Human Genome Sequence Variation and the Genetics of Common Disease
Despite remarkable progress in biomedical research, surprisingly little is known about the specific molecular defects that underlie individual risk of common diseases. As many such disorders cluster in families, inherited differences in DNA sequence play a major role in causing disease. In rare cases, mutation of single gene exerts a strong effect; the study of such disorders has provided a mechanistic understanding of hundreds of human diseases. Common diseases pose a greater challenge, however, as they reflect the combined action of multiple genes (each with a modest contribution) as well as non-genetic factors. Our goal is to develop approaches to identify the genetic underpinnings of common diseases, and apply these tools to understand type 2 diabetes and other endocrine disorders.
Recent advances in genomics promise exciting new avenues to understanding the genetics of common diseases. The completed human genome sequence represents a major step towards a complete catalogue of human genes, making finite the list of possible culprits in disease. Empowered by high-throughput technologies and powerful computations methods, this basic framework is increasingly annotated with critical information about each gene: its spectrum of sequence variation in the population, expression patterns in different cell-types and diseases, and protein-protein interactions. These trends lay the foundation for a fundamentally new approach to disease research, informed by rich knowledge of each gene's characteristics, and global in scope.
We are focusing on two related approaches that together should illuminate fundamental genetic concepts and mechanisms of disease: first, characterizing and cataloguing patterns of genome sequence variation in the human population, and second developing robust methods for relate sequence variants and disease, using type 2 diabetes and prostate cancer as examples. We have participated in the generation of genome-wide maps of common human sequence variants (ÒSNPsÓ), studied the population genetic forces that explain the unusual patterns observed, and are now contributing to the genome-wide Haplotype Map Project. We and our collaborators have identified over 10,000 DNA samples from clinical populations (type 2 diabetes and hormone-responsive cancers), which we use to perform well-powered disease association studies to identify robust relationships between individual gene variants and disease.
In summary, our aim is to develop frameworks and information that allow the genetic dissection of common, polygenic disorders, describing the genetic architecture and specific pathways responsible for type 2 diabetes and hormone-responsive cancers in the population. Success would inform our understanding of basic mechanisms, and point towards improved diagnosis, prevention and treatment of common disorders. Ultimately, we would like to help guide such information back into clinical practice, offering new hope for previously intractable problems.
Links to other websites about the Altshuler Lab
http://www-genome.wi.mit.edu/mpg/
http://www.hms.harvard.edu/dms/bbs/fac/altschulerda.html
Links to information about the recently-announced Broad Institute of MIT, Whitehead, Harvard and Harvard Hospitals
http://www-genome.wi.mit.edu/broad/
http://www-tech.mit.edu/V123/N29/29broad.29n.html
http://www.news.harvard.edu/gazette/daily/0306/19-broad.html
http://www.uh.edu/admin/media/topstories/2003/bglobe/200306/20030620harmit.html
Links to articles about the Altshuler Lab and collaborations
http://www-genome.wi.mit.edu/media/2003/pr_03_diabetes.
http://focus.hms.harvard.edu/2003/July11_2003/genetics.html
htmlhttp://www.news.harvard.edu/gazette/2002/06.13/99-gene.html
http://focus.hms.harvard.edu/2002/June7_2002/genomics.html
http://www-genome.wi.mit.edu/media/press/pr_02_altshul1029.html
http://www.wi.mit.edu/nap/features/nap_feature_affiliate.html
http://www.mgh.harvard.edu/DEPTS/pubaffairs/Issues/052402altshuler.htm
http:// www.hms.harvard.edu/md_phd/01WinterNews.pdf
http://www.fortune.com/fortune/technology/articles/0,15114,389965-3,00.html
http://www.niddk.nih.gov/federal/planning/genetic-roster.htm
http://www.technologyreview.com/articles/hall0203.asp
http://www.incyte.com/insidegenomics/foc/foc_foc_0003/foc_foc_0003_1.shtml
http://gnn.tigr.org/articles/05_02/genetic_variation.shtml
