ANNUAL HIGHLIGHTS The International Mouse Phenotyping Consortium - International Mouse Phenotyping ...
←
→
Page content transcription
If your browser does not render page correctly, please read the page content below
The International Mouse Phenotyping Consortium ANNUAL HIGHLIGHTS
Contents Introduction & Year Review
2020 has brought change, trials and a level We have generated KOs for nearly 10,000
2 Introduction & Year Review of uncertainty not seen in decades. In the face genes, over half the orthologous genome, and
of a global pandemic, the scientific community have already phenotyped over 7,400 KOs – a
has banded together to combat this new health staggering achievement, which we discuss in more
3 2020: New Dimensions for IMPC challenge and continue essential research in detail below.
other areas.
5 Publication Highlights Mouse welfare is a top priority; our animal
We assisted COVID-19 research this year by technicians continued to conduct 24/7 mouse
collating our COVID-19 related resources. You care. Our mouse centres have continued
5
The Deep Genome Project Could Change our
can find COVID-19-related IMPC alleles on our phenotyping throughout the year and our team
Understanding of Disease and Healthcare resource page. We’re also part of the Global at the IMPC Data Coordination Centre, DCC,
Mouse Models for COVID-19 Consortium has continued to load and analyse data, also
6
IMPC Experts are Analysing Gene Essentiality to (GMMCC), a global partnership of genetic and providing data support to all our users.
Find New Possible Causes of Disease genomic centres and repositories. GMMCC aims
to underpin global research into SARS-CoV-2 Like all other disciplines, research in the health
by the efficient delivery of relevant mouse strains and medical sector has been affected by the
7
Researchers Invent New Algorithm to Find Genes
and mouse genetics expertise. pandemic. We believe it is important to celebrate
Linked to Circadian Misalignment the scientific successes and achievements made in
The International Mouse Phenotyping such a difficult climate.
8
Researchers Investigate the Cause of Fam151b- Consortium, IMPC, comprises 21 of the leading
related Retinal Degeneration mouse genetics centres worldwide. We have been
developing a complete functional catalogue of
the mouse genome, linking each gene to disease,
9
Arf1-KO Induces Anti-Tumour Response with enabling a better understanding of how genetic
Protective Vaccination variation in the human population causes disease
and identifying new targets for
11 Consortium Members, Funders and Collaborations therapeutic intervention.
Our mission is to generate a knockout (KO)
13
Gabriella Kids First Pediatric Program (Kids First)
mouse model for all protein-coding genes in the
mouse genome for which there is an orthologue,
14
Illuminating the Druggable Genome (IDG) or equivalent gene, in the human genome. Each
KO mouse line undergoes phenotyping via our
15
Undiagnosed Disease Network (UDN) comprehensive and standardised pipelines to
identify significant changes in phenotype. The
data generated is processed and released on our
16
Centers of Mendelian Genomics (CMG) open-access web portal. Image: IMPC data flow
17 Other Exciting Updates
18 Looking to the future - 2021
Join us as we highlight achievements
across our consortium, celebrating
scientific success in 2020
2020 New Dimensions
for IMPC
The IMPC database grows larger every year. In 2020, we reached a new milestone, generating KOs
Know your Genes - Late Adult Data
for over 9,700 genes. These gold-standard mouse lines represent over half the orthologous genome Adcy1
between mouse and human. Moreover, over 7,400 of these KOs have been phenotyped, generating 98.8
Adenylate cyclase 1 (Adcy1) is found in the nucleus, plasma membrane and synapses. It has
million data points and over 572,000 images! several protein binding functions and both adenylate cyclase and phosphorus-oxygen lyase
activity. Evidence shows Adcy1 is involved in various key biological processes, such as circadian
Genes/Mutant Lines/MP Calls rhythms, brain development and intracellular signal transduction. Adcy1 is also an orthologue for
By Data Release the human ADCY1 gene, which is associated with deafness. (See all disease models associated
with Adcy1 by annotation and orthology or phenotypic similarity.)
10000 120000
■ IMPC phenotyping, found that a viable phenotype was present with both copies of the gene
were knocked out (Adcy1 KO mice homozygous viable.)
