Gary Churchill
Senior Editor

Gary A. Churchill received his SB degree in Mathematics from Massachusetts Institute of Technology in 1983 and PhD in Biostatistics in 1988 from the University of Washington, Seattle. He is currently Professor and the Karl Gunnar Johannsen Chair in Computational Biology at the Jackson Laboratory. Churchill’s research addresses statistical applications in genetics and molecular biology. He has played a central role in the establishment of genetics resources including the Collaborative Cross and Diversity Outbred mouse populations. He is co-director of the JAX Center for Aging Research. He was chosen as a 2019 Fellow of the American Association for the Advancement of Science for his contributions to the field of systems genetics to study aging and metabolic disease.

Why Publish in G3: Genes|Genomes|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.

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

Parent-of-origin effects help determine how lab rats respond to stress.

Although your father and mother each contribute a copy of your genes, these copies don’t always play equal roles. Instead, one parent’s gene can have a disproportionate effect on the offspring’s phenotype, resulting in complex patterns of inheritance. In G3: Genes|Genomes|Genetics, Mont et al. examined such effects in the behavior of lab rats.

One example of parent-of-origin effects (PoE) is genomic imprinting, a phenomenon in which only either the maternal or paternal allele of a gene is expressed. Imprinting is associated with a range of developmental and behavioral phenotypes in mammals, and disruption of certain imprinted genes can cause human diseases like Prader-Willi, Angelman, and Beckwith-Wiedemann syndromes.

Although a great deal of work has been done on PoE in mice, much less is understood in rats, which show more complex behaviors. Thus, the authors began their study with a broad assessment of 199 phenotypes in a large cross of rats for which parental information was available. To look for potential examples of PoE, they developed a way to separate out the portion of trait variance that was dependent on inheritance in the usual sense—where there is no difference between maternally and paternally inherited alleles—from that which contrasts the mother versus the father. The latter component can arise from several causes, including true PoE, maternal effects (i.e. gene expression in the mother that influenced offspring taits), paternal effects (the equivalent for the father), and environmental effects from sharing a cage with the mother and some of the siblings. If there were no PoE, then values for each parent would be equivalent; however, the authors found that they were different for 86% of the phenotypes assessed.

If imprinted loci are known to be rare, why are these PoE-related effects seemingly so pervasive? The rat results are consistent with experiments done in mice, which also found widespread PoE-like phenomena and suggested that these effects may be due in part to the indirect effects of imprinted loci—that is, the effects of imprinting can ripple through the genome to trigger many additional phenotypic consequences.

Of particular note, the authors found that coping behaviors—how the animals reacted to stress—showed some of the most significant differences between maternal and paternal contributions, which is suggestive of PoE. However, confounding variables, such as dominance, can also generate PoE, so further experimentation was required to confirm this finding.

To test for PoE related to coping behaviors, the authors crossed two rat strains: RHA and RLA. Stressed RHA rats tend to display active behaviors, such as fleeing, whereas RLA rats tend to be passive when stressed, either freezing or self-grooming. These behaviors were assessed in the offspring of reciprocal crosses using the elevated zero maze, in which rats are placed in a ring-shaped elevated platform with alternating open and walled sections. The rats are then observed for anxiety-like behaviors around the open sections, since rats prefer closed spaces when they are exploring a new environment. The behavior of offspring in the maze tended to fit the behavior profile of the maternal strain: rats with RHA mothers and RLA fathers exhibited more active behavior (matching their RHA mothers), and vice versa.

The authors suggest that these differences might be due to known differences in epigenetic modifications on neurotransmitter receptor genes in the two rat strains, although further research is needed to define the exact mechanism for this phenomenon.

CITATION:

Coping-Style Behavior Identified by a Survey of Parent-of-Origin Effects in the Rat

Carme Mont, Polinka Hernandez Pilego, Toni Cañete, Ignasi Oliveras, Cristóbal Río-Álamos, Gloria Blázquez, Regina López-Aumatell, Esther Martínez-Membrives, Adolf Tobeña, Jonathan Flint, Alberto Fernández-Teruel, Richard Mott

G3: Genes|Genomes|Genetics October 2018 8: 3283-3291;

http://www.g3journal.org/content/8/10/3283

https://doi.org/10.1534/g3.118.200489

For the first time in nearly 15 years, the rat genetic map has been updated.

Genetic maps help us navigate uncharted data, but to successfully use them to link genes to complex traits, their resolution must be high enough to yield a manageable list of candidate variants. That’s why genetic maps for mice and humans have been routinely updated in recent years as mapping technologies have improved.

