A new associate editor is joining GENETICS in statistical genetics and genomics. We’re excited to welcome Lei Sun to the editorial team.

Lei Sun
Associate Editor
Lei Sun is a Professor in Statistics and Biostatistics at the University of Toronto. She studied mathematics at Fudan University and obtained her PhD in statistics from the University of Chicago in 2001. Her research area is in statistical genetics and genomics, with a focus on robust association methods, multiple hypothesis testing, selective inference, and more recently methods for the X chromosome. In 2017, she received the prestigious Centre de recherches mathématiques-Statistical Society of Canada Prize in Statistics, and in 2020, she served as the President of the Biostatistics Section of the Statistical Society of Canada.

Meiotic recombination in a commonly used laboratory mouse strain showed sensitivity to dietary changes.

Recombination within the germline is a tightly controlled process. But new research suggests that nutrition may introduce some variability into this crucial step in genetic transmission, which could have implications for the design of future genetics studies.

A study published in GENETICS found that genome-wide recombination rates in the spermatogenesis of adult male mice were sensitive to dietary changes, but that the observed changes in crossover frequency differed depending on genetic background.

“Our findings were very unexpected,” says senior author Elena de la Casa-Esperon. “It was hard to believe that a small change in diet could affect recombination, something we thought was very much a protected process.”

Unexpected Environmental Effects

Not many studies had previously examined the impact of environmental factors on recombination and most had studied maturing germline cells in utero or in juvenile animals. In contrast, de la Casa-Esperon and her team used adult males from genetically diverse inbred strains.

“We found that there was a gap in knowledge,” says de la Casa-Esperon. “There were two classic studies in flies and yeast that hinted at the possibility of nutritional effects on levels of recombination, but the possibility of diet effects has largely been neglected in other studies.”

The researchers used immunohistochemistry to evaluate crossover frequency after 24 days of feeding each group of mice one of three diets: a standard “maintenance” diet, a 50% “undernourishment” diet, or a nutrient-rich “breeding” diet.

In two of the three genetic strains studied, recombination rate stayed relatively constant following a switch to the restrictive “undernourishment” diet, indicating that tight control over reproduction is maintained even under stressful conditions. However, the nutrient-rich diet caused a reproducible increase in recombination levels in C57BL/6 mice, one of the most commonly used strains of laboratory mice.

“This wasn’t the kind of study where you find a dramatic effect that’s easy to see—the changes we observed were small, but with large numbers we could see that they were consistent,” says de la Casa-Esperon. “As a scientist looking at these types of phenomena, first you have to convince yourself, then you have to convince others.”

Cautionary Findings and Lingering Questions

Despite her initial surprise, de la Casa-Esperon is now convinced that other researchers need to realize that germline genetic information is more sensitive to environmental factors than previously thought, which could have transgenerational and evolutionary implications. “The take-home message is that there are many environmental variables that affect the traits we study, and we need to be vigilant about the potential effects of these variables on our results,” she says.

She also points out that dietary changes throughout lifetime may be a common occurrence in animal facilities; for instance, pregnant and nursing females are sometimes fed with nutrient-rich “breeding” chows while offspring are later switched to leaner “maintenance” diets. Hence, dietary regimes must be controlled and reported in recombination studies, as they can affect the results.

Next research steps include attempting to isolate the diet components that significantly contribute to changes in recombination levels. Phytoestrogens are promising candidates, since they are known to have epigenetic effects in germline—and these could, in turn, affect recombination. De la Casa-Esperon hopes other groups will study whether diet—and other environmental factors—can alter recombination rates in other species.

CITATION:

Diet effects on mouse meiotic recombination: a warning for recombination studies

Angela Belmonte-Tebar, Estefania San Martin Perez, Syonghyun Nam Cha, Ana Josefa Soler Valls, Nadia D Singh, Elena de la Casa-Esperon

GENETICS

2022:iyab190

https://doi.org/10.1093/genetics/iyab190

From a Kyoto garden to scientific discoveries. 

Since the 17^th century, medaka fish have been bred for their beautiful colors. Shortly after the 1900 re-discovery of Mendel’s laws of inheritance, medaka began to be used for genetic studies. Recessive inheritance of the orange-red (b) and white (r) variants, female-limited appearance of the white phenotype, and an additional allele on the b locus causing variegation (B′) were reported by three professors publishing in Japanese [1–3]. The first medaka article written in English was published in 1921 by Tatsuo Aida (1872-1957). One hundred years after publication of this landmark article in GENETICS, we reflect on Aida’s work and legacy.

When he was four years old, Aida’s samurai father cut off a thief’s arm, which remained a traumatic memory throughout his life. He liked playing in a neighboring farm in Kyoto, where he nursed his interests in zoology. He studied development and phylogeny of Chaetognaths at Tokyo Imperial University, but, due to a conflict with his supervisor, left there before getting his PhD and became a teacher in a high school in Kumamoto, where Soseki Natsume, a Japanese novelist, worked as a colleague. Besides his daily duties, he studied Larvaceans for five years and reported four new species [4]. 

