David Reif was a member of the Working Group that drew experts from 13 countries to a meeting in Lyon, France in order to evaluate the carcinogenicity of the the insecticides gamma-hexachlorocyclohexane (lindane) and dichlorodiphenyltrichloroethane (DDT) and the herbicide 2,4-dichlorophenoxyacetic acid (2,4-D).
It’s 2015, and the link between inherited DNA variation and numerous diseases is well-established. However, an important question remains – how, exactly do these links between genetic variation and disease work? The Genotype-Tissue Expression (GTEx) project, funded by the National Institutes of Health and including a team of researchers from NC State and UNC-Chapel Hill, aims to start answering that question by looking at how genetic variation affects gene expression.
“Important gaps still remain in understanding genetic processes, which vary greatly across the organs and tissues of the human body,” says Fred Wright, professor of statistics and biological sciences at NC State. “We have little understanding of how genetic variants actually cause disease, because we haven’t been able to look at the gene expression part of the equation. GTEx aims to fill the knowledge gap between the DNA you’re born with and actual disease outcomes.”
“You can think of DNA as the controller of a giant genetic switchboard,” explains Wright’s collaborator Andrew Nobel, professor of statistics and operations research at UNC-Chapel Hill. “When DNA switches on a gene, the gene produces proteins with specific functions. In the case of many common diseases, relatively small changes in protein output can have profound effects on disease risk.”
The GTEx project took samples of a large variety of tissues from 175 recently deceased individuals, measuring gene expression in those tissues. First, the researchers established that nearly normal gene activity persists for several hours after death. Then the major task of connecting variation in DNA to expression began. This is where Wright, Nobel and their team came in – to find meaningful correlations among all the “noise.”
“We had data for millions of DNA variants and how each variant was related to gene expression in different tissues,” Wright says. “Since we were looking at multiple tissues, there were gaps and overlaps in the data. We had to come up with a mathematical/statistical model that could assess, for each DNA variant and each gene, the evidence for the variant-gene combination being active for each of the tissues. The data were analyzed all together, but we untangled associations that reflected underlying true biology, versus associations that were happenstance because of sample overlap.”
Initial results were promising. The group found that DNA variants that affect expression tend to do so either in one tissue alone, or in all the examined tissues. Groups within GTEx are now comparing the results of the model to each variant-disease association, helping us further narrow down the genes that the variants affect, and in which tissue. The work may bring us one step closer to personalized therapies for numerous diseases.
The results appear in Science (DOI: 10.1126/science.1262110). NC State co-authors include Yi-Hui Zhou, research assistant professor of biological sciences. Funding was provided by the National Institutes of Mental Health and the NIH Common Fund.
Eric Stone, professor in the Department of Biological Sciences, and Bioinformatics Research Center Professor will receive $200,000 to purchase a NextSeq 500 DNA sequencer that will expedite research projects such as biofuel generation, pollution surveying and remediation, and agricultural crop improvement.
Researchers from North Carolina State University’s Center for Human Health and the Environment (CHHE) have received a five-year, $6.5 million grant from the National Institute of Environmental Health Sciences (NIEHS) to investigate the effects of environmental factors on human health.
The primary mission of the CHHE is to understand how human health, of both individuals and populations, is affected by environmental factors and to use this knowledge to prevent or reduce negative environmental impacts on health. Through interdisciplinary research and collaboration, the CHHE wants to construct a complete picture of how environmental stressors interface with pathways, the genome and epigenome.
The grant will be used to further the CHHE’s work by advancing interdisciplinary research in the field of environmental health and supporting community outreach and engagement regarding environmental health issues.
The NIEHS grant will make the CHHE one of 22 centers across the U.S. dedicated to studying environmental health impacts. “Through the purposeful interfacing of different disciplines, CHHE will build on NC State’s unique research and community outreach strengths to make significant contributions to understand and prevent the adverse impacts of environmental factors on human health” says Rob Smart, William Neal Reynolds Distinguished Professor of Biological Science at NC State and director of the CHHE.
The CHHE was founded in 2011 and brings together 70 investigators from 13 departments and six colleges at NC State and as well as investigators from East Carolina University, Brody School of Medicine, North Carolina Central University, NC Department of Health and Human Services, and RTI NIH Eastern Regional Comprehensive Metabolomics Resource Core.
A mere four days after finishing his Post-Doc at SAMSI and the Bioinformatics Research Center, some results of Chris Nasrallah’s work have appeared in the FiveThirtyEight blog.
Researchers from North Carolina State University and across the U.S. conducted the first large-scale cell-based screening to test variations in environmental chemical sensitivity across a range of human populations and link those variations to genetic data. The data will improve risk assessment, and shed light on the ways in which our genes interact with certain chemicals. Testing chemicals for potential human health hazards involves large-scale programs that test hundreds of chemicals in vitro – by exposing a cell culture to differing concentrations of a chemical and recording various responses in hundreds of assays. However, these cell-based tests are usually derived from either rodents or a small sample of humans.
Current NCSU Bioinformatics Research Center Director, Fred Wright and Texas A&M professor of veterinary integrative biosciences Ivan Rusyn, while both on faculty at UNC-Chapel Hill, partnered with the researchers at the National Institute of Environmental Health Sciences and National Center for the Advancement of Translational Sciences to conduct this large-scale experiment. They obtained cell lines from 1,086 individuals who had volunteered their genetic data as part of the 1,000 Genomes Project. The cell lines represented nine different genetic populations spread over five continents. They then exposed cells to 180 different chemicals at eight different concentrations each.
