John Postlethwait is fascinated by how zebrafish offspring depend on their mom’s genome to get things started. In a study published in the May issue of G3: Genes|Genomes|Genetics, Postlethwait and co-author Catherine Wilson delve into the unique features of the zebrafish sex chromosome, identifying a maternal-to-zygotic-transition (MZT) gene regulatory block.

Zebrafish females are either ZW or WW. ZZ zebrafish are always males, but some fish with a W can sex-reverse to become males. Although sex-biased gene selection is important for understanding characteristics such as sexual dimorphism, little is known about the distribution of sex-biased genes along fish chromosomes.

To learn more about zebrafish sex-biased genes, Wilson and Postlethwait harvested gonads from male and female Nadia-strain zebrafish at three months post-fertilization and performed RNA-seq to compare gene expression patterns in females versus males. Differentially expressed (DE) genes were evaluated with DESeq2 software.

They also analyzed gonads from laboratory strain AB. After several generations of gynogenesis, these fish lack sex chromosomes. Analyzing gonads from AB fish allowed the authors to rule out sex determination as a means of ovary-specific gene silencing.

As expected, substantially more genes showed testis-biased than ovary-biased expression (10,495 to 6,557, respectively). DE genes aligned with these proportions across the genome—with the exception of Chr4, the sex chromosome. Chr4’s long right arm, Chr4R, was cytogenetically and transcriptionally unique. In fact, about 80% of Chr4R genes have no human orthologs.

Importantly, their analysis revealed that a long block of sex chromosome Chr4 features not only the unique silencing of protein-coding genes in egg cells but also encodes RNA molecules for maternal-to-zygotic transfer necessary for making proteins and eliminating the mother’s transcripts.

All egg-laying animals—including, to some extent, humans—begin development using maternally-produced RNA and proteins, which means some embryonic phenotypes depend on the mother’s genotype rather than the embryo’s. The MZT marks the point when the embryo begins to rely on its own RNA and proteins, and it requires complex gene regulation changes.

In contrast to much of the rest of the genome, Chr4R is mainly heterochromatic. Surprisingly, transcription in ovaries was suppressed for nearly all protein-coding genes in this region but still occurred in testes.

This area of suppressed ovary-biased transcription is involved in the MZT transfer of components such as ribosomes and spliceosomes that kickstart embryonic development following fertilization. An adjacent genomic area removes maternal transcripts when the zygote reaches the 1,000-cell stage. 

The study found that gonads from the AB strain followed the same general expression pattern as those from Nadia fish, meaning ovary-specific gene silencing must be related to gonad development, function, or both—not sex determination.

Postlethwait explains that this study lays some groundwork for egg quality research. Pollutants may affect egg quality, and studying non-placental zebrafish makes toxicological effects easier to uncover. Extrapolating such effects to humans requires understanding, among other things, the balance and mechanisms of ovary- and testis-biased expression in developing and adult zebrafish.

Don’t miss the opportunity to hear these outstanding scientists discuss their work. Access the full conference schedule online.

C. elegans 

Sydney Brenner Award

Sneha Ray 

Fred Hutchinson Cancer Research Center  

The Sydney Brenner Dissertation Thesis Award is presented to a graduate student who has completed an outstanding PhD research project in the area of genetics and genomics of C. elegans.

Drosophila 

Larry Sandler Award

Sherzod Tokamov

University of California, Berkeley

The Larry Sandler Award is presented to outstanding recent graduates who have completed a PhD in an area of Drosophila research. The award serves to honor Dr. Sandler for his many contributions to Drosophila genetics and his exceptional dedication to the training of Drosophila biologists. 

Mammalian 

IMGS President’s Award

Jason Bubier

The Jackson Laboratory for Mammalian Genetics

This new award, the IMGS President’s Award, is presented to an early career scientist in recognition of their exceptional accomplishments in independent research in mammalian genetics. The award celebrates their contributions both to the IMGS and the field of genetics as a whole.

