We’re taking time to get to know the members of the GSA’s Early Career Scientist Committees. Join us to learn more about our early career scientist advocates.

Daniela C. Soto
Communication and Outreach Subcommittee
University of California, Los Angeles

Research Interest

What genetic changes underlie our uniquely human traits and behaviors? In the last couple million years of evolution, some fascinating changes took place that make us who we are. My quest as a scientist is to uncover the genes responsible for these phenotypic changes, including their functions, their regulation, and their history. I am a bioinformatician that analyzes tons and tons of data and uses computation, statistics, and biology to make sense of it. During my PhD, I analyzed thousands of human and great ape genomes in search of neurodevelopmental genes that underwent dramatic or subtle changes during the last six million years of evolution, leading to the expansion of the neocortex. This research not only sheds light on our evolutionary history but also has clinical and therapeutical implications. Some neurodevelopmental genes are associated with neurodiversity traits, and their characterization will help us better understand the underlying architecture of the neurodiverse brain, leading to more effective medical and societal approaches.

But we’ve learned many of our human characteristics are not so unique. Some complex behaviors emerged a long time ago and are shared with our fellow mammals. We can learn a lot, for example, about human attachment from the prairie vole, a rodent that has “pair-bonding,” a scientific term akin to love. During my PhD, I was part of the reconstruction of the prairie vole genome, which will be used to look for the genomic changes that led to pair-bonding. Not only can rodents teach us about love, but they can also help us learn about our minds too. In my incoming postdoctoral position, I will use the mouse as a model organism to study depression, one of the most complex and prevalent neuropsychiatric disorders in our modern society. Depression research has the potential to impact millions of lives down the line by enabling better diagnosis and novel therapeutics. Considering the influx of data enabled by the ever-evolving sequencing technologies, there is no better time to interrogate our genomes.

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

My dream is to lead my own research group. Per Richard Feynman’s advice, I have a series of favorite questions always in my mind that I want to tackle. I am especially interested in the workings of our brain and the interplay between genetics and complex human traits and behaviors. My focus is on humans and other great apes, but I believe in the power of animal models and “natural laboratories” to deepen our knowledge of our mammal brains. I am also interested in leveraging the newest technologies; I want to use state-of-the-art genomic sequencing to explore the darker regions of the genome, including structurally variant loci and repeats that have been overlooked before due to technical limitations.

I have a deep admiration for academia, the pursuit of knowledge, the development of innovations, and the training of new generations. That being said, I am always amazed by the wide array of biotechnological and biomedical research taking place in the United States and its tangible impact in society. We saw it firsthand, for example, with the development of the mRNA vaccines during the COVID pandemic. Considering the cutting-edge research occurring in the private sector, I can see myself answering my favorite questions in that context as well.

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

For me, pursuing an academic career has a scope beyond science; it is also a matter of representation. I identify as a Latino woman. (I am Chilean!) Unfortunately, women are underrepresented in bioinformatics and Latino women even more so. In my journey to become a principal investigator, I want to openly advocate for a more welcoming field for young women and other underrepresented groups. I am deeply thankful for the role models that have cleared the path for me in this field, and I strive to pay it back by advocating for the next generations.

Besides my advocacy within academia, I also believe it is important to make science (and genetics) approachable and entertaining for broader audiences. One of my hobbies is listening and reading pop-science books and podcasts. This type of content has tremendous potential to introduce scientific ideas and discoveries to people who otherwise would not have that opportunity. During my academic career, I aim to become an excellent science communicator and writer, using approachable language and entertaining narratives to drive passions for science in young minds of diverse backgrounds. In the long run, I believe this simple approach can attract a more diverse pool of people to our field.

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

I applied to the ECLP because I admire how the program provides complimentary training that scientists might not get otherwise. Academic research often keeps us extremely busy, and we might neglect to develop soft skills that would help our career and enable us to self-actualize. When joining the program, I had the simplest of goals: meet other people passionate about science communication and learn from them. I was not wrong. This was the right place. In my team, there is a group of people generating social media science content about the many funny little details of the wet lab, providing entertainment while demystifying science research for the general public. Others are writing blog posts or generating databases with home experiments for everyone to try from the comfort of their homes.

