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Alan Herbert, MBChB, Ph.D.
Assistant Professor
MBChB, Ph.D., University of Auckland

(617) 414-1254

aherbert@bu.edu

 

 

It is now possible to examine at a genome-scale level how genetic variation in human alters risk of disease, either directly or through secondary risk factors such as obesity. The high resolution of the genomic approaches allows particular chromosomal regions to be identified for further study so that the pathways involved can be defined and drugable components identified. We have just completed a whole genome scan of families from a community-based population in Framingham, Massachusetts, that involved typing 100,000 single nucleotide polymorphisms per individual and identified a common variant that increases risk of obesity. The closest gene INSIG2 is involved in the regulation of fatty acid synthesis. Another variant affecting a gene in the same pathway, ACACA is associated with leanness. Both genes are potential therapeutic targets and we are in the process of initiating a high-throughput screen of candidate drugs using a chemical library available through the NIH/NIGMS - funded Center for Methodologies and Library Development at Boston University.

Analysis of other traits is also underway - data is available for many phenotypes, ranging from hypertension to dyslipidemias (http://gmed.bu.edu). Behavioral data relating to alcohol and cigarette smoking as well as mini-mental status is also being analyzed, potentially providing insight into pathways of addition and also genes that predict successful neurological aging.

The success of our project has encouraged NHLBI to perform a higher density SNP scan in all Framingham Heart Study participants and develop a resource, based at NIH that will allow all qualified investigators access to all the data from the study and thus accelerate the pace of discovery.

We are also applying these approaches to the study of other human populations. We have collaborations with the Howard University Family Study and the Black Women's Health Study. The Delaware Valley Personalized Medicine Project will extend this work directly to the clinic.

These approaches represent the first time that human genetics can be approached in a normal population. One of the hopes is that we will be able to identify not only proteins that affect phenotype, but also instances where non-coding RNAs regulate the read-out of genetic information. Our laboratory is also active in performing experiments to elucidate these molecular pathways.

publications

Djousse L, Karamohamed S, Herbert AG, D'Agostino RB, Cupples LA, Ellison RC. Fucosyltransferase 3 polymorphism and atherothrombotic disease in the Framingham Offspring Study. Am Heart J 2007;153:636-9.

Herbert A, Lenburg ME, Ulrich D, Gerry NP, Schlauch K, Christman MF. Open-access database of candidate associations from a genome-wide SNP scan of the Framingham Heart Study. Nat Genet 2007;39:135-6.

Wilk JB, Herbert A, Shoemaker CM, Gottlieb DJ, Karamohamed S. Secreted Modular Calcium-Binding Protein 2 Haplotypes are Associated with Pulmonary Function. Am J Respir Crit Care Med 2007.

Kiel DP, Ferrari SL, Cupples LA, et al. Genetic variation at the low-density lipoprotein receptor-related protein 5 (LRP5) locus modulates Wnt signaling and the relationship of physical activity with bone mineral density in men. Bone 2006.

Herbert A, Gerry NP, McQueen MB, et al. A common genetic variant is associated with adult and childhood obesity. Science 2006;312:279-83.

Meigs JB, Dupuis J, Liu C, et al. PAI-1 Gene 4G/5G polymorphism and risk of type 2 diabetes in a population-based sample. Obesity (Silver Spring) 2006;14:753-8.

Demissie S, Levy D, Benjamin EJ, et al. Insulin resistance, oxidative stress, hypertension, and leukocyte telomere length in men from the Framingham Heart Study. Aging Cell 2006;5:325-30.

Herbert A, Liu C, Karamohamed S, et al. BMI modifies associations of IL-6 genotypes with insulin resistance: the Framingham Study. Obesity (Silver Spring) 2006;14:1454-61.

Djousse L, Levy D, Herbert AG, et al. Influence of alcohol dehydrogenase 1C polymorphism on the alcohol-cardiovascular disease association (from the Framingham Offspring Study). Am J Cardiol 2005;96:227-32.

Newton-Cheh C, Larson MG, Corey DC, et al. QT interval is a heritable quantitative trait with evidence of linkage to chromosome 3 in a genome-wide linkage analysis: The Framingham Heart Study. Heart Rhythm 2005;2:277-84

Meigs JB, Dupuis J, Herbert AG, Liu C, Wilson PW, Cupples LA. The insulin gene variable number tandem repeat and risk of type 2 diabetes in a population-based sample of families and unrelated men and women. J Clin Endocrinol Metab 2005;90:1137-43.

