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Proc Natl Acad Sci U S A. 2016 Jun 14;113(24):6713-8. doi: 10.1073/pnas.1606460113. Epub 2016 May 31.

Whole-exome sequencing to analyze population structure, parental inbreeding, and familial linkage.

Author information

1
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;
2
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;
3
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY 10065;
4
New York Genome Center, New York, NY 10013;
5
Genetics Unit, Military Hospital Mohammed V, Hay Riad, 10100 Rabat, Morocco;
6
Clinical Immunology Unit of the Pediatric Infectious Disease Service, Ibn Roshd Hospital, Hassan II University, Casablanca 20460, Morocco;
7
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;
8
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.
9
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.

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.

KEYWORDS:

exome sequencing; genotyping array; homozygosity mapping; linkage analysis; population structure

PMID:
27247391
PMCID:
PMC4914194
DOI:
10.1073/pnas.1606460113
[Indexed for MEDLINE]
Free PMC Article

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