Population, Evolutionary and Quantitative Genetics (PEQG) 

James F. Crow Early Career Researcher Award

Olivia Harringmeyer

Harvard University

The James F. Crow Early Career Researcher Award is presented to students and recent PhDs conducting PEQG research. The award serves to honor Professor James F. Crow and his numerous, impactful contributions to the field of genetics. 

Yeast 

Angelika Amon Award

Xiaoxue Snow Zhou 

New York University

The Angelika Amon Award is presented to an outstanding recent PhD graduate. The award serves to honor Dr. Amon for her many discoveries through the use of yeast genetics, and her exceptional dedication to training and mentorship.

Zebrafish 

International Zebrafish Society Genetics Trainee Award

Mollie Sweeny 

Duke University 

The International Zebrafish Society Genetics Trainee Award recognizes excellence in research, in particular discoveries leading to significant scientific or technological advances through the use of zebrafish genetics.

Anna Moyer

Accessibility Subcommittee

University of Alabama at Birmingham

Research Interest:

I don’t remember very much about the birth of my little brother. I remember the way the light flickered onto the diamonds of the carpet as I wished for a new sibling, while spinning in wild circles and holding my older brother’s hands before toppling to the ground. I remember the excitement leading up to his birth, when I knew that I was going to be an older sister. And I remember my disappointment reflected in the picture window, nose to glass, expecting my parents’ arrival from the hospital.

I remember my mother’s tears, and I remember seeing my baby brother and thinking that he was perfect, although a little more wrinkly than I thought he would be. Then the mantra, “Sam has Down syndrome, which means that he has an extra chromosome. He just takes longer to learn things.” After all, how do you explain trisomy 21 to a three-year-old?

As we grew, I learned more about the challenges my brother would face as a person with Down syndrome. Although the median age at death for people with trisomy 21 has increased from just 1 year in 1968 to 49 years in 1997, there are still no FDA-approved treatments for Down syndrome-associated intellectual disability. And as the lifespan of people with Down syndrome continues to increase, more adults with Down syndrome will face the devastating consequences of Alzheimer’s neuropathology and dementia. Despite its status as the most common genetic cause of intellectual disability, affecting 1 in 700 births worldwide, Down syndrome has received relatively little attention from the genetics research community.

Inspired by my brother’s experiences, I completed my PhD in the lab of Dr. Roger Reeves at the Johns Hopkins School of Medicine. My doctoral research focused on abnormal sonic hedgehog signaling in neuronal precursors isolated from a Down syndrome mouse model. To understand which trisomic genes contribute to abnormal brain development, I overexpressed a library of 163 human chromosome 21 genes in a series of sonic hedgehog-responsive cell lines. Whereas previous studies have attempted to link a single trisomic gene to a single Down syndrome-associated phenotype, we found that many chromosome 21 genes may contribute to the dysregulation of a central signaling pathway. These results are significant because they reframe Down syndrome as a complex genetic disorder and suggest that targeting a shared molecular pathway for therapeutic intervention may be more effective than targeting a single chromosome 21 gene.

For my postdoctoral research, I plan to follow up on hits from my overexpression screen using the larval zebrafish model system. Dr. Summer Thyme pioneered a method for high-throughput brain activity and morphology screening of genes linked to neurodevelopmental disorders. We will apply this screening approach to Down syndrome by generating transgenic zebrafish that overexpress the fish orthologs of human chromosome 21 genes. Establishing zebrafish as a Down syndrome model will pave the way for high-throughput drug screens, which are technically challenging in existing animal models of Down syndrome.

As a PhD-trained scientist, you have many career options. What interests you the most?

Witnessing the divide between researchers and patient advocates early in my graduate career crystallized my goal to bridge the gap between people with Down syndrome and the scientists who study them. My ultimate goal is to direct a Down syndrome research lab that spans basic and preclinical research. In particular, I want to center the experiences of people with Down syndrome and their families and use their insights to inform basic research. Although collaboration between patients and scientists has become more common, working effectively with a population that has historically suffered from a lack of self-advocacy and self-determination remains challenging. People with Down syndrome and their families represent an untapped resource for cataloging Down syndrome phenotypes and understanding which outcome measures are most important to the individuals that treatments aim to benefit.