Van Steen K, McQueen MB, Herbert A, et al. Genomic screening and replication using the same data set in family-based association testing. Nat Genet 2005;37:683-91.

Herbert A, Liu C, Karamohamed S, et al. The -174 IL-6 GG genotype is associated with a reduced risk of type 2 diabetes mellitus in a family sample from the National Heart, Lung and Blood Institute's Framingham Heart Study. Diabetologia 2005.

Karamohamed S, Golbe LI, Mark MH, et al. Absence of previously reported variants in the SCNA (G88C and G209A), NR4A2 (T291D and T245G) and the DJ-1 (T497C) genes in familial Parkinson's disease from the GenePD study. Mov Disord 2005.

Herbert A. The four Rs of RNA-directed evolution. Nat Genet 2004;36:19-25.

Ferrari SL, Karasik D, Liu J, et al. Interactions of interleukin-6 promoter polymorphisms with dietary and lifestyle factors and their association with bone mass in men and women from the Framingham Osteoporosis Study. J Bone Miner Res 2004;19:552-9.

Herbert A. Roles for Z-DNA and double-stranded RNA in transcription: Encoding Genetic Information by Shape rather than by Sequence. 2004. In: DNA conformation and transcription. Ohyama T, ed.; Landes Bioscience: Georgetown, TX

Karamohamed S, DeStefano AL, Wilk JB, et al. A haplotype at the PARK3 locus influences onset age for Parkinson's disease: the GenePD study. Neurology 2003;61:1557-61.

Panhuysen CI, Cupples LA, Wilson PW, Herbert AG, Myers RH, Meigs JB. A genome scan for loci linked to quantitative insulin traits in persons without diabetes: the Framingham Offspring Study. Diabetologia 2003;46:579-87.

Karamohamed S, Demissie S, Volcjak J, et al. Polymorphisms in the insulin-degrading enzyme gene are associated with type 2 diabetes in men from the NHLBI Framingham Heart Study. Diabetes 2003;52:1562-7.

Wilk JB, DeStefano AL, Joost O, et al. Linkage and association with pulmonary function measures on chromosome 6q27 in the Framingham Heart Study. Hum Mol Genet 2003;12:2745-51.

Herbert A, Wagner S, Nickerson JA. Induction of protein translation by ADAR1 within living cell nuclei is not dependent on RNA editing. Mol Cell 2002;10:1235-46.

Karasik D, Myers RH, Cupples LA, et al. Genome screen for quantitative trait loci contributing to normal variation in bone mineral density: the Framingham Study. J Bone Miner Res 2002;17:1718-27.

Herbert A, Rich A. The role of binding domains for dsRNA and Z-DNA in the in vivo editing of minimal substrates by ADAR1. Proc Natl Acad Sci U S A 2001;98:12132-7.

Kim YG, Lowenhaupt K, Maas S, Herbert A, Schwartz T, Rich A. The zab domain of the human RNA editing enzyme ADAR1 recognizes Z-DNA when surrounded by B-DNA. J Biol Chem 2000;275:26828-33.

Herbert A, Rich A. RNA processing and the evolution of eukaryotes. Nat Genet 1999;21:265-9.

Schade M, Turner CJ, Kuhne R, et al. The solution structure of the Zalpha domain of the human RNA editing enzyme ADAR1 reveals a prepositioned binding surface for Z-DNA. Proc Natl Acad Sci U S A 1999;96:12465-70.

Schade M, Turner CJ, Lowenhaupt K, Rich A, Herbert A. Structure-function analysis of the Z-DNA-binding domain Zalpha of dsRNA adenosine deaminase type I reveals similarity to the (alpha + beta) family of helix-turn-helix proteins. EMBO J 1999;18:470-9.

Schade M, Behlke J, Lowenhaupt K, Herbert A, Rich A, Oschkinat H. A 6 bp Z-DNA hairpin binds two Z alpha domains from the human RNA editing enzyme ADAR1. FEBS Lett 1999;458:27-31.