When his father died, Aida returned to Kyoto in 1903. Teaching at Kyoto Higher Technical School, he started genetic studies in 1913 in his own home. He chose medaka because the fish could be bred en masse in small flowerpots, sex could be determined from appearance, and color variants were available from local fanciers. Studies of plants or mice would have required much larger spaces. Supported by Genzo Shimazu (a president of Shimadzu Corporation, where Aida was a counselor for zoological specimens), he constructed a breeding farm at his home consisting of 40 concrete tanks of 60 x 60 x 45 cm and 200 Yuzen dyeing pots of 30 cm diameter x 10 cm depth. Recording weather and air/water temperatures every day, he continued his research until 1954 at an age of 83. 

His results were published as three articles in GENETICS. In the first [5], Aida performed a total of 22 crosses of two generations, recorded body color of 17,281 fish (5,304 of which were also analyzed for sex) and demonstrated:

1. Mendelian-recessive and independent inheritance of the b and r phenotypes, 
2. dominant hierarchy of three alleles on the b locus, 
3. female-limited (i.e., sex-linked) inheritance of the r phenotype, and 
4. recombination between the X and Y chromosome. 

These findings, particularly the fourth, impressed the editor, William Castle, who expressly added a footnote and even paid color charges for Aida’s illustrations (Fig. 1). Richard Goldschmidt, also being impressed by this article, visited Aida’s breeding farm during his stay in Japan in 1924. 

Figure 1: Handpainted illustrations from Aida 1921, showing orange-red, white variegated with black, white, brown-black (wild form), orange-red variegated with black, and bIue-black medaka varieties.

In the second article [6], Aida analyzed nine fish (out of 13,065) with exceptional color and sex phenotypes and found that their descendants (16,385 in total) were variously unbalanced in sex ratios. He discussed this phenomenon from a viewpoint of non-disjunction of the sex chromosomes and suggested physiological differences between the X and Y chromosomes cause “one-sided crossing over”; i.e., dominant (functional) alleles tend to be lost from the Y chromosome rather than gained from the X chromosome. He also described new dwarf mutants, fused and wavy, analyzing their 8,930 inter- or back-crossed siblings.

In the third article, color and sex of 14,958 fish were analyzed [7], and Aida reconsidered the second article from a viewpoint of sex reversal, proposing a new hypothesis for sex determination, i.e., the total sum of “sexual exciters” on the X and Y chromosomes determines sex, and the potency of exciters fluctuates at various degrees (either positively or negatively) depending on inner (e.g., recombination or mutation) or outer (e.g., temperature) conditions. At that period, various opinions on sex determinants existed among researchers (e.g., Goldschmidt, Kosswig, Winge, and Bridges). It should be noted that Aida’s hypothesis was intrinsically correct and could explain sex-determining phenomena in other animals. 

These monumental achievements by Aida clearly showed the usefulness and effectiveness of medaka as a research model. Having a non-academic position, however, Aida had no students or colleagues to take over his studies or fish stocks. It was miraculous that in 1954 when Aida stopped his research due to illness, an undergraduate student at Okayama University, Tetsuro Takeuchi (1932-), visited him and became Aida’s first and last student. Aida proposed Takeuchi study a new body-color mutant, color interfere (ci), which was confusing him with its “interfering” phenotype. Aida died in 1957 and Takeuchi was awarded a PhD degree in 1968 for studying ci. Teaching at a college, Takeuchi constructed a breeding farm at his home and kept the ci and other Aida’s strains until now. Without his devoted efforts for decades, Aida’s fish, including the rare recombinants and new mutants, would not have survived to the present. 

After a long dormancy, the medaka color and sex genetics research that Aida initiated a century ago came into bloom. The color genes (b and ci, but still not r) and the male determinant (the Dmy gene) were unveiled [8–10]. An inbred strain derived from Aida’s collection (Hd-rR) enabled quick sequencing of the whole genome [11]. Knowledge of the molecular bases of color perception and mating preference is accumulating [12, 13]. Takeuchi, on reaching the age of 89, decided to close his farm in this memorial year and deposited all strains he had kept for 67 years to the Medaka bioresource project (NBRP Medaka). He also gifted the authors a pair of Aida’s Yuzen dyeing pots.（Figure 2). The NBRP Medaka was initiated in 2002 and has continued for 20 years. Now over 800 strains and 895000 BAC/Fosmid/cDNA clones and other information are available (https://shigen.nig.ac.jp/medaka/top/top.jsp) [14]. This blooming time may not last long in Japan [15], but the number of medaka researchers has markedly increased worldwide in the last 100 years. We imagine even more medaka researchers will appreciate Aida’s work next century, on the 200th anniversary, hopefully alongside important works from today’s era of medaka research. 

