A study from School of Biology Professor Greg Gibson’s group just published in the American Journal of Human Genetics argues that we should be looking not just at the structural parts of genes, but also the regulatory regions around them. The paper demonstrates that there is a burden of rare genetic variants in these regions that associates with abnormal gene expression. It does not show that they cause birth defects, but does suggest that they need to be seriously considered as WGS technology develops.
Gibson explains it in the form of a metaphor about building a house. He says there are two critical components: the bricks and mortar, and the plans for where to put them. If there is a defect in the glass or a crack in a piece of wood, then sooner or later the structure may fall apart. This is what current approaches focus on, the so-called protein coding-regions. But if the architect’s plans call for more windows than the beams can support, or the contractor doesn’t deliver enough concrete, then the consequences can be just as bad.
We now know that a lot more of the genetic component of differences in the way we look and behave, or of what makes us susceptible to different diseases, is in the planning than the structural components. This insight is based on studies of common polymorphisms, namely the millions of genetic differences that we all share. The new study argues that it will also be true of rare genetic variants including new mutations that are specific to a single person.
Graduate student Jing Zhao sequenced the regulatory regions of almost 500 genes from 500 participants in the Georgia Tech-Emory Predictive Health Institute study, and added up the number of rare mutations in people whose expression of those genes was toward the extremes. The result is what she calls a smile plot, because the curve has a high number at either end and low number in the middle. It means that the plans can be off in either direction, making too little or too much transcript for each gene. Explains Gibson, it is as if all the houses with crooked window frames are that way not because of the wood quality, but because each builder made different mistakes when putting the frames in.
Furthermore, there seem to be specific subsets of genes where these events are more or less likely to happen. This is important, because it implies that we may be able to develop algorithms that identify the most likely places for regulation to go wrong, based on the evolutionary conservation of different parts of genes.
Projects such as the President’s Precision Medicine initiative aim to use genomics to help us decipher individual causes of disease. In the next few years, Gibson expects that much larger datasets of tens and eventually hundreds of thousands of people, in many different tissues, will appear. The challenges are as much in the bioinformatics than the technology.
A Burden of Rare Variants Associated with Extremes of Gene Expression in Human Peripheral Blood.
Zhao J, Akinsanmi I, Arafat D, Cradick TJ, Lee CM, Banskota S, Marigorta UM, Bao G, Gibson G.
Am J Hum Genet. 2016 Feb 4;98(2):299-309. doi: 10.1016/j.ajhg.2015.12.023. PMID: 26849112
On April 20, 2010, an explosion on the Deepwater Horizon (DWH) oil rig released a torrent of oil at the seafloor of the Gulf of Mexico, discharging close to 5 million barrels of oil in 87 days. It was the largest accidental oil spill in U.S. history.
Six years hence, the visible signs of the DWH disaster are fading, and the public may be lulled into assuming that all is fixed and well. In fact, many questions remain, and scientists continue to work tirelessly to address them. They include the team of Joel E. Kostka, a professor of biology in Georgia Tech’s College of Sciences. The hope is to develop effective spill mitigation and remediation technologies by understanding the effects of oil spills on marine environments. Kostka’s work on microbial oil degradation seeks to harness natural processes and native microorganisms to address disastrous oil spills.
Kostka’s research is part of the Gulf of Mexico Research Initiative (GoMRI), a 10-year, $500 million independent research program to study the impacts of the DWH oil spill and gain fundamental understanding of the dynamics of such events. Within GoMRI, the Kostka lab is funded under the Center for Integrated Modeling and Analysis of Gulf Ecosystems (C-IMAGE), a research consortium of 19 U.S. and international partners, led by the University of South Florida. Their goal is to advance the understanding of the processes, mechanisms, and environmental consequences of marine oil blowouts.
“We incorporate laboratory experimentation, field-oriented assessments, and modeling to predict the long-term fate and degradation of oil on Gulf ecosystems, especially at the seafloor.” Kostka says. "An especially exciting component of C-IMAGE is that we are comparing the effects of the DWH spill, in the northern Gulf of Mexico, to those of the Ixtoc spill, which occurred in 1979 near Campeche Bay, in the southern Gulf of Mexico." The Ixtoc spill was nearly as large as the DWH spill.
