Gary Churchill discusses genetic diversity in the mouse and how this diversity can be used as a tool for understanding gene function. The video was recorded at the recent KOMP2/IMPC annual meeting, hosted by the National Human Genome Research Institute.
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.
Data release 9.1 has been published on the IMPC website. There is now a total of 5,957 phenotyped mutant lines, and brings the total number of phenotyped genes to 5,570.
Data release 9.1 represents a major data release, with 500 additional genes added to the website. To learn more about the IMPC and its aims click here.
Damian Smedley will give a talk on Wednesday from 9:30am to 9:45am in Ballroom 20A
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. Damian Smedley will describe how the clinical phenotype data collected on each rare disease patient is used in automated variant prioritisation software (Exomiser) to identify 68%, 78% or 81% of diagnoses in the top 1, 3 and 5 matches respectively. This software takes advantage of a number of reference disease and model organism genotype to phenotype databases including the International Mouse Phenotyping Consortium (IMPC).
Guest post by John Morris (ASHG talk: Wed Oct 17, 9:00am – 9:15am in Room 6D)
Osteoporosis is a common, aging-related disease characterized by decreased bone strength and, consequently, increased fracture risk. Bone mineral density (BMD), a non-invasive measurement, is the most clinically relevant risk factor for diagnosing osteoporosis and is highly heritable (i.e. determined by genetics). To understand the genetic determinants of osteoporosis, we performed a genome-wide association study (GWAS) in 426,824 UK Biobank participants to identify regions of the genome associated with BMD estimated from quantitative heel ultrasound (eBMD). This approach is unbiased in that it systematically tests millions of single nucleotide polymorphisms (SNPs) in the human genome—sites of common, uncommon, or rare genetic variation in the general population—for association with eBMD measurements. BMD-associated SNPs can then be used to identify novel bone genes, but such genes would require further study in human cells or animal models to understand their function. Therefore, we collaborated with the Origins of Bone and Cartilage Disease (OBCD, www.boneandcartilage.com) to examine genes in knockout mice. Such genes, when validated by knockout mouse skeletal phenotyping, represent strong candidates for developing new therapies to prevent and treat osteoporosis.
Our eBMD GWAS identified 518 significant regions of the genome, 301 of which were novel findings. Next, to identify target genes, we performed statistical fine-mapping and integrative bone cell functional genomics data analyses. First, by leveraging SNP association summary statistics and SNP-by-SNP correlations, we can identify a subset of plausibly causal SNPs. Then, by intersecting this list of plausibly causal SNPs with genomic characteristics that indicate function (e.g. coding SNPs, osteoblast open chromatin, osteoblast 3D contacts with gene promoters), we can identify a list of target genes likely to be functional in bone cells. These orthogonal approaches resulted in a list of 515 target genes, identified by plausibly causal and putatively functional SNPs, that we found were strongly enriched for known bone genes and osteoporosis drug targets. We sought to examine the effects of as many of these genes as possible in knockout mice and found the OBCD had skeletal phenotyping data on 126. Importantly, the OBCD receives all knockout mouse lines for skeletal phenotyping at random from the International Mouse Phenotyping Consortium (IMPC), therefore it is not known beforehand if a given knockout mouse has a skeletal phenotype. These 126 genes were found to be enriched for outlier skeletal phenotypes, providing strong evidence that our target genes are disease-relevant, and we focused on one such gene in further detail: disheveled-associated activator of morphogenesis 2 (DAAM2).
Mice with hypomorphic Daam2 alleles were found to have increased cortical porosity and markedly reduced bone strength, even though all other cortical bone parameters, including BMD, were normal. We performed further analyses on DAAM2, such as CRISPR-Cas9 mediated knockouts in human osteoblast cell lines, revealing a decreased ability of this crucial bone-forming cell to mineralize. We concluded that DAAM2 is a novel risk gene for osteoporosis meriting further study and highlighted five other strong candidates for follow-up: CBX1, WAC, DSCC1, RGCC, and YWHAE. In summary, we have generated an atlas of genetic influences on osteoporosis in humans and mice, more fully describing its genetic architecture. Human and mouse genetics identified DAAM2 and other genes previously unknown to function in bone biology. We expect the genes identified here to include new drug targets for the treatment of osteoporosis, where novel therapeutic options are a health priority.
We are excited to be attending the the ASHG 2018 Annual Meeting in San Diego next week. We are looking forward to engaging with researchers and to raise awareness of the IMPC as a resource. If you are attending the conference and want to learn more about the IMPC please visit stand 225 in the non-profit section of the exhibition hall. We will be tweeting relevant research and news during the conference so please follow us on Twitter for updates. We are also adding guest blog posts from attendees presenting research that utilize mouse models, click here to read them.
As well as documentation and information about the latest research , we will also be giving out coasters, pens, notebooks and toy mice. Please don’t hesitate to come to our stand if you are interested in hearing more about the IMPC or if you want to pick up some handouts. Pilar Cacheiro and Damian Smedley will also be presenting research that mentions IMPC resources, both on Wednesday the 17th, and we will have copies of the poster on the stand. More information on the aims and uses of IMPC can be found below.
The International Mouse Phenotyping Consortium (IMPC) is an international effort to identify the function of every gene in the mouse genome. The entire genome of many species has now been published and whole genome sequencing is becoming relatively quick and cheap to complete. Despite these advancements the function of the majority of genes remains unknown.
