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Mutation mapping and identification by whole-genome sequencing.

Genetic mapping of mutations in model systems has facilitated the identification of genes contributing to fundamental biological processes including human diseases. However, this approach has historically required the prior characterization of informative markers. Here we report a fast and cost-effective method for genetic mapping using next-generation sequencing that combines single nucleotide polymorphism discovery, mutation localization, and potential identification of causal sequence variants. In contrast to prior approaches, we have developed a hidden Markov model to narrowly define the mutation area by inferring recombination breakpoints of chromosomes in the mutant pool. In addition, we created an interactive online software resource to facilitate automated analysis of sequencing data and demonstrate its utility in the zebrafish and mouse models. Our novel methodology and online tools will make next-generation sequencing an easily applicable resource for mutation mapping in all model systems.

Pubmed ID: 22555591


  • Leshchiner I
  • Alexa K
  • Kelsey P
  • Adzhubei I
  • Austin-Tse CA
  • Cooney JD
  • Anderson H
  • King MJ
  • Stottmann RW
  • Garnaas MK
  • Ha S
  • Drummond IA
  • Paw BH
  • North TE
  • Beier DR
  • Goessling W
  • Sunyaev SR


Genome research

Publication Data

August 2, 2012

Associated Grants

  • Agency: NIDDK NIH HHS, Id: 1R01DK090311
  • Agency: NIMH NIH HHS, Id: 5R01MH084676
  • Agency: NHLBI NIH HHS, Id: P01 HL032262
  • Agency: NHLBI NIH HHS, Id: P01HL032262
  • Agency: NIDDK NIH HHS, Id: R01 DK053093
  • Agency: NIDDK NIH HHS, Id: R01 DK070838
  • Agency: NIDDK NIH HHS, Id: R01 DK090311
  • Agency: NICHD NIH HHS, Id: R01 HD036404
  • Agency: NIMH NIH HHS, Id: R01 MH081187
  • Agency: NIDDK NIH HHS, Id: R01DK070838
  • Agency: NICHD NIH HHS, Id: R01HD036404
  • Agency: NIMH NIH HHS, Id: R01MH081187

Mesh Terms

  • Alleles
  • Animals
  • Chromosome Mapping
  • Chromosomes
  • Crosses, Genetic
  • DNA Mutational Analysis
  • Female
  • Gene Frequency
  • Genomics
  • Homozygote
  • Male
  • Markov Chains
  • Mice
  • Mice, Inbred C57BL
  • Mutation
  • Polymorphism, Single Nucleotide
  • Recombination, Genetic
  • Software
  • Time Factors
  • Zebrafish