Genes/Mutant Lines
7500 90000 ■ Early adults exhibited one significant phenotype affecting the nervous system.
Phenotype Calls
■ Middle-aged adults exhibited one significant phenotype affecting pigmentation.
■ Aged mice exhibited six significant phenotypes affecting the nervous system, pigmentation,
5000 60000 metabolism and hematopoietic/immune system.
IMPC expression data found adult mutant expression in 24 tissue types and embryo expression in
17 tissues types. NCBI mouse ENCODE transcriptome data shows Adcy1 is highly expressed in the
2500 30000 cerebellum and cortex. See available IMPC models and ES cells for this gene.
0 0
1.0 2.0 3.1 3.3 4.0 4.3 6.0 7.0 9.1 10.0 11.0 13.0
Phenotyped genes Phenotyped lines MP calls
CRISPR has allowed us
Data is coming faster, with continuing to knock out genes and
improvements in quality phenotype them much more
quickly than our traditional
IMPC publishes regular data releases (DRs), which mice are aged before they are phenotyped ES cell method
continuing to improve the quality and robustness at 52 weeks or later. This data allows researchers
of data. This year, we’ve published four data to observe the effects of gene knockouts later
releases, DR 10, 11, 12 and 13. There have been
some important changes in our data releases,
in life. This is vital for understanding the
underlying genetics of late-onset disease. Many
GenTaR, our new tracking platform for
phenotyping, is another data change this year –
including updating our statistical program from human diseases are age-related, such as dementia,
read our news post for more information.
PhenStat to OpenStats and our first integration osteoporosis, diabetes, hearing loss and eye issues.
of data from our late adult pipeline (where mice Late adult data will help researchers understand
In 2021, we will still strive for excellence with
are aged before they are phenotyped.) Our next these types of diseases, find relevant candidate
our data – continuing to improve and update
release is coming up, so keep an eye on our genes and identify mouse models that accurately
our resources.
web portal or follow us on @impc for the next represent the late-onset phenotypes.
update.
We will continue to release late adult data in
Phenotypes exhibited by aged individuals are 2021, supporting the ongoing research into
important for understanding gene function. these areas.
Selected mouse lines enter our ageing pipeline, in
3
Highlight 2
Publication Highlights IMPC Experts are Analysing Gene Essentiality to
We reached a record of over 3500 Find New Possible Causes of Disease
IMPC-related publications this
year, even with COVID-19 affecting IMPC researchers published a paper on gene ther cellular lethal or developmentally lethal. De-
research around the world. essentiality this year, introducing a new gene clas- velopmentally lethal genes were also more likely
sification system, Full Spectrum of Intolerance to to be associated with early-onset diseases and/or
Loss-of-function (FUSIL), which identifies genes diseases affecting multiple bodily systems.
associated with disease.
Developmentally lethal genes, therefore, make
FUSIL classifies genes based on organismal via- great targets for further analysis. The researchers
Here are some highlights: bility and cellular viability. Loss of gene function tested the FUSIL system on three large rare disease
is often referred to as a binary concept; lethal or sequencing programs for unsolved diagnostic cases
Highlight 1 viable. This study shows that gene essentiality is which flagged two genes, VPS4A and TMEM63B.
more of a spectrum ranging from cellular lethal,
developmental lethal, subviable, viable with a sig- Two unsolved cases associated with VPS4A showed
The Deep Genome Project Could Change our nificant phenotype, and viable without a signifi- patients with intellectual disability, developmental
cant phenotype. delay, delayed motor development and eye abnor-
Understanding of Disease and Healthcare malities. IMPC knockout mice for VPS4A had
The study found several interesting associations, smaller embryo, abnormal brain development and
Our work across the IMPC aims to identify gene regulation and can have a significant ef- such as how essential genes were almost always ei- spine curvature phenotypes.
every protein-coding gene in the mouse genome, fect on gene function.
which makes up 3-5% of mouse DNA. This is a 3. Translate this genetic information and data
vital first step in understanding gene function. into clinical knowledge. Doctors, Specialists,
Know your Genes - Gene Essentiality
Clinician-Scientists, and Researchers any-
Much of the coding genome still remains ‘dark’.