However, one important map has lagged: the genetic map for rats had not been updated since 2004. As such, the resolution of that map was 100 times lower than the mouse genetic map. Since rats are such an important experimental organism for understanding disease, Littrell et al. set out to construct a new, high-resolution genetic map for lab rats, which they published in G3: Genes|Genomes|Genetics.

With a nearly 50-fold improvement, the new map has a much higher resolution than the previous one. Additionally, the authors created sex-specific gene maps, which had not previously been available for rats. They also examined some particular features of these new maps, finding that rates of recombination were higher on average in females than in males, which is a phenomenon that occurs in many mammal species.

To make it even more useful, the authors also added other data to the map, including the locations of tens of thousands of SNPs. The hope is that this new view of the rat genome will allow geneticists to more effectively explore genetic modifiers of common diseases.

CITATION:

A High-Resolution Genetic Map for the Laboratory Rat

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Imprinted genes can have oppositional effects on adult behavior in mice.

Mammalian genomes show the marks of a genetic tug-of-war between mothers and fathers. These imprinted genes are marked by epigenetic modifications, which means the expression of an imprinted allele depends on whether it was inherited from the mother or the father. A new report in GENETICS expands our understanding of this phenomenon by describing a pair of imprinted genes with opposing effects on adult mouse behavior.

Seeking the evolutionary underpinnings of imprinting has fueled a number of theories and debates. One explanation is based on the conflicting evolutionary pressures on alleles with different parental origins. This theory of intragenomic conflict suggests that the function of imprinting is to control the expression of genes that have opposite effects on maternal and paternal fitness. For example, a paternally inherited allele might favor the growth of offspring as large as possible, but a gene inherited from the mother might instead favor conserving maternal resources for future offspring. Supporting this idea, a number of examples have been found where pairs of genes with antagonistic effects on embryonic growth and early development have inverse patterns of imprinting (i.e. one is expressed only from the paternal allele and the other only from the maternal allele).

In the mouse central nervous system, only the maternal copy of Nesp55 is expressed, while only the paternal copy of Grb10 is expressed. The authors of the GENETICS study previously found that mice lacking maternal Nesp55 make more impulsive choices, but the role of Grb10 was unknown. Given that the two genes have similar expression patterns, the authors hypothesized that they might play related roles.

To address this question, the authors used the same experimental setup they had used for their previous study of Nesp55. They tested mice lacking paternal Grb10 and their wild-type littermates with two different measures of impulsivity. First, they tested impulsive choice by using a delayed reinforcement test, in which mice have to choose between a small reward immediately or a larger reward after a wait. Then, they measured impulsive action by using a stop-signal reaction time test, where mice had to learn to stop a prepotent action in order to get a reward. Although “impulsive choice” and “impulsive action” are deceptively similar terms, they refer to discrete behaviors.

In their previous study, the authors found that mice lacking maternal Nesp55 make more impulsive choices, i.e. they show a preference for a small but quick reward. In this study, mice lacking paternal Grb10 showed the exact opposite phenotype; they made significantly fewer impulsive choices. The behavioral effect was quite specific; all the mice studied showed no change in impulsive action. This suggests that these two genes have opposing effects on this particular aspect of mouse behavior—and this behavior could be subject to conflicting selection pressures, in line with the theory of intragenomic conflict.

This is the first report of imprinted genes acting in opposition in adult behavior, and it suggests that the genomic tug-of-war between parental alleles could have effects that extend into adulthood—far beyond those observed in utero and in early development. The authors suggest that such imprinted genes may even play roles in human disorders that involve impulsivity, like addiction.

CITATION:

Impulsive Choice in Mice Lacking Paternal Expression of Grb10 Suggests Intragenomic Conflict in Behavior

Claire L. Dent, Trevor Humby, Katie Lewis, Andrew Ward, Reiner Fischer-Colbrie, Lawrence S. Wilkinson, Jon F. Wilkins, Anthony R. Isles

GENETICS May 1, 2018 vol. 209 no. 1 233-239; DOI: 10.1534/genetics.118.300898

http://www.genetics.org/content/209/1/233 

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The “hyperspin” long-range enhancer deletion recapitulates disease phenotypes.