I occupy a unique position as a scientist and sibling of a person with Down syndrome. As a scientist, I am drawn to Down syndrome research for its enormous complexity and seeming intractability. My intellectual curiosity drives my desire to understand Down syndrome at the cellular and molecular levels. At the same time, I understand the pressing need to advance discovery in Down syndrome research, given the lack of effective treatments for many Down syndrome-associated phenotypes, including intellectual disability, acute regression, Alzheimer’s neuropathology, and dementia. I hope that my desire to engage with Down syndrome populations also marks a generational shift in how scientists interact with society and communicate new research findings.

In addition to your research, how do you want to advance the scientific enterprise?

Although I identify as a scientist with a disability, I chose to hide the effects of my connective tissue disorder from my colleagues until the unexpected death of a classmate highlighted the importance of advocating for other students with disabilities, chronic illnesses, and mental health conditions. After disclosing my condition more publicly, I founded a committee at the Johns Hopkins School of Medicine to support other students with these conditions. I conceived and implemented an ongoing lecture series featuring disabled scientists and clinicians, including Dr. Kay Jamison, Dr. Chad Ruffin, and Dr. Bonnielin Swenor. I also organized events to connect students with disabilities across the university, such as film screenings, book clubs, and happy hours.

Networking with other students lessened my own sense of isolation and brought to light the rampant academic ableism that systematically excludes disabled scientists from top research institutions. Limited access to affordable healthcare options disproportionately affects trainees with chronic illnesses; students accumulate thousands of dollars of medical debt while in graduate school. Disabled students may face discrimination based on preconceived perceptions of ability; students are forced to switch labs after disclosing mental health conditions to their thesis advisors. The culture of overwork that celebrates long days in the lab may aggravate chronic health conditions; students feel pressured to choose between their health and their scientific productivity.

While some aspects of accessibility are relatively straightforward to implement, such as providing ASL interpretation or large-print materials, improving the culture and climate surrounding disability will require sustained and intentional advocacy. As a scientist-in-training, I hope to advance the scientific enterprise by making academia a safer place for disabled students, who deserve the same support afforded to other underrepresented groups in science and medicine.

As a leader within the Genetics Society of America, what do you hope to accomplish?

Disability is a facet of diversity, and disabled scientists possess invaluable insights into living with the conditions that scientific research aims to treat. As a member of the Early Career Leadership Program, I hope to contribute to the genetics community by advocating for policies that provide equal access to trainees with disabilities. Although individuals with disabilities are underrepresented in biomedical research, trainees with disabilities may not disclose their conditions due to fears of discrimination or mistreatment. This lack of disclosure may hamper community-building between disabled trainees, leaving them feeling isolated and without disabled mentors. Improving the climate surrounding disability in academia is a necessary first step toward allowing disabled trainees to feel safe enough to disclose their conditions.

As a member of the Accessibility Subcommittee, I hope to work towards replacing the question of “How can we make the genetics community more accessible to disabled trainees?” with “What do disabled trainees offer the genetics community?” While the first question focuses on fulfilling minimum legal requirements for accommodations, the second highlights the value of including the perspectives of scientists of all identities, including those with disabilities. Specifically, the Genetics Society of America can support disabled scientists through the following initiatives:

• Improving the accessibility of conferences and other events. COVID-19 has offered both challenges and benefits to scientists with disabilities, and I am interested in understanding how lessons learned from the pandemic can be used to maximize accessibility in the future. As life returns to pre-pandemic “normal,” we must guarantee that disabled scientists who remain at high risk from COVID-19 have access to hybrid/virtual conference options.
• Building community for trainees with disabilities, chronic illnesses, and mental health conditions. Community-building may allow disabled scientists to feel less isolated and share practical ideas for navigating the disability experience in the lab.
• Including disability in existing diversity initiatives. Despite data showing that scientists with disabilities are underrepresented in biomedical research, existing diversity initiatives do not always mention disability along with other aspects of identity.
• Promoting the visibility of successful scientists with disabilities. Highlighting the successes of senior scientists may show students and postdocs that it is possible to have a productive career while navigating the challenges of disability in academic science.
• Challenging the medical model of disability that is implicit in much of genetics research. Most translational research proceeds under the assumption that genetic diseases should be treated, but some disabled individuals may actually take pride in their conditions. Drawing attention to the diverse perspectives of disabled people on treatments for genetic conditions will help to center the patient experience in genetics research.