My own passions align with the team. I want to share the awe of science with general audiences. I believe that if we share science broadly, it will reach the ears of curious kids from historically marginalized groups who might see for the first time a place for themselves in STEM. But science, especially genetics, is hard to share with general audiences, let alone kids! How can we make genetics approachable and fun for kids and teenagers? My goal as a member of the Outreach and Communication Subcommittee is to develop content and material to tackle this issue. I am generating educational science content for families and kids to introduce them to genetics concepts, like illustrations and coloring pages, to provide as resources for the community.  

Previous leadership experience

• Student representative in the Integrative Genetics and Genomics Graduate Group at UC Davis as a vice-chair and mentoring coordinator, as well as member of the Diversity, Equity, and Inclusion committee, where we developed and analyzed a survey assessing diversity and climate in our graduate group.
• Mentor at the UC Davis Biochemistry and Molecular Medicine-Sacramento Charter High School summer research program.
• Volunteer in charge of generating graphics material for the Chilean Bioinformatics Symposium, the Northern California Computational Biology Symposium, the Chilean Society of Plant Genetics, and several other conferences and scientific communities.
• Instructor and panelist in initiatives to provide bioinformatics training to students in the United States and abroad, such as the Central Asia Pacific Genomics Workshop and the California Undergraduate Bioinformatics Virtual Conference.
• Volunteer in the Chilean chapter of Girls in Tech.

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.

AP-2 transcription factors, which control sleep in flies and worms, are confirmed to do the same in mammals.

Humans are not alone in their deep need for sleep. Almost all animals, even tiny nematode worms and fruit flies, suffer when deprived of their Z’s, but little is known about how sleep is controlled. New work published in GENETICS advances our understanding of this mysterious physiological state by pinpointing a key gene family that affects sleep architecture.

Two research groups independently conducted parallel studies on neural crest-derived AP-2 transcription factors in mice. Their work demonstrates that the associated genes play a conserved role in mammalian sleep, though there is some evolutionary divergence and added complexity in mammals compared to invertebrates.

From Worms to Mice

Henrik Bringmann leads the Max Planck Research Group on Sleeping and Waking. In 2013, his laboratory screened C. elegans worms for mutations affecting sleep. AP-2 deletion mutants showed no detectable sleep, suggesting these transcription factors are important regulators of the process. In 2016, Bringmann led another study showing that AP-2 transcription factors are also needed for sleep in Drosophila. 

“Sleep appears to have evolved at least 600 million years ago and has been conserved since then, which suggests that many fundamental principles of sleep regulation are conserved,” said Bringmann. “This said, sleep is more complex in humans than in worms or flies, so we need mammalian models to understand additional levels of complexity.”

The researchers’ next step was to establish whether a similar sleep-regulating role is played by related genes in mammals, the TFAP2 genes. In their most recent study, the team generated mice that were heterozygous knockouts for either Tfap2a or Tfap2b and compared each mutant to wild-type littermates. In addition to analyzing sleep duration and brain waves, they examined symptoms of sleep deprivation such as memory loss and stress resistance.

Since the AP-2 transcription factors promote sleep in invertebrates, researchers initially expected that the equivalent genes would also promote sleep in mice. They were therefore surprised to find that while losing Tfap2bfunction reduced both sleep quality and quantity, Tfap2a mutants slept for the typical amount of time and the quality of their sleep was actually higher than wild-type. This result suggests that the function of AP-2 transcription factors has diverged over the course of evolution, perhaps to allow sleep quality to be fine-tuned in either direction.

Working Backwards from Human Disorders

Meanwhile, another research group also published an article in the same issue of GENETICS examining the effects of two specific TFAP2B mutations in mice. Yu Hayashi of Kyoto University  and University of Tsukuba said his lab was inspired to pursue this avenue of research by a paper in PNAS. That study described multiple human families with mutations in TFAP2B that are associated with a rare disorder known as Char syndrome. Two of these families exhibited symptoms of disordered sleep, including sleepwalking and extremely shortened sleep.

“We were astonished to read about a family that slept just two to three hours per night and had no signs of fatigue. We thought that maybe analyzing this gene can help us understand what sleep is for in the first place,” said Hayashi. “We even thought that maybe this mutation might somehow substitute for the function of sleep. Could there be a way to help humans need less sleep?”

To answer these questions, Hayashi’s team set out to replicate those families’ specific TFAP2B point mutations in mouse models. They measured both how long the mice stayed awake and the duration of different sleep phases compared to wild-type mice and heterozygous knockouts. The results showed that TFAP2B helps determine the amount of nonrapid eye movement sleep (NREMS). However, the effects of the point mutations in mice did not match the symptoms observed in humans—the mice did not sleepwalk or show dramatically shortened sleep.

