Measuring conflict in polyploid genomes

Arabidopsis thaliana, a small flowering plant in the mustard family, was the first plant to have its genome sequenced.  A. thaliana can be thought of as the “mouse model” of botanical research – just as the lab mouse has formed a cornerstone of research in mammals, A. thaliana is used to demonstrate genomic principles that are far-reaching and pertain to multiple plant species. As part of an investigation of polyploidy, Dr. Gavin Conant has extensively analyzed the genes of A. thaliana. Polyploidy simply means that each cell of an organism has more than two sets of chromosomes. Conant explained that duplication events creating such polyploid organisms have occurred across many species throughout the course of evolution, often several times in the same group. Most often, the genome doublings are coupled to a hybridization between two species and help mitigate some of the problems such crosses might otherwise induce. He relates the idea to a more familiar example in mammals.  “For instance, the modern carnivorous marvel liger, which blended the genes of a lion and a tiger, has valuable traits.  However, it will often be sterile, unable to reproduce and thus, sustain itself without direct human intervention,” said Conant. Polyploidy often results from an event in which  two sets of chromosomes are pulled from each parent, instead of the usual single set. Shortly after this conjoining, many of the acquired “extra” genes from the hybrid parents are discharged from the cells and lost altogether. Common sense might dictate that this would be a balanced process, selecting an equal number of genes from each parent. Instead, many geneticists believe that this process of gene selection carries a measure of preference, a term known as biased fractionation, but the evidence for this claim has been controversial.

Conant’s methodology, an algorithmic computer program he designed as a postdoctoral fellow, allowed him to confirm this bias by testing many genomes simultaneously, as opposed to the previous method, which tested one polyploid genome at a time. Beginning as a class research project (taught by Conant) at the University of Missouri, researchers compared the polyploid genomes of Arabidopsis plants against non-polyploid, closely-related species. The objective of the study was to estimate the strength of the bias observed after the polyploidy event. The research team built two models, one with the selection bias built-in, and one without. Utilizing data extracted from Conant’s program, the research team concluded that the loss pattern in the duplicate genes aligned more closely with the bias model, supporting that the genetic fractionation in polyploidy beings is indeed biased. Suspected reasons for this bias vary, but it likely is the result of the combinatorial manner which genes function. “Genes work together in tandem to perform certain functions. To work effectively, those gene groupings must all be from one parent. Matching individual genes together from both parents would be like taking certain parts from the engine block of a Ford and attempting to combine them with engine parts from a Chevy. Those parts are specifically designed to work together for that exact function. This is probably why the polyploidy genome ejects certain genes from one side, instead of maintaining a perfect balance,” Conant explained.

Conant’s findings have practical uses, as many important crops are polyploid, which may enable plants become larger or take on other beneficial characteristics. He further explained that “It’s important to understand this process. Agriculturally, knowing how to make stronger crops is essential to commercial success.”

Prior to joining the Bioinformatics Research Center (BRC) at North Carolina State University, Dr. Conant served as a postdoctoral researcher at Sandia National Labs. He studied biology and mathematics as an undergraduate, while working as an IT specialist. Following the completion of his PhD, he worked in Dublin, Ireland for nearly four years, where he conducted research involving baker’s yeast and its unique fermentation effects, which are likely due to an ancient polyploidy event. It was this background, combined with the clearinghouse of knowledge at the BRC, that facilitated the continued research of Dr. Conant and his fellow researchers.

What’s Next?

Dr. Conant’s lab is now applying similar methodology to eight fish species. Each of these fish contains a polyploid genome, while the gar fish serves as the non-polyploid counterpart. Fish polyploidy events are estimated to have occurred roughly 300 million years ago. Such an early event will be challenging to study – the Arabidopsis polyploidy event has been estimated as occurring only 25 million years ago.

Emery M, Willis MMS, Hao Y, Barry K, Oakgrove K, Peng Y, et al. (2018) Preferential retention of genes from one parental genome after polyploidy illustrates the nature and scope of the genomic conflicts induced by hybridization. PLoS Genet 14(3): e1007267. https://doi.org/10.1371/journal.pgen.1007267

Researchers and co-authors involved with this study include Gavin Conant, Marianne Emery, M. Madeline S. Willis, Yue Hao, Kerrie Barry, Khouanchy Oakgrove, Yi Peng, Jeremy Schmutz, Eric Lyons, J. Chris Pires, and Patrick P. Edger.