You can learn more about Aida’s life and work in an account from Dr. Takeuchi here. Note that the site can be translated into multiple languages using the Google Translate menu on the page.

Figure 3. Photos of Tatsuo Aida and his medaka nursery, courtesy of Tetsuro Takeuchi and Kiyoshi Naruse.

About the authors:

Shoji Fukamachi, Professor, Department of Chemical and Biological Sciences, Japan Women’s University.

Kiyoshi Naruse, Specially appointed Professor, National Institute for Basic Biology. Head of National BioResource Project Medaka, Japan.

REFERENCES

1. Ishikawa, C., 1913 Dobutsugaku Kogi [Zoological Lectures] Vol.1: pp 372. 
2. Toyama, K., 1916 Ichinino Mendel-Seishitsu ni tsuite. [On some Mendelian characters.] Nippon Ikushugakkai Hokoku [Report of Japanese Breeding Society] 1: 1-9.
3. Ishiwara, M., 1917 On the inheritance of body-color in Oryzias latipes. Mitteilungen aus der medizinischen Fakultät Kyushu 4: 43-51.
4. Aida, T., 1907 Appendicularia of Japanese waters. The journal of the College of Science, Imperial University of Tokyo, Japan 23: 1-25. 
5. Aida, T., 1921 On the inheritance of color in a fresh-water fish Aplocheilus latipes Temmick and Schlegel, with special reference to sex-linked inheritance. Genetics 6: 554-573.
6. Aida, T., 1930 Further genetical studies of Aplocheilus latipes. Genetics 15: 1-16.
7. Aida, T., 1936 Sex reversal in Aplocheilus latipes and a new explanation of sex differentiation. Genetics 21: 136-153.
8. Fukamachi, S., Shimada, A., & Shima, A., 2001 Mutations in the gene encoding B, a novel transporter protein, reduce melanin content in medaka. Nature Genetics 28: 381-385.
9. Matsuda, M., Nagahama, Y., Shinomiya, A., Sato, T., Matsuda, C., et al., 2002 DMY is a Y-specific DM-domain gene required for male development in the medaka fish. Nature 417: 559-563.
10. Fukamachi, S., Sugimoto, M., Mitani, H., & Shima, A., 2004 Somatolactin selectively regulates proliferation and morphogenesis of neural-crest derived pigment cells in medaka. Proceedings of the National Academy of Sciences of the United States of America 101: 10661-10666.
11. Kasahara, M., Naruse, K., Sasaki, S., Nakatani, Y., Qu, W., et al., 2007 The medaka draft genome and insights into vertebrate genome evolution. Nature 447: 714-719.
12. Okuyama, T., Yokoi, S., Abe, H., Isoe, Y., Suehiro, Y., et al., 2014 A neural mechanism underlying mating preferences for familiar individuals in medaka fish. Science 343: 91-94.
13. Shimmura, T., Nakayama, T., Shinomiya, A., Fukamachi, S., Yasugi, M., et al., 2017 Dynamic plasticity in phototransduction regulates seasonal changes in color perception. Nature Communications 8: 412.
14. Sasado, T., Tanaka, M., Kobayashi, K., Sato, T., Sakaizumi, M. and Naruse, K. 2010  The National BioResource Project Medaka (NBRP Medaka), An integrated bioresource for biological and biomedical sciences. Experimental Animals 59, 13-23.
15. Fuyuno, I., 2017 What price will science pay for austerity? Nature 543: S10-S15.

Failure of chromosomes to segregate properly results in severe medical conditions, or even death. Yet for a long time, it was challenging to study exactly how chromosomes carry out their complex choreography, due to a lack of robust tools for combining chromosome visualization and genetic experiments. 

Douglas Koshland spent his postdoc studying mammalian chromosome biology in Marc Kirschner’s lab at UC San Francisco. From that experience, he was inspired to develop a cytological assay to enable the study of chromosomes in baker’s yeast. Working with yeast would provide access to the most sophisticated genetic tools, but tiny yeast chromosomes had thus far been impossible to visualize. “At the time that we started these studies, yeast was about the farthest thing that people would use to study chromosome structure,” Koshland recalls. “It had no cytologically visible chromosome structure.” 

Using genetic approaches, Koshland and Alex Strunnikov discovered the SMC family of proteins that were conserved from bacteria to humans and likely played a role in chromosome structure.  To test this hypothesis, Koshland convinced Vincent Guacci, a talented postdoc, to develop a fluorescence in situ hybridization method that allowed researchers to visualize differences in yeast chromosome structure in interphase and mitosis. With this new tool, his lab and others discovered that SMC proteins were key subunits of complexes known as “cohesin” and “condensin” that mediate sister chromatid cohesion and condensation in all eukaryotes.