In the mice that carried the same mutation as the human family with short sleep, female mice showed fragmented sleep, while male mice did not. This result was unforeseen because there was no reported gender difference in the human family. “It was surprising for me to see the gender difference,” said lead author Ayaka Nakai, a graduate student in the Hayashi lab. It is possible that future research may uncover sex differences in sleep regulation.

In terms of generating a model of fatigue-free short sleep, the results did not match their initial hopes—sleep was reduced overall in heterozygous mutant mice, but it was generally fragmented rather than shortened. However, the results clearly established TFAP2B’s important role in sleep architecture and laid the groundwork for learning more about how sleep works.

Next Steps

Ultimately, said Bringmann, “it was satisfying to hear that both approaches converged on the same conclusions regarding TFAP2B’s role in sleep.” Together, these two papers establish that AP-2 transcription factors contribute to sleep control in mammals—just as they do in flies and worms.

The gene’s evolutionary conservation is a key lesson from the study, said Nakai.

For Nakai and Yu, the next research step is creating knockdown mice that have Tfap2b downregulated only in the nervous system. This will allow them to observe the neural effect of a homozygous loss-of-function mutation, which is developmentally lethal if the knockout is genome-wide. Studying a homozygous knockdown may offer clearer insights into how the gene affects neuron specification and activity.

Next, Bringmann is interested in examining other mammalian AP-2 paralogs, but he says invertebrates will continue to be important for identifying other genes that contribute to sleep regulation. “Going back and forth between different models will be the future of sleep research for the next years, and this will be facilitated by looking at homologous genes and conserved principles.”

CITATION:

Functional Divergence of Mammalian TFAP2a and TFAP2b Transcription Factors for Bidirectional Sleep Control

Yang Hu, Alejandra Korovaichuk,  Mariana Astiz, Henning Schroeder, Rezaul Islam, Jon Barrenetxea, Andre Fischer, Henrik Oster and Henrik Bringmann

GENETICS 2020 216: 735-752. 

https://doi.org/10.1534/genetics.120.303533

Sleep Architecture in Mice Is Shaped by the Transcription Factor AP-2β

Ayaka Nakai, Tomoyuki Fujiyama, Nanae Nagata, Mitsuaki Kashiwagi, Aya Ikkyu, Marina Takagi, Chika Tatsuzawa, Kaeko Tanaka, Miyo Kakizaki, Mika Kanuka, Taizo Kawano, Seiya Mizuno, Fumihiro Sugiyama, Satoru Takahashi, Hiromasa Funato, Takeshi Sakurai, Masashi Yanagisawa and Yu Hayashi

GENETICS 2020 216:753-764

https://doi.org/10.1534/genetics.120.303435

A new genome assembly for Antarctic fur seals sheds light on their historic comeback after 19^th century hunting.

In the late 19^th century, the Antarctic fur seal was thought to be effectively extinct. After over a century of overexploitation driven by demand for the seal’s prized pelt, populations at known breeding grounds seemed to have disappeared, making further hunting impossible—and suggesting that the species may even have died out altogether. But in the 1930s, a small breeding population was discovered on South Georgia, a remote island in the southern Atlantic Ocean with no indigenous human inhabitants. Today, the Antarctic fur seal has made a comeback, with a population thought to number as many as two or three million—but a new G3 report by Humble et al. suggests this picture of the seal’s dramatic rebound is incomplete.

As a well-studied species that has undergone a remarkable recovery, the Antarctic fur seal (Arctocephalus gazella) holds great interest for conservation biologists and others seeking to understand the genomic impacts of population changes. In the report, a multinational team of authors describe an improved A. gazella genome assembly and a collection of 677,607 single nucleotide polymorphisms (SNPs), both useful tools for deeper dives into the genetics of the species. Their data also contain clues about how the Antarctic fur seal may have repopulated much of its former range.

Humble et al. found that linkage disequilibrium in A. gazella is on par with that of other vertebrates—a result that may seem strange given that such a severe population bottleneck should increase linkage disequilibrium. However, a separate analysis recently hinted that the population may not have dropped as low as once thought and could have included hundreds of individuals at its minimum. The Antarctic fur seal population also recovered within just a few generations, reducing the amount of time inbreeding and genetic drift would have had to impact linkage disequilibrium.

