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 journalWellcome Open Research.