Publications by authors named "Jeffrey P Townsend"

142 Publications

Getting quantitative on the effects of somatic mutation on cancer.

Oncoscience 2020 Nov 27;7(11-12):83-84. Epub 2020 Oct 27.

Department of Biostatistics, Yale School of Public Health, New Haven, CT, USA.

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http://dx.doi.org/10.18632/oncoscience.521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781488PMC
November 2020

Optimal COVID-19 quarantine and testing strategies.

Nat Commun 2021 01 7;12(1):356. Epub 2021 Jan 7.

Center for Infectious Disease Modeling and Analysis (CIDMA), Yale School of Public Health, New Haven, CT, 06520, USA.

For COVID-19, it is vital to understand if quarantines shorter than 14 days can be equally effective with judiciously deployed testing. Here, we develop a mathematical model that quantifies the probability of post-quarantine transmission incorporating testing into travel quarantine, quarantine of traced contacts with an unknown time of infection, and quarantine of cases with a known time of exposure. We find that testing on exit (or entry and exit) can reduce the duration of a 14-day quarantine by 50%, while testing on entry shortens quarantine by at most one day. In a real-world test of our theory applied to offshore oil rig employees, 47 positives were obtained with testing on entry and exit to quarantine, of which 16 had tested negative at entry; preventing an expected nine offshore transmission events that each could have led to outbreaks. We show that appropriately timed testing can make shorter quarantines effective.
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http://dx.doi.org/10.1038/s41467-020-20742-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7788536PMC
January 2021

Comparative Genomics within and across Bilaterians Illuminates the Evolutionary History of ALK and LTK Proto-Oncogene Origination and Diversification.

Genome Biol Evol 2021 Jan;13(1)

Department of Ecology and Evolutionary Biology, Yale University, New Haven.

Comparative genomic analyses have enormous potential for identifying key genes central to human health phenotypes, including those that promote cancers. In particular, the successful development of novel therapeutics using model species requires phylogenetic analyses to determine molecular homology. Accordingly, we investigate the evolutionary histories of anaplastic lymphoma kinase (ALK)-which can underlie tumorigenesis in neuroblastoma, nonsmall cell lung cancer, and anaplastic large-cell lymphoma-its close relative leukocyte tyrosine kinase (LTK) and their candidate ligands. Homology of ligands identified in model organisms to those functioning in humans remains unclear. Therefore, we searched for homologs of the human genes across metazoan genomes, finding that the candidate ligands Jeb and Hen-1 were restricted to nonvertebrate species. In contrast, the ligand augmentor (AUG) was only identified in vertebrates. We found two ALK-like and four AUG-like protein-coding genes in lamprey. Of these six genes, only one ALK-like and two AUG-like genes exhibited early embryonic expression that parallels model mammal systems. Two copies of AUG are present in nearly all jawed vertebrates. Our phylogenetic analysis strongly supports the presence of previously unrecognized functional convergences of ALK and LTK between actinopterygians and sarcopterygians-despite contemporaneous, highly conserved synteny of ALK and LTK. These findings provide critical guidance regarding the propriety of fish and mammal models with regard to model organism-based investigation of these medically important genes. In sum, our results provide the phylogenetic context necessary for effective investigations of the functional roles and biology of these critically important receptors.
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http://dx.doi.org/10.1093/gbe/evaa228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851593PMC
January 2021

Optimal COVID-19 quarantine and testing strategies.

medRxiv 2020 Nov 8. Epub 2020 Nov 8.

Center for Infectious Disease Modeling and Analysis (CIDMA), Yale School of Public Health, New Haven, CT 06520, USA.

As economic woes of the COVID-19 pandemic deepen, strategies are being formulated to avoid the need for prolonged stay-at-home orders, while implementing risk-based quarantine, testing, contact tracing and surveillance protocols. Given limited resources and the significant economic, public health and operational challenges of the current 14-day quarantine recommendation, it is vital to understand if more efficient but equally effective quarantine and testing strategies can be deployed. To this end, we developed a mathematical model to quantify the probability of post-quarantine transmission that varied across a range of possible quarantine durations, timings of molecular testing, and estimated incubation periods. We found that a 13-day quarantine with testing on entry, a nine-day quarantine with testing on exit, and an eight-day quarantine with testing on both entry and exit each provide equivalent or lower probability of post-quarantine transmission compared to a 14-day quarantine with no testing. We found that testing on exit from quarantine is more effective in reducing probability of post-quarantine transmission than testing upon entry. When conducting a single test, testing on exit was most effective for quarantines of six days or shorter, while testing on day six or seven is optimal for longer quarantines. Optimal timing of testing during quarantine will reduce the probability of post-quarantine transmission, as false-positive results become less likely, enabling case isolation. Based on 4,040 SARS CoV-2 RT-PCR tests, an exit test 96 hours after the start of quarantine for an offshore oil rig population was demonstrated to identify all known asymptomatic cases that previously tested negative at entry, and-moreover-successfully prevented an expected seven or more offshore transmission events, each a serious concern for initiating rapid spread and a disabling outbreak in the close quarters of an offshore rig. This successful outcome highlights the importance of context-specific guidelines for the duration of quarantine and timing of testing that can minimize economic impacts, disruptions to operational integrity, and COVID-related public health risks.
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http://dx.doi.org/10.1101/2020.10.27.20211631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7654919PMC
November 2020

Non-Coding Mutations in Urothelial Bladder Cancer: Biological and Clinical Relevance and Potential Utility as Biomarkers.

