A. Javier López
243B Mellon Institute
Department of Biological Sciences
Carnegie Mellon University
4400 Fifth Avenue
Pittsburgh, PA 15213
Ph.D., Duke University
Postdoctoral Appointment, Stanford University
We are interested in the regulation of alternative pre-mRNA splicing, its contribution to cell function and development, and its disruption in disease. By generating different arrangements of exon sequences, alternative splicing enables a single gene to encode a family of proteins with variations in structure and functional properties. This allows the size of the proteome to greatly exceed the number of genes and increases organismal complexity. Alternative splicing patterns can be regulated developmentally and in response to physiological conditions to exert quantitative and qualitative control over gene expression. Accordingly, disruptions of pre-mRNA splicing are important contributors to inherited disease and cancer. For these reasons it is important to understand the mechanisms by which splicing is regulated and how it is integrated with other developmental and physiological control mechanisms. A better understanding of these mechanisms can contribute to the development of diagnostic, prognostic and therapeutic tools. Recent and current projects in my laboratory have included analysis of splicing regulatory networks and mechanisms during Drosophila development and analysis of alternative splicing in the human dopamine transporter and its disruption by common genetic polymorphisms.
We also study the function, processing and evolution of large introns, which are found in genes with important roles in development and disease. Large introns can take hours or days to be transcribed and may help to ensure correct timing of gene expression during development. Such introns may also modulate recombination rates to reduce interference selection between sites in flanking exons.
We approach these problems through a combination of genetics, molecular biology, biochemistry and bioinformatics applied to Drosophila and mammalian models.
Pope WE et al. Expanding the diversity of mycobacteriophages: Insights into genome architecture and evolution. PLoS ONE 6(1):e16329, 2011. doi:10.1371/journal.pone.0016329
Nimgaonkar VL, Chowdari KV, Prasad KM, Watson A, Mansour H, Wood JA, Lopez AJ. What can be learned from nominally significant/discrepant associations? An illustration using dopamine gene variants and schizophrenia. in “Schizophrenia: The Final Frontier”. Edited by A.S. David, S. Kapur and P. McGuffin. Taylor and Francis Ltd., 2011. ISBN-13: 978-1848720770.
Talkowski ME, McCann KL, Chen, M Y-M, McClain L, Bamne M, Wood J, Chowdari KV, Kirov G, Georgieva L, Toncheva D, Mansour H, Lewis DA, Owen M, O’Donovan M, Papasaikas P, Sullivan P, Sklar P, Ruderfer D and ISC consortium, Yao JK, Leonard S, Thomas P, Miyajima F, Quinn J, Lopez AJ, Nimgaonkar VL. Fine mapping reveals novel alternative splicing of the dopamine transporter. Am J Med Genet B Neuropsychiatr Genet. 153B(8):1434-1447, 2010.
Robertson KL, Yu L, Armitage BA, Lopez AJ and Peteanu LA. Fluorescent PNA probes as hybridization labels for biological RNA. Biochemistry, 45(19):6066-6074, 2006.
Burnette JM, Miyamoto-Sato E, Schaub MA, Conklin J and Lopez AJ. Subdivision of large introns in Drosophila by recursive splicing at nonexonic elements. Genetics, 170(2):661-674, 2005.
Kumar S and Lopez AJ. Negative feedback regulation among SR splicing factors encoded by Rbp1 and Rbp1-like in Drosophila. EMBO J, 24(14):2646-2655, 2005.
Conklin JF, Goldman A and Lopez AJ. Stabilization and analysis of intron lariats in vivo. Methods, 37(4):368-375, 2005.
Miller JM, Oligino T, Pazdera M, Lopez AJ and Hoshizaki DK. Identification of fat-cell enhancers in Drosophila melanogaster. Insect Molecular Biology, 11:67-77, 2002.
Burnette J, Hatton AR and Lopez AJ. Trans-acting factors required for inclusion of regulated cassette exons in the Ultrabithorax mRNAs of Drosophila melanogaster. Genetics, 151:1517-1529, 1999.
Hatton AR, Subramaniam V and Lopez AJ. Generation of alternative Ultrabithorax isoforms and stepwise removal of a large intron by regulated resplicing at exon-exon junctions. Molecular Cell, 2(6):787-796, 1998.
Lopez AJ. Alternative splicing of pre-mRNA: developmental consequences and mechanisms of regulation. Annu. Rev. Genet. 32: 279-305, 1998.
Jarvik JW, Adler SA, Telmer CA, Subramaniam V and Lopez AJ. CD-tagging: a new method for gene discovery and analysis. BioTechniques 50: 896-904, 1996.