Duke Research Blog

Following the people and events that make up the research community at Duke.

Category: Genetics/Genomics (Page 1 of 10)

Captive Lemurs Get a Genetic Health Checkup

DURHAM, N.C. — Careful matchmaking can restore genetic diversity for endangered lemurs in captivity, researchers report.

Ring-tailed lemurs born at the Duke Lemur Center have seen a recent infusion of new genetic material at key genes involved in the immune response, finds a new study.

Thanks to a long-term collaborative breeding program that transfers animals between institutions to preserve genetic diversity, genetic variation at one region was restored to levels seen in the wild.

The findings, published in the journal Ecology and Evolution, are important for the ability of future generations to fight disease.

Baby lemur twins Nemesis and Narcissa were the product of a breeding program developed by the American Association of Zoos and Aquariums to preserve the future genetic health of North America’s captive ring-tailed lemurs. Their mother Sophia was among 62 ring-tailed lemurs recommended for breeding across 20 institutions nationwide in 2016. Photo by David Haring, Duke Lemur Center.

Baby lemur twins Nemesis and Narcissa were the product of a breeding program developed by the American Association of Zoos and Aquariums to preserve the future genetic health of North America’s captive ring-tailed lemurs. Their mother Sophia was among 62 ring-tailed lemurs recommended for breeding across 20 institutions nationwide in 2016. Photo by David Haring, Duke Lemur Center.

Distant primate cousins with long black-and-white striped tails, ring-tailed lemurs live on the African island of Madagascar and nowhere else except in zoos and other captive facilities.

Some studies suggest that as few as 2,500 ring-tailed lemurs live in the wild today. Habit loss, hunting and the illegal pet trade have reduced their numbers by at least 50 percent in recent decades.

An additional estimated 2,500 ring-tailed lemurs live in zoos around the world, where experts work to maintain their genetic health in captivity.

The researchers studied DNA sequence variation at a region of the major histocompatibility complex, or MHC, a part of the genome that helps the immune system identify disease-causing bacteria, viruses and parasites.

Because different MHC gene variants recognize different types of pathogens, greater MHC diversity means animals are able to fend off a wider array of invaders.

The researchers estimated the number of MHC variants in 121 captive individuals born at the Duke Lemur Center and the Indianapolis and Cincinnati Zoos between 1980 and 2010.

They also compared them with 180 wild individuals from southwestern Madadgascar at the Bezà Mahafaly Special Reserve, where the animals regularly interbreed with lemurs from nearby forests.

Not surprisingly, MHC diversity was lower in captivity than in the wild.

Today’s captive ringtails came from a small group of ancestors that carried only a small fraction of the total genetic variation found in the larger wild population. Since their establishment, gene flow between captive populations and wild lemurs has been restricted.

Overall, the researchers found 20 unique MHC variants in the captive population, fewer than half the number in their wild counterparts.

However, efforts to identify good genetic matches across dozens of institutions have helped to preserve and even improve upon the diversity that is left.

For infants born at the Duke Lemur Center, MHC gene diversity remained low but stable for three decades from 1980 to 2010, then increased significantly from 2010 to 2013, researchers found.

Genetic contributions from several transplants contributed to the comeback.

An arranged marriage between ring-tailed lemurs at the Duke Lemur Center in North Carolina produced healthy twins Griselda and Hedwig in 2016. The infants are among 40 to 60 ring-tailed lemur infants born in North American zoos and other facilities each year. Photo by David Haring, Duke Lemur Center.

An arranged marriage between ring-tailed lemurs at the Duke Lemur Center in North Carolina produced healthy twins Griselda and Hedwig in 2016. The infants are among 40 to 60 ring-tailed lemur infants born in North American zoos and other facilities each year. Photo by David Haring, Duke Lemur Center.

The American Association of Zoos and Aquariums (AZA) tries to maintain a genetically healthy population by moving animals between institutions as potential mates. A team of experts uses computer software to help pick the best pairs for breeding.

Between 1980 and 2013, more than 1,160 ring-tailed lemurs were transferred between 217 institutions in North America alone.

In 2009, a male named Randy was transferred from the Saint Louis Zoo to the Duke Lemur Center for pairing with Sprite, a resident female. Experts also brought a mother-daughter pair, Schroeder and Leisl from the Zoo at Chehaw in Georgia, as potential mates for a resident male named Aracus.

