title: Characterization of Greater Middle Eastern genetic variation for enhanced disease gene discovery.
abstract: The Greater Middle East (GME) has been a central hub of human migration and population admixture. The tradition of consanguinity, variably practiced in the Persian Gulf region, North Africa, and Central Asia, has resulted in an elevated burden of recessive disease. Here we generated a whole-exome GME variome from 1,111 unrelated subjects. We detected substantial diversity and admixture in continental and subregional populations, corresponding to several ancient founder populations with little evidence of bottlenecks. Measured consanguinity rates were an order of magnitude above those in other sampled populations, and the GME population exhibited an increased burden of runs of homozygosity (ROHs) but showed no evidence for reduced burden of deleterious variation due to classically theorized 'genetic purging'. Applying this database to unsolved recessive conditions in the GME population reduced the number of potential disease-causing variants by four- to sevenfold. These results show variegated genetic architecture in GME populations and support future human genetic discoveries in Mendelian and population genetics.
authors.affiliation: Howard Hughes Medical Institute, Rockefeller University, New York, New York, USA.|Rady Children's Institute for Genomic Medicine, Department of Neurosciences, University of California, San Diego, La Jolla, California, USA.|Laboratory for Pediatric Brain Disease, Rockefeller University, New York, New York, USA.
authors.forename: Eric M
authors.initials: EM
authors.lastname: Scott
authors.affiliation: Department of Biostatistics, Epidemiology and Scientific Computing, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Anason
authors.initials: A
authors.lastname: Halees
authors.affiliation: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University, New York, New York, USA.
authors.forename: Yuval
authors.initials: Y
authors.lastname: Itan
authors.affiliation: Howard Hughes Medical Institute, Rockefeller University, New York, New York, USA.|Rady Children's Institute for Genomic Medicine, Department of Neurosciences, University of California, San Diego, La Jolla, California, USA.|Laboratory for Pediatric Brain Disease, Rockefeller University, New York, New York, USA.
authors.forename: Emily G
authors.initials: EG
authors.lastname: Spencer
authors.affiliation: Howard Hughes Medical Institute, Rockefeller University, New York, New York, USA.|Rady Children's Institute for Genomic Medicine, Department of Neurosciences, University of California, San Diego, La Jolla, California, USA.|Laboratory for Pediatric Brain Disease, Rockefeller University, New York, New York, USA.
authors.forename: Yupeng
authors.initials: Y
authors.lastname: He
authors.affiliation: Howard Hughes Medical Institute, Rockefeller University, New York, New York, USA.|Rady Children's Institute for Genomic Medicine, Department of Neurosciences, University of California, San Diego, La Jolla, California, USA.|Laboratory for Pediatric Brain Disease, Rockefeller University, New York, New York, USA.
authors.forename: Mostafa Abdellateef
authors.initials: MA
authors.lastname: Azab
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Stacey B
authors.initials: SB
authors.lastname: Gabriel
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, INSERM, Paris, France.|Paris Descartes University, Imagine Institute, Paris, France.
authors.forename: Aziz
authors.initials: A
authors.lastname: Belkadi
authors.affiliation: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University, New York, New York, USA.|Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, INSERM, Paris, France.|Paris Descartes University, Imagine Institute, Paris, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Boisson
authors.affiliation: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University, New York, New York, USA.|Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, INSERM, Paris, France.|Paris Descartes University, Imagine Institute, Paris, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Abel
authors.affiliation: Department of Molecular Biology and Genetics, Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, New York, USA.
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Clark
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.|Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
authors.forename: Fowzan S
authors.initials: FS
authors.lastname: Alkuraya
authors.affiliation: Howard Hughes Medical Institute, Rockefeller University, New York, New York, USA.|St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University, New York, New York, USA.|Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, INSERM, Paris, France.|Paris Descartes University, Imagine Institute, Paris, France.|Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, Paris, France.
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
authors.affiliation: Howard Hughes Medical Institute, Rockefeller University, New York, New York, USA.|Rady Children's Institute for Genomic Medicine, Department of Neurosciences, University of California, San Diego, La Jolla, California, USA.|Laboratory for Pediatric Brain Disease, Rockefeller University, New York, New York, USA.
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Gleeson
mesh_terms: D044466:Asian People / Q000235:genetics*; D015331:Cohort Studies; D003241:Consanguinity; D004194:Disease / Q000235:genetics*; D059472:Exome / Q000235:genetics; D005808:Genes, Recessive; D005819:Genetic Markers / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D005828:Genetics, Population; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006720:Homozygote; D063426:Human Migration; D006801:Humans; D008877:Middle East; D044465:White People / Q000235:genetics*
chemical_list: D005819:Genetic Markers