Human Genetic Variation and Complex Disease
The genome project reveals that humans are 99.9% identical to each other at the DNA sequence level. Each person's unique 0.1% is what determines their genetic susceptibility to disease. We recently completed a novel genome-wide association study to map human complex disease loci in a subset of the Framingham Heart Study (FHS) population. Complex diseases are those such as diabetes, heart disease and osteoporosis, which are caused by gene combinations and environmental factors, and for which the causative genes remain largely unknown. We genotyped each of 1438 individual family members from the first and second generation participants in the FHS for 100,000 SNPs (single nucleotide polymorphisms) using a new microarray-based method. The data were analyzed for association of human genetic variation (SNP genotypes) with each of over 150 clinical phenotypes studied in the FHS. The project was lead by a team of scientists from the Genetics and Genomics department at Boston University and collaborators at the Harvard School of Public Health's Biostatistics department. We employed a novel computational approach that avoids power reduction due to multiple hypothesis testing (PBAT for pedigree based association test). This approach overcomes the major statistical limitation of doing dense SNP association studies. Simulations and power calculations demonstrate an outstanding chance of success. Data were made available to other scientists in order to maximize the utility of the Framingham Heart Study resource in the post-genome era.

Histone Acetylation in DNA repair
Cells that incur mutations in oncogenes and tumor suppressor genes may escape normal growth controls and develop into cancers. Such cells often possess defects in one of the many pathways for DNA repair. Repair pathways such as DNA mismatch repair or double strand break repair are known to be defective in many tumors. We have found a previously unrecognized role for histone acetylation in DNA double strand break repair. While acetylation of histones on conserved N-terminal lysines plays a well documented regulatory role in transcription, the role of histone acetylation in other dynamic processes involving DNA such as repair, recombination or replication remains largely unexplored. We have shown that histone H4 acetylation is required for DNA double-strand break (DSB) repair through the nonhomologous end joining pathway. We show that after a break is formed, a histone acetyl-transferase protein complex (NuA4) is rapidly recruited to the break site to mediate repair via the histone-binding protein Arp4 (above). Our data provide the first evidence for the involvement of reversible histone acetylation in DNA repair and illustrate the remarkable complexity and versatility of histone tail modifications. Future goals include determining precisely how acetylation of histones facilitates joining of broken DNA ends and examining the role of acetylation in DNA replication. Humans contain a related HAT complex that is likely to function similarly. This project is an ongoing collaboration between the Christman and M. Mitchell Smith (a.k.a. Dr. Histone) labs.

Herbert, A., M. E. Lenburg, D. Ulrich, N. P. Gerry, K. Schlauch, M. F. Christman.
Open-access database of candidate associations from a genome-wide SNP scan of the Framingham Heart Study. 2007. Nature Genetics. 39:135-136. Pubmed ID 17262019

Herbert, A., N. P. Gerry, M. McQueen, I. M. Heid, A. Pfeufer, T. Illig, H.-E. Wichmann, T. Meitinger, D. Hunter, F. B. Hu, G. Colditz, A. Hinney, J. Hebebrand, K. Koberwitz, X. Zhu, R. Cooper, K. Ardlie, H. Lyon, J. Hirschhorn, N. M. Laird, M. E. Lenburg, C. Lange and M. F. Christman.
A common genetic variant is associated with adult and childhood obesity. 2006. Science. 5771:279-283. reprint (432 KB, PDF)

Van Steen K., M.B. McQueen, A. Herbert, Raby, H. Lyon, D.L. Demeo, A. Murphy, J. Su, S. Datta, C. Rosenow, M. Christman, E.K. Silverman, N.M. Laird, S.T. Weiss, C. Lange. 2005. Genomic screening and replication using the same data set in family-based association testing. Nature Genetics 37:683-691. reprint (281 KB, PDF)

Carson, J. P., N. Zhiang, G. Frampton, N. P. Gerry, M. E. Lenburg and M. F. Christman. 2004. Pharmacogenomic identification of targets for adjuvant therapy with the topoisomerase poison camptothecin. Cancer Research. 64:2096-104. reprint (251 KB, PDF)

Lenburg, M.E., L.S. Liou, N.P. Gerry, G.M. Frampton, H.T. Cohen, M.F. Christman. 2003. Previously unidentified changes in renal cell carcinoma gene expression identified by parametric analysis of microarray data. BMC Cancer. 3:31. open access article

Bird, A.W., Yu, D.Y., Pray-Grant, M.G., Qiu, Q., Harmon, K.E., Megee, P.C., Grant, P.A., Smith, M.M. and Christman, M.F. (2002). Acetylation of histone H4 by Esa1p is required for DNA double strand break repair. Nature 419, 411-415. reprint (380 KB, PDF)