Transcriptomics of bronchoalveolar lavage cells identifies new molecular endotypes of sarcoidosis

Sarcoidosis is a multisystem granulomatous disease of unknown origin with a variable and often unpredictable course and pattern of organ involvement. In this study we sought to identify specific bronchoalveolar lavage (BAL) cell gene expression patterns indicative of distinct disease phenotypic traits.RNA sequencing by Ion Torrent Proton was performed on BAL cells obtained from 215 well characterised patients with pulmonary sarcoidosis enrolled in the multicenter Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis (GRADS) study. Weighted Gene Co-expression Network Analysis (WGCNA) and non-parametric statistics were used to analyse genome wide BAL transcriptome. Validation of results was performed using a microarray expression data set of an independent sarcoidosis cohort (Freiburg, Germany (n=50)).Our supervised analysis found associations between distinct transcriptional programs and major pulmonary phenotypic manifestations of sarcoidosis including TH1 and TH17 pathways associated with hilar lymphadenopathy, TGFB1 and MTOR signaling with parenchymal involvement, and IL7 and IL2 with airway involvement. Our unsupervised analysis revealed gene modules that uncovered four potential sarcoidosis endotypes including hilar lymphadenopathy with increased acute T cell immune response; extraocular organ involvement with PI3 K activation pathways; chronic and multiorgan disease with increased immune response pathways; and multiorgan with increased IL-1 and IL-18 immune and inflammatory responses. We validated the occurrence of these endotypes using gene expression, pulmonary function tests and cell differentials from Freiburg. Taken together our results identify BAL gene expression programs that characterise major pulmonary sarcoidosis phenotypes and suggest the presence of distinct disease molecular endotypes.

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Transcriptomics of Bronchoalveolar Lavage Cells Identifies New Molecular Endotypes of Sarcoidosis

10.1101/2020.07.24.20161448 ◽

2020 ◽

Author(s):

Milica Vukmirovic ◽

Xiting Yan ◽

Kevin F Gibson ◽

Mridu Gulati ◽

Jonas Christian Schupp ◽

...

Keyword(s):

Gene Expression ◽

Immune Response ◽

Bronchoalveolar Lavage ◽

Pulmonary Sarcoidosis ◽

Genomic Research ◽

Organ Involvement ◽

Phenotypic Traits ◽

Data Set ◽

Hilar Lymphadenopathy ◽

Distinct Disease

Sarcoidosis is a multisystem granulomatous disease of unknown origin with a variable and often unpredictable course and pattern of organ involvement. In this study we sought to identify specific bronchoalveolar lavage (BAL) cell gene expression patterns indicative of distinct disease phenotypic traits. RNA sequencing by Ion Torrent Proton was performed on BAL cells obtained from 215 well characterized patients with pulmonary sarcoidosis enrolled in the multicenter Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis (GRADS) study. Weighted Gene Co-expression Network Analysis (WGCNA) and non-parametric statistics were used to analyze genome wide BAL transcriptome. Validation of results was performed using a microarray expression data set of an independent sarcoidosis cohort (Freiburg, Germany (n=50)). Our supervised analysis found associations between distinct transcriptional programs and major pulmonary phenotypic manifestations of sarcoidosis including; TH1 and TH17 pathways associated with hilar lymphadenopathy; TGFB1 and MTOR signaling with parenchymal involvement, and IL7 and IL2 with airway involvement. Our unsupervised analysis revealed gene modules that uncovered four potential sarcoidosis endotypes including hilar lymphadenopathy with increased acute T cell immune response; extraocular organ involvement with PI3K activation pathways; chronic and multiorgan disease with increased immune response pathways; and multiorgan with increased IL-1 and IL-18 immune and inflammatory responses. We validated the occurrence of these endotypes using gene expression, pulmonary function tests and cell differentials from Freiburg. Taken together our results identify BAL gene expression programs that characterize major pulmonary sarcoidosis phenotypes and suggest the presence of distinct disease molecular endotypes.

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Effects of the domestic thyroid stimulating hormone receptor (TSHR) variant on the hypothalamic-pituitary-thyroid axis and behavior in chicken

Genetics ◽

10.1093/genetics/iyaa050 ◽

2021 ◽

Vol 217 (1) ◽

Author(s):

Amir Fallahshahroudi ◽

Martin Johnsson ◽

Enrico Sorato ◽

S J Kumari A Ubhayasekera ◽

Jonas Bergquist ◽

...

