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== Research Interests ==
== Research Interests ==
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Introns interrupt our genes most of the time and the production of functional mRNAs requires their efficient and accurate removal. The regulation and accuracy of intron removal is significant as an estimated 15% of human disease-associated point mutations disrupt splicing. In contrast to our intron-rich genome, introns are present in less than 5% of Saccharomyces Cerevisiae’s genes. Most S. Cerevisiae genes that contain introns are involved in growth, division, and homeostasis. The expression levels of these genes should be resistant to random fluctuations to prevent undesirable growth- and division- rates as well as inefficient metabolism. Because it is known that introns can increase the efficiency of expression and that introns are targets of negative regulation as well as auto- inhibition, I am examining the influence introns have on expression variability in yeast .</nowiki> |+|
<nowiki> the the of . In , in of . that introns, . expression of these genes to to -as . the -, introns in yeast 1 , and , . , a for and -. To the of lengthI
|-|<nowiki> While the largest yeast intron is only 1, 001 nucleotides, mammalian introns can be extremely large and some are greater than 100, 000 nucleotides. Notwithstanding that it is unknown what function large introns play, there exists a bias for longer introns being present in tissue- and development stage- specific genes. To better understand the influence of intron length in mammalian genes I am engineering synthetic gene networks that rely on different intron lengths to coordinate gene expression .</nowiki> |+|
Intron sequence is the major contributor to gene length for the lion’s share of our genes. In 1970, James Watson invoked transcriptional delays in models describing biological timing for lambda phage and their use of a long late operon. David Gubb, who noted that Drosophila’s Antennapedia and ultrabithorax genes owe their great lengths to large introns, formally distinguished the intron-delay hypothesis in 1986. With the knowledge that the development of the fly’s body plan is sensitive to the proper expression of these genes in space and time, he proposed that intron-length could contribute a time-delay to aid the orchestration of gene expression patterns. Mutants to directly substantiate the intron-delay hypothesis have been either elusive or inappropriately annotated as enhancers. Interestingly, a slightly slower RNA Polymerase mutant allele in the fly shares some phenotypes with ultrabithorax mutants. Gene length has increased during evolution: from short intron-less genes in prokaryotes, to primarily single introns in yeast genes that reach 1 kilobase in length, and to large, multi-intron genes such as the extreme 2.3 megabases encompassed by the human dystrophin gene. While a 2.3 megabases transcriptional unit may take more than 16 hours to transcribe, a functional role for gene length and for the periods of time it takes to transcribe different gene lengths remains unclear. A line of observations and phenomena suggest significant roles for intron-delays, particularly during developmental programs such as the maternal-zygotic transition, somitogenesis, and abdominal segmentation. To begin to address the role of gene length, I applied reductionism to answer three questions related to the intron-delay hypothesis:
1) What is the quantitative impact of intron-length on the timing and precision of gene expression?
2) How does intron-length influence gene expression when, in early G1, transcription must reinitiate after the mitotic constraint?
3) What impact does the intron-delay have on an auto-inhibition network predicted to oscillate with a period proportional to the time-delay?