The human gene damage index as a gene-level approach to prioritizing exome variants.
The protein-coding exome of a patient with a monogenic disease contains about 20,000 variants, only one or two of which are disease causing. We found that 58% of rare variants in the protein-coding exome of the general population are located in only 2% of the genes. Prompted by this observation, we aimed to develop a gene-level approach for predicting whether a given human protein-coding gene is likely to harbor disease-causing mutations. To this end, we derived the gene damage index (GDI): a genome-wide, gene-level metric of the mutational damage that has accumulated in the general population. We found that the GDI was correlated with selective evolutionary pressure, protein complexity, coding sequence length, and the number of paralogs. We compared GDI with the leading gene-level approaches, genic intolerance, and de novo excess, and demonstrated that GDI performed best for the detection of false positives (i.e., removing exome variants in genes irrelevant to disease), whereas genic intolerance and de novo excess performed better for the detection of true positives (i.e., assessing de novo mutations in genes likely to be disease causing). The GDI server, data, and software are freely available to noncommercial users from lab.rockefeller.edu/casanova/GDI.
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065; yitan@rockefeller.edu casanova@rockefeller.edu.
Yuval
Y
Itan
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065;
Lei
L
Shang
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065;
Bertrand
B
Boisson
Human Evolutionary Genetics Unit, Institut Pasteur, 75015 Paris, France; Centre National de la Recherche Scientifique, CNRS URA 3012, Paris, France;
Etienne
E
Patin
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065;
Alexandre
A
Bolze
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065; Group of Primary Immunodeficiencies, Faculty of Medicine, University of Antioquia UdeA, Medellín, Colombia;
Marcela
M
Moncada-Vélez
Neurogenetics Laboratory, Department of Neurosciences, University of California, San Diego, CA 92093-0662;
Eric
E
Scott
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065;
Michael J
MJ
Ciancanelli
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065;
Fabien G
FG
Lafaille
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065;
Janet G
JG
Markle
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065;
Ruben
R
Martinez-Barricarte
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065;
Sarah Jill
SJ
de Jong
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065;
Xiao-Fei
XF
Kong
Bioinformatics Platform, University Paris Descartes, 75015 Paris, France;
Patrick
P
Nitschke
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U.1163, Necker Hospital for Sick Children, 75015 Paris, France; Paris Descartes University, Imagine Institute, 75015 Paris, France;
Aziz
A
Belkadi
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U.1163, Necker Hospital for Sick Children, 75015 Paris, France; Paris Descartes University, Imagine Institute, 75015 Paris, France; Center for Study of Primary Immunodeficiencies, Necker Hospital for Sick Children, Paris, France;
Jacinta
J
Bustamante
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U.1163, Necker Hospital for Sick Children, 75015 Paris, France; Paris Descartes University, Imagine Institute, 75015 Paris, France;
Anne
A
Puel
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U.1163, Necker Hospital for Sick Children, 75015 Paris, France; Paris Descartes University, Imagine Institute, 75015 Paris, France;
Stéphanie
S
Boisson-Dupuis
Institute of Medical Genetics, Cardiff University, Cardiff CF14 4XN, United Kingdom;
Peter D
PD
Stenson
Laboratory of Pediatric Brain Disease, The Rockefeller University, New York, NY 10065; New York Genome Center, New York, NY 10013; Howard Hughes Medical Institute, New York, NY 10065;
Joseph G
JG
Gleeson
Institute of Medical Genetics, Cardiff University, Cardiff CF14 4XN, United Kingdom;
David N
DN
Cooper
Human Evolutionary Genetics Unit, Institut Pasteur, 75015 Paris, France; Centre National de la Recherche Scientifique, CNRS URA 3012, Paris, France;
Lluis
L
Quintana-Murci
APHM & Structural and Genomic Information Laboratory, UMR7256, CNRS Aix-Marseille University, 13288 Marseille, France;
Jean-Michel
JM
Claverie
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U.1163, Necker Hospital for Sick Children, 75015 Paris, France; Paris Descartes University, Imagine Institute, 75015 Paris, France;
Shen-Ying
SY
Zhang
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U.1163, Necker Hospital for Sick Children, 75015 Paris, France; Paris Descartes University, Imagine Institute, 75015 Paris, France;
Laurent
L
Abel
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U.1163, Necker Hospital for Sick Children, 75015 Paris, France; Paris Descartes University, Imagine Institute, 75015 Paris, France; Howard Hughes Medical Institute, New York, NY 10065; Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, 75015 Paris, France yitan@rockefeller.edu casanova@rockefeller.edu.
Jean-Laurent
JL
Casanova
D059472:Exome; D030342:Genetic Diseases, Inborn / Q000235:genetics*; D006801:Humans; D012372:ROC Curve
gene prioritization; gene-level; mutational damage; next generation sequencing; variant prioritization