Power of deep, all-exon resequencing for discovery of human trait genes

Proc Natl Acad Sci U S A. 2009 Mar 10;106(10):3871-6. doi: 10.1073/pnas.0812824106. Epub 2009 Feb 6.


The ability to sequence cost-effectively all of the coding regions of a given individual genome is rapidly approaching, with the potential for whole-genome resequencing not far behind. Initiatives are currently underway to phenotype hundreds of thousands of individuals for major human traits. Here, we determine the power for de novo discovery of genes related to human traits by resequencing all human exons in a clinical population. We analyze the potential of the gene discovery strategy that combines multiple rare variants from the same gene and treats genes, rather than individual alleles, as the units for the association test. By using computer simulations based on deep resequencing data for the European population, we show that genes meaningfully affecting a human trait can be identified in an unbiased fashion, although large sample sizes would be required to achieve substantial power.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Chromosome Mapping
  • Computer Simulation
  • Demography
  • Exons / genetics*
  • Gene Frequency
  • Genetic Variation
  • Humans
  • Meta-Analysis as Topic
  • Models, Genetic
  • Mutation, Missense / genetics
  • Phenotype
  • Polymorphism, Single Nucleotide / genetics
  • Quantitative Trait, Heritable*
  • Receptor, Melanocortin, Type 4 / genetics
  • Selection, Genetic
  • Sequence Analysis, DNA / methods*


  • MC4R protein, human
  • Receptor, Melanocortin, Type 4