Previous leadership experience

• Co-founder of Equal Access in Science and Medicine committee, which advocates for disabled trainees in the Johns Hopkins School of Medicine
• Creator of Accessible Chef, a website of visual recipes to teach basic cooking skills to individuals with intellectual disabilities
• 2021 inductee of the Edward A. Bouchet Graduate Honor Society
• Recipient of the Johns Hopkins Diversity Leadership Award, Johns Hopkins National Disability Employment Awareness Month Award, and Johns Hopkins Accessibility & Inclusion Student Group Award

You can contact Anna Moyer by email at anna.moyer@gmail.com, on Twitter @annajoycemoyer, or on LinkedIn @annajmoyer.

Guest post by Jennifer Tsang.

Years ago, Sarah Edie and Norann Zaghloul pored over 50,000 zebrafish embryos, examining them for developmental phenotypes. They had previously injected each of these embryos with a plasmid expressing a gene from chromosome 21. Their goal was to understand how overexpression of specific genes on chromosome 21 affected early development¹.

Little did they know that their research would become an important resource for COVID-19 research.

Sharing plasmids to the research community

At the time, Edie was a member of Roger Reeves’s lab at Johns Hopkins University School of Medicine where he studied Down Syndrome, and Zaghloul was a postdoc in Nicholas Katsanis’s lab. The team created a library of 164 plasmids—each expressing a different gene from chromosome 21—for the study, and they published their work in the Genetics Society of America’s journal, G3: Genes|Genomes|Genetics. 

“We knew from the time we decided to do the experiment that making this available to the larger research community would be one of the goals of the experiment,” says Reeves. The lab deposited each plasmid with Addgene, the nonprofit plasmid repository that would then distribute the plasmids to researchers.

“We thought primarily people who were involved in Down Syndrome research would be interested in these [plasmids],” says Reeves. Addgene sends a monthly report to depositing labs summarizing the requests they get for their plasmids. “It’s been very interesting to get the monthly report and see the people who are asking for these,” says Reeves. Requests have come from researchers around the world, some work in Down Syndrome and some do not.

From developmental studies to COVID-19

When the COVID-19 pandemic hit, Reeves began to survey genes on chromosome 21. Along with other members of the Trisomy 21 Research Society, he was interested to see if there were ways in which people who have trisomy 21 might be more susceptible or more resistant to the effects of the virus. The first coronavirus paper he read about the biology of SARS-CoV-2 mentioned TMPRSS2. “I said, ‘Wait a minute, that’s on chromosome 21,’” Reeves recalls. TMPRSS2 also happened to be one of the genes Edie and Zaghloul expressed in zebrafish and deposited at Addgene.

During SARS-CoV-2 infection, TMPRSS2 cleaves the SARS-CoV-2 spike protein which is required for viral and cellular membrane fusion. Without cleavage by TMPRSS2, the SARS-CoV-2 virus cannot enter host cells. As research labs shifted to COVID-19 research, Addgene began receiving requests for the TMPRSS2 plasmid. With 175 requests since the beginning of the pandemic, it has become one of the most asked for plasmid for COVID-19 research.

This plasmid is a great example of how two seemingly disparate fields share reagents and how open science allows for a broad reach. Another plasmid generated from the zebrafish study was also used in acute myeloid leukemia research. While researchers looking for these reagents are from different fields than the original study, they were able to find these resources through a centralized source.

This isn’t the only time that reagent sharing through a centralized repository has accelerated the speed of research during the COVID-19 pandemic. A mouse strain containing the hACE2 receptor that allows it to be infected with human SARS-CoV was deposited at Jackson Laboratory in 2007, meaning that scientists could easily get the mice for COVID-19 research. 

