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Autozygosity Mapping with Exome Sequence Data

Authors

  • Ian M. Carr,

    Corresponding author
    • School of Medicine, University of Leeds, Leeds, United Kingdom
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  • Sanjeev Bhaskar,

    1. Genetic Medicine Research Group, Manchester Biomedical Research Centre, Manchester Academic Health Sciences Centre, University of Manchester and Central Manchester Foundation Trust, St Mary's Hospital, Manchester, United Kingdom
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  • James O’ Sullivan,

    1. Genetic Medicine Research Group, Manchester Biomedical Research Centre, Manchester Academic Health Sciences Centre, University of Manchester and Central Manchester Foundation Trust, St Mary's Hospital, Manchester, United Kingdom
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  • Mohammed A. Aldahmesh,

    1. Developmental Genetics Unit, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
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  • Hanan E. Shamseldin,

    1. Developmental Genetics Unit, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
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  • Alexander F. Markham,

    1. School of Medicine, University of Leeds, Leeds, United Kingdom
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  • David T. Bonthron,

    1. School of Medicine, University of Leeds, Leeds, United Kingdom
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  • Graeme Black,

    1. Genetic Medicine Research Group, Manchester Biomedical Research Centre, Manchester Academic Health Sciences Centre, University of Manchester and Central Manchester Foundation Trust, St Mary's Hospital, Manchester, United Kingdom
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  • Fowzan S. Alkuraya

    1. Developmental Genetics Unit, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
    2. Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
    3. Department of Pediatrics, King Khalid University Hospital and College of Medicine, King Saud University, Riyadh, Saudi Arabia
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  • Communicated by A. Jamie Cuticchia

  • Contract grant sponsors: Sir Jules Thorn Charitable Trust (Grant 09/JTA); EPSRC (Grant FP/I000623/1); Cancer Research UK (Grant 600130); KACST (Grants 08MED497-20 and 09-MED941-20 to F.S.A.); DHFMR Collaborative Research Grant (to F.S.A.).

Correspondence to: Ian M. Carr, School of Medicine, University of Leeds, Brenner Building, St. James's University Hospital, Leeds LS9 7TF, UK. E-mail: i.m.carr@leeds.ac.uk

ABSTRACT

Autozygosity mapping is a powerful method for the identification of recessively inherited disease genes using small inbred families. Typically, microarray SNP genotype data are first used to identify autozygous regions as extended runs of homozygous genotypes. Next, candidate disease loci are found by defining regions that are autozygous in all affected patients. Finally, the disease gene is identified by sequencing the genes within the candidate disease loci. However, with the advent of massively parallel sequencing, it is now possible to sample or to completely sequence an individual's genome, or, more commonly, exome. This opens up the possibility of concurrently defining autozygous regions and identifying possibly deleterious sequence variants, using data from a single sequencing experiment. Consequently, we have developed a set of computer programs that identify autozygous regions using exome sequence data. These programs derive their genotyping data either by the ab initio detection of all sequence variants or by the assessment of 0.53 million known polymorphic positions within each exome dataset. Using genotype data derived solely from exome sequence data, it was possible to identify the majority of autozygous regions found by microarray SNP genotype data.

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