Andrew S. McCallion, Ph.D.
Associate Professor, Department of Molecular and Comparative Pathobiology
Education and Training:
- B.Sc.(Hons), The Queen's University of Belfast, Genetics
- Ph.D., University of Glasgow, Genetics
- Project leader and staff scientist, Neuropa Ltd, Glasgow
- Research Associate, Department of Genetics, Case Western Reserve University Medical School
- Research Associate, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University Medical School
Gene regulation is the framework on which vertebrate cellular diversity is built. The substantial cellular diversity that characterizes complex integrated cell populations, such as the human central nervous system, must therefore require immense regulatory complexity. Similarly the cells comprising the embryonic neural crest, a populations which contributes craniofacial cartilage and bone, pigment cells of the skin and hair, neuroendocrine cells and the entire peripheral nervous system to the vertebrate embryo must face similar challenges in choosing the correct fate. These cells go awry in a wide array of human disorders like Parkinson's Disease, Hirschsprung Disease, Psychiatric disorders and Melanoma, and comprise the focus of our efforts.
Although regulatory control acts at many levels, we focus on the roles played by cis-regulatory elements (REs) in controlling the timing, location and levels of gene activation (transcription). However, the biological relevance of non-coding sequences cannot be inferred by examination of sequence alone. Perhaps the most commonly used indicator of non-coding REs is evolutionary sequence conservation. Although conservation can uncover functionally constrained sequences, it cannot predict biological function and regulatory function is not always confined to conserved sequences. At its simplest level, regulatory instructions are inscribed in transcription factor binding sites (TFBS) within REs. Yet, while many TFBS have been identified, TFBS combinations predictive of specific regulatory control have not yet emerged for vertebrates. We posit that motif combinations accounting for tissue-specific regulatory control can be identified in REs of genes expressed in those cell types. Our immediate goal is to begin to identify TFBS combinations that can predict REs with cell-specific biological control - a first step in developing true regulatory lexicons.
As a functional genetic laboratory we develop and implement assays to rapidly determine the biological relevance of sequence elements within the human genome and the pathological relevance of variation therein. In recent year we have developed a highly efficient reporter transgene system in zebrafish that can accurately evaluate the regulatory control of mammalian sequences, enabling characterization of reporter expression during development at a fraction of the cost of similar analyses in mice. We employ a range of strategies in model systems (zebrafish and mice), as well as analyses in the human population, to illuminate the genetic basis of disease processes. Our long-term objective is to use these approaches in contributing to improved diagnostic, prognostic and ultimately therapeutic strategies in patient care.
If you are interested in learning more about the work we do or would like to inquire about positions available within the lab please contact Dr. McCallion (firstname.lastname@example.org). If you would like to support our efforts please contact the Institute at "Join Our Team".
Applying functional genetics to human development and disease
- Transcriptional regulation in development and disease
- Genetics of neurological, neuropsychiatric and neural-crest disorders
- Genetics basis of congenital malformations
- Preceptor-Predoctoral Training Program in Human Genetics
Recognition and Leadership Roles:
- Faculty of 1000, Genomics and Genetics
- Editorial board, GENOME RESEARCH 2006 -
- Member, International Mammalian Genome Society
- Member, American Society of Human Genetics
- Member, Federation of American Societies for Experimental Biology
- Rodent Advisory Committee, Johns Hopkins University
- Rodent Phenotyping CORE committee, Johns Hopkins University
Zachary E. Stine, Jimmy L. Huynh, David Gorkin, Todd Purves, Thomas Novak, Amirali H. Salmasi, Anthony Antonellis, Stacie Loftus, William J. Pavan, John P. Gearhart and Andrew S. McCallion. A transgenic mouse strain directs pan-neural crest expression of Cre recombinase under the control of a distal Sox10 enhancer element. Genesis [Epub ahead of print]
Loïc De Pontual, Sophie Thomas, Norann A. Zaghloul, David M. McGaughey, Hélène Dollfus, Clarisse Baumann, Erica E. Davis, Arnold Munnich, Heather Etchevers, Michel Vekemans, Stanislas Lyonnet, Andrew S. McCallion, Tania Attie-Bitach, Nicholas Katsanis, Jeanne Amiel. The Association Of Bardet-Biedl Syndrome And Hirschsprung Disease Highlights The Role Of The Primary Cilium In ENS Development. Proceedings of the National Academy of Science (USA), 2009; 106(33):13921-6
McGaughey, D.M., Stine, Z.S., Huynh, J., Vinton, RM., McCallion, A.S., Symmetrical Distribution Of Non-Conserved Regulatory Sequences At PHOX2B Is Reflected At The ENCODE Loci And Illuminates A Possible Genome-Wide Trend. (2008) BMC Genomics (In Press)
Loftus SK, Antonellis A, Matera I, Renaud G, Baxter LL, Reid D, Wolfsberg TG, Chen Y, Wang C; NISC Comparative Sequencing Program, Prasad MK, Bessling SL, McCallion AS, Green ED, Bennett DC, Pavan WJ. Gpnmb is a Melanoblast-Expressed, MITF-Dependent Gene. Pigment Cell Melanoma Res. 2008 Nov 1. PMID: 18983539
Antonellis A., Huynh, J., Lee-Lin, S., Vinton, RM., Renaud, G., Loftus, SK., Elliot, Wolfsberg, TG., Green, ED., McCallion, A.S.,Ý and Pavan W.J. Identification Of Neural Crest and Glial Enhancers At The Mouse Sox10 Locus Through Transgenesis In Zebrafish. PLoS Genet. 2008, 4; 9. (Ý, Corresponding author)
Miller RA, Christoforou N, Pevsner J, McCallion AS*, Gearhart JD* (2008) Efficient Array-Based Identification of Novel Cardiac Genes through Differentiation of Mouse ESCs. PLoS ONE 3(5): e2176 doi:10.1371/journal.pone.0002176; *, corresponding authors.