“They saw an immediate improvement in the diversity of the offspring that were born,” said lead author Kathleen Grogan, who conducted the study while working on a doctorate with co-author Christine Drea at Duke University.

Grogan and colleagues are now examining whether MHC gene diversity helps the animals live longer or produce more offspring, as has been shown for other species.

“Not only do these lemurs serve as an assurance against extinction of their Malagasy counterparts, but maintaining as many variations of genes is important for keeping the individual lemurs, as well as the population healthy for any future challenges it may face,” said AZA Species Survival Plan Coordinator Gina Ferrie, a population biologist at Disney’s Animal Kingdom.

Conserving genetic diversity in captive populations over multiple generations is challenging due to their small size and relative isolation, but careful breeding can stem the loss, said Grogan, now a postdoctoral fellow at Pennsylvania State University.

Other authors include Michelle Sauther of the University of Colorado-Boulder and Frank Cuozzo at LaJuma Research Centre in South Africa.

This research was supported by Duke University, the International Primatological Society, Primate Conservation Inc., the University of Colorado-Boulder, the University of North Dakota, the National Science Foundation (BCS 0922465, BCS-1232570, IOS-071900), the Margot Marsh Biodiversity Foundation, the St. Louis Zoo and the American Society of Primatologists.

CITATION:  “Genetic Wealth, Population Health: Major Histocompatibility Complex Variation in Captive and Wild Ring-Tailed Lemurs (Lemur Catta),” Kathleen Grogan, Michelle Sauther, Frank Cuozzo and Christine Drea. Ecology and Evolution, Date. DOI: 10.1002/ece3.3317

Duke Scientists Visit Raleigh to Share Their Work

This post by graduate student Dan Keeley originally appeared on Regeneration NEXT. It is a followup to one of our earlier posts.

As a scientist, it is easy to get caught up in the day-to-day workflow of research and lose sight of the bigger picture. We are often so focused on generating and reporting solid, exciting data that we neglect another major aspect of our job; sharing our work and its impacts with the broader community. On Tuesday May 23rd, a group of graduate students from Duke went to the North Carolina legislative building to do just that.

L-R: Andrew George, Representative Marcia Morey (Durham County), Senator Terry Van Duyn (Buncombe County), Sharlini Sankaran, Dan Keeley, and Will Barclay at the NC legislative building.

Dr. Sharlini Sankaran, Executive Director of Duke’s Regeneration Next Initiative, organized a group of graduate students to attend the North Carolina Hospital Associations (NCHA) “Partnering for a Healthier Tomorrow!” advocacy day at the state legislature in Raleigh. The event gave representatives from various hospital systems an opportunity to interact with state legislators about the work they do and issues affecting healthcare in the state. Andrew George, a graduate student in the McClay Lab, Will Barclay, a graduate student in the Shinohara Lab, and I joined Dr. Sankaran to share some of the great tissue regeneration-related research going on at Duke.

Our morning was busy as elected officials, legislative staff, executive branch agency officials, and staff from other hospital systems stopped by our booth to hear what Regeneration Next is all about. We talked about the focus on harnessing Duke’s strengths in fundamental research on molecular mechanisms underlying regeneration and development, then pairing that with the expertise of our engineers and clinicians. We discussed topics including spine and heart regeneration mechanisms from the Poss Lab, advances in engineering skeletal muscle from the Bursac Lab, and clinical trials of bioengineered blood vessels for patients undergoing dialysis from Duke faculty Dr. Jeffrey Lawson.

It was remarkable to hear how engaged everyone was, we got great questions like ‘what is a zebrafish and why do you use them?’ and ‘why would a bioengineered ligament be better than one from an animal model or cadaver?’.  Every person who stopped by was supportive and many had a personal story to share about a health issue experienced by friends, family, or even themselves. As a graduate student who does basic research, it really underscored how important these personal connections are to our work, even though it may be far removed from the clinic.

Communicating our research to legislators and others at NCHA advocacy day was a great and encouraging experience. Health issues affect all of us. Our visit to the legislature on Tuesday was a reminder that there is support for the work that we do in hopes it will help lead to a healthier tomorrow.

Guest post by Dan Keeley, graduate student in BiologyDan Keeley

Scientists Engineer Disease-Resistant Rice Without Sacrificing Yield

Researchers have developed a way to make rice more resistant to bacterial blight and other diseases without reducing yield. Photo by Max Pixel.

