GSA President Hugo Bellen and Vice-President E. Jane Hubbard are among the co-authors of a recent Perspectives article in Development titled “Model organism databases are in jeopardy.” The article describes the importance of model organism databases (MODs), the threat posed by NIH MOD budget cuts, and possible solutions.

“We are deeply concerned that the support for these vital databases is in jeopardy due to large cuts in their grant budgets. We fear these budget cuts will slow biomedical research worldwide and create increased waste of resources due to duplication of efforts. Indeed, the cuts threaten to erode access to reliable, expertly fact-checked data and cause an increase in mis-information due to the degraded organization of knowledge and information.”

— Bellen et al. 2021

Want to help? The NIH has put out a request for information on user experience with scientific data sources and tools. This brief survey is a great opportunity to let the NIH know how much you value MODs and how reduced funding for these important tools would impact your productivity. The deadline for responses is October 15, 2021. Skip straight to the survey link here.

GSA President Hugo Bellen announces a new seminar series on tools and resources for exploring gene function across organisms. 

Some of us are worried about the future of the research enterprise, especially funding support for science in our favorite model organism. Why worry? One of the main drivers of this concern is that some believe our work is not directly relevant to human biology. This is often based on the idea it is difficult to quickly translate basic discoveries into directly applicable medical paradigms. Yet, the model organisms that many of us study have been the driving force for most biomedical discoveries. More than 90% of the Nobel prizes in Medicine or Physiology in the past 40 years have been awarded for research carried out in model organisms such as mice, rats, Xenopus, worms, and flies. These include the discovery of monoclonal antibodies (mouse), RNAi technology (worms), CRISPR technology (bacteria), cell cycle and cancer (yeast), signaling pathways, and development (flies), and so many others. Such discoveries in fundamental biology have propelled advances in medicine, and I believe they will remain at the forefront.  

Genetics offers numerous important features for such advances, because genetic manipulations are the most elegant type of manipulations for answering biological questions. Is there a less intrusive experiment than changing a single nucleotide among millions or billions of bases and asking: what are the in vivo consequences? The answer is a flat no in my opinion! 

Despite the obvious relevance of our work to human biology, some are averse to a human-centric vision of research for good reasons, as nicely illustrated by the examples above. Diseases should not per se dictate our research because we don’t yet know where the next breakthrough will come from. Serendipity and curiosity are major players in discovery. 

Yet, I see no reason not to search for a middle ground. This is especially the case in the area of genetics, as the evolutionary conservation of genes and their function has been critical to understanding most biological processes across organisms. Forward genetic screens and evolution-based studies in model organisms have led, and will continue to lead, to discovery of many basic aspects of biology as they are unbiased and probe a very diverse set of biological functions.  

Doing biological research is not always a forced choice between creating fundamental knowledge or developing targeted medical applications. Both outcomes can result from the same efforts. Indeed, human genetics has advanced basic biology, from Archibald Garrod helping renew the understanding of Mendel’s laws by studying a rare disease, to prion biology revealed by Creutzfeldt-Jakob disease. The last ten years have seen remarkable changes as another set of scientists—human geneticists—have joined the cohort of screeners. They, like many of us, observe phenotypes (of patients) and attempt to identify the causative genes.  This approach has gained tremendous strength with the ability to sequence all exomes (WES) and genomes (WGS). WES or WGS of an affected individual and a few direct family members allows the identification of variants in one or a few genes that may be causative, especially for very rare diseases. 

Surprisingly, more than 50% of the orthologues of these genes have been poorly characterized in vivo in any organism, leaving a wide knowledge gap. Because an estimated 6,000–13,000 rare disease associated genes remain to be discovered, we have a full plate of genes and variants to tackle. Note that more than 80% of new human disease genes that have been discovered in the past few years are conserved in worm, flies and, more obviously, in vertebrates.

How can a scientist study the function of these genes, especially when the phenotypes associated with the loss of these genes in model organisms may be more subtle than many of the genes that have been characterized already? One productive approach is to generate clean loss-of-function tools using state-of-the-art genetic technologies and then to perform systematic phenotyping at many different levels, including transcriptomics, metabolomics, histological screens, as well as behavioral screens of the many collections of mutants available in yeast, worms, flies, fish, and more recently, mouse. 