Bladder Cancer 2020 Jun 11;6(2):211-213. Epub 2020 Jun 11.

Department of Biostatistics, Yale School of Public Health, New Haven, CT, USA.

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http://dx.doi.org/10.3233/BLC-200278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7390591PMC
June 2020

A multigene phylogeny toward a new phylogenetic classification of .

IMA Fungus 2019 7;10. Epub 2019 Jun 7.

Department of Biostatistics, Yale University, 135 College St, New Haven, CT 06510 USA.

Fungi in the class are ecologically diverse, including mycorrhizas, endophytes of roots and leaves, plant pathogens, aquatic and aero-aquatic hyphomycetes, mammalian pathogens, and saprobes. These fungi are commonly detected in cultures from diseased tissue and from environmental DNA extracts. The identification of specimens from such character-poor samples increasingly relies on DNA sequencing. However, the current classification of is still largely based on morphologically defined taxa, especially at higher taxonomic levels. Consequently, the formal classification is frequently poorly congruent with the relationships suggested by DNA sequencing studies. Previous class-wide phylogenies of have been based on ribosomal DNA markers, with most of the published multi-gene studies being focussed on particular genera or families. In this paper we collate data available from specimens representing both sexual and asexual morphs from across the genetic breadth of the class, with a focus on generic type species, to present a phylogeny based on up to 15 concatenated genes across 279 specimens. Included in the dataset are genes that were extracted from 72 of the genomes available for the class, including 10 new genomes released with this study. To test the statistical support for the deepest branches in the phylogeny, an additional phylogeny based on 3156 genes from 51 selected genomes is also presented. To fill some of the taxonomic gaps in the 15-gene phylogeny, we further present an ITS gene tree, particularly targeting ex-type specimens of generic type species. A small number of novel taxa are proposed: ord. nov., and and fams. nov. The formal taxonomic changes are limited in part because of the ad hoc nature of taxon and specimen selection, based purely on the availability of data. The phylogeny constitutes a framework for enabling future taxonomically targeted studies using deliberate specimen selection. Such studies will ideally include designation of epitypes for the type species of those genera for which DNA is not able to be extracted from the original type specimen, and consideration of morphological characters whenever genetically defined clades are recognized as formal taxa within a classification.
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http://dx.doi.org/10.1186/s43008-019-0002-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7325659PMC
June 2019

Dogs and pigs are transport hosts of Necator americanus: Molecular evidence for a zoonotic mechanism of human hookworm transmission in Ghana.

Zoonoses Public Health 2020 08 11;67(5):474-483. Epub 2020 Jun 11.

Yale School of Medicine, New Haven, CT, USA.

Hookworm infection (Necator americanus and Ancylostoma spp) causes significant morbidity in resource-limited countries. Dog and pig ownership is associated with human infection, although the mechanism through which animals increase risk remains unknown. We first confirmed this association in Kintampo North, Ghana, using a retrospective analysis and serology, followed by a prospective molecular study of animal faeces. As a proxy of exposure to dog faeces, we analysed immunoreactivity of human serum to the zoonotic nematode Toxocara canis. Anti-Toxocara antibodies were present in 62% of samples (n = 89), and reactivity was associated with dog ownership. A subsequent prospective study revealed that 43% of dog and 56% of pig faecal samples contained hookworm eggs by microscopy. PCR analysis confirmed the presence of N. americanus DNA in 47% of samples from dogs and 56% pig samples. Nematode larvae were successfully cultured from samples collected from 36 dogs and seven pigs. These results demonstrate that dogs and pigs have a likely role in the transmission of N. americanus in endemic communities.
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http://dx.doi.org/10.1111/zph.12708DOI Listing
August 2020

Germline variant burden in cancer genes correlates with age at diagnosis and somatic mutation burden.

Nat Commun 2020 05 15;11(1):2438. Epub 2020 May 15.

Breast Medical Oncology, School of Medicine, Yale University, New Haven, CT, USA.

Cancers harbor many somatic mutations and germline variants, we hypothesized that the combined effect of germline variants that alter the structure, expression, or function of protein-coding regions of cancer-biology related genes (gHFI) determines which and how many somatic mutations (sM) must occur for malignant transformation. We show that gHFI and sM affect overlapping genes and the average number of gHFI in cancer hallmark genes is higher in patients who develop cancer at a younger age (r = -0.77, P = 0.0051), while the average number of sM increases in increasing age groups (r = 0.92, P = 0.000073). A strong negative correlation exists between average gHFI and average sM burden in increasing age groups (r = -0.70, P = 0.017). In early-onset cancers, the larger gHFI burden in cancer genes suggests a greater contribution of germline alterations to the transformation process while late-onset cancers are more driven by somatic mutations.
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http://dx.doi.org/10.1038/s41467-020-16293-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7228928PMC
May 2020

Unmatched Level of Molecular Convergence among Deeply Divergent Complex Multicellular Fungi.

Mol Biol Evol 2020 08;37(8):2228-2240

Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Center, Szeged, Hungary.