Although the species has a large, free-ranging population, the researchers found that some individuals were more inbred than others. This may be due in part to the fact that both males and females of the species return to the same breeding grounds each year with great precision—in one study, females were found to return to within one body length of the places they were born. Further, the species is highly polygynous, with one male often siring offspring with over a dozen females in a given season.

Information about fur seal population structure gave the team evidence that A. gazella may have persisted at a small number of the breeding grounds and thus was not limited to South Georgia, where it was first spotted after hunting ceased. Further investigation of how the seal recovered from being critically endangered, including the role of these final holdouts, could provide valuable information to guide conservation of other species facing extinction. And while A. gazella now numbers in the millions, any such insight may one day be important for its preservation, too: climate change and an increase in tourism has begun to put pressure on many Antarctic species, including the resilient fur seal.

CITATION:

RAD Sequencing and a Hybrid Antarctic Fur Seal Genome Assembly Reveal Rapidly Decaying Linkage Disequilibrium, Global Population Structure and Evidence for Inbreeding
Emily Humble, Kanchon K. Dasmahapatra, Alvaro Martinez-Barrio, Inês Gregório, Jaume Forcada, Ann-Christin Polikeit, Simon D. Goldsworthy, Michael E. Goebel, Jörn Kalinowski, Jochen B. W. Wolf, Joseph I. Hoffman
G3: Genes, Genomes, Genetics 2018 8: 2709-2722; https://doi.org/10.1534/g3.118.200171
http://www.g3journal.org/content/8/8/2709

Biologists rely on animal models to answer important questions that can’t be addressed with cells in a dish. Often, these animals are deliberately inbred; a less diverse population of animals means that data obtained from experiments with these animals will be less noisy and easier to interpret, so fewer animals are needed for meaningful results. Other “non-model” organisms like hamsters and gerbils are usually outbred. In theory, this means that the animal population being used has greater genetic variation, but in practice, it simply means that siblings are not intentionally mated to create truly inbred strains. In a report published in G3: Genes|Genomes|Genetics, Brekke et al. set out to determine the amount of genetic variation in separate colonies of supposedly outbred Mongolian gerbils (Meriones unguicalatus).

The authors used high-throughput sequencing to identify single-nucleotide polymorphisms (SNPs) in three separate colonies of gerbils. They found that each population had unique SNPs, suggesting genetic divergence between the populations. This is particularly noteworthy because all three colonies were started using gerbils purchased from the same source—so, ostensibly, they should be genetically indistinguishable. The authors point out that the realities of maintaining an animal colony make it impossible for such similarity to be maintained long term; animals are moved, new colonies are started, and logistical and ethical realities all mean that divergence due to genetic drift and founder effects is the rule, not the exception.

That isolated colonies can harbor dramatic genetic differences may contribute to the so-called replication crisis. If two independent researchers believe they are using genetically identical populations—but they’re not truly the same—their results can be inconsistent or unrepeatable. For example, previous reports have stated that genetic diversity in gerbil populations is relatively low, but these reports are biased by divergence in the “outbred” population being studied. While isolated colonies of laboratory animals are susceptible to becoming less genetically diverse, Brekke et al.’s findings suggest that diversity is maintained across many different populations. Effective breeding using different colonies could capture a range of diversity more representative of wild populations.

Although animal models are often described as either “inbred” or “outbred,” perhaps merely labeling a model as “outbred” is misleading. The authors recommend using sequencing to characterize variation within laboratory animal populations before designing studies, allowing the results to be properly interpreted.

CITATION

Malinois dogs are working animals known for being used by the Secret Service to guard the White House. These dogs, a subtype of the Belgian Shepherd breed, are robust, with an average life expectancy of 10-12 years. But some puppies are afflicted by a genetic condition called spongy degeneration with cerebellar ataxia (SDCA). A puppy diagnosed with SDCA quickly loses all coordination and needs to be put down. In the August issue of G3, Mauri et al. report the genetic cause of one type of SDCA, a finding that will allow breeders to eliminate the problem from their lines.

The group previously showed that there is more than one type of SDCA in Belgian Shepherds. They identified causal mutations in one gene, KCNJ10, but that gene didn’t account for all cases of SDCA. In their current study, they examined the genomes of several other affected puppies and found mutations in a gene called ATP1B2. Since this was a different gene than identified previously, they propose to call the new form of the disorder affecting these puppies SDCA2.

