RAPID COMMUNICATION OFFICIAL JOURNAL www.hgvs.org DIAMUND: Direct Comparison of Genomes to Detect Mutations

ABSTRACT: DNA sequencing has become a powerful method to discover the genetic basis of disease. Standard, widely used protocols for analysis usually begin by compar-ing each individual to the human reference genome. When applied to a set of related individuals, this approach reveals millions of differences, most of which are shared among the individuals and unrelated to the disease being inves-tigated. We have developed a novel algorithm for vari-ant detection, one that compares DNA sequences directly to one another, without aligning them to the reference genome. When used to find de novo mutations in exome sequences from family trios, or to compare normal and dis-eased samples from the same individual, the new method, direct alignment for mutation discovery (DIAMUND), produces a dramatically smaller list of candidate muta-tions than previous methods, without losing sensitivity to detect the true cause of a genetic disease. We demonstrate our results on several example cases, including two family trios in which it correctly found the disease-causing vari-ant while excluding thousands of harmless variants that standard methods had identified