Nature Reviews Genetics 12, 628-640 (September 2011) | doi:10.1038/nrg3046

Article series: Applications of next-generation sequencing

Needles in stacks of needles: finding disease-causal variants in a wealth of genomic data

Gregory M. Cooper1 & Jay Shendure2  About the authors


Genome and exome sequencing yield extensive catalogues of human genetic variation. However, pinpointing the few phenotypically causal variants among the many variants present in human genomes remains a major challenge, particularly for rare and complex traits wherein genetic information alone is often insufficient. Here, we review approaches to estimate the deleteriousness of single nucleotide variants (SNVs), which can be used to prioritize disease-causal variants. We describe recent advances in comparative and functional genomics that enable systematic annotation of both coding and non-coding variants. Application and optimization of these methods will be essential to find the genetic answers that sequencing promises to hide in plain sight.

Author affiliations

  1. HudsonAlpha Institute for Biotechnology, Huntsville, Alabama 35806, USA.
  2. Department of Genome Sciences, University of Washington, Seattle, Washington 98115, USA.

Correspondence to: Gregory M. Cooper1 Email:

Correspondence to: Jay Shendure2 Email:

Published online 18 August 2011