His advances in chromosome biology have not only illuminated fundamental features of the structure of chromosomes, but also provided tools for many others to use. For his achievements, Koshland has been awarded the 2021 Genetics Society of America Medal for outstanding contributions to the field of genetics in the last 15 years. “What Doug likes to do is to find problems that people appreciate are important but hard, then find ways of approaching them,” says Jasper Rine of UC Berkeley, one of the scientists who nominated Koshland for the award. “Doug is a pioneer who opens up the ability to study things that people had not considered approachable.”

The cohesin complex holds the two sister chromatids together after DNA replication, and condensins help pack the DNA into a compact shape. Previously, it had been thought that the helical intertwining of the sister chromatids held the two molecules together until they were untangled by topoisomerases, but that turned out not to be the case. “Doug showed that wasn’t the case at all by clever genetics experiments and also by discovering the proteins that really are responsible,” says Rine. Cohesin proteins hold sister chromatids together, create topologically associated domains, and participate in DNA repair.

“One sort of prophetic thing I got right was to say that given how complicated DNA replication is, there’s no reason to believe higher order chromosome structure is going to be any less complicated.” Koshland recalls. “And this turned out to be true. We’ve spent the last 20-odd years trying to figure out what the dang things do.”

Koshland has continued to pursue complex questions about distinctive chromosome structures by studying them in yeast. For instance, chromosome loops had been observed in mammalian cells, and it was thought that the looping might bring together regulatory elements and the promoters they regulate. “In collaboration with the Darzacq laboratory, we improved the technology for looking at these loops,” Koshland says. “It looks like the looping is just as beautiful in yeast, and very analogous to what you see in mammalian cells.” Yeast don’t generally have distal gene regulatory elements, however, so the function of these yeast chromatin loops, and by extension many mammalian chromatin loops, probably isn’t the regulation of gene expression. With the technology to study the loops in yeast, the power of yeast genetics is now available to establish the physiological relevance of exciting in vitro studies of loops formation, elucidate loop regulation in vivo, and to discover their mysterious biological function.

Another curious chromosomal phenomenon the lab is exploring is the formation of “R-loops,” in which RNA hybridizes back to the DNA it originated from. R-loops cause double-stranded breaks in the DNA, which leads to chromosome instability. Koshland’s lab showed that not only do the R-loops introduce breaks, but they actually interfere with DNA repair. “They both cause the break and then they mess up the repair process,” Koshland says. These structures may be responsible for chromosomal rearrangements seen in cancer cells.

Finally, Koshland’s lab is also studying desiccation tolerance as a window into stress biology. Some organisms, like the resurrection fern, can recover after going through desiccation. Most desiccation tolerant species seemed to have an abundance of two factors: the sugar trehalose and a family of proteins called hydrophilins. Koshland’s group demonstrated that these are both necessary and sufficient for desiccation tolerance. “That was a stunning observation,” Koshland says. Rather than relying on complex, specialized pathways to protect the cell from DNA damage and other effects of stress, all that was needed was a simple sugar and a set of small, intrinsically disordered proteins. “Now the question is understanding exactly how they work,” Koshland says.

Over the years, Koshland has kept his lab on the small side, and as a mentor he is known for his thoughtful manner and intellectual rigor. Plus, “he’s just an incredibly nice person,” says Orna Cohen-Fix of the National Institute of Diabetes and Digestive and Kidney Diseases and a former postdoc in Koshland’s lab.

“When I was starting my own lab, if you asked me at the time who do I want to be when I grow up, I’d say ‘I want to be Doug,’” Cohen-Fix says. “He puts emphasis on getting things right and being thoughtful. It’s more important to him to understand a process than to publish in a high-profile journal.”

Koshland will accept the award and present “Genetics of chromosome biology: to null or not to null” at an online Award Seminar on Tuesday, May 11, at 2 p.m. EDT.

Register for Award Seminar

The Genetics Society of America Medal honors an individual member of the Society for outstanding contributions to the field of genetics in the last 15 years. GSA established the Medal in 1981 to recognize members who exemplify the ingenuity of the GSA membership through elegant and highly meaningful contributions to modern genetics.

After giving a talk in Seattle about chromosome pairing, Chao-ting (Ting) Wu boarded the redeye flight back to Boston and settled in to read a new research paper on an odd new discovery in the human genome. “It was so exciting, I had to get up and walk around on the plane,” she says. “I could not stay in my seat.”

The paper that had Wu pacing the aisle that day was the first report describing DNA sequences called ultraconserved elements (UCEs), from Gill Bejerano in David Haussler’s group at UC Santa Cruz. UCEs are nucleotide sequences more than 200 nucleotides long that are identical in the human, rat, and mouse genomes. It’s incredibly unlikely that a sequence that long could remain unchanged over hundreds of millions of years of evolution, and yet Bejerano reported finding 481 of them.

