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

peer-reviewedBackground: About 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. Results: The 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. Conclusions: Transcriptional 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.Dairy Australia (through the Innovative Dairy Cooperative Research Center

Biochemical and molecular genetics of cystic fibrosis

Cystic fibrosis (CF) is the most common severe recessive genetic disorder in the Caucasian population. In 1938, D. H. Anderson provided the first comprehensive description of the disease and also introduced the name “cystic fibrosis of the pancreas.” Patients with CF suffer from excessive mucus accumulation resulting in severe clinical consequences in the respiratory, gastrointestinal, and genitourinary tracts (see Table I). All these symptoms are consistent with defects of exocrine glands, as suggested by S. Farber in 1945; he called the disease “mucoviscidosis,” a name still popular in some parts of continental Europe. CF patients also have elevated electrolyte levels in their sweat, an observation which, first described by di Sant’Agnese et al. (1953), became the hallmark for CF diagnosis.link_to_subscribed_fulltex