Convergent evolution is pervasive in nature, but it is poorly understood how various constraints and natural selection limit the diversity of evolvable phenotypes. Here, we analyze the transcriptome across fruiting body development to understand the independent evolution of complex multicellularity in the two largest clades of fungi-the Agarico- and Pezizomycotina. Despite >650 My of divergence between these clades, we find that very similar sets of genes have convergently been co-opted for complex multicellularity, followed by expansions of their gene families by duplications. Over 82% of shared multicellularity-related gene families were expanding in both clades, indicating a high prevalence of convergence also at the gene family level. This convergence is coupled with a rich inferred repertoire of multicellularity-related genes in the most recent common ancestor of the Agarico- and Pezizomycotina, consistent with the hypothesis that the coding capacity of ancestral fungal genomes might have promoted the repeated evolution of complex multicellularity. We interpret this repertoire as an indication of evolutionary predisposition of fungal ancestors for evolving complex multicellular fruiting bodies. Our work suggests that evolutionary convergence may happen not only when organisms are closely related or are under similar selection pressures, but also when ancestral genomic repertoires render certain evolutionary trajectories more likely than others, even across large phylogenetic distances.
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http://dx.doi.org/10.1093/molbev/msaa077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7403615PMC
August 2020

Integrative Activity of Mating Loci, Environmentally Responsive Genes, and Secondary Metabolism Pathways during Sexual Development of Chaetomium globosum.

mBio 2019 12 10;10(6). Epub 2019 Dec 10.

Department of Biostatistics, Yale School of Public Health, New Haven, Connecticut, USA

The origins and maintenance of the rich fungal diversity have been longstanding issues in evolutionary biology. To investigate how differences in expression regulation contribute to divergences in development and ecology among closely related species, transcriptomes were compared between , a homothallic pathogenic fungus thriving in highly humid ecologies, and , a heterothallic postfire saprotroph. Gene expression was quantified in perithecia at nine distinct morphological stages during nearly synchronous sexual development. Unlike , expression of all mating loci in was highly correlated. Key regulators of the initiation of sexual development in response to light stimuli-including orthologs of , -dependent gene NCU00309, and -showed regulatory dynamics matching between and Among 24 secondary metabolism gene clusters in , 11-including the cochliodones biosynthesis cluster-exhibited highly coordinated expression across perithecial development. exhibited coordinately upregulated expression of histidine kinases in hyperosmotic response pathways-consistent with gene expression responses to high humidity we identified in fellow pathogen Bayesian networks indicated that gene interactions during sexual development have diverged in concert with the capacities both to reproduce asexually and to live a self-compatible versus self-incompatible life cycle, shifting the hierarchical roles of genes associated with conidiation and heterokaryon incompatibility in and This divergence supports an evolutionary history of loss of conidiation due to unfavorable combinations of heterokaryon incompatibility in homothallic species. Fungal diversity has amazed evolutionary biologists for decades. One societally important aspect of this diversity manifests in traits that enable pathogenicity. The opportunistic pathogen is well adapted to a high-humidity environment and produces numerous secondary metabolites that defend it from predation. Many of these chemicals can threaten human health. Understanding the phases of the life cycle in which these products are made enables better control and even utilization of this fungus. Among its intriguing traits is that it both is self-fertile and lacks any means of propagule-based asexual reproduction. By profiling genome-wide gene expression across the process of sexual reproduction in and comparing it to genome-wide gene expression in the model filamentous fungus and other closely related fungi, we revealed associations among mating-type genes, sexual developmental genes, sexual incompatibility regulators, environmentally responsive genes, and secondary metabolic pathways.
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http://dx.doi.org/10.1128/mBio.02119-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6904875PMC
December 2019

Molecular Biology and Evolution of Cancer: From Discovery to Action.

Mol Biol Evol 2020 02;37(2):320-326

Department of Biostatistics, Yale School of Public Health, New Haven, CT.

Cancer progression is an evolutionary process. During this process, evolving cancer cell populations encounter restrictive ecological niches within the body, such as the primary tumor, circulatory system, and diverse metastatic sites. Efforts to prevent or delay cancer evolution-and progression-require a deep understanding of the underlying molecular evolutionary processes. Herein we discuss a suite of concepts and tools from evolutionary and ecological theory that can inform cancer biology in new and meaningful ways. We also highlight current challenges to applying these concepts, and propose ways in which incorporating these concepts could identify new therapeutic modes and vulnerabilities in cancer.
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http://dx.doi.org/10.1093/molbev/msz242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6993850PMC
February 2020

Modelling microbial infection to address global health challenges.

Nat Microbiol 2019 10 20;4(10):1612-1619. Epub 2019 Sep 20.

Center for Infectious Disease Modeling and Analysis, Yale School of Public Health, New Haven, CT, USA.

The continued growth of the world's population and increased interconnectivity heighten the risk that infectious diseases pose for human health worldwide. Epidemiological modelling is a tool that can be used to mitigate this risk by predicting disease spread or quantifying the impact of different intervention strategies on disease transmission dynamics. We illustrate how four decades of methodological advances and improved data quality have facilitated the contribution of modelling to address global health challenges, exemplified by models for the HIV crisis, emerging pathogens and pandemic preparedness. Throughout, we discuss the importance of designing a model that is appropriate to the research question and the available data. We highlight pitfalls that can arise in model development, validation and interpretation. Close collaboration between empiricists and modellers continues to improve the accuracy of predictions and the optimization of models for public health decision-making.
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http://dx.doi.org/10.1038/s41564-019-0565-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6800015PMC
October 2019

Re: Ming-Jun Shi, Xiang-Yu Meng, Philippe Lamy, et al. APOBEC-mediated Mutagenesis as a Likely Cause of FGFR3 S249C Mutation Over-representation in Bladder Cancer. Eur Urol 2019;76:9-13.

Eur Urol 2020 01 30;77(1):e24-e25. Epub 2019 Aug 30.

