Study springs surprise: single gene mutation can lead to variable outcomes

21 April 2017

Cross-section of a mouse embryo.

Image: Cross-section of a mouse embryo.

Inactivating the same gene in mice that are virtually genetically identical can result in a wide range of different physical features or abnormalities. This surprising finding suggests that the relationship between gene mutation and consequence is more complex than previously suspected.

Researchers from the Deciphering the Mechanisms of Development Disorders (DMDD) consortium, which is coordinated at the Francis Crick Institute, looked at 220 mouse embryos each missing one of 42 different genes.

They imaged and scanned the mouse embryos in minute detail, picking up on even the smallest differences in features - right down to the level of whether the structure of individual nerves, muscles and small blood vessels were different.

Their large-scale study is published in the journal Wellcome Open Research.

Clinicians commonly find that people with the same genetic disease can show different symptoms or be affected with differing severity. In part this is likely to be due to the fact that we all differ in our precise genetic makeup. However, this study in mice shows that even when individuals have virtually identical genomes, the same mutation can lead to a variety of different outcomes amongst affected embryos. 

Dr Tim Mohun, who led the study at DMDD, said: "This is a striking result … It shows us that even with an apparently simple and well-defined mutation, the precise outcome can be both complex and variable. This is a surprising result, and more research into gene function is needed in order to make sense of the finding."

Dr Andrew Chisholm, Head of Cellular and Developmental Sciences at Wellcome, which funds the DMDD, commented: "This study throws new light on what we thought was a fairly straightforward relationship between what's coded in our genes and how we develop. Researchers need to appreciate this added layer of complexity, as well as endeavouring to unpick the intricate processes of genetic control at play."  

The DMDD Programme is funded by Wellcome with support from the Francis Crick Institute. It aims to shed light on the genetic basis of human developmental disorders by studying the effects of 'turning off' individual genes in the mouse genome.

The paper, Highly variable penetrance of abnormal phenotypes in embryonic lethal knockout mice, is published in the journal Wellcome Open Research.

  • Inactivating the same gene in mice that are virtually genetically identical can result in a wide range of different physical features or abnormalities. This surprising finding suggests that the relationship between gene mutation and consequence is more complex than previously suspected.
  • Researchers from the Deciphering the Mechanisms of Development Disorders (DMDD) consortium, which is coordinated at the Francis Crick Institute, looked at 220 mouse embryos each missing one of 42 different genes.