Haplotypes and Informative SNP Selection Algorithms: Don’t Block Out Information Dedicated to Michael Waterman on his 60th Birthday

It is widely hoped that variation in the human genome will provide a means of predicting risk of a variety of complex, chronic diseases. A major stumbling block to the successful identification of association between human DNA polymorphisms (SNPs) and variability in risk of complex diseases is the enormous number of SNPs in the human genome (4,9). The large number of SNPs results in unacceptably high costs for exhaustive genotyping, and so there is a broad effort to determine ways to select SNPs so as to maximize the informativeness of a subset. In this paper we contrast two methods for reducing the complexity of SNP variation: haplotype tagging, i.e. typing a subset of SNPs to identify segments of the genome that appear to be nearly unrecombined (haplotype blocks), and a new block-free model that we develop in this report. We present a statistic for comparing haplotype blocks and show that while the concept of haplotype blocks is reasonably robust there is substantial variability among block partitions. We develop a measure for selecting an informative subset of SNPs in a block free model. We show that the general version of this problem is NP-hard and give efficient algorithms for two important special cases of this problem. Informatics Research, Celera. Current address: The Center for Advancement of Genomics, 1901 Research Blvd., 6th floor, Rockville, MD 20850, [email protected] Informatics Research, Celera/Applied Biosystems, 45 W. Gude Drive, Rockville MD, 20850, [email protected] Informatics Research, Celera. Current address: Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA, 15213, [email protected] Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY, 14853, [email protected] Informatics Research, Celera/Applied Biosystems 45 W. Gude Drive, Rockville MD, 20850, [email protected] Permission to make digital or hard copies of all or part of this work for personal or classroom use is granted without fee provided that copies are not made or distributed for profit or commercial advantage and that copies bear this notice and the full citation on the first page. To copy otherwise, to republish, to post on servers or to redistribute to lists, requires prior specific permission and/or a fee. RECOMB’03, April 10–13, 2003, Berlin, Germany. Copyright 2003 ACM 1-58113-635-8/03/0004 ...$5.00. Categories & Subject Descriptors F.2.0, G.3, G.4, J.3