Department of Biostatistics, Yale School of Public Health, New Haven, CT, USA; Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA; Department of Ecology and Evolutionary Biology, Yale University, New Haven, CT, USA. Electronic address:

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http://dx.doi.org/10.1016/j.eururo.2019.08.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7017921PMC
January 2020

GEM-NET: Lessons in Multi-Institution Teamwork Using Collaboration Software.

ACS Cent Sci 2019 Jul 12;5(7):1159-1169. Epub 2019 Jul 12.

Department of Biostatistics, Yale University School of Public Health, New Haven, Connecticut 06510, United States.

The Center for Genetically Encoded Materials (C-GEM) is an NSF Phase I Center for Chemical Innovation that comprises six laboratories spread across three university campuses. Our success as a multi-institution research team demanded the development of a software infrastructure, GEM-NET, that allows all C-GEM members to work together seamlessly-as though everyone was in the same room. GEM-NET was designed to support both science and communication by integrating task management, scheduling, data sharing, and collaborative document and code editing with frictionless internal and public communication; it also maintains security over data and internal communications. In this Article, we document the design and implementation of GEM-NET: our objectives and motivating goals, how each component contributes to these goals, and the lessons learned throughout development. We also share open source code for several custom applications and document how GEM-NET can benefit users in multiple fields and teams that are both small and large. We anticipate that this knowledge will guide other multi-institution teams, regardless of discipline, to plan their software infrastructure and utilize it as swiftly and smoothly as possible.
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http://dx.doi.org/10.1021/acscentsci.9b00111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6661976PMC
July 2019

The landscape of novel and complementary targets for immunotherapy: an analysis of gene expression in the tumor microenvironment.

Oncotarget 2019 Jul 16;10(44):4532-4545. Epub 2019 Jul 16.

Department of Biostatistics, Yale University School of Public Health, New Haven, CT, USA.

Immunotherapies targeting immune checkpoint proteins CTLA-4, PD-1, and PD-L1 have saved lives, but these therapies have only been effective in some patients. Patients positive for expression of immune checkpoint proteins in the tumor microenvironment show better response to immune checkpoint inhibitors. Consequently, knowledge of which genes are consistently expressed in lymphocytes within the tumor microenvironment can convey potentially effective and complementary new immunotherapy targets. We identified 54 genes that have higher co-expression with the pan T-cell marker than or . In a dataset of 26 patients who received anti-PD-1 therapy, we observed that co-expression between and was higher among responders than non-responders, supporting our correlation-based approach. The genes highlighted in these analyses, which include , , , and , warrant further investigation of their therapeutic potential. We analyzed and ranked genes that were co-expressed with the pan T-cell marker in 9,601 human tumors, spanning 31 cancer types. To further identify targets that may be complementary to existing PD-1 therapy, we examined and ranked genes with high co-expression and relatively low co-expression.
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http://dx.doi.org/10.18632/oncotarget.27027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6642048PMC
July 2019

Comparative Genomics and Transcriptomics During Sexual Development Gives Insight Into the Life History of the Cosmopolitan Fungus .

Front Microbiol 2019 7;10:1247. Epub 2019 Jun 7.

Department of Plant Biology, Michigan State University, East Lansing, MI, United States.

(formerly ) is a cosmopolitan fungus that has been reported from soil, herbivore dung, and as a fruit- and root-rot pathogen of numerous field crops, although it is not known to cause significant losses on any crop. Taking advantage of the fact that this species produces prolific numbers of perithecia in culture, the genome of was sequenced and transcriptomic analysis across five stages of perithecium development was performed to better understand the metabolic potential for sexual development and gain insight into its life history. Perithecium morphology together with the genome and transcriptome were compared with those of the plant pathogen , a model for studying perithecium development. Larger ascospores of and their tendency to discharge as a cluster demonstrated a duality of dispersal: the majority are passively dispersed through the formation of cirrhi, while a minority of spores are shot longer distances than those of The predicted gene number in the genome was similar to that in , but had more carbohydrate metabolism-related and transmembrane transport genes. Many transporter genes were differentially expressed during perithecium development in , which may account for its larger perithecia. Comparative analysis of the secondary metabolite gene clusters identified several polyketide synthase genes that were induced during later stages of perithecium development. Deletion of a polyketide synthase gene in resulted in a defective perithecium phenotype, suggesting an important role of the corresponding metabolite, which has yet to be identified, in perithecium development. Results of this study have provided novel insights into the genomic underpinning of development in , which may help elucidate its ability to occupy diverse ecological niches.
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http://dx.doi.org/10.3389/fmicb.2019.01247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6568001PMC
June 2019

Implementation of Syringe Services Programs to Prevent Rapid Human Immunodeficiency Virus Transmission in Rural Counties in the United States: A Modeling Study.

Clin Infect Dis 2020 03;70(6):1096-1102

Department of Epidemiology, School of Public Health, Brown University, Providence, Rhode Island.

Background: Syringe services programs (SSPs) are effective venues for delivering harm-reduction services to people who inject drugs (PWID). However, SSPs often face significant barriers to implementation, particularly in the absence of known human immunodeficiency virus (HIV) outbreaks.

Methods: Using an agent-based model, we simulated HIV transmission in Scott County, Indiana, a rural county with a 1.7% prevalence of injection drug use. We compared outcomes arising in the absence of an SSP, in the presence of a pre-existing SSP, and with implementation of an SSP after the detection of an HIV outbreak among PWID over 5 years following the introduction of a single infection into the network.