At Addgene, things are no different. Plasmids deposited from research into the 2003 SARS outbreak were already in the repository at the start of the COVID-19 pandemic. CRISPR plasmids deposited in the last few years have also become an important resource for developing CRISPR-based assays for detecting SARS-CoV-2 RNA and nucleic acids from other pathogens. The future of shared materials stored in repositories may be unpredictable at the time of depositing, but these materials have many possibilities.

1. G3: GENES, GENOMES, GENETICS July 1, 2018 vol. 8 no. 7 2215-2223

A Wnt protein involved in the formation of the human ovary plays an important role in female zebrafish sex development.   

Even though zebrafish are a well-studied research model, how these fish develop into males or females remains rather obscure—in part because the sex of lab strains is not determined by sex chromosomes. Research published in GENETICS reveals that one of the genes critical for proper development of mammalian ovaries seems to play a related role in zebrafish, providing insight into this major difference between fish and mammals.

In humans and other mammals, Wnt4 encodes a signaling molecule that antagonizes the male-promoting signal FGF9 and is crucial to the proper development of the ovaries. Though they lack an Fgf9 ortholog, zebrafish have two Wnt4-like genes—wnt4a and wnt4b—so Kossack et al. investigated whether these genes might play a role in zebrafish sexual development.

The authors first performed a phylogenetic analysis to better understand how the Wnt4-like genes have changed over evolutionary time. Zebrafish have two such genes, while mammals only have one, so two evolutionary scenarios are possible: either fish gained an extra copy of the gene, or mammals lost a copy that was originally present. The authors found that the latter scenario is more likely; both reptiles and birds have two such genes, making it more likely that  mammals lost one of their copies. Further analysis revealed that wnt4a is likely the ortholog of mammalian Wnt4, whereas wnt4b was lost in mammals after they split from birds.

The authors next used RT-PCR to examine the expression patterns of the two genes. They detected wnt4a, but not wnt4b, in the ovaries of female zebrafish. In contrast, only wnt4b was detected in the testis of male fish. They also found that wnt4a was dynamically expressed in gonads during development in a non-sex-specific manner.

Fish mutant for wnt4a develop predominantly—though not exclusively—as males, which supports the idea that wnt4a is involved in either differentiation into a female or the maintenance of a female phenotype throughout development. Analysis of mutant embryos during development suggests that wnt4a likely promotes female development since most mutant embryos developed as males rather than “reverting” to males from an initially female phenotype.

Interestingly, wnt4a mutants were unable to produce progeny when mated to each other or to  wild-type. Closer inspection revealed that wnt4a-mutant fish of both sexes had malformed reproductive tracts. Even though viable eggs and sperm could be obtained from their gonads, mutant fish were unable to release their gametes, preventing them from reproducing.

These findings suggest that Wnt4-like genes have been involved in female development of a diverse array of animals—including our fishy ancestors that swam the oceans some 450 millions year ago.

CITATION:

Female Sex Development and Reproductive Duct Formation Depend on Wnt4a in Zebrafish

Michelle E. Kossack, Samantha K. High, Rachel E. Hopton, Yi-lin Yan, John H. Postlethwait, Bruce W. Draper

GENETICS January 2019 211: 219-233; https://doi.org/10.1534/genetics.118.301620

http://www.genetics.org/content/211/1/219

Yeast and zebrafish are among the lab organisms being recruited to the search for rare disease cures.

Rare diseases are not so rare. About 300 million people worldwide live with the more than 7000 individual diseases that are designated “rare” by the US government. But because each of these affect so few individuals, the usual resources and research that lead to new treatments are not available. That’s why scientists have had to get creative.

Studying organisms that may at first glance seem totally unrelated to humans is proving an important tool for understanding and finding treatments for rare disease. In a review in GENETICS, Strynatka et al. outline the ways in which laboratory model organisms are paving the way for life saving therapies, with a particular emphasis on baker’s yeast and zebrafish. Check out the review to learn more about the ingenious methods being applied, but in honor of Rare Disease Day, we’d like to highlight a couple of examples of model organism studies aiding the search for new therapies.