This is where the IMPC comes in, with the goal of phenotyping all 20,000 or so protein coding mouse genes. To achieve this, genes in the mouse genome are switched off 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.
IMPC data can be used in a variety of ways, such as to investigate basic biology mechanisms that can lead to new therapeutic targets or to narrow down a suspected list of genes in patients. In the last few years the IMPC have made major discoveries in parts of the genome that were hitherto unexplored, with new genes discovered relating to areas such as deafness, diabetes, and rare diseases. Summaries of five recent research articles that highlight the diversity of how IMPC data can be used are listed below. These include inferring mammalian gene function, studies on specific human conditions, sex differences in medical research, and even using IMPC data to help in wildlife conservation.
- Advancements in mouse phenomics and its uses for inferring mammalian gene function
- Novel hearing loss genes identified in large study by scientists across the world
- New diabetes genes discovered in latest IMPC research
- Study of unprecedented size reveals how sex ‘blindspot’ could misdirect medical research
- New research suggests laboratory mouse data can help in wildlife conservation
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 https://www.mousephenotype.org/.
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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: https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.2006643
More information on the IMPC: https://www.mousephenotypetest.org/what-is-the-impc/
15 novel genes related to retinal function have been found in research published by Dr. Melanie Samuel and colleagues in Cell Reports. The research reveals previously unknown retinal regulators which will help expand our understanding of the genetic landscape that regulates retinal function and uncover how genes are involved in vision loss and disease.
The retina processes visual information from the world around us and relays it to the brain. This sensory circuit is complex but highly ordered. It is comprised of distinct neural layers, and each layer has an array of different neuron types. These neurons are supported by a rich vascular system.
Vision defects globally affect around 253 million people. Such diseases can arise from disruptions to different parts of the visual circuit. For example, vascular changes can be a sign of diabetic neuropathy and defects in light-sensing photoreceptors can lead to retinitis pigmentosa. Yet many of the genes and mechanisms responsible for vision loss remain unknown.
In this research, Dr. Samuel and colleagues selected a sub-set of animal lines from the IMPC in which individual genes had been modified to eliminate their function. They then developed a specialized pipeline of high-throughput retinal screening to examine the role of these genes in more detail. The criteria for selecting candidate genes included those with human orthologues and those with expression in the retina or brain.
The availability of broad based and comprehensive phenotyping data from the IMPC helped researchers focus their search for genes relating to the retina.
In-depth analysis included examining gene expression, synapse organisation, cell morphology and the patterning of blood vessels.
Of the 102 mutant lines analysed, 16 genes were identified that regulated retinal function, 15 of these were novel and not previously associated with retina function.
A range of diverse observations were seen. Lines were found with altered vessel density and branching, disrupted synaptic organisation and neuron loss.
Here, analysis of blood vessels in the retina shows abnormalities including decreased vessel number (Rnf10) and tortuosity (Adsl) in comparison to the wild type image on the left hand side.
Many of the genes displayed a wide range of cellular functions and may also be important elsewhere in the body. Data available through the IMPC database supported this, as many of the lines had additional phenotypes, including body composition and central nervous system regulation deficits (suggested by altered body composition and open field tests, respectively).
“The results from the study highlight the kind of discoveries that are possible through harnessing the remarkable data and resources available from the IMPC. With these efforts, we hope to continue to map the compendium of genes that regulate the retina and the brain so that we can make progress in treating human neural diseases,” said corresponding author, Dr. Samuel, assistant professor of neuroscience and the Huffington Center on Aging at Baylor College of Medicine.
To read the research click here
Interested in learning more? Dr. Samuel recently told us about her lab’s research in the video ‘What makes us unique? Exploring the role of genetics and neural function’
Other contributors to this work include Nicholas E. Albrecht, Jonathan Alevy, Danye Jiang, Courtney A. Burger, Brian I. Liu, Fenge Li, Julia Wang, Seon-Young Kim, Chih-Wei Hsu, Sowmya Kalaga, Uchechukwu Udensi, Chinwe Asomugha, Ritu Bohat, Angelina Gaspero, Mónica J. Justice, Peter D. Westenskow, Shinya Yamamoto and John R. Seavitt. The authors are affiliated with one or more of the following institutions: Baylor College of Medicine, Texas Children’s Hospital, and the Hospital for Sick Children, Toronto.
An article published in the journal Theriogenology demonstrates that it is possible to cryopreserve mouse spermatozoa at −80 °C. What is more, the cryopreserved sperm can be stored at -80 °C for at least one year before being placed in liquid nitrogen for indefinite storage. The team involved in this research have used a simple and efficient method for freezing spermatozoa of wild type and mutant mouse lines on a C57BL/6N background. Mice with this genetic background are used for a variety of projects, including the IMPC. This technique has the potential to transform the sperm storage process, as it simplifies freezing and facilitates storage and transportation.
In particular, this new method will be useful for laboratories with limited access to liquid nitrogen as well as projects that generate mutant lines using CRISPR/Cas9 who want a more accessible −80 °C freezer option. The results of the study also highlight that mouse spermatozoa are extremely robust and can be stored and transported at −80 °C for a significant amount of time without loss of viability.
Below is a recent video that explains how mouse sperm is currently shipped and stored using dry ice, featuring Martin Fray who was one of the authors of this latest development.