The uniqueness of individuals is due to differences in the combination of genetic, epigenetic and environmental determinants. Understanding the genetic basis of phenotypic variation is a key objective in genetics. Gene expression has been considered as an intermediate phenotype, and the association between gene expression and commonly-occurring genetic variants in the general population has been convincingly established. However, there are few methods to assess the impact of rare genetic variants, such as private SNPs, on gene expression. Here we describe a systematic approach, based on the theory of multivariate outlier detection, to identify individuals that show unusual or aberrant gene expression, relative the rest of the study cohort. Through characterizing detected outliers and corresponding gene sets, we are able to identify which gene sets tend to be aberrantly expressed and which individuals show deviant gene expression within a population. One of our major findings is that private SNPs may contribute to aberrant expression in outlier individuals. These private SNPs are more frequently located in the enhancer and promoter regions of genes that are aberrantly expressed, suggesting a possible regulatory function of these SNPs. Overall, our results provide new insight into the determinants of inter-individual variation, which have not been evaluated by large population-level cohort studies. The paper is in press in PLoS Genetics.
Dr. Ence Yang has been selected by the Finance Committee to receive a financial aid award. These funds are to help offset expenses associated with attending the 28th Fungal Genetics Conference, March 17-22, 2015 at the Asilomar Conference Grounds. Congratulations!
Despite some recent success with genome-wide association studies (GWAS), identifying hypertension (HTN)-susceptibility loci in the general population remains difficult. Here, we present a novel strategy to address the challenge by studying salinity adaptation in the threespine stickleback, a fish species with diverse salt-handling ecotypes. We acclimated native freshwater (FW) and anadromous, saltwater (SW) threespine sticklebacks to fresh, brackish, and sea water for 30 days, and applied RNA sequencing to determine the gene expression in fish kidneys. We identified 1,844 salt-responsive genes that were differentially expressed between FW sticklebacks acclimated to different salinities and/or between SW and FW sticklebacks acclimated to full-strength sea water. Significant overlap between stickleback salt responsive genes and human genes implicated in HTN was detected (P < 10-7, hypergeometric test), suggesting a striking similarity in genetic mechanisms of salt handling between threespine sticklebacks and humans. The overlapping genes included a newly discovered HTN gene—MAP3K15, whose expression in FW stickleback kidneys decreases with salinity. These also included genes located in the GWAS loci such as AGTRAP-PLOD1 and CYP1A1-ULK3, which contain multiple potentially causative genes contributing to HTN susceptibility that need to be prioritized for study. We show evidence that stickleback salt-responsive genes provide valuable information facilitating the identification of human HTN genes. We conclude that threespine sticklebacks may be used as a model, complementary to existing animal models, in human HTN research. [http://stickleback.genomezoo.net/][Open Access]
Our latest study: Signature gene expression reveals novel clues to the molecular mechanisms of dimorphic transition in Penicillium marneffei
Penicillium marneffei is a significant dimorphic fungal pathogen capable of causing lethal systemic infections. It grows in a yeast-like form at mammalian body temperature and a mold-like form at ambient temperature. The thermal dimorphism of P. marneffei is closely related to its virulence. In the present study, we re-sequenced the genome of P. marneffei using Illumina and PacBio sequencing technologies, and simultaneously assembled these newly sequenced reads in different lengths with previously obtained Sanger sequences. This hybrid assembly greatly improved the quality of the genome sequences. Next, we used RNA-seq to measure the global gene expression of P. marneffei at different phases and during dimorphic phase transitions. We found that 27% of genes showed signature expression patterns, suggesting that these genes function at different stages in the life cycle of P. marneffei. Moreover, genes with same expression patterns tend to be clustered together as neighbors to each other in the genome, suggesting an orchestrated transcriptional regulation for multiple neighboring genes. Over-expression of the MADS-box transcription factor, madsA, located in one of these clusters, confirms the function of this gene in driving the yeast-to-mycelia phase transition irrespective of the temperature cues. Our data also implies diverse roles of secreted proteins and non-coding RNAs in dimorphic transition in P. marneffei. The paper is published in PLoS Genetics. More information can be found at pmarneffei.genomezoo.net.