Researchers have successfully developed a novel method that allows for increased disease resistance in rice without decreasing yield. A team at Duke University, working in collaboration with scientists at Huazhong Agricultural University in China, describe the findings in a paper published May 17, 2017 in the journal Nature.

Rice is one of the most important staple crops, responsible for providing over one-fifth of the calories consumed by humans worldwide. Diseases caused by bacterial or fungal pathogens present a significant problem, and can result in the loss of 80 percent or more of a rice crop.

Decades of research into the plant immune response have identified components that can be used to engineer disease-resistant plants. However, their practical application to crops is limited due to the decreased yield associated with a constantly active defense response.

“Immunity is a double-edged sword, ” said study co-author Xinnian Dong, professor of biology at Duke and lead investigator of the study. “There is often a tradeoff between growth and defense because defense proteins are not only toxic to pathogens but also harmful to self when overexpressed,” Dong said. “This is a major challenge in engineering disease resistance for agricultural use because the ultimate goal is to protect the yield.”

Previous studies have focused on altering the coding sequence or upstream DNA sequence elements of a gene. These upstream DNA elements are known as promoters, and they act as switches that turn on or off a gene’s expression. This is the first step of a gene’s synthesis into its protein product, known as transcription.

By attaching a promoter that gives an “on” signal to a defense gene, a plant can be engineered to be highly resistant to pathogens, though at a cost to growth and yield. These costs can be partially alleviated by attaching the defense gene to a “pathogen specific” promoter that turns on in the presence of pathogen attack.

To further alleviate the negative effects of active defense, the Dong group sought to add an additional layer of control. They turned newly discovered sequence elements, called upstream open reading frames (uORFs), to help address this problem. These sequence elements act on the intermediate of a gene, or messenger (RNA, a molecule similar to DNA) to govern its “translation” into the final protein product. A recent study by the Dong lab in an accompanying paper in Nature has identified many of these elements that respond in a pathogen-inducible manner.

The Dong group hypothesized that adding this pathogen-inducible translational regulation would result in a tighter control of defense protein expression and minimize the lost yield associated with enhanced disease resistance.

To test this hypothesis, the researchers started with Arabidopsis, a flowering plant commonly used in laboratory research. They created a DNA sequence that contains both the transcriptional and translational elements (uORFs) and fused them upstream of the potent “immune activator” gene called snc1. This hybrid sequence was called a “transcriptional/translational cassette” and was inserted into Arabidopsis plants.

When plants have snc1 constitutively active, they are highly resistant to pathogens, but have severely stunted growth. Strikingly, plants with the transcriptional/translational cassette not only have increased resistance, but they also lacked growth defects and resembled healthy wild-type plants. These results show the benefits of adding translational control in engineering plants that have increased resistance without significant costs.

The Dong group then sought to apply these findings to engineer disease-resistant rice, as it is one of the world’s most important crops. They created transgenic rice lines containing the transcriptional/translational cassette driving expression of another potent “immune activator” gene called AtNPR1. This gene was chosen as it has been found to confer broad spectrum pathogen resistance in a wide variety of crop species, including rice, citrus, apple and wheat.

The dry yellowish leaves on these rice plants are a classic symptom of bacterial blight, a devastating disease that affects rice fields worldwide. Photo by Meng Yuan.

The transgenic rice lines containing the transcriptional/translational cassette were infected with bacterial/fungal pathogens that cause three major rice diseases — rice  blight, leaf streak, and fungal blast. These showed high resistance to all three pathogens, indicating broad spectrum resistance could be achieved. Importantly, when grown in the field, their yield — both in terms of grain quantity and quality per plant — was almost unaffected. These results indicate a great potential for agricultural applications.

This strategy is the first known use of adding translational control for the engineering of disease-resistant crops with minimal yield costs. It has many advantages, as it is broadly applicable to a variety of crop species against many pathogens. Since this strategy involves activating the plants’ endogenous defenses, it may also reduce the use of pesticides on crops and hence protect the environment.

Additionally, these findings may be broadly applicable to other systems as well. These upstream elements (uORFs) are widely present in organisms from yeast to humans, with nearly half of all human transcripts containing them. “The great potential in using these elements in controlling protein translation during specific biological processes has yet to be realized,” Dong said.

Corresponding author Xinnian Dong can be reached at xdong@duke.edu or (919) 613-8176.

