James Sikela, PhD
Genomic approaches to human disease and evolution
Our laboratory is interested in the development and application of advanced genome technologies, particularly as they apply to our understanding of human disease and human evolution. Areas of special interest include the identification of genetic factors involved in neurogenetic diseases such as alcohol and drug abuse, mental retardation, and cognitive disability, and the use of novel evolutionary genomics approaches to identify genes unique to the human lineage as well as those unique to other primate lineages. Technologies that are used include DNA array-based comparative genomic hybridization (aCGH), high throughput DNA sequencing, gene expression profiling using high density DNA chip technologies, and novel bioinformatics tools for the rapid in silico discovery of genes underlying QTLs for complex traits.
Evolutionary genomics of human cognition: To gain insights into the evolutionary genomics of human, great ape and other primate lineages, we are using aCGH to identify lineage-specific gene duplications or losses that have occurred in these species. Of particular interest are those human lineage-specific genes that underlie the cognitive abilities unique to the human brain, and how such genes, when defective, lead to cognitive disability.
Alcohol and drug abuse: We are using mouse models of alcohol action to identify genes that underlie alcohol-related processes and pathways, as a first step toward identifying human genes that contribute to predisposition to develop alcoholism and alcohol abuse. High throughput genomic approaches, mentioned above, are also being used to search for gene coding or regulatory region sequence variations that underlie QTL for a number of alcohol- or drug-related phenotypes.
Identification of genes underlying birth defects and mental retardation: Novel genome-wide and gene-based approaches, such as aCGH, are being used in human studies to search for gene copy number changes related to mental retardation, birth defects and several other human genetic diseases.
Selected Recent Publications
Fortna, A., Kim, Y., MacLaren, E., Marshall, K., Hahn, G., Meltesen, L., Brenton, M., Hink, R., Burgers, S., Hernandez-Boussard, T., Karimpour-Fard, A., Glueck, D., McGavran, L., Berry, R., Pollack, J.R. and Sikela, J.M. Lineage-specific gene duplication and loss in human and great ape evolution. PLoS Biology, Jul;2(7):E207, 2004.
MacLaren, E.J. and Sikela J.M. Cerebellar gene expression profiling and eQTL analysis in inbred mouse strains selected for ethanol sensitivity. Alcoholism: Clinical and Experimental Research, 29:1568-1579, 2005.
MacLaren, E., Bennett, B., Johnson, T.E., and Sikela, J.M.: Expression profiling identifies novel candidate genes for ethanol sensitivity QTLs. Mammalian Genome, 17: 147-156, 2006.
Sikela, J.M., MacLaren, E.J., Kim, Y., Karimpour-Fard, A., Cai, W-W., Pollack, J., Hitzemann, R., Belknap, J., McWeeney, S., Kerns, R.T., Downing, C., Johnson, T.E., Grant, K.J., Tabakoff, B., Hoffman, P., Wu, C.C., and Miles, M.F.: DNA microarray and proteomic strategies for understanding alcohol action. Alcoholism: Clinical and Experimental Research, 30:700-708, 2006.
Sikela, J.M.: The Jewels of Our Genome: The Search for the Genomic Changes Underlying the Evolutionarily Unique Capacities of the Human Brain. PLoS Genet., May;2(5):e80, 2006.
Popesco, M., MacLaren, E., Hopkins, J., Dumas, L., Cox, M., Meltesen, L., McGavrin, L, Wyckoff, G., and Sikela, J.M.: Human lineage-specific amplification, selection and neuronal expression of DUF1220 domains. Science 313:1304-1307, 2006.
Rhesus Macaque Genome Sequencing and Analysis Consortium: Evolutionary and biomedical insights from the Rhesus Macaque genome. Science 316:222-234, 2007.
Babcock, M., Yatsenko, S., Hopkins, J., Brenton, M., Cao, Q., de Jong, P., Stankiewicz, P., Lupski, J.R., Sikela, J.M., Morrow, B.E.: Hominoid lineage specific amplification of low-copy repeats on 22q11.2 (LCR22s) associated with velo-cardio-facial/DiGeorge syndrome. Hum. Mol. Genet. 16: 2560-2571, 2007.
Dumas, L., Kim, Y.H., Karimpour-Fard, A., Cox, M., Hopkins, J., Pollack, J.R., and Sikela, J.M.: Gene copy number variation spanning 60 million years of human and primate evolution. Genome Research, 17:1266-1277, 2007.