The yeast Saccharomyces cerevisiae has long been a powerful tool for studying the workings of the cell. As a eukaryote, S. cerevisiae shares many genes with humans and other animals, but it is a single-celled organism, so it can be more rapidly studied. Investigations in yeast demonstrated that a gene that is overexpressed in the aggressive childhood cancer rhabdomyosarcoma results in chromosomal instability. This instability made the yeast cells sensitive to drugs that are histone deacetylase inhibitors. Thanks to these insights from yeast, FDA-approved drugs in this class could one day prove useful for treating this rare cancer.

Clues to a treatment for Duchenne muscular dystrophy (DMD), an uncommon but severe disease, were uncovered using the zebrafish Danio rerio. Zebrafish can be grown quickly and boast transparent embryos that provide a remarkable window into body development. The zebrafish model of DMD harbors a premature stop codon in the homolog of the gene dmd, mimicking the human disease. This model led to the discovery that treatment with ataluren, an antibiotic, can promote read-through of this mutant stop codon. In 2014, ataluren was approved for clinical use in DMD by the European Medicines Agency.

Yeast and zebrafish have even been used in concert to identify new ways to treat rare disease. Mutations in the gene SLC25A38 cause a form of congenital sideroblastic anemia that has no effective treatment. This gene’s function remained unknown until studies in yeast showed that it transports glycine into the mitochondrion for heme synthesis. Giving mutant yeast extra glycine allowed them to produce heme at normal levels, “curing” the yeast version of the disease. However, extra glycine did not rescue heme production in zebrafish with a homologous mutation. It turns out that this disparity was due to different folate pathways in the two models. Yeast are able to synthesize folate on their own, whereas animals, like zebrafish and humans, must consume it in their diet. Giving the mutant zebrafish both glycine and folate restored heme production. These results suggested a new avenue for treatment using simple nutrients, rather than costly drugs. Further studies of the pathway in another model organism, the mouse, may reveal more about how to translate this treatment from the fish tank to clinic.

CITATION:

How Surrogate and Chemical Genetics in Model Organisms Can Suggest Therapies for Human Genetic Diseases 

The Genetics Society of America (GSA) is pleased to announce that Steven Farber and Jamie Shuda are the recipients of the 2018 Elizabeth W. Jones Award for Excellence in Education for their extraordinary contributions to genetics education. Farber is a principal investigator at the Carnegie Institution for Science, and Shuda is Director of Life Science Outreach at the University of Pennsylvania’s Institute for Regenerative Medicine.

Left: Jamie Shuda. Right: Steven Farber.

Farber and Shuda are recognized for their creation of an outreach program called BioEYES, which provides K–12 students with hands-on biology experience using live zebrafish. The flagship program brings fish—and the tools to study them—into the classroom for an entire week, during which time students observe much of the fish’s life cycle, from mating to the hatching of larvae.

The selection of zebrafish for the program is a key factor behind its success. Farber recognized that the zebrafish, in addition to being an important model organism in genetics, has several other traits that make it ideal for the classroom. Students are captivated by working with live, moving animals, and it reassures the students that, because the fish are clear, they can be studied with the provided microscopes without harming them. Also, as vertebrates, zebrafish have many body parts in common with humans, and their development can easily be compared to human development. Once the larvae hatch, students can even observe their beating hearts.

In addition to Project BioEYES, the program has expanded to include a new project called Your Watershed, Your Backyard, in which middle-school students grow zebrafish embryos in water samples from their own local watershed to test the effects of pollution. Although this new program is only available in the Baltimore area, Project BioEYES itself is also available in Philadelphia, Salt Lake City, and Melbourne. Recently, BioEYES reached its 100,000^th student, and the program continues to grow.

“BioEYES is an innovative program that harnesses the powerful fascination most of us feel when observing living, behaving organisms and developing embryos,” says Allan Spradling, a researcher at the Carnegie Institution for Science and a Howard Hughes Medical Institute investigator. “It works well with students from all types of economic and cultural backgrounds because interest in and curiosity about life and reproduction is universal.”

GSA named the Elizabeth W. Jones Award for Excellence in Education in honor of the first GSA Excellence in Education Awardee, Elizabeth W. Jones (1939–2008). The Award recognizes a person or group whose efforts have made a “significant, sustained impact on genetics education at any level.” The prize will be presented to Farber and Shuda at the 59^th Annual Drosophila Research Conference, which will take place from April 11^th–15^th, 2018 in Philadelphia.