Results: In the absence of an SSP, the model predicted an average of 176 infections among PWID over 5 years or an incidence rate of 12.1/100 person-years. Proactive implementation averted 154 infections and decreased incidence by 90.3%. With reactive implementation beginning operations 10 months after the first infection, an SSP would prevent 107 infections and decrease incidence by 60.8%. Reductions in incidence were also observed among people who did not inject drugs.

Conclusions: Based on model predictions, proactive implementation of an SSP in Scott County had the potential to avert more HIV infections than reactive implementation after the detection of an outbreak. The predicted impact of reactive SSP implementation was highly dependent on timely implementation after detecting the earliest infections. Consequently, there is a need for expanded proactive SSP implementation in the context of enhanced monitoring of outbreak vulnerability in Scott County and similar rural contexts.
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http://dx.doi.org/10.1093/cid/ciz321DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7319062PMC
March 2020

Metabolism and Development during Conidial Germination in Response to a Carbon-Nitrogen-Rich Synthetic or a Natural Source of Nutrition in .

mBio 2019 03 26;10(2). Epub 2019 Mar 26.

Department of Biostatistics, Yale University, New Haven, Connecticut, USA

Fungal spores germinate and undergo vegetative growth, leading to either asexual or sexual reproductive dispersal. Previous research has indicated that among developmental regulatory genes, expression is conserved across nutritional environments, whereas pathways for carbon and nitrogen metabolism appear highly responsive-perhaps to accommodate differential nutritive processing. To comprehensively investigate conidial germination and the adaptive life history decision-making underlying these two modes of reproduction, we profiled transcription of germinating on two media: synthetic Bird medium, designed to promote asexual reproduction; and a natural maple sap medium, on which both asexual reproduction and sexual reproduction manifest. A later start to germination but faster development was observed on synthetic medium. Metabolic genes exhibited altered expression in response to nutrients-at least 34% of the genes in the genome were significantly downregulated during the first two stages of conidial germination on synthetic medium. Knockouts of genes exhibiting differential expression across development altered germination and growth rates, as well as in one case causing abnormal germination. A consensus Bayesian network of these genes indicated especially tight integration of environmental sensing, asexual and sexual development, and nitrogen metabolism on a natural medium, suggesting that in natural environments, a more dynamic and tentative balance of asexual and sexual development may be typical of colonies. One of the most remarkable successes of life is its ability to flourish in response to temporally and spatially varying environments. Fungi occupy diverse ecosystems, and their sensitivity to these environmental changes often drives major fungal life history decisions, including the major switch from vegetative growth to asexual or sexual reproduction. Spore germination comprises the first and simplest stage of vegetative growth. We examined the dependence of this early life history on the nutritional environment using genome-wide transcriptomics. We demonstrated that for developmental regulatory genes, expression was generally conserved across nutritional environments, whereas metabolic gene expression was highly labile. The level of activation of developmental genes did depend on current nutrient conditions, as did the modularity of metabolic and developmental response network interactions. This knowledge is critical to the development of future technologies that could manipulate fungal growth for medical, agricultural, or industrial purposes.
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http://dx.doi.org/10.1128/mBio.00192-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6437048PMC
March 2019

Combined Aurora Kinase A (AURKA) and WEE1 Inhibition Demonstrates Synergistic Antitumor Effect in Squamous Cell Carcinoma of the Head and Neck.

Clin Cancer Res 2019 06 12;25(11):3430-3442. Epub 2019 Feb 12.

Section of Medical Oncology, Department of Internal Medicine and Yale Cancer Center, Yale University School of Medicine, New Haven, Connecticut.

Purpose: Human papillomavirus (HPV)-negative head and neck squamous cell carcinomas (HNSCC) commonly bear disruptive mutations in , resulting in treatment resistance. In these patients, direct targeting of p53 has not been successful, but synthetic lethal approaches have promise. Although Aurora A kinase (AURKA) is overexpressed and an oncogenic driver, its inhibition has only modest clinical effects in HPV-negative HNSCC. We explored a novel combination of AURKA and WEE1 inhibition to overcome intrinsic resistance to AURKA inhibition. AURKA protein expression was determined by fluorescence-based automated quantitative analysis of patient specimens and correlated with survival. We evaluated treatment with the AURKA inhibitor alisertib (MLN8237) and the WEE1 inhibitor adavosertib (AZD1775), alone or in combination, using and HNSCC models.

Results: Elevated nuclear AURKA correlated with worse survival among patients with p16(-) HNSCC. Alisertib caused spindle defects, G-M arrest and inhibitory CDK1 phosphorylation, and cytostasis in mutant HNSCC FaDu and UNC7 cells. Addition of adavosertib to alisertib instead triggered mitotic entry and mitotic catastrophe. Moreover, in FaDu and Detroit 562 xenografts, this combination demonstrated synergistic effects on tumor growth and extended overall survival compared with either vehicle or single-agent treatment.

Conclusions: Combinatorial treatment with adavosertib and alisertib leads to synergistic antitumor effects in and HNSCC models. These findings suggest a novel rational combination, providing a promising therapeutic avenue for mutated cancers.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-0440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6548643PMC
June 2019

Wagging the long tail of drivers of prostate cancer.

PLoS Genet 2019 01 17;15(1):e1007820. Epub 2019 Jan 17.

Department of Biostatistics, Yale University, New Haven, Connecticut, United States of America.

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http://dx.doi.org/10.1371/journal.pgen.1007820DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6336235PMC
January 2019

APOBEC-induced mutations and their cancer effect size in head and neck squamous cell carcinoma.

Oncogene 2019 05 15;38(18):3475-3487. Epub 2019 Jan 15.

