Andrew S. McCallion, PhD
University of Glasgow, Scotland
Dr. Andrew McCallion is an associate professor of molecular and comparative pathobiology at the Johns Hopkins University School of Medicine. His research focuses on applying functional genetics to human development and disease. Dr. McCallion was part of a research team at Johns Hopkins that identified the two genes that cause Hirschsprung disease, an inherited intestinal disorder.
His research focuses on making the connection between gene sequence (and variation therein) and phenotype through the integrated use of contemporary genomic strategies and model systems (mouse, zebrafish and cell culture).
Dr. McCallion received his B.Sc. in genetics from The Queen's University of Belfast. He earned his Ph.D. in genetics from the University of Glasgow. He completed postdoctoral training at Case Western Reserve University Medical School.
Prior to joining Johns Hopkins, Dr. McCallion was a project leader and staff scientist at Neuropa Ltd. (UK), a biotech startup focused on drug target development for neurodegenerative disorders.
He is a member of the International Mammalian Genome Society, American Society of Human Genetics and Federation of American Societies for Experimental Biology. He serves on the editorial board of Genome Research, and is a Faculty of 1000 faculty member in genomics and genetics.
My group studies how transcriptional regulatory control is encrypted in genomic sequence, and how variation in regulatory sequences may contribute to phenotype variation and disease risk/presentation. In this work my group employs cutting edge genomic and functional genetic approaches in mice, zebrafish and in vitro, integrating them with computational biology. Regulatory sequences underlie the cellular diversity that arises during human development, and how cells respond to environmental and genetic insult. Regulatory mutations underlie an array of human diseases. They play a significant role in disease susceptibility and they form the basis of cellular response to insult, aging and stress. My early work began with studies of neuronal and neural crest development. Efforts in my lab are currently directed at developing cell-type dependent regulatory sequence catalogs and applying them in human population-based studies to predict, identify and validate likely functional variation that associates with disease. In some of our recent work we have generated large catalogs of putative enhancers in various cell types using ChIP-seq and ATAC-seq (melanoctytes, dopaminergic neurons [ventral midbrain, forebrain, olfactory bulb]). Further begun to explore how these data can be used to learn the vocabularies of cell-dependent control inform our understanding of functional non-coding variation and the molecular mechanisms of transcriptional control. Our emerging work has begun to integrate these analyses with studies of transcriptional heterogeneity within cell-types, using single cell RNA-seq to explore specific neuronal populations and define their Gene Regulatory Networks (GRNs). Our efforts are now focused on the development, validation and integration of regulatory sequence catalog information with the development of GRNs in cell populations and tissues of neurobehavioral disease-relevance.
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 population that 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 genetics 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 years, 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.
1. Lee D, Gorkin DU, Baker M, Strober BJ, Asoni AL, McCallion, AS.† and Beer, MA† A method to predict the impact of regulatory variants from DNA sequence. Nature Genetics. 2015 Aug;47(8):955-61. †, Co-corresponding authors
2. Praetorius C, Grill C, Stacey SN, Metcalf AM, Gorkin DU, Robinson KC, Van Otterloo E, Kim RS, Bergsteinsdottir K, Ogmundsdottir MH, Magnusdottir E, Mishra PJ, Davis SR, Guo T, Zaidi MR, Helgason AS, Sigurdsson MI, Meltzer PS, Merlino G, Petit V, Larue L, Loftus SK, Adams DR, Sobhiafshar U, Emre NC, Pavan WJ, Cornell R, Smith AG, McCallion AS, Fisher DE, Stefansson K, Sturm RA, Steingrimsson E. A polymorphism in IRF4 affects human pigmentation through a tyrosinase-dependent MITF/TFAP2A pathway. Cell 2013 Nov 21;155(5):1022-33. doi: 10.1016/j.cell.2013.10.02.
3. Gorkin D, Lee D, Reed X, Fletez-Brant C, Loftus SK, Beer MA, Pavan WJ, McCallion AS. Integration of ChIP-seq and Machine Learning Reveals Enhancers and a Predictive Regulatory Sequence Vocabulary in Melanocytes. Genome Res. 2012;22(11):2290-301.
4. Noonan JP, McCallion AS. Genomics of long-range regulatory elements. Annu Rev Genomics Hum Genet. 2010; 11:1-23. Review.
5. Fisher S, Grice EA, Vinton RM, Bessling SL, McCallion AS. Conservation of RET Regulatory Function from Human to Zebrafish Without Sequence Similarity. Science. 2006. 312, 276-279.