%0 Journal Article
%T The theory of discovering rare variants via DNA sequencing
%A Michael C Wendl
%A Richard K Wilson
%J BMC Genomics
%D 2009
%I BioMed Central
%R 10.1186/1471-2164-10-485
%X We pose and solve the population sequencing design problem and subsequently apply standard optimization techniques that maximize the discovery probability. Emphasis is placed on cases whose discovery thresholds place them within reach of current technologies. We find that parameter values characteristic of rare-variant projects lead to a general, yet remarkably simple set of optimization rules. Specifically, optimal processing occurs at constant values of the per-sample redundancy, refuting current notions that sample size should be selected outright. Optimal project-wide redundancy and sample size are then shown to be inversely proportional to the desired variant frequency. A second family of constants governs these relationships, permitting one to immediately establish the most efficient settings for a given set of discovery conditions. Our results largely concur with the empirical design of the Thousand Genomes Project, though they furnish some additional refinement.The optimization principles reported here dramatically simplify the design process and should be broadly useful as rare-variant projects become both more important and routine in the future.Technological developments continue to dramatically expand the enterprise of DNA sequencing. In particular, the emergence of so-called "next-generation" instruments (NGIs) is opening a new chapter of genomic research [1]. If we characterize sequencing economy by the ratio of project speed to total project cost, NGIs are orders of magnitude superior to their traditional Sanger-based predecessors. Indeed, they are the first systems to demonstrate the economic feasibility of sequencing individual genomes on a large scale [2].Future efforts will undoubtedly use NGIs to address issues in medical sequencing and personal genomics [3], but these instruments are also poised for major contributions at the population level [4,5]. For example, the Thousand Genomes Project (TGP) is focusing on comprehensive identification of va
%U http://www.biomedcentral.com/1471-2164/10/485