“I remember reading it and thinking, how can that be?” Wu says. “How could we have missed this? How can something be so important and so hidden?”

Intrigued, Wu began studying UCEs in her own lab. “They are considered by some to be the longest-standing mystery of the genome era,” she says. “We don’t have an explanation for why any genome would retain even one sequence that long. The reason my lab studies it is this: pairing could be a very simple explanation.”

Wu has spent decades studying how homologous chromosomes pair up. Once considered a quirk of Drosophila’s genome, the idea that chromosomes communicate by coming into contact with each other is now being studied in mammals, fungi, and even plants. “It’s moved from being an ‘artifact’ to possibly being a universal way in which homologous chromosomes can communicate,” Wu says. “That’s been extremely exciting to see.”

Wu’s studies began when she was a graduate student with William Gelbart, who was a professor at Harvard University and a previous awardee of the George W. Beadle Award, and continued in her own laboratory with Jim Morris, a graduate student and now a professor at Brandeis University, and Pam Geyer, a professor at the University of Iowa. These studies focused on transvection, in which gene expression can be regulated by interactions between homologous alleles on different chromosomes. If the basis of UCEs is pairing, she speculates, that could explain why the sequences cannot tolerate changes.

This model aligns two otherwise incongruous observations. First, she and Adnan Derti, a graduate student and now at Auron Therapeutics, discovered that copy number variation of a UCE – a deletion or duplication – is rarely found in healthy individuals. On the other hand, other groups found that some UCEs can be deleted from both chromosomes without causing lethality in mice. The pairing model, however, predicts exactly such outcomes for UCEs whose function is to pair.

Perhaps these perfectly conserved regions act as “guardians of the genome,” she speculates, helping preserve the integrity of the full set of chromosomes. Understanding them could ultimately provide protection from disease.

“She’s always thinking about the weird and the wonderful, and what are the things we have no idea about,” says Jack Bateman, a former postdoc who studied transvection and now heads his own lab at Bowdoin College. “She’s so fun to talk to because she just has these ideas that are different.”

In addition to her work as professor of genetics at Harvard Medical School, she directs the Consortium for Space Genetics and the Personal Genetics Education Project (pgEd), a public engagement program intended to empower citizens to educate themselves about the genomic technologies that pervade our modern society. This team of scientists, social scientists, educators, and community organizers work with schools, teachers, policymakers, filmmakers, communities of faith, and other groups to prompt conversations about the benefits and ethical and social implications of genetics.

For all of these diverse contributions, Ting Wu has been awarded the 2021 George W. Beadle Award from the Genetics Society of America, which recognizes individuals who have made outstanding contributions to the community of genetics researchers beyond an exemplary research career. 

“She’s so passionate about things,” says Pamela Geyer, professor of biochemistry at the University of Iowa, one of the scientists who nominated Wu for the award. “She pushes you to think about things in a different way.”

At some point thinking becomes experimenting, and, eventually, time came to get a good look at the chromosomes, themselves. Thanks to work done in Wu’s lab, geneticists have powerful tools to visualize the 3D shapes of chromosomes and trace the dynamic system as they interact.

This story begins with Ben Williams, a graduate student and now with Helmsley Charitable Trust, whose idea for Oligopaints was demonstrated and then advanced by Brian Beliveau, a graduate student and now an assistant professor at the University of Washington,­ and Eric Joyce, a postdoctoral fellow and now an assistant professor at the University of Pennsylvania. Oligopaints are low-cost fluorescent probes that hybridize to specific locations along the chromosomes and, led by Beliveau, the Wu group and her collaborators, Peng Yin and Xiaowei Zhuang, professors at Harvard Medcial School and Harvard University, respectively, enabled Oligopaints to image chromosomes in super-resolution. “It’s been very exciting,” says Wu. “The super-resolution structures are giving us true measurements of distance, volume, and shape, and we are now looking at greater and greater expanses of the genome. We’re seeing how completely dynamic the genome can be.” 

The infectious enthusiasm that has propelled her lab into uncharted scientific waters has also spilled over into the realm of education. The advent of home genetic testing and personal genomics sparked lots of probing conversations among her lab members about communicating with the public about the social and ethical considerations around advances in genetics.

“Have we communicated enough with everybody, non-scientists, about genetics?” Wu muses. “So that when these technologies come out, they are informed enough to make decisions for themselves about whether they want to use those technologies?”

To learn what questions were percolating through the community, she and her husband, geneticist George Church, and their daughter, Marie, took a road trip across the country to talk to people who had volunteered their DNA for the Personal Genome Project. “These were people from all walks of life,” Wu says. “We came back so much more enriched by their conversations and so much more knowledgeable about the challenges that we had to address.”