To understand the dynamics and impact of oil spills, the Kostka lab studies the microorganisms that break down oil. “We hypothesize that, similar to the breakdown of natural organic matter, biodegradation mediated by microbes is the ultimate fate of most of the spilled oil that enters the marine environment.” Thus, the Kostka lab studies how fast is, and what controls, the microbial degradation of oil in order to direct the management and cleanup of contaminated ecosystems.
During the DWH discharge in 2010, emergency responders used oil plume models to predict where the oil would go. However, microbial degradation of the oil was not included in most of the models, Kostka observes, “even though we know that a lot of the oil will be eaten by microbes.”
The Kostka lab now has measured how fast the oil was degraded in the deep waters and sediments in the northern Gulf of Mexico. “If there was an oil spill today, we could better predict where oil would go,” Kostka says, “because the model could include our measurements of biodegradation speeds under different oceanographic conditions.”
Working with scientists at Florida State University, Kostka and his team have studied the fate of the DWH oil that landed on Florida beaches and the microbes that degraded the oil. “Since beaches are exposed on shore, we could more easily follow the fate of the deposited oil,” Kostka says. “For the first time, we used state-of-the-art metagenomic techniques to track the oil-eating microbes for a period of more than one year after the oil it was deposited at Pensacola Beach in June 2010.”
Metagenomes are made up of all the genes from all the organisms present in the environment. The genetic sequences in the metagenome reveal the functions of microbes in the sample.
“Specific microbial groups were clearly related to how fast and which oil compounds were degraded,” Kostka says. “If there was an oil spill today, we would be able to tell responders how fast the oil would likely be degraded by microbes.”
On the Florida beaches impacted by the DWH discharge, the Kostka lab has also identified microbial groups that could be used as sentinels, or bioindicators, to tell responders whether important ecosystem services – such as organic matter decomposition and nutrient regeneration – are affected by oil exposure on the beach. “Now that we have established a baseline for the microbes present in beaches by using metagenomics, we could also advise environmental managers as to when the ecosystems are restored to close to the original condition.”
One interesting question that the research has raised is whether the Gulf is really a unique environment for microbes that eat oil.
Scientists had believed that because of the abundance of natural oil seeps in the Gulf, microbes there have adapted to oil and are therefore able to degrade oil quickly, Kostka says. However, comparing the rates at which microbes in the Gulf eat oil with those in other oceans such as the Beaufort Sea in the Arctic Ocean indicates that microbes in different waters degrade oil at similar rates under similar environmental conditions, Kostka’s research has found.
“The finding suggests that oil-eating microbes are present nearly everywhere and are capable of responding to oil spills under the right conditions,” Kostka says. This new hypothesis is supported by recent results showing that the plants of the sea – single-celled marine phytoplankton – naturally produce oil-like chemical compounds, which are eaten by other microbes. Thus, chemicals present in crude oil are naturally produced and consumed all the time nearly everywhere in the world’s oceans.
“The microbial potential for oil cleanup or mitigation appears to be naturally present in the world’s oceans,” Kostka says. “We just need to better understand the controls of that potential to be able to enhance cleanup and predict the fate of spilled oil.”
Biology Professor Jeff Skolnick has been awarded $2.44 million by the National Institutes of Health to study how to repurpose FDA approved drugs to treat genetic diseases. The 5 year project is entitled “Interplay of inherent promiscuity and specificity in protein biochemical function with applications to drug discovery and exome analysis” under the General Medical Sciences section. The project focuses on the gap in how to interpret the information in the enormous number of sequenced human exomes in terms of the functional consequences of the observed variations in amino acids and their connection to human diseases. This gap also underlies the failure to develop drugs, without side effects, to treat these diseases. This failure is exacerbated by the fact that a given drug molecule binds to different proteins involved in numerous cellular processes. This project lays out the details as to how and why these problems occur, and in the context of protein structure, how our existing and proposed progress can help surmount them. Skolnick’s group will first elucidate the design principles underlying protein structure and function and then apply them to repurpose FDA approved drugs to treat Mendelian diseases and to identify the genetic variations underlying such diseases. They will examine whether the stereochemical space of small molecule drugs and endogenous metabolites is complete and also the differences in the properties of drugs and metabolites. From these analyses, they will suggest how binding specificity might emerge from a highly promiscuous background. This might enable the design of better drugs with minimal side effects and a better understanding of how cells work. Employing these insights, they then will develop better structure-based approaches to virtual ligand screening and enzyme function inference. The ability to predict enzymatic function is particularly essential as residue mutations associated with loss of enzymatic function are the most important missense mutations associated with Mendelian disease. These approaches will use the conservation of ligand-protein microenvironments in stereochemically similar ligand binding sites or active sites in different proteins, regardless of their evolutionary relationship. They will explore the biochemical consequences of a class of enzymes that they discovered – dizymes, single domain proteins that perform two different enzymatic activities at two different active sites. For representative cases, They will experimentally test their predictions of ligand binding and enzymatic activity and their influence on cellular biochemical function. All developed tools will be combined in a comprehensive exome annotation approach. First, it will identify disease associated residue variations. Then, it will predict diseases a protein might be associated with and suggest the best protein targets. Finally, it will suggest what might be the best drugs to treat the disease.