ATP1B2 encodes a subunit of the enzyme Na⁺/K⁺-ATPase, a protein complex essential for maintaining ion gradients across the cell membrane. In guinea pigs, inhibiting the enzyme causes seizures and makes the brain take on a spongy appearance, similar to that found in dogs with SDCA. Mice without their version of ATP1B2 also have spongy brains and rapidly progressing motor disturbances. Although no ATP1B2 variants have been found in humans, mutations in genes encoding the other subunits of Na⁺/K⁺-ATPase cause neurological problems, such as certain types of migraines and a fast-onset form of Parkinsonism.

The function of ATP1B2 is also similar to that of the gene that causes SDCA1. Both are involved in maintaining potassium homeostasis—especially in the cerebellum—further substantiating the conclusion that mutations in ATP1B2 are the cause of SDCA2. The evidence presented by Mauri et al. will enable development of genetic tests for both types of SDCA. Now that they’ve found that mutations in ATP1B2 cause SDCA2 in dogs, checking people with family histories of cerebellar disorders without known causes for problems with ATP1B2 might provide insight into previously inexplicable conditions.

CITATION:    

Mauri, N.; Kleiter, M.; Dietschi, E.; Leschnik, M.; Högler, S.; Wiedmer, M.; Dietrich, J.; Henke, D.; Steffen, F.; Schuller, S.; Gurtner, C.; Stokar-Regenscheit, N.; O’Toole, D.; Bilzer, T.; Herden, C.; Oevermann, A.; Jagannathan, B.; Leeb, T.

A SINE Insertion in ATP1B2 in Belgian Shepherd Dogs Affected by Spongy Degeneration with Cerebellar Ataxia (SDCA2).
G3, 7(8), 2729-2737.
DOI: 10.1534/g3.117.043018
http://www.g3journal.org/content/7/8/2729

After surviving breast cancer, almost forty percent of female patients are affected by primary ovarian insufficiency (POI). This condition, in which ovaries don’t produce normal amounts of hormones or release eggs regularly, can result in health problems and an inability to have children. But POI isn’t caused by cancer itself—the actual culprit is DNA damage caused by radiation or chemotherapy. In the August issue of GENETICS, Rinaldi et al. report that the drug CHK2iII can preserve egg cells in mouse ovaries treated with ionizing radiation, suggesting it might one day be used to prevent POI resulting from cancer treatments.

The researchers chose CHK2iII to test because it’s an inhibitor of CHK2, an enzyme they had already showed is involved in a cell death pathway triggered by DNA damage. Their previous work indicated that deletion of the gene for CHK2 protects egg cells from dying after exposure to ionizing radiation, making them suspect that they could also protect egg cells by disabling the protein with an inhibitor like CHK2iII. Promisingly, these egg cells were capable of growing into healthy mice, implying that the DNA damage done by the ionizing radiation was repaired.

In their new study, the Rinaldi et al. demonstrate that exposing irradiated mouse ovaries to CHK2iII blocks the CHK2-mediated activation of two proteins involved in cell death after radiation exposure: TAp63 and p53. Most importantly, they showed that the same concentration range of CHK2iII also protected irradiated egg cells from dying.

To make a case for CHK2iII as a potential measure to prevent POI in women undergoing damaging cancer treatments, Rinaldi et al. had to find out whether the eggs could still be used to generate offspring. To do this, they transplanted the treated ovaries into sterile female mice. After mating, these female mice produced normal pups, indicating that the eggs were able to be ovulated and fertilized and to develop normally. More work is needed to determine whether systemic administration of this drug would also prevent fertility loss in female mice treated with radiation or other DNA-damaging cancer therapies

Although it remains to be seen whether this approach would work for humans, a method to prevent egg damage using drugs would likely avoid many of the downfalls of current fertility-preserving methods for  women and girls with a cancer diagnosis. The available techniques are mainly surgical, including saving egg cells or parts of ovaries or preparing embryos via in vitro fertilization and preserving them for later. These procedures are invasive and also require patients to push back cancer treatment until they’re complete. Developing a drug to prevent POI would sidestep these problems, reducing the amount of painful procedures a patient has to undergo and allowing her to start treatment for her cancer immediately—increasing her quality of life and maybe even her chance of survival.