Another approach is to team up with other model organism researchers who are performing similar screens and share data to identify genes and pathways to help define their function. 

A third approach is to identify researchers who are attempting to define the function of certain genes based on their scientific interest but are not even aware that others are interested in orthologues in other species.  The latter challenge can now be solved if open communication and collaborative ventures are explored at the onset. For example, a human geneticist may identify an evolutionarily conserved gene that has been poorly characterized in model organisms and may be interested in collaborating with a model organism researcher. Alternatively, a model organism researcher may have identified a conserved gene and wonder if a human geneticist has identified patients that carry variants in the orthologous human gene. Recent databases and online platforms now allow scientists to explore these unpublished data, connect, and explore or initiate collaborations.  These include GeneMatcher, ModelMatcher, and numerous international ventures designed to match researchers and clinicians with common interests. 

GSA is exploring ways to introduce the model organism community to these approaches.  In addition, there are now many databases that attempt to centralize knowledge from many model organisms to help geneticists explore gene function across evolution, such as the Monarch Initiative and the Alliance of Genome Research, as well as databases to integrate clinical and scientific databases such as MARRVEL. GSA will organize a series of seminars this year to introduce these opportunities and provide tips and tutorials to help explore the available websites and databases. We believe that these seminars will be useful to investigators at all career stages and across different model organisms, as well as for human biologists. We hope this will add a new dimension to research, reveal unanticipated phenotypes, speed up discovery, allow new funding opportunities, and lead to the discovery of new fundamental aspects of biology. 

Sign up for the Seminars Now!

Offshoot of the modENCODE project provides crucial data and strains for understanding gene regulation.

Following a multidisciplinary effort spanning six institutions, researchers working on the modERN (model organism Encyclopedia of Regulatory Networks) project have released a powerful resource for biologists studying the fruit fly Drosophila melanogaster and the nematode worm Caenorhabditis elegans. So far, report Kudron, Victorsen, et al., the project has yielded information about the interactions of 262 transcription factors (TFs) with 1.23 million binding sites in flies, along with 219 TFs with 670,000 binding sites in worms—all of which can be found in a searchable database organized by gene and developmental stage.

Along with announcing the availability of this resource, the group shared findings made during its construction. One such observation is that genomic regions with a large number of TF binding sites are often associated with broadly expressed genes, whereas regions with fewer TF binding sites are more often found near genes that are expressed mainly in specific tissues.

The collection includes 403 worm strains and 427 fly strains, each of which has a different TF tagged with green fluorescent protein. Researchers can obtain stocks through existing resources, the Caenorhabditis Genetics Center and the Bloomington Drosophila Stock Center. The strains have a variety of possible uses—for example, determining expression patterns of TF genes of interest.

Choosing flies and worms for the modERN project was a logical choice for multiple reasons, not least of which being that so much is known about these important model organisms. The authors also note that a major advantage of working with flies and worms for this project is that they can be studied as whole, living organisms at all developmental stages, which is not possible with human subjects. And since many fly and worm TFs are homologous to human TFs, it’s likely that research fueled by modERN data will provide a treasure trove of useful leads for biologists studying humans as well.

CITATION:

The ModERN Resource: Genome-Wide Binding Profiles for Hundreds of Drosophila and Caenorhabditis elegans Transcription Factors
Michelle M. Kudron, Alec Victorsen, Louis Gevirtzman, LaDeana W. Hillier, William W. Fisher, Dionne Vafeados, Matt Kirkey, Ann S. Hammonds, Jeffery Gersch, Haneen Ammouri, Martha L. Wall, Jennifer Moran, David Steffen, Matt Szynkarek, Samantha Seabrook-Sturgis, Nader Jameel, Madhura Kadaba, Jaeda Patton, Robert Terrell, Mitch Corson, Timothy J. Durham, Soo Park, Swapna Samanta, Mei Han, Jinrui Xu, Koon-Kiu Yan, Susan E. Celniker, Kevin P. White, Lijia Ma, Mark Gerstein, Valerie Reinke, Robert H. Waterston
Genetics 2018 208: 937-949; https://doi.org/10.1534/genetics.117.300657
http://www.genetics.org/content/208/3/937

The Genetics Society of America (GSA) is pleased to announce that Philip Hieter is the recipient of the 2018 George W. Beadle Award, bestowed in honor of his outstanding contributions to the genetics research community. Hieter is Professor of Medical Genetics in the Michael Smith Laboratories at the University of British Columbia.

