Genome-wide analysis of polymorphisms affecting splicing and human disease

• Main Author: Raistrick, Christopher A.
• Published: University of Bristol 2011
• Subjects: 616.042
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.551307

Genetic polymorphism is an integral part of hereditary disease research, and cases have been demonstrated where alleles correlate with alternative splicing in pre-mRNA. A category of polymorphisms, termed splice translational efficiency polymorphisms (STEPs, classified following a discovery of such a polymorphism in the insulin gene (INS)) affect the splicing of untranslated regions leading in cases. to differential protein expression, whilst maintaining protein quality. Through the disruption of conserved splice regulatory elements, these present an unexplored mechanism for complex disease susceptibility. Studies into the conservation of the branch point sequence have suggested a degenerate sequence and location flexibility, making the confirmation of polymorphisms that may alter a branch point difficult. Further, the correlation between polymorphisms and disease is thought to indicate functionality near the associated variant. However, determining regions that are most likely to contain the functional variant is hindered by a potential for confounding where genes are selected by physical proximity in the reference sequence, instead of genetic distance (recombination interval). This misleading inference may lead to follow-up studies exploring incorrect pathways thought to be associated with a disease or trait.