Christoforou, N.,* Miller, R.A.,* Hill, C.M., Jie, C.C., McCallion, A.S., and Gearhart. J.D. The characterization of ES-derived cardiac precursor cells demonstrates their multipotentiality and identifies novel cardiac genes. J. Clin. Invest. Feb. 2008.
McGaughey, D.M., Vinton, R.M., Huynh, J., Al-Saif, A., Beer, M., and McCallion, A.S. Metrics of sequence constraint overlook regulatory sequences in an exhaustive analysis at phox2b. Genome Research, In press.
Xie J, Bessling SL, Cooper TK, Dietz HC, McCallion AS, Fisher S. Manipulating Mitotic Recombination in the Zebrafish Embryo Through RecQ Helicases. Genetics. 2007 Jun;176(2):1339-42.
Fisher, S., Grice, E.A., Vinton, R.., Bessling, S.L., Urasaki, A., Kawakami, K. and McCallion, A.S. (2006) Evaluating the biological relevance of putative enhancers using Tol2 transposon-mediated transgenesis in zebrafish. Nature protocols 1, 1297-1305.
Cranston, A.N., Carniti, C., Oakhill, K., Radzio-Andzelm, E., Stone, E.A., McCallion, A.S., Hodgson, S., Clarke, S., Mondellini, P., Leyland, J., Pierotti, M.A., Whittaker, J., Taylor, S.S., Bongarzone, I. & Ponder, B.A.J. (2006) RET is constitutively activated by novel tandem substitutions that alter the active site resulting in MEN2B. Cancer Research 66(20):10179-87.
Montague, P., McCallion, A.S., Davies, R.W., and Griffiths, I.R. (2006) Myelin-associated oligodendrocytic basic protein: a family of abundant CNS myelin proteins in search of a function. Dev Neurosci. 28(6):479-87.
Fisher S, Grice EA, Vinton RM, Bessling SL and McCallion AS. (2006) Conservation of RET Regulatory Function from Human to Zebrafish Without Sequence Similarity. Science. 2006 Mar 23; [Epub ahead of print]
Grice EA, Rochelle ES, Green ED, Chakravarti A, McCallion AS. (2005) Evaluation of the RET regulatory landscape reveals the biological relevance of a HSCR-implicated enhancer. Hum Mol Genet. 14 (24)
Kashuk, C.S., Stone, A.E., Grice, E.A., Portnoy, M.E., Green, E.D., Sidow, A., Chakravarti, A. and McCallion, A.S. (2005) Phenotype:Genotype correlation in HSCR and MEN2 facilitated comparative analysis of the RET protein sequence. Proceedings of the National Academy of Science (USA) 102: 8949-8954.
Sproat-Emison, E.E.,* McCallion, A.S.,* Kashuk, C.S., Bush, R.T., Grice, E., Lin, S., Portnoy, M.E., NISC Comparative Sequencing Program, Cutler, D.J., Green, E.D. and Chakravarti, A. (2005) A common, sex-dependent mutation in a putative RET enhancer underlies Hirschsprung disease susceptibility. Nature, 434 (7035): 857-63. (*, Authors contributed equally).
McCallion, A.S., Sproat-Emison, E.E., Kashuk, C.S. Bush, R.T., Kenton, M. Carrasquillo, M.M., Jones, K.W., Kennedy, G.C., Portnoy, M., Green, E.D., and Chakravarti, A (2003) Genome-wide association study and mouse model identity interaction between RET nad EDNRB pathways in Hirschsprung disease. Cold Spring Harb Symp Quant Biol. LXVII
McCallion, A.S., Stames, E, Conlon, R.A., and Chakravarti, A. (2003) Phenotype variation in two-locus mouse models of Hirschsprung disease: Tissue specific interaction between and ., 1826-31. Ret and Ednrb. PNAS 100, 1826-31.
Carrasquillo, M.M., McCallion, A.S., Puffenberger, E.P., Kashuk, C.S. Nouri, N. and Chakravarti, A. (2002) Genome-wide association study and mouse model identify interaction between RET and EDNRB pathways in Hirschsprung disease. Nat Genet 32,237-244.
Chakravarti, A., McCallion, A.S. and Lyonnet, S. (2000, revised 2003). Hirschsprung Disease. Chapter 251 in, The metabolic and molecular bases of inherited disease. Scriver, Beaudet, Valle and Sly; 8th edition, McGraw-Hill, New York.
McCallion, A.S., Chakravarti, A. (2004) RET, Hirschsprung disease and multiple endocrine neoplasia type 2. In Inborn Errors of Development. Editors Epstein, C., Erickson, R., and Wynshaw-Boris, A. Oxford University Press (San Francisco) References
Andrew McCallion, PhD