Alternative splicing in mammalian brain
- Author(s): Zhang, Yida
- Advisor(s): Xing, Yi
- et al.
Post-transcriptional regulation is a set of important biological functions taking place during the genetic information flow from DNA to RNA. Alternative splicing is one of the post-transcriptional regulation mechanisms, which creates enormous diversity at the RNA level. Compared with other tissues, alternative splicing is highly abundant in brain. Emerging evidence shows that alternative splicing plays an important role in many neurological disorders. In this dissertation, the regulation of alternative splicing in mammalian brain and its relationship with neurological disorders was investigated. Based on our study, we demonstrated the importance of alternative splicing in neurological disorders, which provides insights of disease prevention and treatment.
The first part of the dissertation studies the genetic regulation of alternative splicing in human brain and its implications in neurological disorders. A major question in genetics is how variants of ubiquitously expressed genes produce tissue- and cell type-specific phenotypes. One mechanism is through affecting alternative splicing that may contribute to disease. We investigated splicing quantitative trait loci (sQTLs) in 1,209 samples from 13 human brain regions, using RNA-seq and genotype data from the GTEx project. Hundreds of sQTLs were identified in each brain region. Some sQTLs were shared across brain regions, whereas others displayed regional specificity. These ‘regionally ubiquitous’ and ‘regionally specific’ sQTLs showed distinct positional distributions of single nucleotide polymorphisms (SNPs) within and outside essential splice sites, respectively, suggesting their regulation by divergent molecular mechanisms. Integrating the binding motifs and expression patterns of RNA binding proteins with exon splicing profiles, we uncovered likely causal variants of brain region specific sQTLs. Overall, our study reveals widespread regional variation of sQTLs in human brain, and demonstrates that such variation can be used to fine map causal variants of sQTLs and their associated neurological diseases.
The second part of the dissertation focuses on sexual dimorphism of mammalian brain. Women and men showed difference in terms of neurological disorders. Previous studies investigated this sex difference using neuroanatomy and behavioral approaches. However, little is known about the underlying molecular mechanism. As an important post-transcriptional regulatory mechanism, we studied sexual dimorphic alternative splicing in mammalian brain through the female specific expression of the long noncoding RNA (lncRNA) Xist. This study is still ongoing.