This work was supported by the US National Science Foundation (www.nsf.gov) under grant number NSF-IOS-1339156 (YH, EL, JCP and GCC) and by the US Department of Energy (www.doe.gov) under contract Number DE-AC02-05CH11231 (KB, KO, YP, JS). The work conducted by the U.S. Department of Energy Joint Genome Institute, a DOE Office of Science User Facility, is supported by the Office of Science of the U.S. Department of Energy under the contract number above. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Paper of the Month Awarded to Bioinformatics Alum

Connection between genes, response to environmental chemicals

NIEHS grantees developed a new method to identify individual-level genetic variation in response to chemical exposures. The approach, which linked zebrafish studies and bioinformatic approaches, might help identify new genetic factors that explain differences in chemical sensitivity.

To find chemicals with patterns of differential biological responses, the researchers analyzed high-throughput screening data from zebrafish exposed to thousands of individual chemicals. Instead of focusing on particular compounds, the team looked at individually sequenced zebrafish from a diverse population and sought differences in susceptibility.

The screening data pointed to abamectin, a commonly used antiparasitic, as a candidate chemical in which exposure produced different responses in zebrafish. The researchers generated genome-wide sequence data for individual zebrafish that were susceptible or resistant to effects of abamectin exposure. That data led them to a genetic region known as sox7 that was associated with the gene-environment effect. Targeted follow-up experiments confirmed that the susceptible zebrafish expressed a lower level of the sox7 gene than the resistant individuals.

According to the authors, the approach provided a quick way to sort through the exposome of chemicals and to look for relationships between genetics and environmental exposure, rather than being limited to preselected candidate exposures. The ability to identify individual-level genetic variation that affects response to individual chemical environments may bring new precision to personalized toxicity prediction and understanding of how risk may differ across communities.

Citation: Balik-Meisner M, Truong L, Scholl EH, La Du JK, Tanguay RL, Reif DM. 2018. Elucidating gene-by-environment interactions associated with differential susceptibility to chemical exposure. Environ Health Perspect 126(6):067010.

https://factor.niehs.nih.gov/2018/9/papers/dert/index.htm#a3

Polyploidy occurrences

Polyploidy occurs when two complete genomes from each of two parents, potentially of differing species, merge to form an offspring with four total copies of that/those genome/genomes. Polyploid is common in flowering plants and seems to give rise to important evolutionary innovations. However, it is unstable, and descendants of polyploid founders rapidly lose many of their duplicate genes. Previous analyses have argued that the losses tend to favor one of the parental genomes: however, methodological concerns have led to some doubt on this point.  By modeling the resolution of these three polyploidy events across 21 genomes (10 plants and 11 yeasts), we confirm the existence of this bias in loss patterns and present new data to suggest that one source of the bias is selection to maintain function in co-adapted complexes from the alternative parental genomes.

Researchers Find Vitamin D Receptor is Target for Disruption by Environmental Chemicals

New research from North Carolina State University sheds light on the ways in which environmental chemicals can affect vitamin D receptors (VDR). The work shows that compounds identified as possible VDR disruptors in the Tox21 database interact with VDR in vitro and supports the efficacy of high throughput screening programs to identify compounds of interest.

“Most people think of vitamin D as only a vitamin, but in the body vitamin D is converted to a hormone, so VDR is part of the endocrine system which regulates hormonal function,” says Seth Kullman, professor of biological sciences at NC State. “If something – an endocrine disrupting chemical, for example – interferes with the hormone’s function at different times of development or aging, it could drastically alter physiology of a number of important systems.”

Researchers Find Vitamin D Receptor is Target for Disruption by Environmental Chemicals

New research from North Carolina State University sheds light on the ways in which environmental chemicals can affect vitamin D receptors (VDR). The work shows that compounds identified as possible VDR disruptors in the Tox21 database interact with VDR in vitro and supports the efficacy of high throughput screening programs to identify compounds of interest.

“Most people think of vitamin D as only a vitamin, but in the body vitamin D is converted to a hormone, so VDR is part of the endocrine system which regulates hormonal function,” says Seth Kullman, professor of biological sciences at NC State. “If something – an endocrine disrupting chemical, for example – interferes with the hormone’s function at different times of development or aging, it could drastically alter physiology of a number of important systems.”

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Researchers Find Vitamin D Receptor is Target for Disruption by Environmental Chemicals

Statistician Wright Named Goodnight Innovation Distinguished Professor

Congratulation to the BRC’s very own, Fred Wright, professor in the Departments of Statistics and Biological Sciences and director of the Bioinformatics Research Center, for being named as a Goodnight Innovation Distinguished Professor. The professorship was made possible by a gift from longtime NC State supporters Jim and Ann Goodnight.

