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).
Gang is selected to receive a George Bush Presidential Library Foundation Travel Grant. The intent of this award is to provide educational opportunities to Texas A&M students in support of travel to conferences, research projects study, or interships in the US or abroad. Gang is selected by CVM college because of his exemplary academic record and the opportunity for travel in pursuit of his educational objectives. Gang will be using this award to attend SMBE 2013.
Increasing evidence suggests that the variance (as opposed to the mean) among phenotypes may be genotype-dependent. Conventional eQTL analysis focuses on the mean, instead of the variance, of gene expression. In a paper published in Genetics, Amanda Hulse and James Cai perform an analysis that identifies what we describe as evQTL—loci associated with the variances of gene expression among three possible genotypes of a biallelic SNP. The discovered evQTL provide orthogonal information, unavailable in existing eQTL literature, on genetic control of gene expression. The evQTL can act in single-SNP and multiple-SNP effects. Detecting evQTL may represent a novel method for effectively screening for genetic interactions. [Read on...]
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