There are many genes for which we have no func-
where in the world will be able to use this in- Vps4a ■ Early adults exhibited six significant phenotypes
affecting the nervous system, integument, immune
and hematopoietic systems and vision.
formation to study the role of genes in health Vacuolar protein sorting 4A (Vps4a) is found in the cytosol,
tional information at all and, as a consequence, and disease and find new targets for therapies. endosome, nucleus and plasma membrane. It has a few ■ Two embryonic phenotypes were found at E18.5,
we are ignorant of their role in disease. We know protein binding functions and ATPase activity. Evidence affecting growth and size. See embryo viewer.
even less about the role of the non-coding portion 4. Ensure fast and easy access to this data for suggests Vps4a is involved in processes such as the
cell cycle, cell division, vesicle budding, and endosomal IMPC expression data found adult mutant expression in 26
of the genome (which makes up 95%) in disease. integration into the clinical decision-making transport. Vps4a is also an orthologue of the human gene tissue types, with a further three tissues having ambiguous
Researchers are only just beginning to understand process. By streamlining the production and VPS4A. See disease models associated with Vps4a by expression. Embryo expression was found in all 62 tissue
annotation and orthology or phenotypic similarity. types tested, suggesting Vps4a expression is widespread
how non-coding DNA can regulate gene function analysis of these mouse models, clinicians during development. NCBI mouse ENCODE transcriptome
and contribute to disease. could diagnose patients more easily. Rapid data shows Vps4a is most highly expressed in the testis
■ IMPC phenotyping found that a lethal phenotype and cerebellum in adulthood and the central nervous
administration of targeted therapies would in- was present with both copies of the gene that were system (CNS) during development. See available IMPC
Forty-four leading scientists, clinicians, and aca- crease the chances of treatments being effective knocked out (Vps4a KO mice homozygous lethal.) models and ES cells for this gene.
demics authored an editorial in Genome Biology to earlier in a patient’s course of disease.
raise awareness of how limited our understanding
They firmly believe that generating knockout TMEM63B was mutated in one clinical case, with Genes data focus page. Our researchers are
is of the function of the majority of our genes and intellectual disability, abnormal movement and working on an IMPC haploessential screen to
their products. In addition to IMPC members, the models for coding and non-coding genes will
brain morphology symptoms. IMPC knockout support the discovery of essential genes associated
authors of this editorial include numerous human transform biology, medicine, and global health.
mice for this gene had phenotypes like abnormal with disease. Our FUSIL and haploessential data
geneticists and clinical researchers. Together, they The Deep Genome Project will develop and de- behaviour and hyperactivity. will be incorporated into our upcoming Essential
laid out a four-step plan on how to illuminate the liver a better understanding of the genome and Genes Data Portal where researchers can submit
dark genome. improve the current resources that researchers and The majority of rare disease patients remain un- gene lists to find human and mouse essential
clinicians use for the study of disease, efficient diagnosed due to a lack of detection or due to the scores. Through this, the IMPC will continue to
diagnoses, development of treatments, and im- difficulty in interpreting a variant in an unchar- support the discovery of novel candidate genes
1. Study the protein-coding section of the mouse proved patient care. acterized gene. Undiagnosed patients also often linked to rare disease.
genome (3-5%.) The IMPC is working to- suffer from physical, social and financial costs.
Full IMPC article: Full IMPC article:
wards completing this step. This includes in- FUSIL, as an open-access resource, can be used mousephenotype.org/news/how-impc-experts-are-
mousephenotype.org/news/impc-editorial-how-the-
troducing human coding variants into mice to deep-genome-project-could-change-our-understanding- to identify candidate genes linked to rare disease. categorically-analysing-gene-essentiality-to-find-new-
explore their function and providing a critical of-disease-and-transform-healthcare Clinicians and researchers can use FUSIL to more possible-genetic-causes-of-disease
pathway for understanding the role of human Journal Paper:
easily prioritise candidate genes for studies, mak- Journal Paper:
genetic variation in disease. Lloyd, K.C.K., Adams, D.J., Baynam, G. et al. The Deep ing it easier to find the causes of undiagnosed cases CACHEIRO, P., et al. (2020). Human and mouse
essentiality screens as a resource for disease gene
Genome Project. Genome Biol 21, 18 (2020). and de novo genetic disorders. discovery. Nature Communications. Published online 31 01;
2. Target the non-coding section of the genome doi.org/10.1186/s13059-020-1931-9
DOI: 10.1038/s41467-020-14284-2
5
(95%.) Non-coding DNA has vital roles in Find out how we’re using FUSIL on our Essential 6
Highlight 3 Highlight 4
Researchers Invent New Algorithm to Find Genes Researchers Investigate the Cause of Fam151b-
Linked to Circadian Misalignment related Retinal Degeneration
Researchers from our consortium After they tested the algorithm against genes Researchers from the MRC Human thelium damage, light toxicity and nerve cell pat-
member CAM-SU Genomic Resource Center, known to disrupt circadian rhythms (which were Genetics Unit (Institute for Genetics and Mo- terning issues. The exact cause of the degeneration
Soochow University, have developed a ma- flagged successfully) they tested it against the 750 lecular Medicine, University of Edinburgh), in remained unclear.
chine-learning algorithm to identify candidate mutant mouse models. The algorithm flagged 88 collaboration with the Mary Lyon Centre (MRC
genes linked to disruption of circadian behaviour, genes, which were further narrowed down by the Harwell Institute) and the Roslin Institute (Uni- This study creates a platform for future research
eating behaviour and other cyclical biological pro- researchers to a group of five: Slc7a11tm1b/tm1b, Rhb-
dl1+/tm1.1, Spop+/tm1b, Oxtr tm1.1/tm1.1 and Ctc1+/tm1b.
versity of Edinburgh), recently used IMPC data to into Fam151b’s gene function and how it may re-
cesses.
Mice in these mutant lines shared similar pheno- inform their research into Fam151b. late to human disease, as well as research into the
Circadian misalignment can be caused by lifestyle types, had statistically significant differences from Fam151 family on a larger scale. An understanding
or genetics. It can promote conditions such as wild-type mice and had an effect size greater than We previously flagged Fam151b as a gene linked of the underlying mechanisms involved in photo-
sleep disorders, depression, seasonal affective dis- 1.2. to eye morphology and retinal degeneration, spe- receptor loss is vital for the production of treat-
order, bipolar disorder, and metabolic disorders. cifically ‘abnormal retina morphology’ at a signifi- ments. The mouse model in this study could be
Research into circadian misalignment is crucial for The researchers further investigated Slc7a11. The cance of 2.55 x 10-38. Research into this gene could used to find effective therapies for photoreceptor
our understanding of complex health issues. Slc7a11tm1b/tm1b mutant line expressed early activi- improve our understanding of the retina and reti- loss, which is a leading cause of blindness.
ty onset and potentially impaired metabolism due nal diseases, such as retinitis pigmentosa (RP) and
Indirect calorimetry (IC) data was collected from to altered glucose tolerance. They generated an Full IMPC article:
other conditions that lead to blindness. mousephenotype.org/blog/2020/10/12/researchers-
five IMPC centres: the Riken BioResource IMPC knockout model for this gene and found investigate-the-cause-of-fam151b-related-retinal-
Center, The Centre for Phenogenomics, the In- that the mice had disrupted light/dark cycles. They degeneration
stitut Clinique de la Souris, the Wellcome Trust also found that Slc7a11 plays a role in suprachias- Findlay et al. first determined whether Fam151b
Journal Paper:
Sanger Institute and Helmholtz Zentrum Mu- matic nucleus (SCN) neuron synchronisation and had similar functions to its C. elegans homologue, Findlay, A.S., McKie, L., Keighren, M. et al. Fam151b, the
nich. With this data, Zhang et al. compared 750 messaging between cells. menorin (mnr-1.) They ran the gene through sev- mouse homologue of C.elegans menorin gene, is essen-
knockout mouse models to 2000 wild-type mice, tial for retinal function. Sci Rep 10, 437 (2020).
eral databases, including HHPred which matched doi.org/10.1038/s41598-019-57398-4
examining differences between food intake and ac- the Fam151 profile with the Phospholipase D do-
tivity peaks over time. main of a spider (Sicarius terrosus) toxin. Other
statistically significant matches included members
of the ‘Phospholipase D and glycerophosphodi- Image: Ventus55 / CC BY-SA
Know your Genes - Circadian Rhythms ester phosphodiesterase’ (GDPD) families. These
GDPD members, like other PLC-like phosphodi-
Slc7a11 ■ IMPC phenotyping, found that a viable phenotype
was present with both copies of the gene were esterase enzymes, have a TIM barrel fold that is
knocked out (Slc7a11 KO mice homozygous viable.) also found in menorin and Fam151b proteins.
Solute carrier family 7 member 11 (Slc7a11) is found in
the plasma membrane, cytoskeleton and endoplasmic ■ Early adults exhibited five significant phenotypes,
reticulum and has transmembrane transporter activity. affecting the metabolism, vision, hearing and size/ Fam151b is expressed at low levels in most tis-
Evidence suggests Slc7a11 is involved in processes such as growth.
cell death, cell proliferation, homeostasis, visual learning
sues, including the retinal pigmented epithelium
and synapse organisation regulation, among many others. IMPC expression data is not currently available for (RPE), retina, iris, ciliary body, lens and cornea.
Slc7a11 is also an orthologue of the human gene SLC7A11. this gene. NCBI mouse ENCODE transcriptome data
See disease models associated with Slc7a11 by annotation shows Slc7a11 is highly expressed in the thymus and
and orthology or phenotypic similarity. subcutaneous and genital fat pads. See available IMPC The Mary Lyon Centre (MRC Harwell Insti-
models and ES cells for this gene.
tute), one of our consortium members, generated
a Fam151b knockout mouse model (Fam151bKO/
KO
). Findlay et al. examined this model across sev-
The SCN is our internal master clock that regu- behaviour. Future research into the genetic back- eral weeks and found “a patchwork pattern from
lates our innate circadian rhythms. Slc7a11’s ap- ground of circadian misalignment is vital for our fundal imaging indicative of retinal degeneration”
parent role in entrainment to light/dark cycles and understanding of an ever-growing list of condi- at week 11. Histological analysis found a “severe
the synchronisation of SCN neuron activity sug- tions. reduction in the length of the outer segments of
gests it could play a role in circadian misalignment Full IMPC article: the photoreceptors [and reduction] in the num-
if disrupted by a mutation. Zhang et al. concluded mousephenotype.org/news/researchers-invent-new-algo-
ber of nuclei…found in the outer nuclear layer
rithm-to-find-genes-linked-to-
that the algorithm could successfully find novel circadian-misalignment (ONL.)”
candidate genes for this condition.
Journal Paper:
Zhang T, Xie P, Dong Y, Liu Z, Zhou F, Pan D, et al. (2020) Degeneration began occurring around day 15 at
This algorithm can be used for future dataset anal- High-throughput discovery of genetic determinants of
eye-opening, after which it gradually progressed.
circadian misalignment. PLoS Genet 16(1): e1008577.
ysis, opening new research possibilities into cir- doi.org/10.1371/journal.pgen.1008577 They examined several possible causes for this
cadian misalignment for metabolism, sleep and degeneration, ruling out retinal pigmented epi-
7
Highlight 5
Arf1-KO Induces Anti-Tumour Response with
Protective Vaccination
IMPC Arf1 embryonic stem cells were used in
a study investigating the Arf1-mediated lipid me-
tabolism pathway’s role in sustaining Cancer Stem
stress and, as a result, induced DAMPS and DC
infiltration, enhancing the T-cell infiltration.
Arf1 knockdown was not directly cytotoxic to
“If the results are reproducible
Cells (CSCs) and how disrupting this pathway
would affect tumour growth and number.
tumour cells and, after further tests, it was deter-
mined that the anti-tumour effect was via DCs-
ATP-IFN-γ-mediated T-cell immunity. Knock-
in humans, DAMP-mediated anti-
Wang et al. knocked out Arf1 from a known mod-
el for CSCs (Lgr5-CreERT2/Apcf/f ). The generat-
down also prevented tumour metastasis.
tumour immune therapy could be
ed Lgr5/Arf1/Apc mice had a dramatic reduction Vaccination with knockout Arf1 cells also proved
in stem cell tumour numbers and a significant
increase in lifespan.
successful in protecting animals from developing
tumours. The vaccination was effective against
a breakthrough for the treatment
of reoccurring tumours”
melanomas and a variety of histological types like
Wang et al. found that “the Arf1-regulated lipoly- colon cancer and breast carcinomas. Arf1 inhibi-
sis pathway selectively sustains stem cells, progen- tion triggered a localised T-cell immune response
itors and cells enriched with CSCs in mice and that then attacked cancer throughout the body.
that disrupting the pathway in these cells results in
lipid droplet accumulation, mitochondrial defects If results like the above are reproducible in hu-
and cell necrosis.” mans, DAMP-mediated anti-tumour immune
therapy could be a breakthrough for the treatment
Arf1 depleted mice showed evidence of a T-cell of reoccurring tumours, particularly those with
immune response, with dendritic cells (DCs) and high Arf1 expression. When used in conjunction
inflammatory DCs also significantly increased. with other already effective treatments or with the
“Knocking out Arf1 in Lgr5+ [intestinal] stem addition of successful checkpoint blockades, this
cells triggers T-cell infiltration and activation, method could prove even more effective.
leading to CSC death and prolonged survival.”
Full IMPC article:
Similar effects were seen on liver CSCs, potentially mousephenotype.org/blog/2020/04/27/arf1-ko-
via downregulation of PD-L1. induces-anti-tumour-response-with-protective-
vaccination
Knocking out Arf1 also affected other aspects of Journal Paper:
the immune system. They found Arf1 inhibition Wang, G., Xu, J., Zhao, J. et al. Arf1-mediated lipid me-
tabolism sustains cancer cells and its ablation induces
may induce inflammasome-mediated cell necro- anti-tumor immune responses in mice. Nat Commun11,
sis/pyroptosis. Arf1 inhibition or ablation also in- 220 (2020).
duced key DAMPS, as well as ER-stress markers. doi.org/10.1038/s41467-019-14046-9
They concluded that Arf1 inhibition triggers ER
10
Consortium Members,
Funders and Collaborations
2020 has been an important year for
the growth of the IMPC consortium and
the further development of critical research
programmes with our collaborators.
Firstly, we’d like to welcome our new
consortium member, the Institute of
Laboratory Animal Sciences (ILAS) at the
Chinese Academy of Medical Sciences,
Beijing. ILAS is a comprehensive national
research centre for laboratory animals and
comparative medicine. They integrate
the conservation, breeding, and supply
of laboratory animals and animal disease
models, combining the comparative study
of medical technology with technical
training.
We want to thank all of our consortium
members for their exceedingly hard work
in 2020. The IMPC, as an international
collaborative effort, integrates data from
many mouse centres across the globe.
The expertise and capabilities of our 21
consortium members are the backbone of
the IMPC.
We’d also like to thank all our funders
from 2020. Without their support, we
wouldn’t have made the substantial progress
we have made this year.
Lastly, we would like to thank our collaborators,
whose partnerships enable us to have a
continued and increasing global impact with
our data and resources. Here are some of our
collaborator highlights from 2020
11
Gabriella Miller Kids First Pediatric
Research Program
Kids First aims to uncover new facial weakness, diaphragmatic hernias (CDH),
biological insights into childhood cancer and adolescent idiopathic scoliosis and much more.
structural birth defects. Children with birth
defects have an increased risk of developing The IMPC and Kids First are collaborating on
childhood cancer, suggesting that these disorders a pilot project to create mouse strains to study,
may share genetic pathways. Kids First is using phenotype, and validate coding and non-coding
whole genome sequencing and the Gabriella genetic variants (e.g. missense, structural variants,
Miller Kids First Data Resource, a large-scale copy number variants, INDELS, frameshifts)
database of clinical and genetic data, to discover identified from Kids First datasets.
new genetic pathways between these disorders.