Philip Hieter

Geneticists across the model organism and human genetics communities recognize Hieter for his dedication to uniting human biologists with those who work on model organisms such as mice, fruit flies, worms, and yeast. The resulting collaborations are crucial to advancing our knowledge of biology, including human health and disease; connecting model organism researchers and human biologists with one another speeds progress for both groups, facilitates mechanistic understanding of disease gene functions, and helps uncover novel disease mechanisms and candidate therapeutic targets.

In 1997, when few genome sequences were available, Hieter helped create XREFdb, a public database that linked the functional annotations of genes studied in model organisms with the phenotypic annotations on the human and mouse genetic maps. This resource provided cross-species candidate genes for mammalian phenotypes, including human diseases, and stimulated interactions between basic scientists working on various organisms and the medical genetics community. He has also founded and co-led several multidisciplinary meetings that bridged the gap between biologists working on humans and those working on model organisms. Hieter and Jeannie Lee, a professor at Harvard Medical School and the Massachusetts General Hospital (and 2018 GSA President), were co-chairs of 2016’s Allied Genetics Conference, which brought together over 3,000 attendees from seven different genetic research communities to exchange ideas and findings.

As the 2012 GSA President, Hieter continued to foster closer relationships among different groups of life scientists. “As president of the GSA, Phil had a strong focus on bridging the many separate communities of the Society as well as increasing the interactions of the GSA community with members of the human genetics community,” says Stanley Fields, professor at the University of Washington and 2016 GSA President.

To help biological insights reach patients, Hieter co-founded, in 2014, the Canadian Rare Diseases: Models and Mechanisms National Network, a consortium that connects clinician scientists identifying gene mutations in patients that cause rare diseases to basic scientists analyzing the corresponding genes in model organisms. This network funds pilot studies to expedite collaboration between the two groups, conduct model organism-based functional studies of disease gene variants, and develop new therapeutic strategies using model organisms.

In addition to having connected research communities, Hieter and his lab have made many significant contributions to our understanding of chromosome biology, including the dissection of yeast centromeres and the identification of genes involved in genome stability. Their contributions to the yeast community include physical mapping methods, synthetic lethality screen approaches for identifying cross-species candidate genes as potential cancer drug targets, and a widely used set of vectors and yeast host strains that have been instrumental in work that has led to countless discoveries in recent decades.

The George W. Beadle Award was created by GSA to honor the memory of George W. Beadle (1903–1989), the 1946 GSA President. Beadle and his colleague Edward L. Tatum were awarded the Nobel Prize for Physiology or Medicine in 1958 for work that linked genetics to biochemistry, providing a major part of the foundation for the field of molecular biology. In addition to being a GSA President, Beadle served society in several leadership roles—for instance, as chairman of the National Academy of Sciences Committee on the Biological Effects of Atomic Radiation—and demonstrated a strong commitment to science outreach and education.

The Prize will be presented to Hieter at the 2018 Yeast Genetics Meeting, a GSA Conference to be held August 20–26 at Stanford University.

For many of the roughly 300 million people around the world with rare diseases, the road to diagnosis can be long, painful, expensive, and disheartening. Around eighty percent of very infrequently seen undiagnosed diseases are estimated to have a genetic basis, but even with modern DNA sequencing techniques, the causes are often unclear. In these cases, clinicians and their basic scientist collaborators are increasingly turning to laboratory models like fruit flies and zebrafish to help diagnose disease—and gain clues about how to treat it.

The teamwork between clinicians and model organism researchers goes both ways: clinicians can find candidate genes in patients to test in model organisms, or basic scientists can identify candidate disease genes through research on their organism of choice. In a review appearing in the September issue of GENETICS, Wangler et al. describe numerous tools clinicians and basic scientists have at hand to help them work together on puzzling rare diseases.

One such tool is GeneMatcher, a website that connects researchers who may be separately investigating the same genes. Using GeneMatcher, clinicians can find potential collaborators working on model organisms.

