The existence of variation is central to the field of genetics. However, finding genetic variation has often proven to be difficult, expensive and slow. The promise of genomics lies in the ability to conduct experiments that characterize genome-wide patterns of variation. These studies have typically been carried out in large industrial genome sequencing centers that reduce costs through economies of scale. Next-generation genomics technologies offer the promise of a genome sequencing center on every laboratory bench, producing vast quantities of genomic variation data at an ever-reduced cost. Technological innovations, such as microarray-based resequencing, can enable single laboratories to conduct genome-wide experiments that in the past would have only been possible in larger centers. Our research aims to harness these cutting-edge technologies to solve important problems in human, model organism (like Drosophila) and microbial systems.

Our research projects focus on a diverse collection of problems. Current projects include:

Identifying Autism Susceptibility Genes By High-Throughput Chip Resequencing (Principle Investigator): The four-fold excess of affected males with autism and genetic linkage findings strongly suggests a role for X-linked genes. Approximately 20% of patients with Fragile X syndrome, a disorder cause by a trinucleotide repeat sequence at FMR1, exhibit symptoms consistent with the DMS IV diagnosis of autism. In spite of this evidence for the role of FMR1 as a cause or genetic modifier contributing to autism, the gene has not been comprehensively resequenced in any large patient populations. We are conducting high-throughput, highly accurate microarray-based resequencing of a 270kb X chromosome region that includes the FMR1 and FMR2 genes among a large collection of male affected sibpairs (cases) from the Autism Genetic Resource Exchange (AGRE) sample collection and controls. Developing methods and analyzing the dense resequencing datasets we produce is also a goal of this project. Our ultimate aim is to identify genetic variants that either cause or act as susceptibility alleles in the development of autism.

Drosophila Population Genomics Project (DPGP, www.dpgp.org: Co-Investigator): This project is collaboration between scientists at University of California at Davis, Johns Hopkins and Emory University. Publicly available human and model organism reference genomic sequences provide a foundation for revolutionary advances in population genomics, the genomic-scale detection of DNA sequence variants and investigation of their role in affecting disease risk. However, even as the first population genomic data emerge, solid paradigms of description and analysis have not yet appeared. For example, integration of population genomic polymorphism and associated phenotypic variation into genomic annotations is an essential yet daunting task. To directly address the basic challenge of population genomics we are proposing to begin an effort to obtain the complete sequence of 50 Drosophila melanogaster genomes. The Drosophila strains and their associated genomic polymorphisms will become objects of intense and diverse functional analyses and annotation. The goals of this proposal are (1) to develop and validate an appropriate resequencing technology, (2) to establish a sustainable, high quality resequencing capacity, and (3) to provide preliminary results and analysis that demonstrate the high added value of genomic coverage of population polymorphism.

Resequencing the FMR1 Gene To Identify Novel Mutations Causing Mental Retardation. This project, carried out in collaboration with Dr. Stephen T. Warren's laboratory, aims to perform comprehensive resequencing in male patients with unexplained mental retardation to identify novel mutations in FMR1.

Behavioral-genetic prediction of risk for schizophrenia in children with 22q11 Deletion Syndrome (Co-Investigator): This project is a collaboration with Dr. Joe Cubells.  The 22q11 Deletion Syndrome (22q11DS) is a common chromosomal disorder associated with high risk for behavioral problems, including a very high risk for schizophrenia. Identification of 22q11DS children at highest risk for that devastating disorder is an urgent priority, as evidence shows that early intervention can prevent or lessen the impact of schizophrenia. Our role in the project is to perform microarray-based resequencing and analysis on selection portion sof the hemizygous region of 22q11.

Resequencing Biodefense Pathogens: This project is carried out with Dr. Timothy Read of the Biological Defense Research Directorate at the Naval Medical Research Center. Current projects focus on exploring the population genomics of biodefense pathogens (such as B. anthracis, Y. pestis, F. tularemia) and closely related non-pathogenic relatives using high-throughput resequencing technologies.

Development of Open-Source Tools for Resequencing Arrays (RAs) - RATools: RAs are one of the main technologies used in our laboratory on a variety of projects. Development of the RATools software package is an ongoing project carried out in collaboration with Dr. David Cutler at Johns Hopkins and collaborators in the DPGP projects. RATools is freely available at http://x-dpgp.ucdavis.edu.

Boyce, T. M., M. E. Zwick, C. F. Aquadro. 1989. Mitochondrial DNA in the Bark Weevils: Size, structure and heteroplasmy. Genetics 123: 825-836.

Boyce, T. M., M. E. Zwick, C. F. Aquadro. 1994. Mitochondrial DNA in the Bark Weevils: Phylogeny and evolution in the Pissodes strobi species group (Coleoptera: Curculionidae). Molecular Biology and Evolution 11(2): 183-194.

Zwick, M. E., J. L. Salstrom, C. H. Langley. 1999. Genetic Variation in Rates of Nondisjunction: Association of two naturally occurring polymorphisms in the chromokinesin nod with increased rates of nondisjunction in Drosophila melanogaster. Genetics 152: 1605-1614.

Zwick, M. E., D. J. Cutler, C. H. Langley. 1999. Classic Weinstein: Tetrad analysis, genetic variation and achiasmate segregation in drosophila and humans. Genetics 152: 1615-1629.

Cutler, D. J., M. E. Zwick, M. M. Carrasquillo, C. T. Yohn, K. P. Tobin, C. Kashuk, D. J. Mathews, N. A. Shah, E. E. Eichler, J. A. Warrington, A. Chakravarti. 2001. High-throughput variation detection and genotyping using microarrays. Genome Research 11(11): 1913-25.

Lin S., D. J. Cutler, M. E,Zwick, A. Chakravarti. 2002. Haplotype inference in random population samples. American Journal of Human Genetics 71(5): 1129-37.

Mitchell A. A., M. E. Zwick, A. Chakravarti, D. J. Cutler. 2004.  Discrepancies in dbSNP confirmation rates and allele frequency distributions from varying genotyping error rates and patterns. Bioinformatics 20(7): 1022-32.

Zwick, M. E., F. Mcafee, D. J. Cutler, T. D. Read, J. Ravel, G. R. Bowman, D. R. Galloway, A. Mateczun. Microarray based resequencing of multiple B. anthracis isolates. Genome Biology 6(1): R10.  Available online at http://genomebiology.com/2004/6/1/R10.

b. Review articles:

Zwick, M. E., D. J. Cutler, A. Chakravarti. 2000. Patterns of Genetic Variation in Mendelian and Complex Traits. Annual Review of Genomics and Human Genetics 1: 387-407.

c. Symposium contributions:

Zwick, M. E. The central role of variation in human genetics. 2002. Jurimetrics 42(2): 133-139.

d. Book chapters:

Zwick, M. E., D. J. Cutler, A. Chakravarti. 2001. Genetic Variation Analysis of Neuropsychiatric Traits. Methods in Genomic Neuroscience 1: 289-302.

e. Other publications: