The UK's 100,000 Genomes Project



Published 16th November 2018

The 100,000 Genomes Project is applying whole genome sequencing in a diagnostic setting to rare disease and cancer patients from the National Health Service (NHS) of the UK. In the video below Damian Smedley describes how clinical phenotype data is collected on each rare disease patient and how this work takes advantage of a number of reference disease and model organism genotype to phenotype databases including the International Mouse Phenotyping Consortium. The video was recorded at the recent KOMP2/IMPC annual meeting, hosted by the National Human Genome Research Institute.



The entire genome of many species has now been sequenced, but the function of the majority of genes still remains unknown. This is where the International Mouse Phenotyping Consortium (IMPC) comes in, with the goal of characterising all 20,000 or so protein-coding mouse genes. To achieve this, genes are systematically inactivated then mice are put through a standardised phenotyping platform, with tests undertaken across a broad range of biological systems.

The consortium is comprised of 19 research institutions, 5 national funders and 11 countries. Each centre focuses on particular genes, applies standardised tests and then records the resulting data. After this, phenotype analysis is conducted and the resulting data and statistics made freely available to the research community. As well as completing large scale comparative studies, the overall aim of the project is to create a platform for this data where researchers and clinicians can search for genes, phenotypes or diseases of interest to help them understand human biology, health and disease.

Professor Steve Brown, the IMPC chair says “The IMPC is rising to the challenge of generating a complete functional catalogue of the mouse genome. Since its inception in 2011, it has made great strides with a third of the genome already analysed. Moreover, many startling and hitherto undiscovered features of the mammalian genome landscape have been revealed.”

There are now over 6,000 genes with mouse mutant data on an isogenic genetic background (C57BL/6N) on the IMPC website, all of which can be viewed and downloaded for free. In its initial stages the knock out lines used for IMPC were all made in ES cells by homologous recombination, all containing a lacZ reporter and many of them generating conditional mouse lines. However, as for many areas of developmental biology, new gene editing technologies, in particular CRISPR/Cas9, have condensed the process of generating knockout mouse lines. Advancements such as this have improved production and will allow all 20,000 genes to be characterised in the next few years.

Around a third of knockout genes are embryonic lethal and consequently developmental biology is an integral part of the IMPC project. In particular, there is an extensive embryo phenotyping pipeline that includes systematic harvest of embryos at set stages, capture of morphology by 3D imaging (OPT or microCT, depending on embryonic stages) and evaluations of morphological abnormalities in mutant embryos. These procedures can allow direct insight into the window of lethality for each mouse line, but they also provide valuable information on gene function. For example, accurate measurements of organ size and shape can be collected using microCT scan data, or macroscopic observations undertaken by a trained researcher. Importantly, all 3D data sets are available to download from the website for further in-depth analysis by specialist researchers.

In the last few years the IMPC has made major discoveries about parts of the genome that were up to now unexplored, with novel genes discovered relating to areas such as embryonic development, deafness, diabetes, and rare diseases. Recent high profile publications have included research focusing on inferring mammalian gene function, studies on specific human conditions, sexual dimorphism in mouse research, and even using IMPC data to help in wildlife conservation. New methods and analysis tools have also been developed under the umbrella of the IMPC, such as PhenStat, an extensive library of functions that analyse the phenotypical data. Another example is illustrated by a recent article that highlights a new bioimage informatics platform for high-throughput embryo phenotyping. Although this platform was built for the IMPC, the software tools that facilitate the analysis and dissemination of 3D images can be used by other researchers, and is available under an open-source licence. Indeed, sharing resources across the research community is a crucial aspect of the IMPC, and mutant mouse lines can be obtained from the website.

The IMPC is continuing to deliver data and mouse models for the developmental biology field and ultimately will be part of the effort to understanding and treating genetic conditions in humans. More information on the latest research of the IMPC can be found on our blog, and you can search the IMPC database for free at

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New research finds that scientists are still studying the same 10% of human genes and ignoring the rest, highlighting the importance of international projects such as the IMPC.

Historical bias is a key reason why biomedical researchers continue to study the same 10 percent of all human genes while ignoring many genes known to play roles in disease, according to a study publishing in PLOS Biology. The researchers involved in this study suggest this bias is bolstered by research funding mechanisms and social forces. The International Mouse Phenotyping Consortium (IMPC) aims to address this issue by creating a platform that characterizes all 20,000 protein-coding mouse genes, which can then give valuable information into homologous genes in the human genome.

Recent studies have reported that researchers actively study only about 2,000 human protein-coding genes, so the researchers set out to find why. They compiled 36 distinct resources describing various aspects of biomedical research and analyzed the large database for answers. The team found that well-meaning policy interventions to promote exploratory or innovative research actually result primarily in additional work on the most established research topics — those genes first characterized in the 1980s and 1990s, before completion of the Human Genome Project. The researchers also discovered that postdoctoral fellows and Ph.D. students who focus on poorly characterized genes have a 50 percent lower chance of becoming an independent researcher.

The researchers applied a systems approach to the data — which included chemical, physical, biological, historical and experimental data — to uncover underlying patterns. In addition to explaining why some genes are not studied, they also explain the extent to which an individual gene is studied. And they can do that for approximately 15,000 genes.

The Human Genome Project — the identification and mapping of all human genes, completed in 2003 — promised to expand the scope of scientific study beyond the small group of genes scientists had studied since the 1980s. But the Northwestern researchers found that 30 percent of all genes have never been the focus of a scientific study and less than 10 percent of genes are the subject of more than 90 percent of published papers.

“The bias to study the exact same human genes is very high,” said Amaral, the Erastus Otis Haven Professor of Chemical and Biological Engineering and a co-author of the study. “The entire system is fighting the very purpose of the agencies and scientific knowledge which is to broaden the set of things we study and understand. We need to make a concerted effort to incentivize the study of other genes important to human health.”

The International Mouse Phenotyping Consortium

This new research highlights the need for projects such as the IMPC, in which the aim is to characterize approximately all 20,000 or so protein coding genes. To achieve this, genes in the mouse genome are switched off, or ‘knocked out’, then standardised physiological tests undertaken across a range of biological systems. This data is then made freely available to the research community. As well as completing large scale comparative studies, the overall aim of the project is to create a platform for this data where researchers/clinicians can search for genes or diseases of interest to help them understand human health and disease. Data for over 6,000 genes is now available on the IMPC website and the project should therefore help address some of the main issues outlined above.

“The IMPC is leveling the playing field by freely providing robust phenotype data for poorly characterized genes. Nothing pleases me more than helping researchers overcome these barriers and discover new research areas none of us have dreamed of. This will be lasting legacy of the IMPC and is why our global partners continue to generate and phenotype mutant mice every day.” said Terry Meehan, a member of IMPC, and the Mouse Informatics Coordinator at the European Bioinformatics Institute.

Lluis Montoliu, researcher at the National Center for Biotechnology (CNB-CSIC) and member of the IMPC said “In the scientific community we all know of ‘famous’ genes and genes that are not so. Fashions also prevail in the scientific community and, indeed, there are many very relevant genes that, due to their difficulty and scarce literature, remain largely unknown. For example, huntingtin, whose gene causes Huntington’s deadly neurodegenerative disease. The IMPC aims to generate and phenotype mutant mice for each and every one of the 20,000 genes, whether or not they are famous, in order to correlate the data obtained with their homologous genes in the human genome.”

PLOS Biology research article:

More information on the IMPC:


Scientists from the University of Cambridge have identified a potential therapeutic target in the devastating genetic disease Hutchinson-Gilford Progeria Syndrome (HGPS), which is characterised by premature ageing. The research utilises IMPC resources through the use of mouse phenotypic data.

The paper is published in Nature Communications, with preclinical data showing that chemical inhibition or genetic deregulation of the enzyme N-acetyltransferase 10 (NAT10) leads to significant health and lifespan gains in a mouse model of HGPS.

HGPS is a rare condition: patients have an average life expectancy of around 15 years, suffering a variety of symptoms including short stature, low body weight, hair loss, skin thickening, problems with fat storage, osteoporosis, and cardiovascular disease, typically dying of a heart attack.

The disease arises from specific mutations in the gene for the protein Lamin A, which lead to production of a shorter, dysfunctional protein that accumulates in cells, specifically in the membranes surrounding the nucleus. This causes disorganisation of chromatin (the ‘packaging’ around DNA), deregulated transcription, accumulation of DNA damage and defective cell proliferation.

By screening candidate molecules for an effect on nuclear membranes in human HGPS patient-derived cells in vitro, the authors have previously identified a small molecule called remodelin as an effective ameliorative agent. They then identified which component of the cells was being affected by remodelin: an enzyme with a variety of cell functions, called NAT10.

Their aim in the new study was to take these findings into a mouse model with the same genetic defect as HGPS patients, to see whether inhibiting NAT10 – either chemically by administration of remodelin or genetically by engineering reduced production of NAT10 – could ameliorate the disease. The results show that these approaches indeed significantly improved the health of the diseased mice, increased their lifespan, and reduced the effects of the HGPS mutation across a variety of measures in body tissues and at the cellular level.

The research was led by Dr Gabriel Balmus from the Wellcome Trust/ Cancer Research UK Gurdon Institute and Dr Delphine Larrieu from the Cambridge Institute for Medical Research, University of Cambridge; and Dr David Adams from the Wellcome Sanger Institute.


Senior author Professor Steve Jackson commented: “We’re very excited by the possibility that drugs targeting NAT10 may, in future, be tested on people suffering from HGPS. I like to describe this approach as a ‘re-balancing towards the healthy state’.

“We first studied the cell biology to understand how the disease affects cells, and then used those findings to identify ways to re-balance the defect at the whole-organism level. Our findings in mice suggest a therapeutic approach to HGPS and other premature ageing diseases.”


Research article:

Nat10 gene on the IMPC website:

Glucose is the energy that fuels cells, and the body likes to store glucose for later use. But too much glucose can contribute to obesity, and scientists have long wanted to understand what happens within a cell to tip the balance.

To solve this riddle, researchers at UT Southwestern’s Cecil H. and Ida Green Center for Reproductive Biology Sciences examined specialized compartments inside the cell to reveal the role of a molecule termed NAD+ in turning on genes that make fat cells.

The study utilised IMPC resources for the generation of Nmnat1 conditional knockout mice. Frozen Nmnat1tm1a(EUCOMM)Wtsi embryos on a C57BL/6N background were obtained and recovered at UT Southwestern’s Transgenic Core Facility. The research is reported in the journal Science.

NAD+ is found in every cell of the body and some scientists believe that boosting its production may be tied to better health and to the slowing down of the aging process.

What is NAD+?

NAD+ stands for nicotinamide adenine dinucleotide. It’s a molecule found inside cells in the body that helps transfer energy between molecules.

Why is it important?

NAD+ is believed to play important roles in longevity, aging, and diseases ranging from neurodegenerative disorders to cancer.

UT Southwestern biologists examined individual compartments inside cells that house NAD+ molecules to determine how they control genes that are essential to the fat-storing process – knowledge that could help in a wide range of ailments, including metabolic disorders, neurodegenerative diseases, inflammation and aging, and cancer.

“This compartmentalization ends up having profound effects on gene expression in the nucleus, as well as metabolism in the cytoplasm,” (the jellylike substance outside the cell’s nucleus), said Dr. W. Lee Kraus, Director of the Green Center and senior author on the research. “We found that these processes play key roles in fat cell differentiation and in cancer cells.”

“The previous thinking in the field was that NAD+ was evenly distributed throughout cells and moved freely between different subcellular compartments,” said Dr. Kraus, Professor of Obstetrics and Gynecology and Pharmacology. “We showed that NAD+ is actually compartmentalized – there are separate nuclear and cytoplasmic pools of NAD+ whose levels change under certain cellular conditions.”

Accounting for the levels of NAD+ biosynthesis separately rather than in their totality helped increase the understanding of the biology involved, said first author Dr. Keun Ryu, a postdoctoral researcher in Obstetrics and Gynecology.

“Our study provides a new understanding of NAD+ biology,” he said.

Research article:

A recent study in the journal Nature Medicine utilises IMPC-generated mouse lines as a basis for their discovery. A summary of this research article, and how it may help human patients with osteoporosis, is given in a guest post below. This investigation is a great example of how IMPC resources can be used by the research community and exemplifies how mouse phenomics may help in the development of treatments for human disease.


Guest post by Maureen Salamon

A molecule promoting blood vessel growth in bone can create an environment suitable for bone-building, representing a potential target for new drugs to treat osteoporosis and fractures, according to new research by Weill Cornell Medicine scientists.

The findings, published in Nature Medicine, show that a substance best known for spurring nerve growth, called SLIT3, both reversed the bone-weakening effects of osteoporosis and helped fractures heal when administered in mice. The multi-center research effort could fuel drug development efforts targeting the SLIT3 pathway in humans, enabling a new approach for blood vessel-directed therapy to treat bone loss, persistent fractures and fragile bones.

Existing drugs for osteoporosis work in one of two ways: Either they block the cells that destroy bone or they promote bone formation by cells called osteoblasts. “But only those promoting new bone formation will help you actually heal a bone fracture,” said co-senior study author Dr. Matthew Greenblatt, an assistant professor of pathology and laboratory medicine at Weill Cornell Medicine. “Our findings have potentially demonstrated a third category: drugs that target blood vessel formation within bone, prompting new bone to form.”

Osteoporosis, which causes bones to thin and become brittle, leads to nearly 9 million fractures worldwide each year, or one every three seconds, according to the International Osteoporosis Foundation. Women are disproportionately affected, and the risk increases with age. One in two women and one in five men will have an osteoporotic fracture during their lifetimes, and these fractures kill as many women each year as breast cancer.

“Osteoporosis and skeletal fractures due to osteoporosis are both common and deadly,” Greenblatt said.

To counteract that trend, Greenblatt has been investigating the cellular causes of osteoporosis in an effort to promote bone growth. Prior research using mice genetically engineered to lack an adaptor protein known as SHN3 showed that its absence conferred high bone mass. Building on that discovery, Greenblatt and his team decided to examine the resulting changes in bone blood vessels. “We used those mice as a means to find the signals coming from osteoblasts to control the specific type of blood vessels present in bone,” he said.

The researchers were surprised to find that osteoblasts secreted unchanged amounts of almost all known factors promoting blood vessel growth, but SLIT3 levels rose significantly. And when the mice were genetically altered to delete SLIT3, they exhibited low bone mass.

“We next asked if we could use SLIT3 to treat mice with skeletal disease, especially osteoporosis and fracture healing,” Dr. Greenblatt said. “When we gave the rodents SLIT3, it reversed their osteoporosis and made their fractures heal faster and stronger.

“To my knowledge, this is the first example that we can develop a drug to treat bone disease in mice not by targeting the bone-forming cells,” he said, “but instead by targeting special types of blood vessels that exist in bone.”

Further research is needed to determine the best way to deliver SLIT3 to the bone in humans. SLIT3-pathway drugs could also be used in combination with existing drugs to improve patient outcomes.

“Only a small fraction of patients who’ve had a hip fracture and really require medication to prevent additional fractures get the drugs they need. Many people aren’t aware of how debilitating and deadly these kinds of fractures are,” Greenblatt said. “Having a totally new category of bone drugs that work on different sets of cells could open up new opportunities for treatment.”

In addition to benefiting seniors with osteoporosis, Greenblatt hopes his research will also help patients with bone injuries that aren’t healing properly, such as those who’ve undergone orthopedic surgery or have fragile bones due to genetic diseases.

“Some of those people’s fractures don’t heal because they can’t grow the right type of blood vessels at the site of the fracture,” he said. “That’s what we think SLIT3 will do: help with that growth and promote healing.”


Research article: Targeting skeletal endothelium to ameliorate bone loss

Maureen Salamon is a freelance writer for Weill Cornell Medicine. This article was originally published in the Cornell Chronicle and is re-published with copyright permission.

Nishanth Ulhas Nair discusses his recent article in Scientific Reports: Putative functional genes in idiopathic dilated cardiomyopathy

Link to article:

The International Mouse Phenotyping Consortium (IMPC) has been predominantly interested in using mouse models to understand human health and disease. In a new study in the journal Conservation Genetics researchers have found another intriguing use of IMPC data.

By comparing genetic functional data from the IMPC with other non-human animals, it may be possible to identify genes relevant for the normal development in those species. For example, by comparing mouse genetic functional data with genomic data for selected species with specific diseases, improved breeding management could be implemented.

To test this potential application researchers at the European Bioinformatics Institute (EMBL-EBI) and Queen Mary University London (QMUL), alongside colleagues from the IMPC, compared genetic functional data from mice with genomic data from gorillas, showing how such analyses could aid in the identification of genes essential for healthy development.

As well as gorillas, the researchers highlighted other examples, including cheetahs, polar bears, wolves, pandas and cattle. This type of analysis could improve the current management approaches to breeding endangered species, by allowing researchers to identify the matches that are most likely to produce healthy offspring or select breeders to preserve genetic variation relevant for adaptation.

Genes associated with fat metabolism can be a real asset for species like polar bears

Heart disease is a common cause of death for gorillas in captivity and cheetahs suffer from impaired fertility both in captivity and in the wild. By identifying gorilla genes linked to heart disease or cheetah genes linked to infertility, researchers could help better understand the cause for the condition, which is the first step to envisage ways to prevent it. Similarly, this type of data could help identify genes linked to adaptation in certain mammals. For example, genes associated with fat metabolism can be a real asset for species like polar bears, which have diets rich in fats in the extreme environment of the Arctic.

Impaired fertility is common in cheetahs both in captivity and in the wild

“When the number of individuals of a species dramatically decreases, loss of genetic variation also takes place”, explains Violeta Muñoz-Fuentes, Biologist at EMBL-EBI. “This can result in many offspring not surviving, or exhibiting genetic defects linked to fertility or health problems.”

“Many zoos and wildlife conservation centres are seeing excellent results through their breeding programmes. Currently, many focus on minimising inbreeding. By adding a functional genetic dimension to the selective process, conservation geneticists can identify the crosses that would, for example, avoid a gene variant linked to disease in the offspring. It is nevertheless important to keep in mind that for a genetic rescue approach to be successful in the long term, the conditions that led to the decrease of individuals need to be removed; otherwise, the accumulation of deleterious alleles will likely take place again”.

Number of IMPC significant phenotypes for selected mammalian species (source:

Although this type of research is still in its early stages, gene functional knowledge is a powerful tool for maximising adaptive genetic diversity within a species and even for reducing genetic variants that negatively affect an individuals’ health and survival. With the accumulation of gene function annotation by the IMPC, as well as technical advancements in gene editing such as CRISPR/Cas9, the hope is that this method of comparing genome information between laboratory mice and endangered wildlife will help in future conservation projects.

The IMPC aims to produce and phenotype knockout mouse lines for 20,000 genes

The IMPC would like to encourage conservation geneticists, conservation centres and zoos to get in touch if they are interested in using IMPC data for conservation purposes.

A new study by the Psychiatric Genomics Consortium has identified 44 genetic loci that are linked to major depression in humans. The research was published in the journal Nature Genetics.

This is the largest study to date looking at genetic risk factors for depression, a condition that affects more than 300 million people around the world.


Melanie Samuel discusses her research in neural development and disease, and explains how she has used IMPC data.




Published 20th April 2018

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