Jizhou Yang has been selected to be a recipient of the Texas A&M University Walter W. Lechner Estate Scholarship and will be designated a Lechner Scholar. This one-time scholarship is to be used toward tuition, fees, and other related educational expenses.
Our latest study: Additive, epistatic, and environmental effects through the lens of expression variability QTLs in a twin cohort
Gene expression levels can vary across individuals in the general population and between monozygotic twins. Both genetic and nongenetic factors are assumed to contribute to the variable expression. However, little evidence supporting this notion has been obtained from empirical data. Here, we used the expression data from a large twin cohort to dissect genetic and nongenetic effects on the formation of expression variability QTLs (evQTLs)—i.e., genetic loci associated with or linked to variants that influence the variance of gene expression. Our findings have implications for understanding divergent sources of gene expression variability.
Human mitochondria contain multiple copies of a circular genome made up of double-stranded DNA (mtDNA) that encodes proteins involved in cellular respiration. Transcript abundance of mtDNA-encoded genes varies between human individuals, yet the level of variation in the general population has not been systematically assessed. In the present study, we revisited large-scale RNA sequencing data generated from lymphoblastoid cell lines of HapMap samples of European and African ancestry to estimate transcript abundance and quantify expression variation for mtDNA-encoded genes. In both populations, we detected up to over 100-fold difference in mtDNA gene expression between individuals. The marked variation was not due to differences in mtDNA copy number between individuals, but was shaped by the transcription of hundreds of nuclear genes. Many of these nuclear genes were co-expressed with one another, resulting in a module-enriched co-expression network. Significant correlations in expression between genes of the mtDNA and nuclear genomes were used to identify factors involved with the regulation of mitochondrial functions. In conclusion, we determined the baseline amount of variability in mtDNA gene expression in general human populations and catalogued a complete set of nuclear genes whose expression levels are correlated with those of mtDNA-encoded genes. Our findings will enable the integration of information from both mtDNA and nuclear genetic systems, and facilitate the discovery of novel regulatory pathways involving mitochondrial functions.
Penicillium marneffei is a significant opportunistic fungal pathogen in Southeast Asia. This species is unique in that it is the only dimorphic member of the genus. It undergoes multicellular hyphal growth and asexual development (conidiation) in the environment at 25°C and unicellular yeast growth in macrophages at 37°C. Both the thermal dimorphism and the ability to survive inside host macrophages are important for P. marneffei to establish infection. We employ genomic and transcriptomic methodologies to study the molecular basis for the temperature-dependent dimorphic switching program in P. marneffei PM1. The information generated from this study provides the foundation for future work directed at characterizing the underlying mechanisms of cellular development in this fungus. [Read on...]
Ishita Mandhan who is working on a project evaluating the impact of loss-of-function mutations on gene transcription receives the ECEN Undergraduate Research Award. The purpose of this one-time scholarship is to encourage and support research for undergraduate students. Donor representative of the program is Dr. Chanan Singh, Regents Professor, Irma Runyon Chair Professor at the Electrical and Computer Engineering Department, TAMU.
The 1000 genomes toxicity screening project is led by Prof. Ivan Rusyn. The goals of this project are to (i) develop toxicogenetic expression quantitative trait loci (eQTL) mapping tools, perform transcription factor network inference and integrative pathway assessment; (ii) perform toxicogenetic modeling of liver toxicity in cultured mouse hepatocytes; (iii) discover chemical-induced regulatory networks using population-based toxicity phenotyping in human cells. For details, see NIEHS-NCATS-UNC DREAM Toxicogenetics Challenge (syn1761567).
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