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Maja Bucan, Ph.D.

Professor of Genetics
Department of Genetics and
Interim Director, Penn Center for Bioinformatics
Chair, Genomics and Computational Biology Graduate Group
415 Curie Boulevard
528 Clinical Research Building
Philadelphia, PA 19104
(215) 898-0020 fax: (215) 573-5892
email:   bucan@pobox.upenn.edu
Click here for selected publications since Dr. Bucan's arrival at Penn

RESEARCH INTERESTS

Genetic dissection of complex behaviors in mice and human; Functional genomics, Bipolar disorder, Autism

RESEARCH TECHNIQUES

Genomics and complex trait analysis, Analysis of rodent behavior, Bioinformatics

RESEARCH SUMMARY

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.

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. earlybird , a mutant originally identified by virtue of its short circadian period, was one of more than dozen ENU-induced behavioral mutants identified in the screen (Kapfhamer et al., 2002). earlybird mice carry a point mutation in Rab3A's GTP-binding pocket, a highly conserved domain in all GTPases. Mice with mutations ( earlybird and the knockout allele) in this most abundant synaptic protein have subtle and highly pleiotropic behavioral phenotypes, and are remarkably sensitive to changes in genetic background (Yang et al., 2006). Phenotypes of Rab3A mutants, 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.

Recent genetic and neuroimaging studies showed that “ autism's cause may reside in abnormalities at the synapse” ( Garber, Science 317, 190-191. 2007). In collaboration with the Center for Applied Genomics at CHOP, we have started to genotype child-parent trios from the Autism Genetics Resource Exchange (AGRE) collection by probing over half million SNPs. Our preliminary data support previous studies showing that there is wide-spread copy number variation (CNV) in the human genome, including small duplications and deletions, which are either inherited or arose de novo in the child. In my view, the high rate of random mutations and the need to assess the phenotypic consequences of these CNVs represent new challenges in studies of complex disease. Again, we will need new methods, which will certainly combine computational and experimental approaches ( neurogenome.org/CNV ; Wang et al., in press). Over the last several years, we have used our expertise, and that of neuroscientists at Penn, to gather genomic, expression and phenotypic data on hundreds of genes expressed in pre- and post-synaptic neurons (Neurogenome.org/SynapseDB). Comparative sequence analysis and high-throughput molecular and genetic methods are used to identify highly conserved coding and non-protein coding elements surrounding these genes and to define sequences controlling the neuronal expression (Hadley et al., 2006). 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.

To identify candidate genes for bipolar disorder and other human diseases with anomalies in sleep and rest:activity patterns, we used gene array technology and bioinformatic analysis of data from a variety model organisms, such as mice, rats and flies to annotate over 3700 human genes likely to be controlled by the circadian clock, or the homeostatic mechanism that regulates sleep (Yang et al., submitted; www.neurogenome/CycleDB). 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 (Balsalobre et al., Cell 93:929-37, 1998) . 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., submitted). We also show that both lymphoblastoid and fibroblast cell lines may serve as an appropriate model system for experimental validation of copy number variants detected by genotype analysis.

There is another aspect of my research that can be traced back to my graduate and postdoctoral work—a love for scientific collaboration. I love it when members of my laboratory and I can contribute to the work of other laboratories on campus. Similarly, our work on linking genes and genomes to behavior in mice and humans critically depends on collaborations with psychiatrists, neuroscientists, computational biologists, and statistical geneticists and human geneticists (see links to web pages of our collaborators).

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