The prolonged and severe seizures suffered by those with pyridoxine-dependent epilepsy (PDE) can lead to brain dysfunction and death if not treated. Standard antiepileptic drugs are typically ineffective for people with this rare genetic disorder—instead, they need high doses of vitamin B6 in the form of pyridoxine or pyridoxal 5′-phosphate. But even with this supplementation, people with PDE often have lingering problems, and over 75% experience neurodevelopmental delays.

Although more than sixty years have passed since PDE was first described, and treatment remains inadequate for resolving all the condition’s comorbidities, little is known about the pathophysiology of PDE. This is partially because no animal model has been available to study PDE—until now. In this month’s issue of GENETICS, Pena et al. report that they have generated zebrafish with mutations in the same gene that causes PDE when mutated in humans. This gene, ALDH7A1, encodes an enzyme called antiquitin, which is important for the breakdown of the amino acid lysine.

The researchers used CRISPR/Cas9-based gene editing to alter the fish version of the gene, rendering it nonfunctional. They found that fish carrying two damaged copies of the gene develop recurrent seizures at an early age, just like humans with PDE do. Without intervention with vitamin B6, the fish’s seizures result in death. The fish also have the same biochemical abnormalities as humans with PDE do, including a buildup of toxic lysine byproducts. The researchers also found several other previously unknown biochemical abnormalities in the fish’s brains, which may help understand the disorder.

The fact that these fish recapitulate human PDE so well—at both the biochemical and organismal levels—will make them a valuable model for further studying the condition. Not only are zebrafish commonly used model organisms with a multitude of tools available for manipulating their genetics, they’re also often used in epilepsy research with many established protocols for studying the topic, making them an ideal choice for investigating this challenging disorder.

CITATION:

Pena, I.; Roussel, Y.; Daniel, K.; Mongeon, K.; Johnstone, D.; Weinschutz Mendes, H.; Bosma, M.; Saxena, V.; Lepage, N.; Chakraborty, P.; Dyment, D.; van Karnebeek, C.; Verhoeven-Duif, N.; Vu Bui, T.; Boycott, K.; Ekker, M.; MacKenzie, A. Pyridoxine-Dependent Epilepsy in Zebrafish Caused by Aldh7a1 Deficiency.
GENETICS, 207(4), 1501-1518.
DOI: 10.1534/genetics.117.300137
http://www.genetics.org/content/207/4/1501

Model Organism Databases (MODs) and the Gene Ontology Consortium play a crucial “behind-the-scenes” role in the work of model organism geneticists and many other biomedical researchers. This guest post by the newly-formed Alliance of Genome Resources announces the group’s intention to integrate the efforts of the MODs and other genome resources. You can learn more about these plans and the work of the MODs at GSA’s The Allied Genetics Conference in July. Stay tuned for more details!

An Alliance of Genome Resources has been formed to provide better support for the biological sciences via an integration of shared data, standardization of data models and interfaces, and unified outreach to researchers, educators and the public. The initial members of the Alliance are the Gene Ontology Consortium and six model organism databases: Saccharomyces Genome Database, WormBase, FlyBase, Zebrafish Model Organism Database, Mouse Genome Database and Rat Genome Database. The integration of these projects will not decrease the types of data, tools and community support that are currently provided by these resources but rather will provide the best displays and tools currently in use and allow us to efficiently develop new tools in a collaborative manner. As we move toward deeper integration of our content and software we will provide easy-to-use cross-organism queries of the extensive data available in the component resources. Also, future integration of other resources will benefit all biologists.

The Alliance of Genome Resources will continue the tradition of these community resources by enabling researchers to leverage the published results and datasets from well-studied organisms for their daily research. By integrating high-quality expertly curated information, the Alliance will continue to provide researchers access to data, information and knowledge found in published and publicly available sources that would require many lifetimes to assemble.