That trip sparked her to co-found the Personal Genetics Education Project, or pgEd, with Bateman and Dana Waring, who is the Education Director. The program started by visiting local high schools and making presentations in biology classrooms. Realizing that they wouldn’t get too far just visiting individual schools, the team began publishing curriculum and teacher training materials to spread genetics education into more classrooms, particularly those where students might not have a strong background in genetics or biology. But Wu emphasizes that the goal isn’t to teach the nuts and bolts of DNA, or recruit students into STEM careers. Rather, she says, pgEd seeks to spark curiosity and debate, such that when students encounter genetic technology in their lives, they feel qualified to ask questions. 

“We’re not talking about what DNA bases are,” she says. “We’re talking about interesting things people might want to know to help them navigate their lives. When people are interested, they start asking questions. We’re hoping that when a physician comes along and says, ‘we’re going to do this DNA test,’ they aren’t silent, thinking, ‘oh, this person knows a lot more than I do.’ Instead, they will feel confident enough to ask questions, and I think that is the greatest protection you can give somebody. Laws are helpful, but one-on-one in a doctor’s office, you need the confidence that you can hold your own in a conversation about genetics. That’s what we’re going for.”

pgEd, whose activities are coordinated by Marnie Gelbart, Director of Programs, has spread well beyond schools into TV and film, congressional briefings, and faith communities. Recently, Gelbart, Robin Bowman (Professional Development Associate), and Nadine Vincentin (Research Fellow) worked on the public engagement programming and educational resources that accompanied the Ken Burns PBS documentary “The Gene: An Intimate History.” They have also been working closely with The Learning Center for the Deaf on lessons and curricula in American Sign Language, with Mohammed Hannan (Community Liaison) extending their engagement within communities. “It’s been amazing to see it grow,” says Bateman. “They’ve done so many things. They’ve done congressional briefings. How do these things happen? They happen because it’s Ting.”

The George W. Beadle Award honors individuals who have made outstanding contributions to the community of genetics researchers. Wu will accept the award at the 62^nd Annual Drosophila Research Conference (#Dros21) and will present an Award Seminar online on April 29^th from 1-2 pm EDT.

Interested in learning about public engagement from pgEd? GSA has partnered with pgEd for a program on inclusive public engagement for geneticists. Sign up now for the “Discussing Genetics” webinar series and join us for additional training workshops coming soon. 

“Why are chromosomes so different? Genetic conflicts and genome evolution”

Congratulations also to this year’s Larry Sandler Award runners up:

• Kristina Stapornwongkul (Advisor: Jean-Paul Vincent)
• J. Dylan Shropshire (Advisor: Seth Bordenstein)
• Jiefu Li (Advisor: Liqun Luo)

About the awardees:

Ching-Ho Chang was born in Taiwan. He went to the National Taiwan University and graduated in 2009 with a Bachelor of Science degree in Life Science. He received his Master’s degree from the Institute of Ecology and Evolutionary biology at the National Taiwan University in 2011 under the mentorship of Dr. Chau-Ti Ting, studying the evolution of neo-sex chromosomes in Drosophila albomicans using genetics and computational biology. He continued his interest in chromosome evolution during his Ph.D. work by combining genetics, computational biology, and cytology to study the evolution of Drosophila centromeres, Y chromosomes, and meiotic drive under the guidance of Dr. Amanda Larracuente at the University of Rochester. As a graduate student, he held the Ernst Caspari and Messersmith Fellowships from the University of Rochester and a Government Scholarship to Study Abroad from the Ministry of Education, Taiwan. He earned his doctoral degree in Biology from the University of Rochester in 2020. Dr. Chang is currently a postdoctoral fellow with Dr. Harmit Malik at the Fred Hutch Cancer Research Center, studying the function and evolution of sperm chromatin using Drosophila. 

Kristina Stapornwongkul did her Masters at the University of Heidelberg and then moved to London to do a Wellcome Trust-funded PhD in Jean-Paul Vincent’s lab at the Crick Institute. Since February, she is a postdoctoral fellow at EMBL Barcelona.

Dylan Shropshire received his PhD from the Bordenstein lab at Vanderbilt University and is currently an NSF postdoctoral research fellow in Brandon Cooper’s lab at the University of Montana.

Jiefu Li did his Ph.D. thesis research with Prof. Liqun Luo at Stanford University. He developed proteomic and genetic tools to study cell-surface signaling in the precise assembly of Drosophila olfactory circuits.

Courtesy of Lernestorod via Pixabay

Written by members of the GSA Early Career Scientist Communication and Outreach Subcommittee: Carla Bautista Rodriguez, Université Laval; Zach Grochau-Wright, University of Arizona; Angel F. Cisneros Caballero, Université Laval

Disrupting the complex and delicate balance of a genome can have devastating consequences. In humans, for example, extra copies of individual chromosomes can result in diseases, and whole-genome duplications often occur in cancer. However, extra genome copies can also provide advantages. From our morning coffee to pharmaceutical production to the origins of vertebrates, genome duplication has had many implications for our lives. Research in model organisms is helping illuminate how and why.

