Human-specific splicing regulation in neurogenesis and disease

Duke University, Durham NC

Investigators

Abstract

Project Summary The cortex is responsible for many of our uniquely human cognitive abilities and distinguishes our closest evolutionary relatives. Humans diverged from chimpanzees ~7mya and have accumulated several genomic differences that could help explain human-specific aspects of cortical development. Many of the genomic differences between humans and chimpanzees are in non-coding elements where they have been traditionally studied as regulators of gene expression. In this proposal, I provide preliminary evidence that indicates additional roles for these human-specific sequences in post-transcriptional gene expression. Over 40% of these human- specific sequences are found within introns where I hypothesize, they contribute to the regulation of splicing during human-specific neurodevelopment. In Aim 1, I will test the function of intronic human-specific sequences to enhance and repress splice sites and ultimately alter species-specific isoform expression. Next as a proof of concept, in Aim 2 I will investigate the consequences of changes in splicing and isoform production in neurodevelopment. Specifically, I will be testing changes in splicing associated with an Autism-associated SNP in the intron of Tenascin C (TNC). The SNP is located in a human-specific sequence and reverts the intronic sequence back towards the chimpanzee sequence. The proposed research will define a novel mechanism of action for human-specific non-coding regions of the genome in the regulation of post-transcriptional RNA processing during cortical development and disease.