title: Rapid and accurate large-scale genotyping of duplicated genes and discovery of interlocus gene conversions.
abstract: Over 900 genes have been annotated within duplicated regions of the human genome, yet their functions and potential roles in disease remain largely unknown. One major obstacle has been the inability to accurately and comprehensively assay genetic variation for these genes in a high-throughput manner. We developed a sequencing-based method for rapid and high-throughput genotyping of duplicated genes using molecular inversion probes designed to target unique paralogous sequence variants. We applied this method to genotype all members of two gene families, SRGAP2 and RH, among a diversity panel of 1,056 humans. The approach could accurately distinguish copy number in paralogs having up to ∼99.6% sequence identity, identify small gene-disruptive deletions, detect single-nucleotide variants, define breakpoints of unequal crossover and discover regions of interlocus gene conversion. The ability to rapidly and accurately genotype multiple gene families in thousands of individuals at low cost enables the development of genome-wide gene conversion maps and 'unlocks' many previously inaccessible duplicated genes for association with human traits.
authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington, USA.
authors.forename: Xander
authors.initials: X
authors.lastname: Nuttle
authors.forename: John
authors.initials: J
authors.lastname: Huddleston
authors.forename: Brian J
authors.initials: BJ
authors.lastname: O'Roak
authors.forename: Francesca
authors.initials: F
authors.lastname: Antonacci
authors.forename: Marco
authors.initials: M
authors.lastname: Fichera
authors.forename: Corrado
authors.initials: C
authors.lastname: Romano
authors.forename: Jay
authors.initials: J
authors.lastname: Shendure
authors.forename: Evan E
authors.initials: EE
authors.lastname: Eichler
mesh_terms: D020690:GTPase-Activating Proteins / Q000235:genetics*; D005785:Gene Conversion; D018628:Gene Dosage; D020131:Genes, Duplicate; D014644:Genetic Variation; D015894:Genome, Human; D060005:Genotyping Techniques / Q000191:economics / Q000379:methods*; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D059765:Homologous Recombination; D006801:Humans; D015335:Molecular Probes; D012204:Rh-Hr Blood-Group System / Q000235:genetics
chemical_list: D020690:GTPase-Activating Proteins; D015335:Molecular Probes; D012204:Rh-Hr Blood-Group System; C026410:Rho(D) antigen; C501995:SRGAP2 protein, human
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