A probabilistic disease-gene finder for personal genomes (original) (raw)

1. Chad Huff1,3,
2. Hao Hu1,3,
3. Marc Singleton1,
4. Barry Moore1,
5. Jinchuan Xing1,
6. Lynn B. Jorde1 and
7. Martin G. Reese2
8. 1Department of Human Genetics, Eccles Institute of Human Genetics, University of Utah and School of Medicine, Salt Lake City, Utah 84112, USA;
9. 2Omicia, Inc., Emeryville, California 94608, USA
10. ↵3 These authors contributed equally to this work.

Abstract

VAAST (the Variant Annotation, Analysis & Search Tool) is a probabilistic search tool for identifying damaged genes and their disease-causing variants in personal genome sequences. VAAST builds on existing amino acid substitution (AAS) and aggregative approaches to variant prioritization, combining elements of both into a single unified likelihood framework that allows users to identify damaged genes and deleterious variants with greater accuracy, and in an easy-to-use fashion. VAAST can score both coding and noncoding variants, evaluating the cumulative impact of both types of variants simultaneously. VAAST can identify rare variants causing rare genetic diseases, and it can also use both rare and common variants to identify genes responsible for common diseases. VAAST thus has a much greater scope of use than any existing methodology. Here we demonstrate its ability to identify damaged genes using small cohorts (n = 3) of unrelated individuals, wherein no two share the same deleterious variants, and for common, multigenic diseases using as few as 150 cases.

Footnotes

• ↵4 Corresponding author.
  E-mail myandell{at}genetics.utah.edu.

• [Supplemental material is available for this article.]

• Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.123158.111.

• Received March 9, 2011.

• Accepted June 8, 2011.

• Copyright © 2011 by Cold Spring Harbor Laboratory Press

Freely available online through the Genome Research Open Access option.