The IMPC and Kids First will continue to
Kids First has now over 5,000 families collaborate, investigating more genes to find links
and 14,000 participants in 23 studies. In between birth defects and childhood cancer.
collaboration with IMPC mouse centres, they’re
investigating genes that have been implicated in
Illuminating the Druggable Genome IDG
Around 3,000 genes are part of the 41% of IDG’s target genes across 25 groups of
druggable genome. However, less than 10% of phenotypes, including ageing, reproductive,
druggable proteins are targeted by FDA-approved immunity, craniofacial, nervous, renal,
drugs. IDG is a program to identify and collect cardiovascular and many more.
information on genes within druggable protein
families, specifically genes that are not well- Information sharing between the KOMP2 and
studied. These protein families include kinases, IDG projects allows researchers to prioritize
G-protein coupled receptors and ion channels. understudied genes and increase the pace and
IDG is integrating this data into a single resource, scientific depth of phenotyping studies. The
Pharos, and is also helping support technology combination of IDG’s human protein/gene data
development for the study of druggable proteins. with the IMPC’s phenotype and mouse model
data helps researchers to find candidate genes
The IMPC (KOMP2) is generating knockout for drug discovery. It also accelerates our ability
mouse strains for the IDG project. Human genes to discover new biological insights and apply
that IDG are studying can be mapped to mouse findings to health and disease.
orthologues. The IMPC can then generate and
phenotype knockout mouse models for these
orthologues. The IMPC currently has data for
14
Centers for Mendelian Genomics CMG
The CMG use genome-wide sequencing the identification of Mendelian conditions. We
and other methods to discover the genetic basis have KO models and data for over 2,000 of the
underlying Mendelian traits. They accelerate genes CMG are investigating.
discoveries by sharing their data, knowledge and
effective approaches via reaching out to individual Over eight and a half years, CMG has made
investigators and coordinating with other rare over 2,600 novel discoveries. This includes
disease programs worldwide. variants associated with congenital diaphragmatic
hernias, Robinow syndrome, Mayer-Rokitansky-
Discovery and understanding of genetic variants Kuster-Hauser syndrome and TBX6-associated
that underlie human Mendelian disorders will congenital scoliosis (TACS.)
assist in the faster diagnosis of patients and lead
to new therapeutic approaches. The IMPC aims to continue to provide KO
models for projects like CMG and the Mendelian
We collaborate with the CMG by prioritising Genomics Research Center. Through this, we
genes with putative Mendelian variants for the will continue to support the solving of unsolved
generation and analysis of null mutants via the rare disease cases, increase our understanding of
IMPC pipeline. Our mouse models support the molecular mechanisms of disease and find
the functional investigation of candidate genes, potential therapeutic targets.
mechanistic evaluation of candidate variants and
Undiagnosed Disease Network UDN
Our collaborations are not
The UDN is a study that aims to improve The UDN uses IMPC data and mouse models to
diagnosis and care for patients with undiagnosed assist diagnoses. Our phenotype data can provide limited to this year’s highlights!
diseases and facilitate research into the aetiology evidence to support the pathogenicity of variants
of undiagnosed disease. De novo and rare associated with rare and undiagnosed disease
mutations are difficult to diagnose. In many cases. Our mouse models provide resources Our continued work with other collaborators such as
cases, rare mutations can be found only in a for functional studies for pathogenicity and MMPC | Genomics England | Rare Disease Foundation
single-family. The inability to discover the causes therapeutic approaches.
for a patient’s symptoms can lead to difficulty UK Biobank | Care4Rare | INFRAFRONTIER | 3i | Monarch
finding affective treatments, extensive stress and The UDN has now reached over 1400 evaluated Initiative and more is vital for our aims. These collaborations
financial difficulties. participants and, with an additional 400 not only support our global reach and impact but enable
participants accepted and 333 under-review
Many of these mutations can also be severely applications, they will continue to make progress the vital step of translating our data into clinical knowledge
physically disabling and have wide-ranging throughout 2021. At the IMPC, we aim to and results.
symptoms, such as craniofacial deformities, continue to support the UDN study with our
intellectual disabilities, growth issues, and resources, supporting the UDN’s aim to give
immunological and haematological irregularities. valuable diagnoses to those with rare mutations. Check out our collaborators page for more information.