Dr. Sam Brown, Associate Professor of Biology, was just awarded a $600K, 3 year grant from the Simons Foundation for a project entitled “How do quorum-sensing bacteria sense and respond to their social and physical environment?”This project investigates collective decision making in bacteria by exploring how bacteria collectively sense and respond to their environment via a form of cell-cell communication known as quorum-sensing (QS). Despite the widespread interest in QS from molecular mechanisms to social evolution and pathogen control, there is still controversy over the basic evolutionary function of QS – in short, why do bacteria use QS? The standard answer is that cells produce extracellular signals to serve as a proxy for cell density – more signal implies more bacteria. However, inferences to density can be confounded as signal concentration will also vary with changes in the physical environment (diffusion, flow) and other aspects of social organization (spatial patterning, genotypic mixing), leading to a list of alternative hypotheses (e.g. diffusion, efficiency, and genotype sensing).
Current functional hypotheses and mathematical models focus on the limits of inference to physical and/or social environmental variation, given the production and sensing of a single signal type. However, molecular characterization of QS systems often reveals the use of
multiple distinct extracellular signal molecules. To overcome this persistent gap between
functional hypotheses and molecular mechanism we will develop and test theory on the functional roles and limits of multi-signal QS, using the widely studied environmental generalist microbe Pseudomonas aeruginosa (PA). Our central hypotheses are that QS bacteria can (1) simultaneously resolve their social and physical environment, via non-linear processing of multiple signals with differing environmental properties and (2) use simple signal-mediated rules to limit collective behaviors to clonal high density, low diffusion, low flow environments. The proposed research will leverage Georgia Tech’s expertise in spatial math modeling, ‘lab-on- a-chip’ environmental manipulation, high-throughput microbial imaging and evolutionary microbiology.
Biology major June Y. (Austin) Moon has been awarded the Virginia C. and Herschel V. Clanton Jr. Scholarship, for a top pre-medical student in the College of Sciences. Moon participates in undergraduate research with the School of Biology’s Yuhong Fan, in whose lab he studies differentiation of mouse embryonic stem cells. He served as treasurer of the American Red Cross Club at Georgia Tech and is now the advocacy coordinator of the American Medical Student Association at Georgia Tech. A total of six undergraduate awardees in the College of Sciences were announced at the College’s Advisory Board meeting on April 22, 2016, by Associate Dean for Academic Affairs David M. Collard.
Moon was honored along with the five other undergraduate awardees in the campus-wide Student Honors Celebration on April 20, 2016. “That event is an important opportunity in the academic calendar year to recognize the outstanding accomplishments of our students,” says Associate Dean Collard. Moon also joined the College of Sciences Advisory Board Members, Dean Paul M. Goldbart, and guests at the College’s awards presentation and lunch on April 22.
“Introducing our award winners to members of our Advisory Board is a particular honor,” says Associate Dean Collard. “It is something I look forward to each year.”
G. David Williamson, senior science adviser at the Centers for Disease Control and Prevention (CDC), has been elected as a vice president of the American Statistical Association (ASA).
Williamson is senior science adviser and executive director of the Statistical Advisory Group at the CDC and an adjunct professor in the department of biostatistics and bioinformatics in the school of public health at Emory University and at Georgia Southern University. Prior to that, he was the associate director of science at the CDC’s National Center for Injury Prevention and Control; chief science officer in the Office of Surveillance, Epidemiology and Laboratory Services; and director of the Division of Health Studies.
