Hundreds of genes that play a crucial role in eye development and disease identified

A new study vastly increases the number of known genes associated with eye development and anatomy. Using data from the International Mouse Phenotyping Consortium (IMPC) researchers found 347 genes with eye related phenotypes, 75% of which were not previously known to be associated with eyesight.

The research, published in Communications Biology, marks a crucial step forward in the effort to identify the cause of impaired vision in people around the world. Eyesight problems frequently have a genetic origin, and often a mutation in just a single gene is involved. However, the genetic contribution of many eye related issues remains poorly understood.

“This is extremely valuable for people with hereditary eye disease,” said Ala Moshiri, associate professor of ophthalmology and vision science in the University of California, Davis School of Medicine and Eye Center. “The whole ophthalmic community is going to start using these data.”

This new study, led by researchers from University of California, Davis, utilises IMPC data to identify genes associated with eye anatomy. This is a prime example of how the IMPC is transforming genetic research by vastly increasing the number of genes associated with particular anatomies. The goal of the IMPC is to create a functional catalogue of the mammalian genome through using a standardised phenotype pipeline in knockout mouse. A project on this scale, comprising 20 laboratories in 12 countries, is required to complete a database of all 20,000 or so genes. The current study is based on 4364 genes, and even since the analysis for this study was completed the number of phenotyped genes available to study has risen to over 5,000.

Steve Brown the chair of the IMPC said: The work of the IMPC is transforming our understanding of the genetic landscape and the genes and pathways that are involved with diverse disease systems. For each system we study we are finding a huge range of genes that hitherto have never been associated with the disease. These findings, including the novel genes associated with eye disease reported here, will illuminate our understanding of the underlying genetics and deliver significant advances in genetic diagnosis and potential new targets for therapeutic intervention.

To study how many genes are associated with eye development and disease the researchers used all relevant phenotypes that are collected as part of the IMPC project. These include anatomical abnormalities affecting the entire eye as well as specific structures, including the cornea, iris, lens, retina, choroid and optic nerve.

There are still around 14,000 knockout genes to study so the total number of genes associated with eye anatomy and function is likely much higher than 347. Additionally, mice in this study were only examined up to 16 weeks of age, meaning some genes with late-onset phenotypes may have been overlooked. However, this study represents a major step forward, with hundreds of novel genes linked to vision identified.

“In 2018, if someone has a form of hereditary blindness, we can identify the cause 50 to 75 percent of the time,” Moshiri said. “In the remaining cases, we know the mutation is there but we don’t know where to look. Now eye centers that do DNA sequencing can call back patients and screen them for these new genes.”

From this research it has also been possible to look at associations between eye phenotypes and systemic abnormalities, since comprehensive phenotyping of all organ systems are performed as part of the IMPC project. For example, knockouts of several genes described in this study were found to also be associated with kidney disease. This highlights the IMPC’s broad-based approach as being an effective way of allowing further in depth associations for particular genes and diseases.

As well as allowing new insight into gene function and pathways for inherited eye diseases, this study is also a platform on which future work can contribute to our understanding of complex human eye disorders. For example, in patients with rare forms of hereditary ocular disease geneticists can now scan whole genome sequencing data of individuals to see if vision loss may be linked to genes identified in this study.


Link to research article: Identification of genes required for eye development by high-throughput screening of mouse knockouts
DOI: https://doi.org/10.1038/s42003-018-0226-0

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