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Customer case study Field of study: Evolutionary Biology Discovery of Gene Network Linked to Shifting Phenotype Offers Lessons in Evolution New research from Dartmouth bioinformatician Thomas Hampton and collaborators used a dual-stressor system to discover important aspects of evolution in a fish with unique phenotypic plasticity. QIAGEN’s Ingenuity Pathway Analysis helped them make the connection. Sample to Insight Thomas Hampton is no stranger to making sense of massive data sets. In fact, he’s built his career around solving mega-scale information problems. As a senior bioinformatics analyst at the Geisel School of Medicine at Dartmouth College and part of the Dartmouth Toxic Metals Superfund Research Program, Hampton deploys his expertise for a range of studies, from cancer to epithelial cells’ pathogen response to mercury in seafood. He focuses largely on gene expression, and uses Ingenuity Pathway Analysis (IPA) from QIAGEN to accelerate his research. In one recent study, Hampton and his Morphing mummichog collaborators used IPA to characterize genes underlying an important biological Hampton and his collaborators, including mechanism in Fundulus heteroclitus , a type Joseph Shaw at Indiana University and John of killifish. Their results were published Colbourne at the University of Birmingham, in Molecular Biology and Evolution in a chose to study killifish for a most unusual trait: paper entitled “Natural Selection Canalizes the fish is equally happy in fresh water or Expression Variation of Environmentally in salt water, due to its ability to change the Induced Plasticity-Enabling Genes.” morphology and function of its gills as needed to adjust for salinity levels in the water. “This is The paper sheds light on a poorly understood really special. They can remodel their gills on but critical trait in killifish, and would not have a week-to-week basis,” Hampton says. “This been possible without conducting a dual- would be like if anytime we needed to fly, we stressor study, Hampton says. Such studies just sprouted a pair of wings.” are rare in science because of concerns about “ That’s what Ingenuity helped us figure out. It’s an interesting result that suggests that evolution has acted not just on genes but on gene networks to make phenotypic plasticity happen. 2 confounding variability, but Hampton and his The on-demand ability to remodel its gills team were able to carefully craft their experi- makes this particular killifish, known as the ments and use IPA to determine the meaning of mummichog, interesting for research related to the gene expression data they generated. The wound healing or biological regeneration. It result is a new look at the scale of evolution is also an intriguing model for understanding in killifish, which may contribute to a better effects of climate change, since it can tolerate appreciation of how evolution functions in changes such as shifting salinity levels that other organisms too. are associated with global warming. At its Discovery of Gene Network Linked to Shifting Phenotype Offers Lessons in Evolution most basic level, remodeling a gill is a stress Fortunately, the team used IPA to dig deeper, response, so elucidating this mechanism in looking at the genes on a network level. killifish could also have a broader impact on “We found that the genes that facilitate phe- figuring out stress reactions in general. The notypic plasticity seem to be less connected work was funded by the National Institute of to other genes, almost as if they’re in their Environmental Health Sciences. own little world, ready to be activated in one direction or another to facilitate this process To study gill remodeling, the scientists had to without a lot of cross-talk from other systems,” use two different stressors: first, the fish were Hampton says. “That’s what Ingenuity helped moved from fresh water to salt water; second, us figure out. It’s an interesting result that they were exposed to trace amounts of arsenic suggests that evolution has acted not just on in the water to inhibit the mummichog’s ability genes but on gene networks to make pheno- to transform. While killifish, like many organ- typic plasticity happen.” isms, can tolerate arsenic well, previous work had shown that even small amounts of the toxin In the paper, Hampton and his co-authors could prevent the gill remodeling process. As write, “These findings also provide a gen- the killifish were exposed to both stressors, eralized, conceptual framework of how Hampton and his team interrogated gene genes might interact with the environment expression with custom arrays to reveal what and evolve towards the development of was going on. plastic traits.” Of