Document Type
Article
Publication Date
1-31-2020
Keywords
JMG, JAXCC
JAX Source
Nat Commun 2020 Jan 31; 11(1):655
Volume
11
Issue
1
First Page
655
Last Page
655
ISSN
2041-1723
PMID
32005800
DOI
https://doi.org/10.1038/s41467-020-14284-2
Abstract
The identification of causal variants in sequencing studies remains a considerable challenge that can be partially addressed by new gene-specific knowledge. Here, we integrate measures of how essential a gene is to supporting life, as inferred from viability and phenotyping screens performed on knockout mice by the International Mouse Phenotyping Consortium and essentiality screens carried out on human cell lines. We propose a cross-species gene classification across the Full Spectrum of Intolerance to Loss-of-function (FUSIL) and demonstrate that genes in five mutually exclusive FUSIL categories have differing biological properties. Most notably, Mendelian disease genes, particularly those associated with developmental disorders, are highly overrepresented among genes non-essential for cell survival but required for organism development. After screening developmental disorder cases from three independent disease sequencing consortia, we identify potentially pathogenic variants in genes not previously associated with rare diseases. We therefore propose FUSIL as an efficient approach for disease gene discovery.
Recommended Citation
Cacheiro P,
Muñoz-Fuentes V,
Murray SA,
Dickinson M,
Bucan M,
Nutter L,
Peterson K,
Haselimashhadi H,
Flenniken A,
Morgan H,
Westerberg H,
Konopka T,
Hsu C,
Christiansen A,
Lanza D,
Beaudet A,
Heaney J,
Fuchs H,
Gailus-Durner V,
Sorg T,
Prochazka J,
Novosadova V,
Lelliott C,
Wardle-Jones H,
Wells S,
Teboul L,
Cater H,
Stewart M,
Hough T,
Wurst W,
Sedlacek R,
Adams D,
Seavitt J,
Tocchini-Valentini G,
Mammano F,
Braun R,
McKerlie C,
Herault Y,
de Angelis M,
Mallon A,
Lloyd K,
Brown S,
Parkinson H,
Meehan T,
Smedley D,
Consortium GR,
Consortium IP.
Human and mouse essentiality screens as a resource for disease gene discovery. Nat Commun 2020 Jan 31; 11(1):655
Comments
This open access article is licensed under a Creative Commons Attribution 4.0 International License