Our early origins

Genomes contain the information needed for the development and metabolism of living organisms. As humans, our genome is composed of 46 chromosomes. These come in 23 pairs because we inherit one half of each pair from our parents. However, organisms sometimes receive unusual numbers of chromosomes. These events can range from receiving extra copies of individual chromosomes to extra copies of the whole genome!

The number of chromosome copies an organism has is referred to as ploidy. For example, haploids have one full set of chromosomes, diploids (like humans) have two, and polyploids have more than two. One of the ways ploidy can change is through errors in cell division. Cells have to replicate their genome before they divide, so  they can assign a full copy to each of their daughter cells. However the cells fail to divide sometimes, which results in a whole-genome duplication. Changes in ploidy can also result from the interbreeding of different species. This happens particularly often in plants.

When these extra copies are passed onto future generations, they can become a source for novel genetic material. One example is hinted at by curious patterns in the human genome. Some human chromosomes have long stretches of similar genes organized in the same order. Genome-scale analyses across a range of vertebrate species showed that many of these long stretches come in four copies. What is the origin of these groups of four? One possibility could be many successive duplications of individual genes. However, this is unlikely because it would require a very large number of individual events. The most likely explanation is that the ancestor of all vertebrates underwent two rounds of whole-genome duplication. These early events could have set the stage for the evolution of vertebrates and the subsequent origin of many different species, including humans.

When more is more: genome duplication and adaptation

Sometimes, polyploidy can be an advantage. Selmecki and colleagues performed an experiment where they generated haploid, diploid, and tetraploid strains of the model organism Saccharomyces cerevisiae, also known as baker’s yeast. They grew each strain in an environment where the complex sugar raffinose was the primary source of carbon. Raffinose is more difficult to metabolize than simpler sugars like glucose, so this new environment placed selective pressure on the yeast strains to adapt to the new source of energy. Selmecki and colleagues found that tetraploid yeast strains adapted faster than haploid and diploid strains to this challenging environment. The scientists then used mathematical modeling and whole genome sequencing to examine what allowed tetraploids to adapt so rapidly. They reasoned that, for duplicated genes, as long as one of the copies retains its function, the other copies can accumulate mutations that might otherwise be harmful to fitness. These additional mutations ultimately mean more genetic variation for natural selection to act on the population. Thus, the increase in variation probably helped tetraploids find the beneficial mutations for raffinose metabolism quickly.

Genome duplications have played a major role in generating the diversity of plant species we see today. They have been associated with 15% and 31% of speciation events in flowering plants and ferns, respectively. One reason for this is that polyploid plants are unable to reproduce with parent species due to different chromosome numbers. Similar to the yeast experiment above, polyploid plants have been found to evolve into different ecological niches faster than their diploid relatives. Again, this has been linked to increased genetic diversity following polyploidization.

Polyploids make food, drink, and drugs

Polyploid species have been widely used by humans for thousands of years. Today, humans still benefit from polyploidy in fields such as agriculture, industry, and biotechnology.

You can thank a polyploid for your morning coffee, for example, since coffee plants are tetraploid. This is not an isolated case; domesticated crops tend to be polyploids more often than their wild relatives. Some of these crops are widely used, including wheat crops, which are tetraploid or hexaploid, and potato crops, which have ploidy ranging from diploid, triploid, tetraploid, to pentaploid. Fruits also show high ploidy levels, like octoploid strawberries. The reason there are so many polyploid crops is because they usually have larger cells and organs than their diploid progenitors, allowing more biomass to be obtained from a single plant.

Polyploid microorganisms are also used in industrial applications. Since polyploidy tends to increase the ability of microbes to resist environmental stresses, it has been widely used in the brewing industry where cells must endure high osmotic stress and high alcohol concentrations. For instance, beer and baking yeasts and some wine hybrid strains are usually triploid and tetraploid. This is explained by the fact that the increase in ploidy is not only accompanied by an increase in size, but also, greater respiratory activity.

Recently, polyploidy has been used to make biotechnological products. For instance, ploidy has been manipulated for the enhanced production of phyto-pharmaceuticals. Since polyploidization increases the size of cells and organs and plant organs are the source of secondary metabolites, increasing ploidy can improve the bioproduction of these metabolites. For instance, tetraploids of Cannabis sativa showed an 80% increase in marijuana-like activity, and triploids or tetraploids of Papaver somniferum showed an increase of 100% in morphine concentration.

Nature constantly offers unexpected innovations. All these examples reveal that unusual numbers of chromosomes are not always harmful, and have had important evolutionary implications. In fact, genome duplications have helped shape our world, leaving a lasting impact on our economic activities and on our own human genome.