“Fred Wright is a key leader in interdisciplinary research in our college and across NC State,” said Chris McGahan, dean of the College of Sciences. “Gifts from generous donors like the Goodnights allow us to support and amplify his incredible work.”

Wright is an internationally known biostatistician who joined the NC State faculty in 2013. His wide-ranging research interests include genomic bioinformatics, toxicogenomics and the statistical principles underlying high-dimensional data analysis.

Wright has been principal investigator on numerous grants, with activities ranging from development of new methods of gene mapping to expression-quantitative trait mapping for multiple tissues. He was also principal investigator of an EPA-funded STAR Center to apply genomics principles to long-standing problems in toxicology. He is a key investigator in the International Cystic Fibrosis Genetic Modifier Consortium, which seeks to unravel the unexpected complexities of this disease, and in the GTEx Consortium, which seeks to assess genetic regulation in multiple human tissues.

Wright has been awarded over $15 million in research grants over the course of his career. He has authored or coauthored more than 150 scientific publications and delivered more than 80 invited presentations. He is a fellow of the American Statistical Association and of Delta Omega, the public health honor society.

Jim Goodnight is CEO and a co-founder of SAS, the world’s largest privately held software company. SAS emerged from NC State’s Department of Statistics when Goodnight was on its faculty in the 1970s. Ann Goodnight, a 1968 College of Humanities and Social Sciences graduate, is the senior director of community relations at SAS. She is a member of the NC State Board of Trustees and the Friday Institute National Advisory Board. The Goodnights are generous supporters of the College of Sciences and the university, establishing several professorships and the Goodnight Scholars Program and serving as co-chairs of the Think and Do the Extraordinary Campaign for NC State.

ChemMaps Lets Researchers Navigate the Chemical Universe

Researchers from North Carolina State University have created a new online service – ChemMaps – that allows users to interactively navigate the chemical space of over 8,000 drugs and 47,000 environmental compounds in 3D and real time. ChemMaps is designed to be a central resource for students and researchers who want to easily visualize and study complicated sets of chemical structures. The first release of the free-to-use website is available at www.chemmaps.com.

 

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Designing the Next Generation of Hair Dyes

Designing the Next Generation of Hair Dyes

North Carolina State University researchers have created the largest publicly available chemical database of hair dye substances as a resource for developing a new generation of hair color products that are safer for consumers, stylists and the environment.

The online Hair Dye Substance Database contains detailed information about the structure and properties of 313 substances in current and past commercial hair dyes. Using computer-based classification – what’s known as cheminformatics – researchers grouped the dyes into clusters with similar structures and properties. The results revealed some surprises and promising new avenues for research.

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Building 3-D models of molecules with RealityConvert

Denis Fourches wants to make the search for new drugs faster and less expensive. So he uses powerful computers to help model interactions between chemical compounds and biological targets to predict the compound’s effectiveness, thus narrowing the field of potential drug candidates for testing and saving researchers time and money.

Now he has a new tool in his arsenal – a computer program that will allow anyone to rapidly create three-dimensional models of molecules for 3-D printing as well as augmented and virtual reality applications, making it easier to study these complex biomolecular structures.

“Large and complex biomolecules like proteins make it difficult for researchers and students to accurately visualize their structure or how they might interact with a given compound,” says Fourches, assistant professor of chemistry at NC State. “But if we can easily build an accurate 3-D model of the protein into a virtual reality or augmented reality environment, we can enable a much better perception of the geometrical and structural characteristics of that molecule.”

RealityConvert is a software tool that converts molecular objects – such as proteins and drugs – to high quality 3-D models. It generates 3-D molecular and biomolecular models in standard file formats that are compatible with the vast majority of augmented and virtual reality programs as well as 3-D printing tools. The conversion is fast and the program is specifically geared toward generating models for various chemicals and small proteins. Fourches is already utilizing the program with his undergraduate organic chemistry students. RealityConvert is open access and freely available to the public.

“The ultimate goal of RealityConvert is to facilitate and boost the development of augmented reality and virtual reality content for bioinformatics and cheminformatics applications,” Fourches says. “These technologies allow for stunning and immersive experiences, offering untapped opportunities for both research and education purposes.”

The latest version of the program is available on Fourches’ GitHub platform and on its website.

Funding for RealityConvert was provided by the NC State Chancellor’s Faculty Excellence Program.

The above article and video can be found here: Building 3-D models of molecules with RealityConvert