The modular architecture of modern websites will allow the Alliance to maintain the uniqueness of each research community – and each user – through customization. We will present a common view of information whenever possible. A common website will have distinct entry points for the different communities and tools that will maintain the community-building features of our current resources. By joining the Alliance of Genome Resources, the member organizations pledge mutual support, as well as support of research communities having interests in common with those of the Alliance, with the goal of delivering facile information retrieval for all biologists. We will definitely need your support in obtaining sufficient funding for these efforts.

The first plenary talk at the fast approaching Allied Genetics Conference (TAGC) will be given by Leonard Zon.  His talk is certain to provide an exciting start to the joint meeting sessions.

Zon is the Grousbeck Professor of Pediatric Medicine at Harvard, Director of the Stem Cell Program at Boston Children’s Hospital, and an HHMI researcher. His lab uses zebrafish to study blood and hematopoietic development, as well as related cancers. Among his many contributions to this field, one of his favorites was the identification of the long-elusive yolk sac iron transporter, ferroportin1, which when mutated results in anemic fish. He went on to show that this novel gene was also present in the mammalian placenta, and human patients with mutations in Ferroportin1 had iron imbalance disorders. “It was the first time a zebrafish gene predicted a human disease,” Zon recalls.

            “I really love that [with zebrafish] you have a system where you can see a process in vivo.” Leonard Zon 

During his presentation at TAGC, he plans to highlight three different stories that began in zebrafish, all centered around the common theme of using a model system for the development of therapeutics. This includes discussing a drug that increases blood stem cells, as well as a drug that treats melanoma, both of which are now in clinical trials. He’ll also describe the discovery of a third drug that treats a rare form of anemia.

Zon is especially excited about the variety of model organisms represented at TAGC, and is looking forward to the community building that will come from the experience. “I love going to these conferences,” Zon said. “The GSA has been involved in the zebrafish conferences for the past couple of years, and they put on great meetings. When I look back, the zebrafish meeting has been a very important part of the field, setting the tone for experiments over an every other year period. It’s quite amazing.”

He is also encouraging members of his own lab to not only attend TAGC, but to actively participate. In fact, it is a “lab rule” that anyone attending a conference must submit an abstract. “I do that because it’s very important to have people present their work. Science is about communication, how you give a talk, how you give a poster, how you get people to view your science in a different way,” he said.

Zon’s belief in the importance of communicating science extends to outreach as well. In 2002, as a response to strict restrictions on federal funding for stem cell research, he founded the International Society for Stem Cell Research. Today the society has over 4,000 members, and helps provide a cohesive voice for the stem cell research community to the public, media, and policy makers. “We should be doing everything we can to educate the public,” Zon said. He also stressed the importance of professional societies like GSA in educating the public.

While reminiscing about past conferences, Dr. Zon placed his favorite memories into two categories: science and networking. He recalled both the experience of attending groundbreaking presentations, as well as giving talks of his own. As a postdoc, he was extremely proud to discuss cloning the transcription factor Gata. Zon also fondly remembers myriad social experiences at conferences over the years.e’s met some of his closest friends while attending meetings. “I have many, many stories about everything from great presentations, [for example] watching Shinya Yamanaka give the first lecture on the [iPS cell] reprogramming factors, to hanging out at parties with a bunch of friends. All of these were just wonderful, wonderful experiences,” he recalls.

Though Zon has long been a leader in the zebrafish community, he advises young scientists to pursue as many diverse experiences as possible because it is difficult to predict the direction a career will take. “If you had told me as a postdoc that I would become a zebrafish researcher, I would have no idea how I got there because during my postdoc I was doing transcription factor biology, and I certainly never came close to touching a fish or a frog,” he said. “You will use all the experiences you’ve ever had when you’re doing my job, so the best is to get a number of diverse experiences so you can draw from those when you’re running your own lab.” He also advises young scientists to put a lot of faith in their mentors, and collect as many as possible. “They will have tremendous impact on your career, and can really help you make the best decisions.”

Kristin Fenker

About the author: Kristin Fenker is a graduate student in the Human Genetics Department at the University of Utah, where she studies genes involved in C. elegans sperm development. She also has a passion for science communication, in particular improving public understanding of science.