CITATION:

Rinaldi, V.; Hsieh, K.; Munroe, R.; Bolcun-Filas, E.; Schimenti, J. Pharmacological Inhibition of the DNA Damage Checkpoint Prevents Radiation-Induced Oocyte Death.
GENETICS, 206(4), 1823-1828.
DOI: 10.1534/genetics.117.203455
http://www.genetics.org/content/206/4/1823

Over twenty years ago, somatic cell nuclear transfer (SCNT) let scientists successfully clone the first mammal—Dolly the sheep. Despite advances since then, the efficiency of this process remains low. In the July issue of G3, Srirattana and St. John report a method to deplete cattle donor cells of mitochondrial DNA and efficiently generate blastocysts from these depleted donors.

In SCNT, a nucleus taken from a mature, differentiated somatic donor cell is placed into an oocyte whose nucleus has been removed. Together, this newly created cell goes on to form an embryo whose nuclear genome is identical to the donor cell’s. The low efficiency of SCNT is thought to be partially due to incomplete epigenetic reprogramming of the new embryo. In fact, treatment of embryos with the histone deacetylase inhibitor trichostatin A (TSA) is widely used to enhance SCNT in mouse.

Nuclear DNA isn’t the only genetic information in the cell, though. Mitochondria house a distinct genome that is maternally inherited, and mitochondrial DNA (mtDNA) from donor cells can be randomly transmitted from the donor cell to the embryo. The mixing of mtDNA from the two initial cells complicates the process of SCNT.

Normally, an organism inherits its mtDNA from its mother, but SCNT embryos have two different sets of mtDNA—donor cell and oocyte—to deal with, and the interplay between the two can cause genomic instability, aneuploidy, poor embryo quality and implantation rates, and metabolic defects.

To combat this problem, Srirattana and St. John depleted the mtDNA from cattle donor cells by using 2’,3’-dideoxycytidine (ddC), which inhibits the mtDNA-specific DNA polymerase gamma but doesn’t affect nuclear DNA. They compared embryos made from mtDNA-depleted cells to nondepleted cells, and they looked at the effect of TSA treatment on both depleted and nondepleted cells.

They found that mtDNA-depleted donor cells can generate viable blastocysts that contain only oocyte mtDNA—as is the case in blastocysts formed by sperm fertilization. Donors depleted of mtDNA had a lower rate of blastocyst generation than nondepleted cells, but the use of TSA brought the blastocyst rate back to that of nondepleted donors. Srirattana and St. John also showed that gene expression differed between blastocysts created from depleted and nondepleted cells; they found that differentially expressed genes were largely involved in embryonic development, suggesting the use of mtDNA-depleted donor cells can alter development of the cloned embryos.

This work demonstrates that depleting mtDNA from donor cells is an effective tool for creating SCNT embryos with mitochondrial genomes inherited only from the oocyte. Such embryos will hopefully avoid some of the problems created by mixing incompatible mitochondrial genomes and may one day make SCNT easier and more efficient for cattle scientists and others who rely on this cloning technique.

CITATION:

Manipulating the Mitochondrial Genome To Enhance Cattle Embryo Development
Kanokwan Srirattana, Justin C. St. John
G3: Genes, Genomes, Genetics July 2017 7: 2065-2080;
https://doi.org/10.1534/g3.117.042655
http://www.g3journal.org/content/7/7/2065

Palm fronds crunch under a researcher’s foot as she hikes through a rainforest in Madagascar looking for a spot to release a tiny, omnivorous ball of fur with bulging eyes—a mouse lemur. This creature, the smallest type of primate, is an important research subject: it has just yielded a blood sample, skin cells, and an abundance of physical and behavioral data. The researcher and her team have big plans for the little lemur—they hope it will soon become a genetic model organism that will help us better understand many aspects of primate biology, behavior, and health, including lemur and human diseases.

In the June issue of GENETICS, Ezran et al. explain their decision to pursue genetic research on these diminutive primates. The idea began as a project for three high school laboratory interns to find an appropriate model organism for primate genetics—no small feat, given that there are over 500 known primate species.

The genetic models we currently depend on, such as mice, can’t recapitulate all of primate biology. Genetic research on mice has led to countless important discoveries, but their physiology and behavior differ in many ways from that of humans and other primates. For example, in humans, the fatal lung disease cystic fibrosis is caused by dysfunction in a single gene, but mice with the same defective gene do not show symptoms of the disease. Human-like behavior, such as the use of tools and sophisticated vocal communication, is also impossible to study in the existing genetic model organisms, so it’s critical to find genetic models closer to humans on the evolutionary tree.

