Joel Graber

Genetics of mRNA Processing

 

A mammalian genome is made up of some twenty to twenty-five thousand protein coding genes. For perspective, the nematode genome has approximately nineteen thousand. Where does the obvious difference in complexity between these extremes come from, if not in the absolute number of protein coding genes? One suggestive possibility lies in the capacity of mammalian genes to generate multiple isoforms, generating variant transcripts and proteins from the same genomic coordinates. Current estimates are that each protein coding gene in the mammalian genome codes on average two protein isoforms and six or transcript isoforms, significantly higher numbers than found in less complex organisms. We are especially interested in the discrepancy between these two numbers, as it implies the existence of multiple distinct transcripts that translate to the same final protein product, further implying variation in the untranslated regions (UTR) that flank the protein coding sequence in the mature transcript. UTRs are noted for their role in post-transcriptional regulation of gene expression, providing regulatory elements that mediate more precise control of expression than is afforded by solely transcriptional control.

A complete model of gene regulation requires understanding control at all stages of activation from transcription initiation through mRNA through final protein product. Response to environmental changes, such as diet, involves changes in expression at multiple stages of activation. The genetic bases for differences in post-transcriptional processing, such as alternative splicing and alternative polyadenylation, remain poorly understood. Despite recent gains in understanding of the functional significance and individual variation in alternative mRNA processing, transcriptome analysis is still often limited to assessment of a single representative “expression level” for each gene, regardless of the number of isoforms or their functional differences. Our work is focused on the genetic basis for alternative mRNA processing in response to various factors, including the regulatory sequence elements that mediate the response. Increased understanding of the role of genetic variation in response to diet has potentially broad implications for obesity and other human health conditions.

Specifically, we are:

Developing methods to identify and characterize genes that change the distribution of expressed isoforms in response to such factors as diet, gender, and genetic background.

Developing methods to Identify and characterize the specific regulatory sequence elements that modulate mRNA processing, and thus control the selection among alternative isoforms.

Center related publications

Patterns of recombination activity on mouse chromosome 11 revealed by high resolution mapping
Billings T, Sargent EE, Szatkiewicz JP, Leahy N, Kwak IY, Bektassova N, Walker M, Hassold T, Graber JH, Broman KW, Petkov PM.
PLoS One. 2010 Dec 8;5(12):e15340. PMCID: PMC2999565. [ Full Text ]

CGDSNPdb: a database resource for error-checked and imputed mouse SNPs
Hutchins LN, Ding Y, Szatkiewicz JP, Smith RV, Yang H, de Villena FP, Churchill GA, Graber JH.
Database (Oxford). 2010 Jul 6;2010:baq008. Print 2010. PMCID: PMC2911843. [ Full Text ] [ datasets 1 ] [ datasets 2 ]

A customized and versatile high-density genotyping array for the mouse
Yang H, Ding Y, Hutchins LN, Szatkiewicz J, Bell TA, Paigen BJ, Graber JH, de Villena FP, Churchill GA.
Nat Methods. 2009 Sep;6(9):663-6. PMCID: PMC2735580. [ Full Text ] [ datasets ]

Position-dependent motif characterization using non-negative matrix factorization
Hutchins LN, Murphy SM, Singh P, Graber JH.
Bioinformatics. 2008 Dec 1;24(23):2684-90. PMCID: PMC2639279. [ Full Text ]

The recombinational anatomy of a mouse chromosome
Paigen K, Szatkiewicz JP, Sawyer K, Leahy N, Parvanov ED, Ng SH, Graber JH, Broman KW, Petkov PM.
PLoS Genet. 2008 Jul 11;4(7):e1000119. PMCID: PMC2440539 [ Full Text ]

Evidence of a large-scale functional organization of mammalian chromosomes
Petkov PM, Graber JH, Churchill GA, DiPetrillo K, King BL, Paigen K.
PLoS Biol. 2007 May;5(5):e127; author reply e128. PMCID: PMC1868061 [ Full Text ]

Patterns and mechanisms of genome organization in the mouse
Graber JH, Churchill GA, Dipetrillo KJ, King BL, Petkov PM, Paigen K.
J Exp Zoolog A Comp Exp Biol. 2006 Sep 1;305(9):683-8.

 

Joel Graber

 

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