Department of Biostatistics, Yale School of Public Health, New Haven, CT, USA.

Recent studies have revealed the mutational signatures underlying the somatic evolution of cancer, and the prevalences of associated somatic genetic variants. Here we estimate the intensity of positive selection that drives mutations to high frequency in tumors, yielding higher prevalences than expected on the basis of mutation and neutral drift alone. We apply this approach to a sample of 525 head and neck squamous cell carcinoma exomes, producing a rank-ordered list of gene variants by selection intensity. Our results illustrate the complementarity of calculating the intensity of selection on mutations along with tallying the prevalence of individual substitutions in cancer: while many of the most prevalently-altered genes were heavily selected, their relative importance to the cancer phenotype differs from their prevalence and from their P value, with some infrequent variants exhibiting evidence of strong positive selection. Furthermore, we extend our analysis of effect size by quantifying the degree to which mutational processes (such as APOBEC mutagenesis) contributes mutations that are highly selected, driving head and neck squamous cell carcinoma. We calculate the substitutions caused by APOBEC mutagenesis that make the greatest contribution to cancer phenotype among patients. Lastly, we demonstrate via in vitro biochemical experiments that the APOBEC3B protein can deaminate the cytosine bases at two sites whose mutant states are subject to high net realized selection intensities-PIK3CA E545K and E542K. By quantifying the effects of mutations, we deepen the molecular understanding of carcinogenesis in head and neck squamous cell carcinoma.
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http://dx.doi.org/10.1038/s41388-018-0657-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6499643PMC
May 2019

Effect Sizes of Somatic Mutations in Cancer.

J Natl Cancer Inst 2018 11;110(11):1171-1177

Department of Biostatistics, Yale School of Public Health, New Haven, CT.

A major goal of cancer biology is determination of the relative importance of the genetic alterations that confer selective advantage to cancer cells. Tumor sequence surveys have frequently ranked the importance of substitutions to cancer growth by P value or a false-discovery conversion thereof. However, P values are thresholds for belief, not metrics of effect. Their frequent misuse as metrics of effect has often been vociferously decried, even in cases when the only attributable mistake was omission of effect sizes. Here, we propose an appropriate ranking-the cancer effect size, which is the selection intensity for somatic variants in cancer cell lineages. The selection intensity is a metric of the survival and reproductive advantage conferred by mutations in somatic tissue. Thus, they are of fundamental importance to oncology, and have immediate relevance to ongoing decision making in precision medicine tumor boards, to the selection and design of clinical trials, to the targeted development of pharmaceuticals, and to basic research prioritization. Within this commentary, we first discuss the scope of current methods that rank confidence in the overrepresentation of specific mutated genes in cancer genomes. Then we bring to bear recent advances that draw upon an understanding of the development of cancer as an evolutionary process to estimate the effect size of somatic variants leading to cancer. We demonstrate the estimation of the effect sizes of all recurrent single nucleotide variants in 22 cancer types, quantifying relative importance within and between driver genes.
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http://dx.doi.org/10.1093/jnci/djy168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6235682PMC
November 2018

Developmental Dynamics of Long Noncoding RNA Expression during Sexual Fruiting Body Formation in Fusarium graminearum.

mBio 2018 08 14;9(4). Epub 2018 Aug 14.

Department of Plant Biology, Michigan State University, East Lansing, Michigan, USA

Long noncoding RNA (lncRNA) plays important roles in sexual development in eukaryotes. In filamentous fungi, however, little is known about the expression and roles of lncRNAs during fruiting body formation. By profiling developmental transcriptomes during the life cycle of the plant-pathogenic fungus , we identified 547 lncRNAs whose expression was highly dynamic, with about 40% peaking at the meiotic stage. Many lncRNAs were found to be antisense to mRNAs, forming 300 sense-antisense pairs. Although small RNAs were produced from these overlapping loci, antisense lncRNAs appeared not to be involved in gene silencing pathways. Genome-wide analysis of small RNA clusters identified many silenced loci at the meiotic stage. However, we found transcriptionally active small RNA clusters, many of which were associated with lncRNAs. Also, we observed that many antisense lncRNAs and their respective sense transcripts were induced in parallel as the fruiting bodies matured. The nonsense-mediated decay (NMD) pathway is known to determine the fates of lncRNAs as well as mRNAs. Thus, we analyzed mutants defective in NMD and identified a subset of lncRNAs that were induced during sexual development but suppressed by NMD during vegetative growth. These results highlight the developmental stage-specific nature and functional potential of lncRNA expression in shaping the fungal fruiting bodies and provide fundamental resources for studying sexual stage-induced lncRNAs. is the causal agent of the head blight on our major staple crops, wheat and corn. The fruiting body formation on the host plants is indispensable for the disease cycle and epidemics. Long noncoding RNA (lncRNA) molecules are emerging as key regulatory components for sexual development in animals and plants. To date, however, there is a paucity of information on the roles of lncRNAs in fungal fruiting body formation. Here we characterized hundreds of lncRNAs that exhibited developmental stage-specific expression patterns during fruiting body formation. Also, we discovered that many lncRNAs were induced in parallel with their overlapping transcripts on the opposite DNA strand during sexual development. Finally, we found a subset of lncRNAs that were regulated by an RNA surveillance system during vegetative growth. This research provides fundamental genomic resources that will spur further investigations on lncRNAs that may play important roles in shaping fungal fruiting bodies.
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http://dx.doi.org/10.1128/mBio.01292-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6094484PMC
August 2018

Genomic Comparison Among Global Isolates of Serovars Copenhageni and Icterohaemorrhagiae Identified Natural Genetic Variation Caused by an Indel.