Keyword(s):

Gene Expression ◽

Hormone Receptor ◽

Thyroid Stimulating Hormone ◽

Phenotypic Traits ◽

Wild Type ◽

Data Set ◽

Red Junglefowl ◽

Pituitary Thyroid Axis ◽

And Behavior ◽

Stimulating Hormone

Abstract Domestic chickens are less fearful, have a faster sexual development, grow bigger, and lay more eggs than their primary ancestor, the red junglefowl. Several candidate genetic variants selected during domestication have been identified, but only a few studies have directly linked them with distinct phenotypic traits. Notably, a variant of the thyroid stimulating hormone receptor (TSHR) gene has been under strong positive selection over the past millennium, but it’s function and mechanisms of action are still largely unresolved. We therefore assessed the abundance of the domestic TSHR variant and possible genomic selection signatures in an extensive data set comprising multiple commercial and village chicken populations as well as wild-living extant members of the genus Gallus. Furthermore, by mean of extensive backcrossing we introgressed the wild-type TSHR variant from red junglefowl into domestic White Leghorn chickens and investigated gene expression, hormone levels, cold adaptation, and behavior in chickens possessing either the wild-type or domestic TSHR variant. While the domestic TSHR was the most common variant in all studied domestic populations and in one of two red junglefowl population, it was not detected in the other Gallus species. Functionally, the individuals with the domestic TSHR variant had a lower expression of the TSHR in the hypothalamus and marginally higher in the thyroid gland than wild-type TSHR individuals. Expression of TSHB and DIO2, two regulators of sexual maturity and reproduction in birds, was higher in the pituitary gland of the domestic-variant chickens. Furthermore, the domestic variant was associated with higher activity in the open field test. Our findings confirm that the spread of the domestic TSHR variant is limited to domesticated chickens, and to a lesser extent, their wild counterpart, the red junglefowl. Furthermore, we showed that effects of genetic variability in TSHR mirror key differences in gene expression and behavior previously described between the red junglefowl and domestic chicken.

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Defining Immune Response Signatures in DLBCL As Potential Predictive Biomarkers for Outcome to Immunotherapy

Blood ◽

10.1182/blood.v126.23.2663.2663 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2663-2663

Author(s):

Matthew A Care ◽

Stephen M Thirdborough ◽

Andrew J Davies ◽

Peter W.M. Johnson ◽

Andrew Jack ◽

...

Keyword(s):

Gene Expression ◽

Immune Response ◽

Network Analysis ◽

Gene Expression Data ◽

Research Funding ◽

Data Sets ◽

Expression Data ◽

Data Set ◽

Gene Correlation ◽

Cancer Types

Abstract Purpose To assess whether comparative gene network analysis can reveal characteristic immune response signatures that predict clinical response in Diffuse large B-cell lymphoma (DLBCL). Background The wealth of available gene expression data sets for DLBCL and other cancer types provides a resource to define recurrent pathological processes at the level of gene expression and gene correlation neighbourhoods. This is of particular relevance in the context of cancer immune responses, where convergence onto common patterns may drive shared gene expression profiles. Where existing and novel immunotherapies harness the immune response for therapeutic benefit such responses may provide predictive biomarkers. Methods We independently analysed publically available DLBCL gene expression data sets and a wide compendium of gene expression data from diverse cancer types, and then asked whether common elements of cancer host response could be identified from resulting networks. Using 10 DLBCL gene expression data sets, encompassing 2030 cases, we established pairwise gene correlation matrices per data set, which were merged to generate median correlations of gene pairs across all data sets. Gene network analysis and unsupervised clustering was then applied to define global representations of DLBCL gene expression neighbourhoods. In parallel a diverse range of solid and lymphoid malignancies including; breast, colorectal, oesophageal, head and neck, non-small cell lung, prostate, pancreatic cancer, Hodgkin lymphoma, Follicular lymphoma and DLBCL were independently analysed using an orthogonal weighted gene correlation network analysis of gene expression data sets from which correlated modules across diverse cancer types were identified. The biology of resulting gene neighbourhoods was assessed by signature and ontology enrichment, and the overlap between gene correlation neighbourhoods and WGCNA derived modules associated with immune/host responses was analysed. Results Amongst DLBCL data, we identified distinct gene correlation neighbourhoods associated with the immune response. These included both elements of IFN-polarised responses, core T-cell, and cytotoxic signatures as well as distinct macrophage responses. Neighbourhoods linked to macrophages separated CD163 from CD68 and CD14. In the WGCNA analysis of diverse cancer types clusters corresponding to these immune response neighbourhoods were independently identified including a highly similar cluster related to CD163. The overlapping CD163 clusters in both analyses linked to diverse Fc-Receptors, complement pathway components and patterns of scavenger receptors potentially linked to alternative macrophage activation. The relationship between the CD163 macrophage gene expression cluster and outcome was tested in DLBCL data sets, identifying a poor response in CD163 -cluster high patients, which reached statistical significance in one data set (GSE10846). Notably, the effect of the CD163-associated gene neighbourhood which correlates with poor outcome post rituximab containing immunochemotherapy is distinct from the effect of IFNG-STAT1-IRF1 polarised cytotoxic responses. The latter represents the predominant immune response pattern separating cell of origin unclassifiable (Type-III) DLBCL from either ABC or GCB DLBCL subsets, and is associated with a trend toward positive outcome. Conclusion Comparative gene expression network analysis identifies common immune response signatures shared between DLBCL and other cancer types. Gene expression clusters linked to CD163 macrophage responses and IFNG-STAT1-IRF1 polarised cytotoxic responses are common patterns with apparent divergent outcome association. Disclosures Davies: CTI: Honoraria; GIlead: Consultancy, Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding; Bayer: Research Funding; Takeda: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; GSK: Research Funding; Pfizer: Honoraria; Celgene: Honoraria, Research Funding. Jack:Jannsen: Research Funding.

