The International Mouse Phenotyping
Consortium is generating and phenotyping -
assessing the morphological and physiological characteristics of -
knockout mutations for all of the protein-coding genes in the mouse
genome to create a catalog of mouse genes that shows what each gene
The Consortium aims to discover new functions for the roughly
20,000 genes shared with humans, and makes all of the mouse strains
available to provide a platform for dissecting the mechanisms of human
‘Roughly a third of all genes in the mammalian genome are essential for life. The large-scale discovery of these genes and how it will impact understanding of human disease has been described in a new study.’
Roughly a third of all genes in the mammalian genome are essential for life, revealed the work carried out by IMPC that included researchers from eight phenotyping centers representing
over 30 institutions world-wide. This new article in Nature
describes the large-scale discovery of those
genes and how it will impact understanding of mammalian development and
study, published the
results of the first 1,751 genes characterized by the IMPC, including
the finding that nearly one third are essential for life. This includes
410 lines that are fully lethal, and an additional 198 for which fewer
than half of the expected number of mutants were identified.
Using a new, standardized phenotyping pipeline and mouse strains
on a single C57BL/6N genetic background, the researchers established
both the time of embryo death and the nature of the lethal features for
these lines, discovering many novel characteristics that shed light on
the function of these genes. The incorporation of high-resolution 3D
imaging and automated, computational analysis of the images allowed the
team to gather detailed data rapidly, thus enabling the discovery of new
features at an unprecedented scale.
The team also showed that identification of essential genes in
the mouse provides a window on human disease, including the discovery of
a number of novel cases in which human disease genes overlap with
essential genes. In addition, in collaboration with the ExAC Consortium,
they showed that human orthologs of mouse essential genes - human genes
that have a common ancestor with mouse essential genes - are
significantly depleted for loss-of-function mutations in humans, and
that these genes are thus strong candidates for undiagnosed human
JAX Senior Research Scientist Steve Murray, corresponding
author of the study, noted that "when looking across the seven or eight
embryos generated for each knockout, we found variations in features at a
surprising frequency. We expect diversity when we look across different
genetic backgrounds, but this is the first large-scale documentation of
pervasive variable expressivity in a defined genetic background."
"This paper is really focused on defining the phenotypes
associated with genes that are essential to embryonic and post-natal
development. This group of genes is particularly exciting because many
of these genes that are essential in mouse are also linked to diseases
in humans and the paper reports the efforts to build a catalog of these
findings for the community, complete with 3D images of the defects that
were observed," said co-first author Dr. Mary E. Dickinson, professor
and Kyle and Josephine Morrow Endowed Chair of molecular physiology and
biophysics at Baylor College of Medicine.
Co-author Dr. Mark Henkelman, director of the Mouse Imaging
Center in Toronto, says, "What sets this study apart is the use of
high-throughput 3D imaging with automated analysis to identify novel
features that would have easily been missed by gross inspection. The
results using 3D imaging are striking and are surely going to set a new
standard for the field."
"This freely available and accessible dataset provides
significant new gene-feature associations to enable scientists to
prioritize gene candidates identified in their preclinical and discovery
research," said co-first author Dr. Ann Flenniken, manager of the
Clinical Phenotyping Core at The Center for Phenogenomics in Toronto.
Co-author Dr. Maja Bucan, professor of genetics at the Perelman
School of Medicine at the University of Pennsylvania notes that "the
sheer amount of new data reported in this paper is impressive. We
compared the genes analyzed in this paper with a list of known human
disease genes, which made it possible to identify for the first time the
mutant phenotypes in the mouse for 52 human disease genes."
"The IMPC effort has provided an unparalleled model organism
resource for functional genomics studies," said co-first author Xiao Ji,
doctorate candidate at the Graduate Group in Genomics and Computational
Biology, Perelman School of Medicine.
"The work of the consortium will contribute significantly to our
understanding of the genetic bases for human diseases including spina
bifida and cardiovascular defects amongst many others," said co-first
author Dr. Lydia Teboul, head of molecular and cellular biology at MRC
Harwell Institute, in the UK.
As current estimates indicate that only a small percentage of
genes are studied by the broad research community, the researchers note
in the paper, the systematic approach to phenotyping and unrestricted
access to data and mouse models provided by the IMPC promises to fill
this large gap in our understanding of mammalian gene function.
"This paper is just the tip of the iceberg," said Dickinson. "We
want the scientific community to know even more about IMPC efforts and
that they have access to the mice as well as the phenotype data. This
work is an enormous boon of information for researchers."
All data and images generated by the project are available to the
research community, disseminated via an open-source web portal in real
time without embargo. The mouse models generated are also available to
other researchers who may be investigating particular pathways or