Front Cell Infect Microbiol 2018 19;8:193. Epub 2018 Jun 19.

Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, United States.

Leptospirosis is a worldwide zoonosis, responsible for more than 1 million cases and 60,000 deaths every year. Among the 13 pathogenic species of the genus , serovars belonging to serogroup Icterohaemorrhagiae are considered to be the most virulent strains, and responsible for majority of the reported severe cases. Serovars Copenhageni and Icterohaemorrhagiae are major representatives of this serogroup and despite their public health relevance, little is known regarding the genetic differences between these two serovars. In this study, we analyzed the genome sequences of 67 isolates belonging to serovars Copenhageni and Icterohaemorrhagiae to investigate the influence of spatial and temporal variations on DNA sequence diversity. Out of the 1072 SNPs identified, 276 were in non-coding regions and 796 in coding regions. Indel analyses identified 258 indels, out of which 191 were found in coding regions and 67 in non-coding regions. Our phylogenetic analyses based on SNP dataset revealed that both serovars are closely related but showed distinct spatial clustering. However, likelihood ratio test of the indel data statistically confirmed the presence of a frameshift mutation within a homopolymeric tract of gene (related to LPS biosynthesis) in all the serovar Icterohaemorrhagiae strains but not in the Copenhageni strains. Therefore, this internal indel identified can genetically distinguish serovar Copenhageni from serovar Icterohaemorrhagiae with high discriminatory power. To our knowledge, this is the first study to identify global sequence variations (SNPs and Indels) in serovars Copenhageni and Icterohaemorrhagiae.
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http://dx.doi.org/10.3389/fcimb.2018.00193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6018220PMC
July 2019

Optimal Rates for Phylogenetic Inference and Experimental Design in the Era of Genome-Scale Data Sets.

Syst Biol 2019 01;68(1):145-156

Department of Ecology and Evolutionary Biology, Yale University, New Haven, 165 Prospect Street, CT 06525, USA.

With the rise of genome-scale data sets, there has been a call for increased data scrutiny and careful selection of loci that are appropriate to use in an attempt to resolve a phylogenetic problem. Such loci should maximize phylogenetic information content while minimizing the risk of homoplasy. Theory posits the existence of characters that evolve at an optimum rate, and efforts to determine optimal rates of inference have been a cornerstone of phylogenetic experimental design for over two decades. However, both theoretical and empirical investigations of optimal rates have varied dramatically in their conclusions: spanning no relationship to a tight relationship between the rate of change and phylogenetic utility. Herein, we synthesize these apparently contradictory views, demonstrating both empirical and theoretical conditions under which each is correct. We find that optimal rates of characters-not genes-are generally robust to most experimental design decisions. Moreover, consideration of site rate heterogeneity within a given locus is critical to accurate predictions of utility. Factors such as taxon sampling or the targeted number of characters providing support for a topology are additionally critical to the predictions of phylogenetic utility based on the rate of character change. Further, optimality of rates and predictions of phylogenetic utility are not equivalent, demonstrating the need for further development of comprehensive theory of phylogenetic experimental design. [Divergence time; GC bias; homoplasy; incongruence; information content; internode length; optimal rates; phylogenetic informativeness; phylogenetic theory; phylogenetic utility; phylogenomics; signal and noise; subtending branch length; state space; taxon and character sampling.].
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http://dx.doi.org/10.1093/sysbio/syy047DOI Listing
January 2019

Potential effectiveness of long-acting injectable pre-exposure prophylaxis for HIV prevention in men who have sex with men: a modelling study.

Lancet HIV 2018 09 13;5(9):e498-e505. Epub 2018 Jun 13.

Center for Infectious Disease Modeling and Analysis, School of Public Health, Yale University, New Haven, CT, USA; Department of Ecology and Evolutionary Biology, Yale University, New Haven, CT, USA; Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA.

Background: Oral pre-exposure prophylaxis (PrEP) prevents HIV infection in men who have sex with men (MSM); however, adherence is an ongoing concern. Long-acting injectable PrEP is being tested in phase 3 trials and could address challenges associated with adherence. We examined the potential effectiveness of long-acting injectable PrEP compared with oral PrEP in MSM.

Methods: We used an agent-based model to simulate HIV transmission in a dynamic network of 11 245 MSM in Atlanta, GA, USA. We used raw data from studies in macaque models and pharmacokinetic data from safety trials to estimate the time-varying efficacy of long-acting injectable PrEP. The effect of long-acting injectable PrEP on the cumulative number of new HIV infections over 10 years (2015-24) was compared with no PrEP and daily oral PrEP across a range of coverage levels. Sensitivity analyses were done with varying maximum efficacy and drug half-life values.

Findings: In the absence of PrEP, the model predicted 2374 new HIV infections (95% simulation interval [SI] 2345-2412) between 2015 and 2024. The cumulative number of new HIV infections was reduced in all scenarios in which MSM received long-acting injectable PrEP compared with oral PrEP. At a coverage level of 35%, compared with no PrEP, long-acting injectable PrEP led to a 44% reduction in new HIV infections (1044 new infections averted [95% SI 1018-1077]) versus 33% (792 infections averted [763-821]) for oral PrEP. The relative benefit of long-acting injectable PrEP was sensitive to the assumed efficacy of injections received every 8 weeks, discontinuation rates, and terminal drug half-life.