15
Other Exciting Updates
Given the extraordinary circumstances of To help our users, we also produced a free and
2020, the IMPC has had to adapt and change, virtual IMPC course and webinar this year. New
particularly seeking out new opportunities and older users from various biology disciplines
for virtual engagement with our users. We’ve can learn how to fully take advantage of our
been undergoing user experience (UX) testing resources. Check them out if you want to learn
throughout the year and have been building and how to get started with our data, how to order
improving our web portal behind the scenes. mouse models or how IMPC resources are being
We’ll be rolling out these changes in 2021 when used in studies of genetic disease, development
testing is complete, offering a new, more fluid and sexual dimorphism, amongst other topics.
and easier to use portal.
We were also very active on social media in 2020!
Normally, you could expect to see us at some of We post all our article highlights, data release
the largest genetic conferences of the year. This announcements and conference information
year, we still made it to the virtual versions of on our @impc Twitter account. You can also
ESHG and ASHG as attendees or exhibitors. follow @geneoftheday for quick and exciting
It’s great to see that, even as countries entered snapshots of IMPC data.
lockdowns across the world, the scientific
community continued to perform and share
excellent work.
Know your Genes - IMPC Data Looking to the Future - 2021
Lep IMPC’s vision to generate a complete a major challenge but will open up new vistas on
catalogue of mammalian gene function is the functional relationships between the non-
Leptin (Lep) is found in the cytosol, cytoplasm and extracellular space. It has DNA, leptin and
signalling receptor binding functions and hormone activity. Evidence suggests Lep is involved in progressing at a rapid pace, providing a critical coding genome and human disease.
a wide range of processes, such as the regulation of transcription and phosphorylation, ovulation, springboard for future research into human
placenta development, cytokine production, circadian rhythms, blood pressure, metabolism, disease and the development of new therapeutic In 2021, we’re planning to attend three
and signal transduction. Lep is also an orthologue of the human gene LEP, which is associated approaches. With over half of the protein- conferences: Genomics of Rare Disease, ESHG
with leptin deficiency and obesity. See all disease models associated with Lep by annotation and
coding portion of the genome available as mouse and ASHG. These and other conferences are
orthology or phenotypic similarity.
mutants, we are looking forward in 2021 to reach exciting opportunities to reach our existing
our target of 9,000 phenotyped mouse genes – audience as well as new users. We’ll display our
■ IMPC phenotyping, found that a viable phenotype was present with both copies of the gene
were knocked out (Lep KO mice homozygous viable.) providing functional information on half of the resources, highlighting the best of IMPC-related
orthologous mouse and human genomes. research, providing support and learning and
■ Early adults exhibited 20 significant phenotypes, affecting the nervous system, cardiovascular
system, integument, skeleton, metabolism, vision and reproductive system. collaborating with the scientific community. We
We’re also excited to begin work on our aims hope to see you there!
IMPC expression data found adult mutant expression in only three tissue types – brown and to use the mouse as a key tool to analyse the
white adipose tissue and testis. NCBI mouse ENCODE transcriptome data shows Lep is highly function of human genetic variation and its
expressed the subcutaneous and genital fat pads. See available IMPC models and ES cells for this
impact on disease. First, this includes introducing
gene.
human coding variants into mice to explore their
function. Second, we aim to begin to explore the
non-coding section of the mouse genome. This is
Would you like to keep track of our progress throughout the
year? Follow us on social media @impc | @geneoftheday
and sign-up to our seasonal newsletter for regular updates.
17You can also read