Williamson earned his PhD in biostatistics from Emory University in 1987; two master’s degrees in statistics and biology from Virginia Tech and Georgia Southern, respectively; and an undergraduate degree in biology from the Georgia Institute of Technology in 1973.
Among his appointments with the ASA, Williamson became a fellow in 2004 and was Joint Program Committee chair of JSM in 2000. Active in ASA awards and committees, he also served as vice chair of the Committee on Meetings from 1999–2002; chair (and member) of the Karl Peace Award from 2012–2015; member of the Strategic Initiative on Visibility and Impact in Policy Task Force in 2009–2010; and program chair of the Statistics in Epidemiology Section in 1997.
About the American Statistical Association
The ASA is the world’s largest community of statisticians and the oldest continuously operating professional science society in the United States. Its members serve in industry, government and academia in more than 90 countries, advancing research and promoting sound statistical practice to inform public policy and improve human welfare. For additional information, please visit the ASA website at www.amstat.org.
School of Biology Professor and Harry and Linda Teasley Chair Mark E. Hay has been elected a Fellow of the Ecological Society of America (ESA). ESA fellows are members who have made outstanding contributions to a wide range of fields served by ESA, including, but not restricted to, those that advance or apply ecological knowledge in academia, government, non-profit organizations, and the broader society. They are elected for life.
Hay is being recognized for advancing the science of ecology. Specifically, Hay is credited for seminal contributions to understanding community organization, consumer-prey interactions, and the chemical cues regulating biotic interactions in aquatic ecosystems.
An experimental ecologist, Hay has been revolutionizing marine conservation and management and is a founder of the field of marine chemical ecology. For the past four decades, he has led scientific expeditions to remote regions to study the processes and mechanisms that control the organization, function, and sustainability of natural ecosystems.
“Mark links the design of field experimentation with laboratory analysis in ways that reinforce, and often revise or invent, ecological theory,” comments Alan P. Covich, a professor of ecology at the University of Georgia.
Among Hay’s seminal contributions, James A. Estes singles out the identification and demonstration of the interplay between plant secondary metabolites and species interactions in ocean systems. Estes is a professor of ecology and evolutionary biology at the University of California, Santa Cruz. These early research findings, Estes says, have led to key discoveries – such as the multiple functionality of secondary metabolites – and “an integrated view of the ecological importance of plant secondary metabolites across marine, freshwater, and terrestrial ecosystems.”
Notably, Hay’s pioneering work was carried out in remote areas of the world, like Fiji, that otherwise would lack long-term ecological research, comments Mary E. Power, a professor of integrative biology at the University of California, Berkeley. “Mark and his graduate students overcame logistical and cultural challenges to maintain prolonged field studies of reefs in remote tropical areas.”
And according to Georgia Tech School of Biology Professor Joshua S. Weitz, through outreach, education, and communication efforts, Hay “has transformed conservation practices for coral reefs and helped support the next generation of marine ecologists.”
Recently, Hay’s work has enabled scientists to “listen” to the conversations of marine organisms, carried out with chemical signals. Hay is learning to treat marine environmental collapse by understanding the chemical communication of critical marine organisms.
“Mark’s accomplishments make us beam with pride,” says College of Sciences Dean Paul M. Goldbart. “Mark is an exemplary scientist and educator, inspiring students and colleagues alike.”
In April, Hay received the Georgia Tech Outstanding Faculty Research Author Award, in recognition of his highly impactful publications.
A skilled science communicator, Hay has shared his discoveries with various nonexpert audiences, including village chiefs in Fiji. His work has been featured in the Wall Street Journal, the New York Times, BBC, NPR, and other global media outlets. For being at the forefront of conservation science, Hay received the prestigious Lowell Thomas Award from the Explorers Club in 2015.
For More Information Contact
A. Maureen Rouhi
Director of Communications
College of Sciences
Science and technology may not be one’s first thoughts at the mention of Colombia, the Latin American country that is emerging from more than half a century of armed conflict. Much about Colombia is lost in stereotypes, including its robust educational system, according to King Jordan. “Colombia has consistently defied my expectations arising from what we hear in the news,” he says.