In recent years, improvements in genetic testing have made it much easier to discover the causes of rare genetic diseases, but sequence data can also present new puzzles. Take split hand/-foot malformation-1 syndrome (SHFM1), which causes limb deformities, such as joined fingers, and sometimes deafness. Candidate culprits were mutations in the genes DLX5 or DLX6, since defects in either gene cause SHFM1-like malformations in mice. But few people with SHFM1 carry the equivalent mutations.

In a recent mouse study, Johnson et al. found new clues to the mystery. The team examined deaf mice with a naturally occurring mutation they named hyperspin, which causes rapid circling behavior typical of mice with inner ear defects. They found that the hyperspin mice had inner ear malformations that recapitulate those seen in Dlx5-knockout mice—and the same features are sometimes part of the SHFM1 phenotype. The new mutation lies in the gene Slc25a13 and consists of a large deletion that spans introns as well as the exons that encode the majority of the SLC25A13 protein.

Despite the fact that hyperspin disrupts so much of the Slc25a13’s coding sequence, the researchers found that nonfunctional SLC25A13 protein wasn’t to blame for the mice’s phenotype. Completely knocking out Slc25a13 yielded mice with normal hearing and no indication of the hyperspin inner ear abnormalities. Instead, there were signs that a noncoding sequence in Slc25a13 regulates the expression of Dlx5, which is 660 kilobases away from the hyperspin deletion. Mouse embryos homozygous for the hyperspin mutation had strongly reduced expression of Dlx5 in the otic vesicle, which could have caused the inner ear defects they observed.

Unlike Dlx5-knockout mice, hyperspin mice can survive to adulthood, providing researchers a new model system for studying how a lack of Dlx5 affects inner ear function across the lifespan. This work also illustrates how pursuing unexpected occurrences, like this chance mutation in a lab mouse, can open new avenues of research.

CITATION:

Deletion of a Long-Range Dlx5 Enhancer Disrupts Inner Ear Development in Mice
Kenneth R. Johnson, Leona H. Gagnon, Cong Tian, Chantal M. Longo-Guess, Benjamin E. Low, Michael V. Wiles, Amy E. Kiernan
Genetics 2018 208: 1165-1179; https://doi.org/10.1534/genetics.117.300447
http://www.genetics.org/content/208/3/1165

A reanalysis of genes tied to life span in mice reveals only a select few affect aging.

Like it or not, you are always getting older. The mechanisms responsible for this fact of life, non-negotiable as it is, remain poorly understood. To identify genes that drive the aging process, researchers typically look for those that affect lifespan. On the surface, interpreting such studies might seem simple: if animals with a mutation live longer or shorter than their wild-type counterparts, the mutation must have some effect on aging, right? Not necessarily; many mutations change the rate at which animals die, not the rate at which they age. In a report in GENETICS, de Magalhães et al. demonstrate the importance of this distinction by reanalyzing a set of genes previously connected to aging in mice. Their results have broad implications for interpreting studies of longevity.

To reevaluate these genes, the authors calculated the “demographic” rate of aging in the corresponding mutants, which reflects age-dependent mortality. The Gompertz-Makeham law of mortality states that the effective human death rate is made up of both age-dependent factors (e.g. heart disease) and age independent-factors (e.g. lightning strikes). When the age-independent factors leading to death are rare (like with laboratory mice), the law can be simplified into just the Gompertz equation. This equation describes the exponential increase in mortality rate with age, and by applying it to data from previous mouse studies, the authors were able to determine which genes affect the demographic rate of aging.

Most of the genes the authors analyzed turned out to affect mouse longevity in an age-independent manner. Only two out of 30 genes that increased lifespan did so by decreasing the demographic rate of aging. Similarly, only five out of 24 genes that shorten mouse lives increased the demographic rate of aging. While all of these genes are undeniably important for lifespan, the select few identified to influence the aging process are better candidates for studying the details of how organisms change as they age.

The authors also offered some insight into how studies of aging and longevity in mice are conducted, noting significant variation in the life span of control animals from study to study. This variation suggests that differences in how animals were housed and cared for, as well as other random factors, could be influencing the results of aging studies. Such variation must be taken into consideration as future studies attempt to unravel the biological complexities behind getting old.

CITATION:

A Reassessment of Genes Modulating Aging in Mice Using Demographic Measurements of the Rate of Aging

João Pedro de Magalhães, Louise Thompson, Izabella de Lima, Dale Gaskill, Xiaoyu Li, Daniel Thornton, Chenhao Yang, Daniel Palmer

GENETICS April 2018; 208: 1617-1630. DOI: 10.1534/genetics.118.300821

http://www.genetics.org/content/208/4/1617

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

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