The data revealed that, for some chemicals, the range of sensitivity among individuals was greater than previously thought. The NC State team, including faculty members Alison Motsinger-Reif and Yi-Hui Zhou, was instrumental in discovering several genetic variations that correlated to chemical sensitivity. Most of the genes involved are associated with the way foreign substances get transported across cell membranes.
‘This broad, cross-disciplinary academic-governmental partnership is a model that will fuel important discoveries in environmental health and biomedical sciences,” Rusyn says. “We are very grateful to all who committed time, effort and resources to this important undertaking.”
“This is a great first step,” Wright says, “but ultimately we want to match other biological data and the chemical structures, to find out why genetic differences affect toxicity of some chemicals but not the others. In addition to giving us more personalized information about chemical dangers and helping us determine safe exposure levels for these substances, the data could help us design safer chemicals for everyday use.”
Last fall, William Neal Reynolds Professor of Statistics and Genetics, Zhao-Bang Zeng, Ph.D. published a new paper entitled, ‘Mapping epistatic quantitative trait loci’. A link to his paper can be found here.
The Bioinformatics Consulting and Services Core (BCSC) has received a subcontract to partner with the UNC Superfund Research Program to provide assistance in biostatistics and bioinformatics, starting with the 2014-2015 grant year. BCSC staff members Elizabeth Scholl, Ph.D., and Allison Dickey, Ph.D., provide consulting assistance to Superfund investigators at UNC-Chapel Hill and NCSU, under the direction of Superfund Bioinformatics leader Fred Wright, Ph.D. “The BCSC provides important infrastructure to the Superfund Research Program, as well as a combination of expertise in biostatistics and bioinformatics,” says Wright. Adds Dr. Alison Motsinger-Reif, Director of the BCSC, “this is the sort of partnership that benefits both NCSU and UNC, maximizing efficiency by combining our collective talents.”
The UNC Superfund Research Program (UNC SRP) seeks to understand the human health and environmental risks associated with exposure to toxic chemicals found at hazardous waste sites (sph.unc.edu/superfund-pages/srp/). Research projects span biomedicine and engineering approaches in environmental sciences, with principal investigators across both institutions.
BRC investigators played an active part in the kickoff workshop for the Beyond Bioinformatics [http://www.samsi.info/programs/2014-15-program-beyond-bioinformatics-statistical-and-mathematical-challenges-bioinformatic]
program organized by the Statistical and Applied Mathematical Sciences Institute (SAMSI), and will be playing key roles in the program throughout the 2014-2015 academic year. SAMSI, located in the Research Triangle Park, is the only research center funded by the National Science Foundation to advance the discipline of statistics. The convergence of statistical and biological sciences, along with SAMSI activities, make this an especially intellectually rich time for bioinformatics at N.C. State. The year-long program “Beyond Bioinformatics: Statistical and Mathematical Challenges” includes working groups on a variety of topics, including statistical issues that arise in evolutionary inference and analysis of Big Data.
The “Dependence in Evolutionary Models” working group includes N.C. State bioinformaticians Xiang Ji, Chris Nasrallah, Jeremy Ash, and Jeff Thorne. Additional organizers include N.C. State mathematician Seth Sullivant, and Duke statistician Scott Schmidler. The working group has also brought in internationally acclaimed visitors, including Jotun Hein (Oxford University), David Pollock (University of Colorado Denver), Richard Goldstein (University College London), and Ziheng Yang (University College London). Professors Hein, Yang, Sullivant, Schmidler, and Thorne are teaching a related graduate course on statistical molecular evolution at the SAMSI facility in Fall 2014. The evolution working group is concentrating on two questions: 1. How can evolutionary inferences be made when changes at one position in a DNA sequence influence the rate of changes at other positions?; and 2. Which evolutionary scenarios can and cannot be disentangled by making inferences from DNA sequence data?
The “Multiple Hypothesis Testing and Simultaneous Inference” working group is organized by Yi-Hui Zhou and Fred Wright from the BRC, with graduate student fellow Ajay Kumar from the NCSU department of Statistics. The working group is inspired by the critical need to perform false positive control in the presence of large numbers of statistical tests. Related problems are posed by the desire to perform inference on effect sizes for numerous parameters, such as effects of SNPs on disease risk, etc. This working group will consider current work on multiple testing and simultaneous inference, considering complicating situations posed by new technologies or special sampling situations.
The Bill & Melinda Gates Foundation recently announced that it has awarded a $12.4 million grant to North Carolina State University to develop genomic tools for the improvement of the sweet potato, which is an important staple in several African countries. The grant provides funding for genomic and bioinformatics tool development, as well as new data to help improve drought and pest resistance. Led by principal investigator Dr. Craig Yencho in the NCSU Department of Horticulture, the NCSU team includes BRC researchers Drs. Zhao-Bang Zeng and Dahlia Nielsen, and other investigators at NCSU and several partner universities.
The grant draws on the wide range of expertise in statistical genetics and bioinformatics at NCSU. Dr. Zeng’s group will develop tools in for mapping important traits, while Dr. Nielsen will oversee transcriptomic assembly and related bioinformatics development.
See the full news release [http://news.ncsu.edu/2014/09/nc-state-receives-sweet-potato-grant/] for more details.