The researchers considered many factors. The candidate would need short reproduction times and relatively large numbers of offspring to allow many genetic crosses on a practical timescale, but these traits are found in few primates. The ideal model would also be small, inexpensive to maintain, and easy to work with—it’s no use trying to do genetics with large or dangerous animals. They also took conservation status into account; if a species might be threatened by using it as a model, it was ruled out.

With all these factors in mind, the group settled on the genus Microcebus: the mouse lemurs. They’re about twice as closely related to humans as are rodents, they’re the fastest-developing primates, they have large litter sizes, they are abundant—and working with them in the wild is virtually free. There’s also an existing body of research on natural mouse lemur populations detailing their biology, evolutionary relationships, and the structure of their populations. Studies of these wild lemurs have shown they have good memories and communicate vocally in their social groups, making them excellent models for those aspects of human behavior. And demonstrating their amenability to laboratory studies, several research colonies already exist around the world; one such colony has been studied for over 50 years. A final benefit of using these animals is that there’s a large amount of standing genetic variation in their native populations—so finding interesting mutations can be as simple as sifting through existing variants.

Ramping up research on mouse lemurs could even have benefits for the local Malagasy people. Ezran et al. describe a high school program they have established in Madagascar’s Vatovavy-Fitovinany Region, an area known for its rich rainforests. The program aims to train the students as citizen scientists using the natural laboratory surrounding their school. One day, these students may be the researchers following the lives of these tiny primates and identifying the genes that influence them, putting their skills to use in learning from their bountiful natural environment.

CITATION:

Ezran, C.; Karanewsky, C.; Pendleton, J.; Sholtz, A.; Krasnow, M.; Willick, J.; Razafindrakoto, A.; Zohdy, S.; Albertelli, M.; Krasnow, M. The Mouse Lemur, a Genetic Model Organism for Primate Biology, Behavior, and Health.
GENETICS, 206(2), 651-664.
DOI: 10.1534/genetics.116.199448
http://www.genetics.org/content/206/2/651

Whether a thunderclap drives your dog to cower behind the couch or leaves it unfazed may be determined in part by genetics. In the June issue of GENETICS, Ilska et al. analyze genetic contributors to canine personality traits—such as fear of loud noises—using owners’ reports of their pets’ behavior.

The researchers chose this survey-based method in place of standardized behavior testing both to create a large body of data and to eliminate any influence of a foreign testing environment on the dogs’ behavior. They measured 12 different traits, from trainability to tendency to bark, using a 101-item questionnaire called the Canine Behavioral Assessment and Research Questionnaire (C-BARQ) that was originally designed to screen potential guide dogs. Then they looked for relationships between these traits and aspects of the dogs’ pedigrees and genotypes.

Of these traits, the most heritable were fear of noises and ability to play fetch. Perhaps surprisingly, many of the genetic factors linked to fetching ability were not related to other aspects of trainability. Aggression toward strangers and other dogs was also heritable, but aggression toward owners was not, likely because humans have placed strong selective pressure on dogs to be loyal and gentle toward their owners, leading to low genetic variance. Some traits were also related to each other—trainability had an inverse relationship with “unusual behavior,” a finding that probably wouldn’t shock most dog owners.

Some of the variants associated with the personality traits were located near genes with known neurological functions. For example, dogs that were prone to agitation often carried a variant near the gene for tyrosine hydroxylase, which is involved in the synthesis of the neurotransmitter dopamine. In humans, dopamine dysfunction is implicated in psychological conditions such as attention deficit-hyperactivity disorder, and some variants of the tyrosine hydroxylase gene are associated with the tendency to experience negative emotions and excitability—both traits related to impulsivity.

Because the study was conducted only on Labrador Retrievers in the United Kingdom, the authors caution that other dog breeds may differ in how heritable different personality traits are. But in any case, just like human personalities, it seems that dog personalities have a strong genetic component. So if your dog stares at you blankly next time you throw it a ball, don’t succumb to frustration—fetching just may not be in its genes.

CITATION:

Ilska, J.; Haskell, M.; Blott, S.; Sánchez-Molano, E.; Polgar, Z.; Lofgren, S.; Clements, D.; Wiener, P. Genetic Characterisation of Dog Personality Traits.
GENETICS, 206(2), 1101-1111.
DOI: 10.1534/genetics.116.192674
http://www.genetics.org/content/206/2/1101