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Next-generation human genetics

Over the past five years, a new generation of technologies has reduced the cost of DNA sequencing by more than four orders of magnitude, democratizing the field by putting the sequencing capacity of a major genome center in the hands of individual investigators [1]. To exploit this paradigm shift, we have developed new technical methods and analytical strategies for disease gene discovery based on whole exome and whole genome sequencing. Our results to date include proof of concept [2] and the first demonstration [3] that exome sequencing of a small number of individuals can be applied to solve Mendelian, single-gene, disorders such as Miller syndrome [3] and Kabuki syndrome [4]. Recently, we have also demonstrated that exome or genome sequencing of parent-child trios can be used to rapidly identify candidate genes for complex disorders such as autism [5]. We are currently extending these strategies to additional simple and complex diseases of unknown etiology.


  1. 1.

    Shendure J, Ji H: Next-generation DNA sequencing.Nat Biotechnol 2008, 26:1135–1145.

  2. 2.

    Ng SB, Turner EH, Robertson PD, Flygare SD, Bigham AW, Lee C, Shaffer T, Wong M, Bhattacharjee A, Eichler EE, Bamshad M, Nickerson DA, Shendure J: Targeted capture and massively parallel sequencing of 12 human exomes.Nature 2009, 461:272–276.

  3. 3.

    Ng SB, Buckingham KJ, Lee C, Bigham AW, Tabor HK, Dent KM, Huf CD, Shannon PT, Jabs EW, Nickerson DA, Shendure J, Bamshad MJ: Exome sequencing identifies the cause of a mendelian disorder.Nat Genet 2010, 42:30–35.

  4. 4.

    Ng SB, Bigham AW, Buckingham KJ, Hannibal MC, McMillin MJ, Gildersleeve HI, Beck AE, Tabor HK, Cooper GM, Mefford HC, Lee C, Turner EH, Smith JD, Rieder MJ, Yoshiura K, Matsumoto N, Ohta T, Niikawa N, Nickerson DA, Bamshad MJ, Shendure J: Exome sequencing identifiesMLL2mutations as a cause of Kabuki syndrome.Nat Genet 2010, 42:790–793.

  5. 5.

    O’Roak BJ, Deriziotis P, Lee C, Vives L, Schwartz JJ, Girirajan S, Karakoc E, Mackenzie AP, Ng SB, Baker C, Rieder MJ, Nickerson DA, Bernier R, Fisher SE, Shendure J, Eichler EE: Exome sequencing in sporadic autism spectrum disorders identifies severede novomutations.Nat Genet 2011, 43:585–589.

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Correspondence to Jay Shendure.

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  • Genome Sequencing
  • Candidate Gene
  • Complex Disease
  • Analytical Strategy
  • Paradigm Shift