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Interleukin-2 Receptor Gene Expression by Bronchoalveolar Lavage Lymphocytes in Pulmonary Sarcoidosis

American Review of Respiratory Disease ◽

10.1164/ajrccm/140.1.82 ◽

1989 ◽

Vol 140 (1) ◽

pp. 82-88 ◽

Cited By ~ 34

Author(s):

Joachim Müller-Quernheim ◽

Martin Krönke ◽

Jànos Strausz ◽

Michael Schykowski ◽

Rudolf Ferlinz

Keyword(s):

Gene Expression ◽

Bronchoalveolar Lavage ◽

Receptor Gene ◽

Interleukin 2 ◽

Pulmonary Sarcoidosis ◽

Interleukin 2 Receptor ◽

Receptor Gene Expression

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Discordant expression profile between RNA and protein for the genes involved in immune response network in adenovirus type 2 infected cells

10.1101/302851 ◽

2018 ◽

Author(s):

Hongxing Zhao ◽

Maoshan Chen ◽

Alberto Valdés ◽

Sara Bergström Lind ◽

Ulf Pettersson

Keyword(s):

Gene Expression ◽

Immune Response ◽

Expression Profiles ◽

Late Phase ◽

Adenovirus Type ◽

Transcriptional Level ◽

Data Set ◽

Cellular Genes ◽

Cellular Immune

AbstractAlternation of cellular genes expressions during Adenovirus type 2 (Ad2) infection in IMR-90 cells was studied using paired-end sequencing and stable isotope labeling of amino acids in cell culture mass spectrometric analysis (SILAC-MS). At transcriptional level, cellular genes involved in different pathways revealed distinct expression profiles. At early phase, the genes involved in regulation of cellular immune response, cellular signaling and cell growth control were among the most deregulated. Later follows, in an orderly fashion, genes involved in cell cycle control, DNA replication and further on genes engaged in RNA processing and protein translation. Comparison of cellular gene expression at transcriptional and posttranscriptional levels revealed low correlation. Here we highlight the genes which expose opposite expression profiles with an emphasis on key factors that play important roles in cellular immune pathways including NFκB, JAK/STAT, caspases and MAVS. Transcription of many of these genes was transiently induced early, but became down-regulated in the late phase. In contrast, their expressions at protein level were up-regulated early and so sustained until late phase of infection. Suppression at the transcriptional level and enhancement at the protein level of immune response genes most likely illustrate counteractions between Ad2 and its host cell.ImportanceOur paper comprises a state of the art quality transcriptomics data set unravelling the alterations in gene expression that take place during different phases of an adenovirus infection. The information allows us to draw conclusion about the cellular pathways that are perturbed by the virus. The data set also provides an important resource for scientists in general for future studies on mechanisms behind host/virus interactions in efforts to design tools for combatting virus infections.Moreover, our paper includes novel proteomics information unravelling an unexpected role of post transcriptional events in cellular gene expression, demonstrating that the current picture of the adenovirus replication cycle is simplified.

