Abstract
Despite advances in next generation sequencing technologies, determining the genetic basis of ocular disease remains a major challenge due to the limited access and prohibitive cost of human forward genetics. Thus, less than 4,000 genes currently have available phenotype information for any organ system. Here we report the ophthalmic findings from the International Mouse Phenotyping Consortium, a large-scale functional genetic screen with the goal of generating and phenotyping a null mutant for every mouse gene. Of 4364 genes evaluated, 347 were identified to influence ocular phenotypes, 75% of which are entirely novel in ocular pathology. This discovery greatly increases the current number of genes known to contribute to ophthalmic disease, and it is likely that many of the genes will subsequently prove to be important in human ocular development and disease.
Highlights
To address the fundamental problems in traditional methods of studying genetic mechanisms in cellular biology and genetic contributions to disease, the International Mouse Phenotyping Consortium (IMPC) was established in 2011 as a network of highly specialized academic centers with expertise in highthroughput mouse mutagenesis and comprehensive phenotyping[9,10]
The IMPC has generated over 7000 genotype confirmed mutant strains, and has completed standardized phenotyping across 11 organ systems for 4364 of these genes
Literature searches identified 42 genetic phenotypes known to exist in vertebrates (Known Phenotype), 44 genes described to cause an ocular phenotype differing from the phenotype described in the present study (Novel Phenotype), and most interestingly, 261 genes (75% of genes with ocular phenotypes) with no prior ocular implication (Novel Gene)
Summary
The goal of the IMPC is to create the first functional catalog of the mammalian genome by using the proven methodology of phenotype screening of targeted gene mutagenesis in mice, which has been successful in identifying novel pathologic loci across a wide range of organ systems[11,12,13,14,15]. Many novel genes previously unknown to be involved with mammalian ophthalmic diseases are presented, demonstrating successful identification of mouse mutants with early and delayed onset ocular phenotypes. The numerous novel pathologic loci revealed here serve as a powerful resource for human ocular geneticists to scan whole genome sequencing data in patients with presumed hereditary ocular disease who do not have common mutations of known disease genes. The murine loci identified in this manuscript, if validated in human patient populations, would greatly increase the number of known ocular disease genes found over the past three decades since the discovery of rhodopsin gene mutations in families with retinitis pigmentosa[16,17]
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