Herbert A, Rich A. RNA processing in evolution. The logic of soft-wired genomes. Ann N Y Acad Sci 1999;870:119-32.

Herbert A, Rich A. RNA processing and the evolution of eukaryotes. Nat Genet 1999;21:265-9.

Schade M, Turner CJ, Lowenhaupt K, Herbert A, Rich A, Oschkinat H. Solution structure of the Z-DNA binding domain Za from the human RNA editing enzyme ADAR1. Proceedings of the National Academy of Science, USA 1999;96:(in press).

Herbert A, Rich A. Left handed Z-DNA: structure and function. 1999. In: Structural Biology and Functional Genomics. E.M. B, S. P, eds.; Kluwer Academic Publishers: Netherlands: 53-72.

Schwatrz T, Shafer K, Lowenhaupt K, Hanlon EB, Herbert A, Rich A. Crystallizaton and preliminary studies of the DNA binding domain, Za, from ADAR1 complexed to left-handed DNA. Acta Crystallographica 1999;D55:1362-4.

Schwartz T, Rould MA, Lowenhaupt K, Herbert A, Rich A. Specific Recognition of left-handed Z-DNA: Co-crystal structure of the Za DNA recognition motif of ADAR1 at 2.1A resolution. Science 1999;284:1841-5.

Schwartz T, Lowenhaupt K, Kim Y-G, et al. Proteolytic dissection of Zab, the Z-DNA binding domain of human ADAR1. Journal of Biological Chemistry 1999;274:2899-906.

Berger I, Winston W, Manoharan R, et al. Spectroscopic characterization of Z-alpha, a novel DNA binding domain from human ADAR1. Biochemistry 1998;37:13313-21.

Liu Y, Herbert A, A. R, Samuels CE. Double-stranded RNA-specific adenosine deaminase nucleic acid binding properties. Methods 1998;15:199-205.

Herbert A, Schade M, Lowenhaupt K, et al. The Z-alpha domain from human ADAR1 binds to the Z-DNA conformer of many different sequences. Nucleic Acids Research 1998;26:3486-93.

Kim Y-G, Kim PS, Herbert A, Rich A. Construction of a Z-DNA specific restriction endonuclease. Proceedings of the National Academy of Science, USA 1997;94:12875-9.

Bass BL, Nishikura K, Keller W, et al. A standardized Nomenclature for adenosine deaminases that act on RNA. RNA 1997;3:947-9.

Herbert A, Kim Y-G, Alfken J, Nishikura K, Rich A. A Z-DNA binding domain from the human editing enzyme dsRNA adenosine deaminase. Proceedings of the National Academy of Science, USA 1997;94:12875-9.

Herbert A, Rich A. The biology of left-handed Z-DNA. J Biol Chem 1996;271:11595-8.

Herbert A, Lowenhaupt K, Spitzner J, Berger I, Rich A. A biological role for Z-DNA. 1996. In: Biological Structure and Dynamics. Proceedings of the Ninth Conversation. H SR, Sarma MH, eds.; Adenine Press: Albany, NY: 189-97.

Herbert A. RNA editing, introns and evolution. Trends in Genetics 1996;12:6-9.

Herbert A, Lowenhaupt K, Spitzner J, Rich A. Double-stranded RNA adenosine deaminase binds Z-DNA in vitro. Nucleic Acids Symp Ser 1995:16-9.

Herbert A, Lowenhaupt K, Spitzner J, Rich A. Chicken double-stranded RNA adenosine deaminase has apparent specificity for Z-DNA. Proc Natl Acad Sci U S A 1995;92:7550-4.

Wolfl S, Vahrson W, Herbert A. Analysis of left-handed Z-DNA in vivo, in DNA and Nucleoprotein Structure in Vivo. 1995. Saluz HP, Wiebauer K, eds.; R. G. Landes Company: Austin, TX: 137-59.

Herbert AG, Spitzner JR, Lowenhaupt K, Rich A. Z-DNA binding protein from chicken blood nuclei. Proc Natl Acad Sci U S A 1993;90:3339-42.

Herbert AG, Rich A. A method to identify and characterize Z-DNA binding proteins using a linear oligodeoxynucleotide. Nucleic Acids Res 1993;21:2669-72.

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