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The potential of microarrays to assist shrimp breeding and production: a review

Australian Journal of Experimental Agriculture ◽

10.1071/ea05060 ◽

2005 ◽

Vol 45 (8) ◽

pp. 901 ◽

Cited By ~ 3

Author(s):

K. J. Wilson ◽

E. de la Vega

Keyword(s):

Gene Expression ◽

Quantitative Trait ◽

Linkage Mapping ◽

Genetic Linkage ◽

Selective Breeding ◽

Genomic Research ◽

Phenotypic Traits ◽

Genomic Information ◽

Breeding Programs ◽

Genetic Linkage Mapping

The shrimp aquaculture industry is a relatively new livestock industry, having developed over the past 30 years. Thus, it is poised to take advantage of new technologies from the outset of selective breeding programs. This contrasts with long established livestock industries, where there are already highly specialised breeds. This review focuses specifically on the potential application of microarrays to shrimp breeding. Potential applications of microarrays in selective breeding programs are summarised. Microarrays can be used as a rapid means to generate molecular markers for genetic linkage mapping, and genetic maps have been constructed for yeast, Arabidopsis and barley using microarray technology. Microarrays can also be used in the hunt for candidate genes affecting particular traits, leading to development of perfect markers for these traits (i.e. causative mutations). However, this requires that microarray analysis be combined with genetic linkage mapping, and that substantial genomic information is available for the species in question. A novel application of microarrays is to treat gene expression as a quantitative trait in itself and to combine this with linkage mapping to identify quantitative trait loci controlling the levels of gene expression; this approach may identify higher level regulatory genes in specific pathways. Finally, patterns of gene expression observed using microarrays may themselves be treated as phenotypic traits in selection programs (e.g. a particular pattern of gene expression might be indicative of a disease tolerant individual). Microarrays are now being developed for a number of shrimp species in laboratories around the world, primarily with a focus on identifying genes involved in the immune response. However, at present, there is no central repository of shrimp genomic information, which limits the rate at which shrimp genomic research can be progressed. The application of microarrays to shrimp breeding will be extremely limited until there is a shared repository of genomic information for shrimp, and the collective will and resources to develop comprehensive genomic tools for shrimp.

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Risk-focused differences in molecular processes implicated in SARS-CoV-2 infection: corollaries in DNA methylation and gene expression

Epigenetics & Chromatin ◽

10.1186/s13072-021-00428-1 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Chaini Konwar ◽

Rebecca Asiimwe ◽

Amy M. Inkster ◽

Sarah M. Merrill ◽

Gian L. Negri ◽

...

Keyword(s):

