymorphic variation.ResultsThe current investigation identified 178 bovine poly-Q encoding genes (Q ≥ 5) and within this group, 26 genes with orthologs in both human and mouse that did not contain poly-Q repeats. The bovine poly-Q encoding genes typically had ubiquitous expression patterns although there was bias towards expression in epithelia, brain and testes. They were also characterised by unusually large sizes. Analysis of gene ontology terms revealed that the encoded proteins were strongly enriched for functions associated with transcriptional regulation and many contributed to physical interaction networks in the nucleus where they presumably act cooperatively in transcriptional regulatory complexes. In addition, the coding sequence CAG repeats in some bovine genes impacted mRNA splicing thereby generating unusual transcriptional diversity, which in at least one instance was tissue-specific. The poly-Q encoding genes were prioritised using multiple criteria for their likelihood of being polymorphic and then the highest ranking group was experimentally tested for polymorphic variation within a cattle diversity panel. Extensive and meiotically stable variation was identified.ConclusionsTranscriptional diversity can potentially be generated in poly-Q encoding genes by the impact of CAG repeat tracts on mRNA alternative splicing. This effect, combined with the physical interactions of the encoded proteins in large transcriptional regulatory complexes suggests that polymorphic variations of proteins in these complexes have strong potential to affect phenotype.

Signatures of selection in mammalian clock genes with coding trinucleotide repeats: Implications for studying the genomics of high‐pace adaptation

“…Coding trinucleotide repeats have been observed in clock genes that facilitate the regulation of reproductive timing and social behaviors (Johnsen et al, 2007;Liedvogel & Sheldon, 2010;Liedvogel et al, 2009), genes associated with neuroprocesses (Whan et al, 2010), developmental homeobox genes, and transcription factors (Mularoni et al, 2010). For closely related species, their higher rates of mutation propose a mechanism for the convergence of pole-ward allele sizes following climate-induced range expansion.…”

Global assessment of genomic variation in cattle by genome resequencing and high-throughput genotyping

“…Of these SNPs, 1,051,772 SNPs were located inside genic regions, including 27,722 coding SNPs of which 11,545 are predicted to cause either non-synonymous amino acid substitutions in proteins or to generate gain or loss of 182 stop codons. Eighty-one SNPs were located inside transcriptional splice sites, including 46 acceptor sites and 35 donor sites, and they have the potential to cause alternative splicing transcripts [ 68 - 70 ]. Using SIFT [ 71 , 72 ] and PolyPhen [ 72 ] to predict the effect of missense mutations, we found 286 homozygous and 530 heterozygous SNPs that were predicted to be deleterious to protein function.…”

“…Thus, indels at the N- and C-termini of proteins may be less functionally constrained than indels at other protein locations. We also analyzed the possible functional importance of coding indels in genes that are known to be involved in disease (OMIM database [ 70 ]). Of the 24 indels found in 20 disease genes, 18 of the indels were not multiples of 3 n, which would induce frame shifts in these genes (Additional file 6 ).…”

Trinucleotide Repeats: A Structural Perspective

“…Additionally, a detailed analysis of the human polyQ database () (Robertson et al, 2011) also indicated that the majority of polyQ-containing proteins display domains involved in development (Homeobox domain-containing proteins, Fibroblast growth factor receptor), chromatin remodeling (Bromodomain and PHD-containing proteins), and signal transduction (PDZ domain-containing proteins), all biological processes that are highly dependent on protein–protein interactions and associated with the formation of multicomponent protein complexes. As for humans, analysis of bovine polyQ proteins revealed an enrichment for large multi-domain transcriptional regulators (Whan et al, 2010). …”

“…It is currently accepted that the majority of repeat-containing proteins perform roles in processes that require the assembly of large multiprotein or protein/nucleic acid complexes (Faux et al, 2005; Hancock and Simon, 2005; Whan et al, 2010). Supporting this notion is the fact that homopolymeric amino acid-repeats are considered to be unstructured (Gojobori and Ueda, 2011) and that intrinsically unstructured regions are suggested to constitute macromolecular docking sites, which become structured only when bound to cognate ligand partners (Huntley and Golding, 2002; Simon and Hancock, 2009).…”