title: Whole-exome sequencing to analyze population structure, parental inbreeding, and familial linkage.
abstract: Principal component analysis (PCA), homozygosity rate estimations, and linkage studies in humans are classically conducted through genome-wide single-nucleotide variant arrays (GWSA). We compared whole-exome sequencing (WES) and GWSA for this purpose. We analyzed 110 subjects originating from different regions of the world, including North Africa and the Middle East, which are poorly covered by public databases and have high consanguinity rates. We tested and applied a number of quality control (QC) filters. Compared with GWSA, we found that WES provided an accurate prediction of population substructure using variants with a minor allele frequency > 2% (correlation = 0.89 with the PCA coordinates obtained by GWSA). WES also yielded highly reliable estimates of homozygosity rates using runs of homozygosity with a 1,000-kb window (correlation = 0.94 with the estimates provided by GWSA). Finally, homozygosity mapping analyses in 15 families including a single offspring with high homozygosity rates showed that WES provided 51% less genome-wide linkage information than GWSA overall but 97% more information for the coding regions. At the genome-wide scale, 76.3% of linked regions were found by both GWSA and WES, 17.7% were found by GWSA only, and 6.0% were found by WES only. For coding regions, the corresponding percentages were 83.5%, 7.4%, and 9.1%, respectively. With appropriate QC filters, WES can be used for PCA and adjustment for population substructure, estimating homozygosity rates in individuals, and powerful linkage analyses, particularly in coding regions.
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, 75015 Paris, France; Imagine Institute, Paris Descartes University, 75015 Paris, France;
authors.forename: Aziz
authors.initials: A
authors.lastname: Belkadi
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, 75015 Paris, France; Imagine Institute, Paris Descartes University, 75015 Paris, France; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, United Kingdom;
authors.forename: Vincent
authors.initials: V
authors.lastname: Pedergnana
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, 75015 Paris, France; Imagine Institute, Paris Descartes University, 75015 Paris, France;
authors.forename: Aurélie
authors.initials: A
authors.lastname: Cobat
authors.affiliation: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY 10065;
authors.forename: Yuval
authors.initials: Y
authors.lastname: Itan
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, 75015 Paris, France; Imagine Institute, Paris Descartes University, 75015 Paris, France;
authors.forename: Quentin B
authors.initials: QB
authors.lastname: Vincent
authors.affiliation: New York Genome Center, New York, NY 10013;
authors.forename: Avinash
authors.initials: A
authors.lastname: Abhyankar
authors.affiliation: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY 10065;
authors.forename: Lei
authors.initials: L
authors.lastname: Shang
authors.affiliation: Genetics Unit, Military Hospital Mohammed V, Hay Riad, 10100 Rabat, Morocco;
authors.forename: Jamila
authors.initials: J
authors.lastname: El Baghdadi
authors.affiliation: Clinical Immunology Unit of the Pediatric Infectious Disease Service, Ibn Roshd Hospital, Hassan II University, Casablanca 20460, Morocco;
authors.forename: Aziz
authors.initials: A
authors.lastname: Bousfiha
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, 75015 Paris, France; Imagine Institute, Paris Descartes University, 75015 Paris, France;
authors.forename: Alexandre
authors.initials: A
authors.lastname: Alcais
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, 75015 Paris, France; Imagine Institute, Paris Descartes University, 75015 Paris, France; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY 10065;
authors.forename: Bertrand
authors.initials: B
authors.lastname: Boisson
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, 75015 Paris, France; Imagine Institute, Paris Descartes University, 75015 Paris, France; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY 10065; Howard Hughes Medical Institute, New York, NY 10065; Pediatric Haematology-Immunology Unit, Necker Hospital for Sick Children, 75015 Paris, France jean-laurent.casanova@rockefeller.edu laurent.abel@inserm.fr.
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, 75015 Paris, France; Imagine Institute, Paris Descartes University, 75015 Paris, France; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY 10065; jean-laurent.casanova@rockefeller.edu laurent.abel@inserm.fr.
authors.forename: Laurent
authors.initials: L
authors.lastname: Abel
mesh_terms: D003241:Consanguinity; D005260:Female; D008040:Genetic Linkage; D055106:Genome-Wide Association Study; D006720:Homozygote; D006801:Humans; D008297:Male; D008877:Middle East; D009656:North America
keywords: exome sequencing; genotyping array; homozygosity mapping; linkage analysis; population structure