Gene Expression ◽

Risk Factors ◽

Dna Methylation ◽

Bronchoalveolar Lavage ◽

Molecular Basis ◽

Expression Patterns ◽

Data Set ◽

Susceptibility Factors ◽

Increased Risk ◽

Methylation Patterns

Abstract Background Understanding the molecular basis of susceptibility factors to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is a global health imperative. It is well-established that males are more likely to acquire SARS-CoV-2 infection and exhibit more severe outcomes. Similarly, exposure to air pollutants and pre-existing respiratory chronic conditions, such as asthma and chronic obstructive respiratory disease (COPD) confer an increased risk to coronavirus disease 2019 (COVID-19). Methods We investigated molecular patterns associated with risk factors in 398 candidate genes relevant to COVID-19 biology. To accomplish this, we downloaded DNA methylation and gene expression data sets from publicly available repositories (GEO and GTEx Portal) and utilized data from an empirical controlled human exposure study conducted by our team. Results First, we observed sex-biased DNA methylation patterns in autosomal immune genes, such as NLRP2, TLE1, GPX1, and ARRB2 (FDR < 0.05, magnitude of DNA methylation difference Δβ > 0.05). Second, our analysis on the X-linked genes identified sex associated DNA methylation profiles in genes, such as ACE2, CA5B, and HS6ST2 (FDR < 0.05, Δβ > 0.05). These associations were observed across multiple respiratory tissues (lung, nasal epithelia, airway epithelia, and bronchoalveolar lavage) and in whole blood. Some of these genes, such as NLRP2 and CA5B, also exhibited sex-biased gene expression patterns. In addition, we found differential DNA methylation patterns by COVID-19 status for genes, such as NLRP2 and ACE2 in an exploratory analysis of an empirical data set reporting on human COVID-9 infections. Third, we identified modest DNA methylation changes in CpGs associated with PRIM2 and TATDN1 (FDR < 0.1, Δβ > 0.05) in response to particle-depleted diesel exhaust in bronchoalveolar lavage. Finally, we captured a DNA methylation signature associated with COPD diagnosis in a gene involved in nicotine dependence (COMT) (FDR < 0.1, Δβ > 0.05). Conclusion Our findings on sex differences might be of clinical relevance given that they revealed molecular associations of sex-biased differences in COVID-19. Specifically, our results hinted at a potentially exaggerated immune response in males linked to autosomal genes, such as NLRP2. In contrast, our findings at X-linked loci such as ACE2 suggested a potentially distinct DNA methylation pattern in females that may interact with its mRNA expression and inactivation status. We also found tissue-specific DNA methylation differences in response to particulate exposure potentially capturing a nitrogen dioxide (NO2) effect—a contributor to COVID-19 susceptibility. While we identified a molecular signature associated with COPD, all COPD-affected individuals were smokers, which may either reflect an association with the disease, smoking, or may highlight a compounded effect of these two risk factors in COVID-19. Overall, our findings point towards a molecular basis of variation in susceptibility factors that may partly explain disparities in the risk for SARS-CoV-2 infection.

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Multi-OMICS and Molecular Biology Perspective in Buffalo Genome

Journal of Buffalo Science ◽

10.6000/1927-520x.2021.10.04 ◽

2021 ◽

pp. 21-31

Author(s):

Suranjana Sikdar ◽

◽

Tuhin Das ◽

Emran Hossain Sajib ◽

Kazi Mahbub Ur Rahman Rahman ◽

...

Keyword(s):

Gene Expression ◽

Whole Genome Sequencing ◽

Genome Sequencing ◽

Expression Profiling ◽

Phenotypic Diversity ◽

Genomic Research ◽

Phenotypic Traits ◽

Whole Genome ◽

Single Nucleotide ◽

Geographical Regions

The bovine species buffalo was domesticated from its wild strain Bubalus arnee and is widely used livestock in southern Asia. There are two distinct types of Buffalo- the swamp buffalo (B. bubalis kerebau) and the river buffalo (B. bubalis bubalis), which diverged from the wild Asian water buffalo and then evolved in separate geographical regions. Several research studies performed on buffalo, like- characterization of trait-specific Single Nucleotide Polymorphism (SNP), genetic and phenotypic diversity, gene prediction and function annotation, mapping of the draft genome, have helped our understanding of the buffalo genome. Some advanced discovery as identification of Single Nucleotide Variant (SNVs), Simple Sequence Repeats (SSR) marker and their association with various phenotypic traits, MicroRNA's expression profiling, whole-genome sequencing, etc. have also enabled us to track the chromosomal evolution, physiological processes, and gene expression of buffalo. Proper enhancement of these traits can lead us to apply multi-omics-based tools for better animal health and production. Recent advancement in genomic research on buffalo is being accelerated with the association of modern tools like- Genome-Wide Association Study (GWAS), genotyping by sequencing, epigenomic screening, microRNA's expression profiling, microarray technology, and whole-genome sequencing. All these tools bear great significance in breed up-gradation, identification of the phylogenetic relationship between species in proteome and genomic level, study gene expression level, diagnose diseases or developmental stages, phenotypic diversity, etc. All this knowledge paved the way for better optimization of production efficiency, product quality, and resistance to certain health hazards.

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TREM-1 and TREM-2 Expression on CD14+ Cells in Bronchoalveolar Lavage Fluid in Pulmonary Sarcoidosis and Hypersensitivity Pneumonitis in the Context of T Cell Immune Response

Mediators of Inflammation ◽

10.1155/2020/9501617 ◽

2020 ◽

Vol 2020 ◽

pp. 1-9

Author(s):

M. Suchankova ◽

J. Urban ◽

M. Ganovska ◽

E. Tibenska ◽

K. Szaboova ◽

...