An associate professor in the School of Biology and the director of Georgia Tech’s Bioinformatics Graduate Program, Jordan is poised to contribute to the country’s education and development of a knowledge-based economy. For six weeks beginning on June 20, 2016, he will conduct a Fulbright-supported workshop at Universidad Tecnológica del Chocó (UTech) to train Colombians in the use of databases and computer programs to analyze genomic information. He will also help develop a curriculum for a post-Bachelor specialization in bioinformatics.
Bioinformatics is where computer science and biology intersect. Scientists in the field develop and apply computational tools to address fundamental biological problems. Bioinformatics analyses of human genome sequences can uncover individuals’ genetic ancestry, as well as traits such as predisposition to disease. At Georgia Tech, Jordan uses bioinformatics to investigate the relationship between human genetic variation and health.
This summer trip continues Jordan’s years-long collaboration with Colombia and other Latin America countries as they strive to build national capacity for bioinformatics research.
Latin American populations have a mixture of ancestry from Africa, Europe, and the Americas, and Colombia’s ancestry is particularly diverse, Jordan says. The genetic mixing that occurred in the region over the past 500 years has created genome sequences that, Jordan says, “are novel in containing combinations of ancestry-specific alleles that never previously existed on the same genomic background. We want to understand the health-related implications of the emergence of this novel set of admixed genomes in Latin America.”
Colombia has about 11 million inhabitants of African descent, making it the country with the third highest population of African descendants in the Americas, after Brazil and the U.S. Located on the Pacific Coast, the state of Chocó has a uniquely African genetic heritage with admixture from Europe and the Americas, Jordan says.
The people of Chocó have an intense interest in both genetic ancestry and predisposition to disease, says Miguel Medina. The UTech professor of biology first met Jordan in 2014 at a conference where Jordan presented bioinformatics analyses of genomes from inhabitants of Medellín, who are predominantly of European descent. Medina invited Jordan to do similar work on the inhabitants of Chocó, 94% of whom are of African descent. To help establish bioinformatics formally in UTech, Medina and Jordan applied for a Fulbright grant to support Jordan’s visit this summer as a Fulbright Specialist in Biology Education.
Despite a number of studies on the genetic ancestry of Colombians, little research has focused on the Afro-Colombian population. Characterizing the genetic heritage of Chocó would a fuller picture of the scope of ancestry in Latin American populations, Jordan says, as well as reveal connections between genetic ancestry and health.
Working with the National Institutes of Health, Jordan and Medina have built a database of genomic sequences from samples provided by 100 inhabitants of Chocó. This pilot project was funded by the Denning Global Engagement Seed Fund, from Georgia Tech’s Office of the Vice-Provost for International Initiatives. That funding flowed from Georgia Tech’s strategic goal to expand its global footprint, Jordan explains. However, he emphasizes, the samples and the data generated by that funding belong to the people of Chocó.
For data analysis, UTech has formed a collaborative research partnership with BIOS, Colombia’s Center for Bioinformatics and Computational Biology; Georgia Tech; and the PanAmerican Bioinformatics Institute. Called ChocoGen, the project aims discover and characterize the genetic heritage of the people of Chocó. ChocoGen researchers are analyzing the genomic sequences of donors from Chocó to characterize their genetic ancestry; the quantity and nature of admixture between ancestral populations; and the possible relationship between ancestry, admixture, and genetic determinants of health and disease.
Over the course of six weeks this summer, Jordan will be training a diverse group of Colombian bioinformatics enthusiasts, teaching, and developing curriculum. And with Medina, Jordan will meet with government leaders to secure funding for future research and development in bioinformatics. His hope is not only to set the stage for a new research activity to take root but also to ensure that it grows strong.
For More Information Contact
A. Maureen Rouhi
Director of Communications
College of Sciences
For plants and animals fleeing rising temperatures, varying precipitation patterns and other effects of climate change, the eastern United States will need improved “climate connectivity” for these species to have a better shot at survival.
Western areas of the U.S. provide greater temperature ranges and fewer human interruptions than eastern landscapes, allowing plants and animals there to move toward more hospitable climates with fewer obstacles. A new study has found that only 2 percent of the eastern U.S. provides the kind of climate connectivity required by species that will likely need to migrate, compared to 51 percent of the western United States.
