【报告题目】：Ultraconserved nonsense:gene regulation by alternative splicing & RNA surveillance
【报告人】：STEVEN E. BRENNER
Professor, Department of Plant & Microbial Biology,
Affiliated Professor, Department of Molecular & Cell Biology,
Affiliated Professor, Department of Bioengineering,
University of California, Berkeley.
Nonsense-mediated mRNA decay (NMD) is a cellular RNA surveillance system that recognizes transcripts with premature termination codons and degrades them. Using RNA-Seq, we discovered thousands of natural alternative splice forms that appear to be targets for NMD. From these, we have been able to gain insight into the mechanism of NMD. Further, we found that this coupling of alternative splicing and RNA surveillance is used as a means of gene regulation. All conserved members of the human SR family of splice regulators have an “unproductive” alternative mRNA isoform targeted for NMD degradation. Preliminary data suggest that this is used for creating a network of auto- and cross-regulation of splice factors. Strikingly, and each alternative splice is associated with an ultraconserved or highly-conserved region of ~100 or more nucleotides of perfect identity between human and mouse--amongst the most conserved regions in these genomes. Further, we found that the most ancient known alternative splicing event is in this family and creates an alternate transcript to be degraded by NMD. Despite conservation since the pre-Cambrian, when the genes duplicate they change their regulation, so that nearly every human SR gene has its own distinctive sequences for unproductive splicing. As a result, this elaborate mode of gene regulation has ancient origins and can involve exceptionally conserved sequences, yet after gene duplication it evolves swiftly and often.
This talk will also include a brief discussion of interpreting individual genomes:
The super-exponential increase in sequencing capabilities over the past five years has yielded a plethora of complete genomes and exomes. We have been using sequencing technology to understand the provide diagnoses for newborns with enigmatic disease, and to provide genetic bases for inherited diseases. Through the Critical Assessment of Genome Interpretation, we have been evaluating the ability of tools routinely used in clinical diagnoses to accurately predict the phenotypic consequences of genetic variation, with some unexpected successes and disconcerting failures impacting research and clinical practice.
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