About the authors:

Carla Bautista Rodriguez

Zach Grochau-Wright

Angel F. Cisneros Caballero

Acknowledgments:

We would like to thank Jacob Steenwyk, Axelle Marchant, Diana Ascencio, and Souhir Marsit for useful comments.

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

Rapid genomic changes observed in Candida albicans soon after exposure to the oral cavity.

Whether or not you treat your body like a temple, it presents a hostile and rapidly-changing environment for the many microorganisms that call you home. In contrast to the microbes that hang out inside humans, those that are cultured in the lab can expect predictable conditions designed to help them thrive. But could the real-world stresses of the host environment contribute to a pathogen’s ability to adapt? A new report in GENETICS sheds some light on this question, showing the surprisingly immediate genomic effects of exposing fungal populations to the inside of a mouth.

Forche et al. studied the effects of infection on population variability in the fungus Candida albicans, which is normally a harmless commensal bystander but, under the right conditions, can cause opportunistic infections. One of the places this can happen is in the mouth, which is one of the few locations where C. albicans can grow as either a commensal or a pathogen. The authors took C. albicans that had been cultured in vitro and briefly infected the oral cavity of mice, then collected the fungi at intervals over a few days and analyzed them for genotypic and phenotypic changes.

The authors found that as few as 24 hours in the mouths of mice was enough to increase the diversity of colony appearance. Genotypic differences, including aneuploidy and loss of heterozygosity, became more common, too. Although the authors note that the transition from in vitro to in vivo systems—and back again—may be a contributing factor, this observation nonetheless demonstrates the astonishingly rapid diversification of C. albicans during infection. Among the genotypic differences identified, changes in chromosome number were relatively common; in particular, trisomy 6 was identified in C. albicans isolates from multiple mice. The authors suggest that this variation might confer advantages during infection, which could be a promising direction for future study.

They also analyzed the number of genetic events (e.g. aneuploidy, recombination) in different isolates, and strikingly, they found that isolates with more than five such events were more common than would be expected by chance. This was not true of C. albicans cultured in vitro, suggesting that a subpopulation of highly variable C. albicans were overrepresented after exposure to the oral niche. Whether the dramatic genetic rearrangements in these rare individuals are beneficial in the long-run—and how the host responds to such variation—remain questions to be explored.

CITATION:

Rapid phenotypic and genotypic diversification after exposure to the oral host niche in Candida albicans

Anja Forche, Gareth Cromie, Aleeza C. Gerstein, Norma V. Solis, Tippapha Pisithkul, Waracharee Srifa, Eric Jeffery, Darren Abbey, Scott G. Filler, Aimée M. Dudley, Judith Berman

Genetics July 2018 209: 725-741; https://doi.org/10.1534/genetics.118.301019

http://www.genetics.org/content/209/3/725

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The Y chromosome has an unanticipated role in sex-biased intron retention in Drosophila.

Differences between males and females in sexually dimorphic species stem in part from disparities in gene expression. This sex-biased expression can be achieved through numerous means, one of which is alternative splicing. In a recent study, Wang et al. investigated differences in one type of alternative splicing, called intron retention, in male and female fruit flies—and, in the process, they discovered an unanticipated role for the Y chromosome.

To survey intron retention in five parts of the fly (accessory gland, brain, ovary, testis, and whole body), the team used RNA-seq data from both the modENCODE project and their own lab. They found intron retention was pervasive: across all tissues of both sexes, they identified 21,664 instances of intron retention, the majority of which were previously unknown.

The retained introns most often interrupted coding sequences and included a premature stop codon. Since transcripts with premature stop codons are often targeted for nonsense-mediated decay, this intron retention could be a means of downregulating the genes in question. Among the genes with the most intron retention in the testis compared to the ovary were many involved in egg formation, lending credence to the idea that the intron retention is used to downregulate these genes. Also supporting this notion, Wang et al. found that transcripts with greater intron retention in one sex were also less abundant in that sex. However, it is possible that some transcripts with retained introns could yield functional proteins, opening the possibility that sex-biased intron retention could be used for more than simple downregulation of genes—a topic for future study.

Unexpectedly, the group also found that females carrying a Y chromosome in addition to their usual two X chromosomes had differences in intron retention compared to XX female flies. These differences were similar to the ones they observed when they compared intron retention in wild-type flies’ testes and ovaries, demonstrating that the mere presence of a Y chromosome has a major impact on intron retention. The Y chromosome in fruit flies—as in humans— contains a small number of protein-coding genes. By demonstrating the powerful effect a Y chromosome can have on intron retention, this study provides valuable insight into the often-unrecognized functions of sex chromosomes.

CITATION:

The Y Chromosome Modulates Splicing and Sex-Biased Intron Retention Rates in Drosophila
Meng Wang, Alan T. Branco, Bernardo Lemos
Genetics 2018 208: 1057-1067; https://doi.org/10.1534/genetics.117.300637
http://www.genetics.org/content/208/3/1057