CITATION:  “uORF-Mediated Translation Allows Engineered Plant Disease Resistance Without Fitness Costs,” Guoyong Xu, Meng Yuan,   Chaoren Ai, Lijing Liu, Edward Zhuang, Sargis Karapetyan, Shiping Wang and Xinnian Dong. Nature, May 17, 2017. DOI: 10.1038/nature22372

 

Guest post by Jonathan Motley

The Road to a Tastier Tomato

This week, I discovered that I’ve lived life deprived of a good tomato.

As a tomato-lover, I was surprised to learn from Professor Harry Klee of the University of Florida that the supermarket tomatoes I’ve enjoyed throughout my 18-year existence are all flavorless compared to the tomatoes of the past. He spoke at Duke as a guest of the University Program in Genetics and Genomics on Feb. 28.

It turns out that commercial tomato growers, by breeding more profitable (i.e. higher-yield, redder-color, larger-fruit) tomato varieties over the past 50 years, inadvertently excluded what Klee believes is the most important tomato trait of all:

Commercial tomato growers have bred larger, redder tomatoes that are less flavorful than heirloom and older varieties. Image courtesy of Harry Klee.

Flavor.

Apparently, I was one of very few people unaware of this issue. The public outcry in response to the increasing flavorlessness of commercial tomatoes began over a decade ago, when Klee first began to study tomato genetics.

From his research, Klee has drawn several important, unexpected conclusions, chief among them:

1: Flavor has more to do with smell than taste;

2: Lesser-known biochemical compounds called “volatiles” influence the flavor of tomatoes more than sugars, acids, and other well-known, larger compounds;

3: These “volatiles” are less present in modern tomato varieties than in tastier, older, and heirloom varieties;

But fear not—

4: Tomatoes can be back-bred to regain the genes that code for volatile compounds.

In other words, Klee has mapped the way back to the flavorful tomatoes of the past. His work culminated in a cover story of the Jan. 27 issue of Science. The corresponding paper describing the analysis of over 300 tomato strains to identify the chemicals associated with “good” and “bad” tomatoes.

Dr. Harry Klee and collaborators in his lab at the University of Florida. Image courtesy of Harry Klee.

To prove that modern tomatoes have less of the compounds that make them tasty, Klee and his team recruited a panel of 100 taste-testers to rank 160 representative tomato varieties. According to Klee, the team “developed statistical models to explain the chemistry of ‘liking’ [tomatoes],” then narrowed down the list of compounds that correlated with “liking” from 400 to 26. After tracing these 26 compounds to genetic loci, they used whole-genome sequencing to show that these loci are less expressed in modern tomatoes than in “cerasiforme” (i.e. old) and heirloom tomato varieties.

Further studies showed that tomato weight is inversely correlated with sugar content—in other words, “a gigantic fruit doesn’t taste as good,” Klee said.

If Klee can convince tomato growers that consumers value flavor over size, color, and quantity, then he might just single-handedly put flavorful tomatoes back on the shelves. Nevertheless—and despite the publicity surrounding his work—Klee understands it make take a while before commercial tomato growers see the light.

Klee and his team of scientists have genetically mapped the way back to the tasty tomatoes of the past. Image courtesy of Harry Klee.

“Growers get no more money if the tomato tastes good or bad; they’re paid for how many pounds of red objects they put in a box…[but] we can’t just blame the modern breeders. We’ve been selecting bigger and bigger fruit for millennia, and that has come at the cost of reducing flavor,” Klee said.

Post by Maya Iskandarani

Science Meets Policy, and Maybe They Even Understand Each Other!

As we’ve seen many times, when complex scientific problems like stem cells, alternative energy or mental illness meet the policy world, things can get a little messy. Scientists generally don’t know much about law and policy, and very few policymakers are conversant with the specialized dialects of the sciences.

A screenshot of SciPol’s handy news page.

Add the recent rapid emergence of autonomous vehicles, artificial intelligence and gene editing, and you can see things aren’t going to get any easier!

To try to help, Duke’s Science and Society initiative has launched an ambitious policy analysis group called SciPol that hopes to offer great insights into the intersection of scientific knowledge and policymaking. Their goal is to be a key source of non-biased, high-quality information for policymakers, academics, commercial interests, nonprofits and journalists.

“We’re really hoping to bridge the gap and make science and policy accessible,” said Andrew Pericak, a contributor and editor of the service who has a 2016 masters in environmental management from the Nicholas School.

