Pinpointing rare disease mutations

Mouse and human genetic knockout data used to identify rare disease genes. Image credit: Spencer Phillips

Pinpointing rare disease mutations

30 Jan 2020 - 16:05


  • Scientists have compiled mouse and human cell knockout data to categorise genes based on how essential they are for survival and organism development
  • The research creates a resource that can be used by other scientists to further investigate candidate genes potentially involved in developmental disorders
  • The work could help identify new mutations causing rare genetic diseases 

31 January 2020, Cambridge – Researchers at EMBL’s European Bioinformatics Institute (EMBL-EBI) and Queen Mary University of London have led a study to categorise which genes are essential for supporting life. The results from this study could be a useful new resource to help researchers identify mutations responsible for rare childhood diseases.

Identifying which genes are linked to a rare disease is one of the most difficult challenges geneticists face. The low prevalence of these diseases within the population makes it difficult to research and fully understand their causes. However, huge advances in the diagnosis of rare diseases are now being made thanks to innovations in sequencing technology.

This research, published in Nature Communications, compares knockout mice viability and phenotyping data from the International Mouse Phenotyping Consortium (IMPC) with human cell lines provided by the Broad Institute’s Project Achilles to create categories indicating how crucial a gene is to producing viable life.

The researchers also identified new mutations likely responsible for rare childhood diseases by comparing their data with unsolved cases of genetic disorders identified in the 100,000 Genomes Project and the Deciphering Developmental Disorders (DDD) datasets.

Defining genes essential for life

"Loss of gene function is often referred to as a binary concept; lethal or viable," says Violeta Muñoz-Fuentes, Biologist, Mouse Informatics at EMBL-EBI. "In this study we show that gene essentiality is more of a spectrum ranging from cellular lethal, developmental lethal, subviable, viable with a visible phenotype, and viable without a visible phenotype."

The scientists define these categories for 3819 genes to create an open access database that can be used to benefit other researchers and provide insight for clinical applications.

“When you sequence a person’s genome it’s not always one mutation that stands out as altering a gene’s function,” says Terry Meehan, Coordinator of Mouse Informatics at EMBL-EBI. “We currently don’t have a handle on which genes are important for development and which have a minor impact.”

Loss of function gene categories

Cellular lethal: genes essential for cell viability

Developmental lethal: genes essential for organism development

Viable: organisms fully develop

Subviable: organism survival is less than expected

Diagnosing rare disorders

“This study combines multiple sources of data from large scale projects to identify new candidate genes that, when mutated, are likely to have a causal relationship with rare human disorders,” says Pilar Cacheiro, Research Fellow at Queen Mary University of London. “Nearly 6% of the population are affected by these diseases during their lives.”

Advances in whole genome sequencing (WGS) are changing the way we research and diagnose rare genetic diseases. However, the majority of rare disease patients remain undiagnosed due to a lack of detection or because a previously unknown gene is disrupted. This study furthers our understanding of rare disease genes by providing clinicians and researchers with an open access resource, which can be used to identify high-quality candidates for rare disease mutations.

“Of particular interest for application to healthcare, we demonstrate that the set of genes that are essential for organism development is particularly associated with known human developmental disorders,” says Damian Smedley, Reader in Computational Genomics at Queen Mary University of London.“This provides candidates for undiscovered causative genes for these conditions.”

Several high-scoring candidates from this study have been added to the open access resource GeneMatcher, used by researchers and clinicians all over the globe to share gene information. You can also freely access the study data in EMBL-EBI’s Biostudies and at the International Mouse Phenotyping Consortium.

Source article

CACHEIRO, P., et al. (2020). Human and mouse essentiality screens as a resource for disease gene discovery. Nature Communications. Published online 31 01; DOI: 10.1038/s41467-020-14284-2

Contact the news team

Oana Stroe
Senior Communications Officer
+44 (0)1223 494 369

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