The research, reported June 13 in the journal Proceedings of the National Academy of Sciences, for the first time quantifies the concept of climate connectivity in the United States. The paper suggests that creating climate-specific corridors between natural areas could improve that connectivity to as much as 65 percent nationwide, boosting the chances of survival by more species. The issue is especially critical in the Southeast, which could provide routes to cooler northern climates as temperatures rise.
“Species are going to have to move in response to climate change, and we can act to both facilitate movement and create an environment that will prevent loss of biodiversity without a lot of pain to ourselves,” said Jenny McGuire, a research scientist in the School of Biology at the Georgia Institute of Technology. “If we really start to be strategic about planning to prevent biodiversity loss, we can help species adjust effectively to climate change.”
Creating and maintaining connections between natural areas has long been thought critical to allowing plants and animals to move in search of suitable climate conditions, she explained. Some species will have to move hundreds of kilometers over the course of a half-century.
McGuire and her collaborators set out to determine the practicality of that kind of travel and test whether these human initiatives could improve migration to cooler areas. Using detailed maps of human impact created by David Theobald at Conservation Partners in Fort Collins, Colorado, they distinguished natural areas from areas disturbed by human activity across the United States. They then calculated the coolest temperatures that could be found by moving within neighboring natural areas.
Co-authors Tristan Nuñez from the University of California Berkeley, Joshua Lawler from the University of Washington, Brad McRae from the Nature Conservancy and others created a program called Climate Linkage Mapper. They then used this program to find the easiest pathways across climate gradients and human-disturbed regions to connect natural areas.
“A lot of these land areas are very fragmented and broken up,” McGuire said. “We studied what could happen if we were to provide additional connectivity that would allow species to move across the landscape through climate corridors. We asked how far they could actually go and what would be the coolest temperatures they could find.”
With its relatively dense human population and smaller mountains, the eastern part of the United States fell short on climate connectivity. The western part of the country – with its tall mountains, substantial undisturbed natural areas and strict conservation policies – provided much better climate connectivity.
Improving connectivity would require rehabilitating forests and planting natural habitats adjacent to interruptions such as large agricultural fields or other areas where natural foliage has been destroyed. It could also mean building natural overpasses that would allow animals to cross highways, helping them avoid collisions with vehicles.
Not only will animals have to move, but they’ll also need to track changes in the environment and food, such as specific prey for carnivores and the right plants for herbivores. Some birds and large animals may be able to make that adjustment, but many smaller creatures may struggle to track the food and climate they need.
“A lot of them are going to have a hard time,” said McGuire. “For plants and animals in the East, there is a higher potential for extinction due to an inability to adapt to climate change. We have a high diversity of amphibians and other species that are going to struggle.”
The negative impacts of climate change won’t affect all species equally, McGuire said. Species with small ranges or those with specialist diets or habitats will struggle the most.
“Not all plants and animals will have to move,” she explained. “There is a subset of them that will be able to hunker down where they are. There will be some species that are really widespread and will end up just having some population losses. But especially for species that have smaller ranges, there will be some loss of biodiversity as they are unable to jump across agricultural fields or major roadways.”
The Southeast, especially the coastal plains from Louisiana through Virginia, could create a bottleneck for species trying to move north away from rising temperatures and sea levels. “The Southeast ends up being a really important area for a lot of vertebrate species that we know are going to have to move into the Appalachian area and even potentially farther north,” she added.
In future work, the researchers hope to examine individual species to determine which ones are most likely to struggle with the changing climate, and which areas of the country are likely to be most impacted by conflicts between humans and relocating animals.
“We see a lot of species’ distributions really start to wink out after about 50 years, but it is tricky to look at future predictions because we will have a lot of habitat loss predicted using our models,” McGuire said. “Change is perpetual, but we are going to have to scramble to prepare for this.”
The research was supported by the U.S. National Park Service and by the Packard Foundation.
CITATION: Jenny L. McGuire, Joshua J. Lawler, Brad H. McRae, Tristan Nuñez, and David Theobald, “Achieving climate connectivity in a fragmented landscape,” (Proceedings of the National Academy of Sciences, 2016). www.pnas.org/cgi/doi/10.1073/pnas.1602817113
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Writer: John Toon