course, seeing the expression levels from 135,000 probes is not inherently helpful. “If you measure all the genes in something, some are going to go up and some are going to go “Let Ingenuity Do Its Thing” down and you’re going to have a big problem on your hands trying to characterize what it Hampton’s lab covers a lot more than kil- means biologically,” Hampton says. That’s lifish. Stress response is a common theme why he uses IPA: “Ingenuity really jump-starts among his current projects, which include that process.” the evaluation of pathogen response from airway epithelial cells in humans; studies of In the killifish experiment, even gene expres- Daphnia water fleas; and cancer research, sion analysis was not terribly insightful. “The including melanoma and renal cell carci- kinds of genes engaged in this plasticity noma. He also hopes to follow up the mum- response were not that interesting, viewed from michog experiment with a project analyzing a distance,” Hampton says. “It looks like a these fish going from salt water to fresh to bunch of different genes that are not related see whether the same patterns of reduced to anything that makes a tremendous amount connectivity emerge. of sense.” Discovery of Gene Network Linked to Shifting Phenotype Offers Lessons in Evolution 3 “ Through it all, Hampton is glad to have IPA have to take courses or read vast manuals to When you get to who have been on diagnostic odysseys. RGI Ingenuity Variant Analysis is one tool in his toolbox. He uploads expression data get started,” he they’ve says. these dynamically derived networks, you’re going toto obtain enables patients genome or exome used for RGI patients, and Haraksingh says from arrays as well as from RNA-seq experisee things [with Upstream sequencing, often supported by “we crowdfundthat of he use makes the application a been making frequent ments and let Ingenuity doitsits ease thing,” Recently, Hampton has Regulator Analysis] that youing. neverBut would have still a lot there’s of data interpretation natural fityield for volunteers who other Regulator Analysis tool says. Reports from the application both use of come IPA’s from Upstream imagined because you required to get usefulexpected information to backgrounds. “It allows people who aren’t and back unexpected findings, allowing to get the bigger picture of what’s going on. don’t know the genes andpatients. you don’t know their the standard Often, analysis perexperts in genomics to quickly ask questions Hampton to get back to the lab more quickly He also focuses on network analysis, which relationships to each other. formed by sequencing to centers is not sufficient about the data without having to worry aboutfor putting findings in test new hypotheses. has proven valuable That’s hugely important, because you can’t be an these rare and particularly for understanding putting all the components together to make context. “When youthe get to these dynamically expert on every gene. challenging cases. best informatics pipelines,” she networks, says. “Variant IPA’s intuitive interface is one reason Hampton derived you’re going to see things Analysis is so intuitive and easy to use thathave imagined because uses it regularly. He remembers that even the that you never would “As the director of RGI’s 2.0 it, initiaable pick it upyou quickly.” first Science time he used “within they’re a couple of to hours, don’t know the genes and you don’t know tive, I lead a team of 12 researchers with the without any explanation whatsoever, I was their relationships to each other,” he says. mission of analyzing the genomic andprogress.” mediUltimately, Haraksingh hopes hugely that the deep because you can’t be actually making That’s not the case “That’s important, cal data from our patients try to figure out shethe canIPA provide patients will yield with tomost software. “You analysis can learn an to expert on every gene.” what’s going on,” Haraksingh says. Ultimately, progress, if not the exact answer, for each case interface on an as-needed basis. You don’t the volunteers write an in-depth research report — be it a new genetic lead or connecting the for each patient that is used to refer the case patient to a specialist who can provide more to outside specialists or garner knowledge for insight. “It’s been extremely gratifying to apply future research from RGI’s global network of my expertise in the nonprofit sector,” she says. scientists. QIAGEN Silicon Valley V 1700 Seaport Blvd. Third Floor Tel. +1 650 381 5100 Redwood City ty, CA 94063 Fax. +1 650 381 5190 info@ing genuityy.com www.ing genuityy.com © QIAGEN 2015. All Rights Reserved. Impact of Human Variation on Disease 4 Discovery of Gene Network Linked to Shifting Phenotype Offers Lessons in Evolution