Keyword(s):

Immune Response ◽

T Cell ◽

Correlation Analysis ◽

Bronchoalveolar Lavage ◽

Alveolar Macrophages ◽

Hypersensitivity Pneumonitis ◽

Bronchoalveolar Lavage Fluid ◽

Lavage Fluid ◽

Pulmonary Sarcoidosis ◽

Granuloma Formation

Background. Sarcoidosis and hypersensitivity pneumonitis (HP) are immunologically mediated processes caused by hypersensitivity reaction accompanied by similar features including lymphocytic alveolitis and granuloma formation. Recent studies describe the role of TREM receptors in T cell activation, differentiation, and granuloma formation. Alveolar macrophages activation via TREM receptors may be the key factor mediating subsequent immune response. The aim of the study was to analyse TREM-1 and TREM-2 expression to identify further molecular mechanisms participating in the immunopathogenesis of sarcoidosis and HP. Methods. Flow cytometry was performed to analyse TREM-1 and TREM-2 expression on CD14+ cells in bronchoalveolar lavage fluid from patients having sarcoidosis or HP and a control group. Results. The study proved increased TREM-1 expression on alveolar macrophages in pulmonary sarcoidosis and diminished TREM-1 expression in HP-Sarcoidosis: median: 76.7; HP: median: 29.9; control: median: 53.3, (sarcoidosis versus HP: p<0.001; sarcoidosis versus control: p<0.05). TREM-2 expression was increased in both, sarcoidosis and HP-sarcoidosis: median: 34.79; HP: median: 36.00; control: median: 12.98, (sarcoidosis versus control: p<0.05; HP versus control: p<0.05). Correlation analysis showed negative correlation between TREM-1 and total number of CD8+ cytotoxic T cells. In sarcoidosis TREM-1 expression decreased with changes of HRCT image, decrease in CD4/CD8 ratio and decrease in DLCO. Conclusions. Differences in TREM receptor expression in sarcoidosis (increase in TREM-1 and TREM-2) and HP (increase in TREM-2) and correlation analysis suggests that activation via TREM may participate in typical immunological characteristics of sarcoidosis and HP.

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Intraspecies Transcriptional Profiling Reveals Key Regulators of Candida albicans Pathogenic Traits

mBio ◽

10.1128/mbio.00586-21 ◽

2021 ◽

Vol 12 (2) ◽

Author(s):

Joshua M. Wang ◽

Andrew L. Woodruff ◽

Matthew J. Dunn ◽

Robert J. Fillinger ◽

Richard J. Bennett ◽

...

Keyword(s):

Gene Expression ◽

Candida Albicans ◽

Phenotypic Variation ◽

Expression Profiles ◽

Transcriptional Profiling ◽

Phenotypic Traits ◽

Specific Gene ◽

Data Set ◽

Content Type ◽

New Genes

ABSTRACT The human commensal and opportunistic fungal pathogen Candida albicans displays extensive genetic and phenotypic variation across clinical isolates. Here, we performed RNA sequencing on 21 well-characterized isolates to examine how genetic variation contributes to gene expression differences and to link these differences to phenotypic traits. C. albicans adapts primarily through clonal evolution, and yet hierarchical clustering of gene expression profiles in this set of isolates did not reproduce their phylogenetic relationship. Strikingly, strain-specific gene expression was prevalent in some strain backgrounds. Association of gene expression with phenotypic data by differential analysis, linear correlation, and assembly of gene networks connected both previously characterized and novel genes with 23 C. albicans traits. Construction of de novo gene modules produced a gene atlas incorporating 67% of C. albicans genes and revealed correlations between expression modules and important phenotypes such as systemic virulence. Furthermore, targeted investigation of two modules that have novel roles in growth and filamentation supported our bioinformatic predictions. Together, these studies reveal widespread transcriptional variation across C. albicans isolates and identify genetic and epigenetic links to phenotypic variation based on coexpression network analysis. IMPORTANCE Infectious fungal species are often treated uniformly despite clear evidence of genotypic and phenotypic heterogeneity being widespread across strains. Identifying the genetic basis for this phenotypic diversity is extremely challenging because of the tens or hundreds of thousands of variants that may distinguish two strains. Here, we use transcriptional profiling to determine differences in gene expression that can be linked to phenotypic variation among a set of 21 Candida albicans isolates. Analysis of this transcriptional data set uncovered clear trends in gene expression characteristics for this species and new genes and pathways that were associated with variation in pathogenic processes. Direct investigation confirmed functional predictions for a number of new regulators associated with growth and filamentation, demonstrating the utility of these approaches in linking genes to important phenotypes.

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