The program also will serve as a practical training ground for students who aspire to live and work in that rarefied space between two realms, and will provide them with published work to help them land internships and jobs, said SciPol director Aubrey Incorvaia, a 2009 masters graduate of the Sanford School of Public Policy.

Aubrey Incorvaia chatted with law professor Jeff Ward (center) and Science and Society fellow Thomas Williams at the kickoff event.

SciPol launched quietly in the fall with a collection of policy development briefs focused on neuroscience, genetics and genomics. Robotics and artificial intelligence coverage began at the start of January. Nanotechnology will launch later this semester and preparations are being made for energy to come online later in the year. Nearly all topics are led by a PhD in that field.

“This might be a different type of writing than you’re used to!” Pericak told a meeting of prospective undergraduate and graduate student authors at an orientation session last week.

Some courses will be making SciPol brief writing a part of their requirements, including law professor Jeff Ward’s section on the frontier of robotics law and ethics. “We’re doing a big technology push in the law school, and this is a part of it,” Ward said.

Because the research and writing is a learning exercise, briefs are published only after a rigorous process of review and editing.

A quick glance at the latest offerings shows in-depth policy analyses of aerial drones, automated vehicles, genetically modified salmon, sports concussions and dietary supplements that claim to boost brain power.

To keep up with the latest developments, the SciPol staff maintains searches on WestLaw, the Federal Register and other sources to see where science policy is happening. “But we are probably missing some things, just because the government does so much,” Pericak said.

Post by Karl Leif Bates

Nature vs. Nurture: Predicting Our Futures

Sitting in The Connection at the Social Science Research Institute in Gross Hall was intimidating. I was surrounded by distinguished people: professors, visiting professors from distinguished universities, researchers, and postdocs, all of whom had gathered together to view a showing of the documentary, Predict My Future: The Science of Us.

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Dr. Terrie Moffitt, a Duke professor. Image courtesy of Moffitt and Caspi.

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Dr. Avshalom Caspi, a Duke professor. Image Courtesy of Moffitt and Caspi.

Predict My Future documents the work of Terrie Moffitt and Avshalom Caspi, two Duke professors who study people in Dunedin, New Zealand. They have followed the lives of all the children born within a year in Dunedin for the last 40 years to measure genetics, personal habits, environment, jobs, physical attributes, and etc.  The Dunedin Longitudinal Study is the largest study of its kind and offers deep insights into how children become adults.

The episode, “The Early Years,” first posed the questions, “Why do some people become successful and others become outcasts? Why are we the way that we are?” By tracking all of these personal factors and some  behaviors, including risky sexual activities, criminal activities, and drinking and smoking habits, the Dunedin Longitudinal Study can answer these questions. The researchers can tell which children are likely to become “problem children,” “geniuses,” and so on, based on the child’s personality type.

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Q&A Session After the Viewing of the Documentary. Image Courtesy of Duke SSRI and Taken By Shelbi Fanning.

The study first identified five different personality types in young children, and researchers discovered that the children’s’ personality types did not change in adulthood. The three personality types that are typically associated with doing well in life, having better health, having friends, and being more successful are: “well-adjusted,” “reserved,” and “confident.” The two personality types associated with having poorer quality of life in adulthood are “inhibited” and “undercontrolled.”

Then, the study identified other factors that lead to serious consequences later in life or simply predict futures. Children who experienced delays in walking and in talking were likely to have issues with brain development. Boys with these traits typically disliked school, did poorly in school, and were more likely to be involved in criminal activity.

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The full house watching the documentary. Image Courtesy of Duke SSRI and Taken by Shelbi Fanning.

The amount of sleep children received between the ages of five and eleven would determine obesity in adulthood. Adults who received the least amount of sleep as children tended to be obese by age 32.

Schizophrenia, researchers discovered, starts developing in young children, not just adults as had previously been thought. About half of the 11-year-olds in the study who said they had seen or heard things that weren’t there had developed schizophrenia two decades later.

Watching more TV was associated with a higher likelihood of smoking and having anxiety. Regardless of IQ or environment, children who watched more TV were more likely to leave school without qualifications.

The important lesson the documentary emphasized was that having a good childhood is important. Warm, sensitive, stimulating, family-feeling invoking environments are great protective factors to risk factors.

Overall, this was a brilliant, stimulating, easy-to-understand documentary.

meg_shieh_100hedPost by Meg Shieh

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