Another mechanism that connects clinicians with model organism researchers is the Canadian Rare Diseases Models and Mechanisms Network (RDMM). Via the RDMM, a clinician can submit a proposal to work with a model organism researcher—or vice versa. Uniquely, they can also use the tool to apply for quick-turnaround grants to fund their investigations of potential disease-causing variants.

Patients themselves can also contribute to this research. People with rare diseases that have resisted diagnosis by any other means can apply to the Undiagnosed Diseases Program (UDP) to spur investigations of their conditions. Not only have patients been diagnosed using the UDP’s combination of detailed clinical investigation and genetic analysis, but new disease genes have also been discovered. For example, mutations in the gene NT5E were found to cause a rare arterial calcification disorder—and as an unexpected bonus, this finding hinted that adenosine metabolism might be linked to more common vascular disorders as well.

The UDP has now been expanded into the Undiagnosed Diseases Network (UDN), a decentralized program involving researchers at several institutions. Using the UDN, a patient is first screened to see if their disease matches a known genetic condition after an extensive phenotypic work-up and sequencing of the whole genome or exome. If not, clinical findings and candidate genetic variants are sent to the Model Organisms Screening Center (MOSC). The MOSC starts by searching databases of known information about the candidate variants to determine which are worth testing in model organisms. The MOSC then looks for other individuals with similar clinical presentations and possible genetic causes.

Once the list of candidate genes is narrowed down, the MOSC researchers design experiments in flies or zebrafish to acquire more knowledge. The MOSC teams aim to match the variant in the human patient’s gene in the model organism. The goal is to learn more about the function of the gene, to determine whether the gene variant found in the patient is the likely cause of the disease, and to understand how the variant may cause problems.

Wangler et al. conclude by endorsing the continued support of these tools by government agencies such as the National Institutes of Health. Only with this financial backing, they say, will crucial improvements in the diagnosis and treatment of rare genetic diseases be possible. And since our understanding of rare diseases often drives discoveries about more common diseases, this research could even have more far-reaching impacts.

CITATION:

Wangler, M.; Yamamoto, S.; Chao, H.; Posey, J.; Westerfield, M.; Postlethwait, J.; Members of the Undiagnosed Diseases Network (UDN); Hieter, P.; Boycott, K.; Campeau, P.; Bellen, H. Model Organisms Facilitate Rare Disease Diagnosis and Therapeutic Research.
GENETICS, 207(1), 9-27.
DOI: 10.1534/genetics.117.203067
http://www.genetics.org/content/207/1/9

Transparent research starts with an unambiguous parts list. To help promote the wider use of identifiers and recognized symbols in biological research, FlyBase (with input from other model organism databases) is developing a resource for tracking and reporting reagents in a more standardized way, aiding curation into research databases.

The GSA journals are now encouraging authors to use this Reagent Table and to provide input to help the community develop and improve the concept.

The Reagent Table is provided as a spreadsheet template, a format that is convenient and flexible for the researcher, easily used by readers of research publications, and allows bulk downloads for database curation. The table is designed for use in the lab, as a research project is conducted. Unambiguous identification of not only reagents, but the specific genes studied is particularly helpful for genetic and genome databases, as well as for other researchers, helping avoid confusion around genes with similar names or symbols.

The template, detailed instructions, and an example file are available in the journals’ Instructions for Authors. Please send feedback and suggestions to genetics-gsa@thegsajournals.org.

Guest post by the Alliance of Genome Resources.

If you want to help the Alliance please take a short survey at: https://www.surveymonkey.com/r/GSA-AllianceSurvey

Six of the founding members of the Alliance of Genome Resources (Saccharomyces Genome Database, WormBase, FlyBase, Zebrafish Model Organism Database, Mouse Genome Database and the Gene Ontology Consortium) attended GSA’s The Allied Genetics Conference in Orlando from July 13-17. It was a great opportunity for these individual resources to talk about their new collaboration to integrate their content and software into a single resource that benefits biologists, educators, and clinicians alike.

The model organism databases have a long history of reaching out to their respective communities for feedback on new developments and input on future directions. Carrying on this tradition, the Alliance has created a short survey to obtain feedback on how best to provide human disease information in relation to model organisms. In addition, the Alliance is asking for input on the prioritization of website visualizations, tools and data type curation.

Thank you for continued support!