Maja Bucan, Ph.D.
Professor of Genetics,
Department of Genetics, School of Medicine
Genomics and Computational Biology Graduate Group
528 Clinical Research Building, 415 Curie Boulevard
Philadelphia, PA 19104
(215) 898-0020; Fax: (215) 573 5892
Genetic dissection of complex behaviors in mice and human; Functional genomics, Bipolar disorder, Autism
Genomics and complex trait analysis, Analysis of rodent behavior, Bioinformatics,
Research in my laboratory involves identification of the genetic basis of behavioral and psychiatric disorders. To complement ongoing efforts in human psychiatric genetics, my laboratory embarked over the last several years on two main projects: a screen for novel behavioral mutations in the mouse and the functional annotation of the mammalian genome using bioinformatics approaches. We are now less involved in studies of behavioral traits in the mouse and main projects in the laboratory involve human genetic studies of neurodevelopmental and psychiatric disorders.
Behavioral genetics in the mouse
: In behavioral screens, the progeny of mice treated with a chemical mutagen (ENU – N-ethyl-nitroso-urea) were observed for phenotypes that may correspond to endophenotypes of psychiatric disorders (Tarantino and Bucan, 2000). Mice were subjected to a battery of assays including tests for neuromuscular function, anxiety, exploratory behavior, sensorimotor gating, activity monitoring, learning and memory, among others (Kapfhamer et al., 2002; Yang et al., 2006). Phenotypes of several mutants found in our screen, as well as the findings of other groups that mutations in synaptic genes in flies, worms and mice lead to a wide range of behavioral anomalies, directed our interests to the role of synaptic genes in human disease.
Genetics of Autism Spectrum Disorders
: In our genetic studies we take advantage of the Autism Genetics Resource Exchange (AGRE
), the largest publicly available collection of well-characterized families with multiple children with autism or associated disorders. To identify genes likely to contribute to ASD etiology, we used high-density genotype data for the AGRE collection and contrasted results to those obtained for healthy controls. Our results reveal tremendous complexity, i.e. diverse mix of common and rare genetic variants, many of which act in pathways that form and maintain connections between neurons (Wang et al., 2009; Glessner et al., 2009; Bucan et al., 2009). More work in a larger number of individuals will be required to determine which of the rare alleles, including copy number variants (CNVs), are indeed related to the ASDs and how they act to shape risk. (see more on Center for Autism Research
Genetics of Bipolar Disorder
: After many years of modeling behavioral phenotypes in the mouse, we are currently exploring the utility of established cell lines from patients with bipolar disorder. Recent studies have shown that, like the circadian pacemaker in the brain, cultured cells harbor self-sustaining and cell-autonomous circadian clocks that persist even during cell division. By monitoring circadian cycling of gene expression, we showed that the basic circadian machinery is not disrupted in fibroblasts of bipolar patients, although subtle inter-individual differences in the expression level of several core clock genes may lead to phenotypic differences (Yang et al., 2009a). We also show that both lymphoblastoid and fibroblast cell lines for individuals in a large three-generation family segregating mental illness may serve as an appropriate model system for experimental validation of rare copy number variants detected by genotype analysis (Yang et al., 2009b).
Functional annotation of ASD and BPD susceptibility loci
: The high rate of rare mutations and the need to assess the phenotypic consequences of copy number variants represent new challenges in studies of complex disease. We will need new methods, which will certainly combine computational and experimental pathway-based approaches. We have developed novel approaches for the analysis of genomic data. Comparative sequence analysis and high-throughput molecular and genetic methods are used to identify highly conserved coding and non-protein coding elements surrounding candidate genes for complex diseases (Hadley et al., 2006; Lui et al., 2009). Informative genetic interactions between members of the Rab family, syntaptotagmins, sytaxins, neuroligans and neurexins, together with our insights into groups of co-regulated genes is generating a resource that will be critical for our understanding of new gene- and CNV- associations in human neurodevelopmental and psychiatric disorders. (see more on Penn Center for Bioinformatics).
Look at our tools:
Pathway-based analysis of GWA data
Kapfhamer D., Valledares O, Sun, Y., Nolan P., Rux J., Arnold S., Veasey, S.and Bucan M. (2002) The role of Rab3A in regulation of rest/activity behavior and sleep, Nature Genetics 32, 290-5.
Hadley D., Murphy T., Ungar L., Kim J., Bucan M, (2006) Patterns of Sequence Conservation in Presynaptic Neural Genes, Genome Biology 7, R105.
Yang S., Van Dongen, H., Wang K., Berrettini W., Bucan M. (2009) Assessment of circadian function in fibroblasts derived from bipolar patients. Molecular Psychiatry 14, 143-55 [E-pub Feb 2008]
Wang K., Li M., Bucan M., (2007) Pathway-based approaches for analysis of genome-wide association studies, Am. J. of Human Genetics 81, 6.
Wang K, Li M, Hadley D, Liu R, Glessner J, Grant S, Hakonarson H, Bucan M (2007) High-resolution copy number variation detection: application of an integrated hidden Markov Model on whole-genome SNP genotyping data. Genome Research 17, 1665-1674.
Yang S., Wang K., Gregory B., Berrettini W., Wang L., Hakonarson H., Bucan M. (2008) Genomic Landscape of a Three-generation Pedigree Segregating Affective Disorder, PLoS ONE 4:e4474.
Glessner J.T., et al., (2008) Autism genome wide copy number variation reveals ubiquitin and neuronal genes, Nature, 459; 569-73.
Wang K+, Zhang+ H, Ma+ D, et al., (2009) Common genetic variants on 5p14.1 associate with autism spectrum disorders. Nature, 459:528-33.
Bucan M+., Abrahams B.S+., Wang K+., et al., (2009) Genome-wide analysis of exonic copy number variants identify novel autism susceptibility genes, PLoS Genetics 5: e1000536.
Liu R., Hannenhalli S. and Bucan M, Motifs and cis-regulatory modules mediating the expression of genes co-expressed in presynaptic neurons (2009) Genome Biology, [e-pub July 1].
back to top
Last updated: 06/03/2013
The Trustees of the University of Pennsylvania