Interpretation: Long-acting injectable PrEP has the potential to produce larger reductions in HIV transmission in MSM than oral PrEP. However, the real-world, population-level impact of this approach will depend on uptake of this prevention method and its effectiveness, as well as retention of patients in clinical care.

Funding: National Institute on Drug Abuse and National Institute of Mental Health.
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http://dx.doi.org/10.1016/S2352-3018(18)30097-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6138558PMC
September 2018

Analysis of mutation, selection, and epistasis: an informed approach to cancer clinical trials.

Oncotarget 2018 Apr 27;9(32):22243-22253. Epub 2018 Apr 27.

Department of Biostatistics, Yale School of Public Health, Yale University, New Haven, CT, USA.

Currently, drug development efforts and clinical trials to test them are often prioritized by targeting genes with high frequencies of somatic variants among tumors. However, differences in oncogenic mutation rate-not necessarily the effect the variant has on tumor growth-contribute enormously to somatic variant frequency. We argue that decoupling the contributions of mutation and cancer lineage selection to the frequency of somatic variants among tumors is critical to understanding-and predicting-the therapeutic potential of different interventions. To provide an indicator of that strength of selection and therapeutic potential, the frequency at which we observe a given variant across patients must be modulated by our expectation given the mutation rate and target size to provide an indicator of that strength of selection and therapeutic potential. Additionally, antagonistic and synergistic epistasis among mutations also impacts the potential therapeutic benefit of targeted drug development. Quantitative approaches should be fostered that use the known genetic architectures of cancer types, decouple mutation rate, and provide rigorous guidance regarding investment in targeted drug development. By integrating evolutionary principles and detailed mechanistic knowledge into those approaches, we can maximize our ability to identify those targeted therapies most likely to yield substantial clinical benefit.
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http://dx.doi.org/10.18632/oncotarget.25155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5976461PMC
April 2018

Neutral Theory and the Somatic Evolution of Cancer.

Mol Biol Evol 2018 06;35(6):1308-1315

Department of Biostatistics, Yale University, New Haven, CT.

Kimura's neutral theory argued that positive selection was not responsible for an appreciable fraction of molecular substitutions. Correspondingly, quantitative analysis reveals that the vast majority of substitutions in cancer genomes are not detectably under selection. Insights from the somatic evolution of cancer reveal that beneficial substitutions in cancer constitute a small but important fraction of the molecular variants. The molecular evolution of cancer community will benefit by incorporating the neutral theory of molecular evolution into their understanding and analysis of cancer evolution-and accepting the use of tractable, predictive models, even when there is some evidence that they are not perfect.
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http://dx.doi.org/10.1093/molbev/msy079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5967571PMC
June 2018

CDKN2A Copy Number Loss Is an Independent Prognostic Factor in HPV-Negative Head and Neck Squamous Cell Carcinoma.

Front Oncol 2018 4;8:95. Epub 2018 Apr 4.

Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT, United States.

Background: HPV infection is associated with high p16 expression and good prognosis in head and neck squamous cell carcinomas (HNSCCs). Analysis of CDKN2A, the gene encoding p16, may further elucidate the association between p16 expression and prognosis. We sought to determine whether CDKN2A copy number loss was associated with poor survival in HPV-negative HNSCCs.

Methods: The Cancer Genome Atlas HNSCC clinical and genomic data were obtained and integrated. Patients <80 years old with a primary tumor in the oral cavity, oropharynx, hypopharynx, or larynx were included. Stratifying by copy number loss status, CDKN2A mRNA and p16 protein expression levels were examined and overall survival (OS) and disease-free survival (DFS) were evaluated.

Results: 401 patients with HPV-negative HNSCC were identified. 146 patients demonstrated CDKN2A copy number loss. The CDKN2A copy number loss group expressed significantly lower levels of CDKN2A mRNA and p16 protein than did the non-copy number loss group. Median OS for patients with and without CDKN2A copy number loss was 16.5 and 46.6 months, respectively ( = 0.007). Median DFS for both groups was 11.6 and 19.2 months, respectively ( = 0.03). In both univariate and multivariable analyses, stage IV designation, receipt of chemotherapy and CDKN2A copy number loss were predictive of OS.

Conclusion: CDKN2A copy number loss predicted poor survival independently of other patient and treatment factors and may be a clinically useful prognostic factor.
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http://dx.doi.org/10.3389/fonc.2018.00095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5893829PMC
April 2018

Lvr, a Signaling System That Controls Global Gene Regulation and Virulence in Pathogenic .

Front Cell Infect Microbiol 2018 23;8:45. Epub 2018 Feb 23.

Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, United States.

Leptospirosis is an emerging zoonotic disease with more than 1 million cases annually. Currently there is lack of evidence for signaling pathways involved during the infection process of . In our comprehensive genomic analysis of 20 spp. we identified seven pathogen-specific Two-Component System (TCS) proteins. Disruption of two these TCS genes in pathogenic strain resulted in loss-of-virulence in a hamster model of leptospirosis. Corresponding genes and ) are juxtaposed in an operon and are predicted to encode a hybrid histidine kinase and a hybrid response regulator, respectively. Transcriptome analysis of mutant strains with disruption of one () or both genes () revealed global transcriptional regulation of 850 differentially expressed genes. Phosphotransfer assays demonstrated that LvrA phosphorylates LvrB and predicted further signaling downstream to one or more DNA-binding response regulators, suggesting that it is a branched pathway. Phylogenetic analyses indicated that and evolved independently within different ecological lineages in via gene duplication. This study uncovers a novel-signaling pathway that regulates virulence in pathogenic (Lvr), providing a framework to understand the molecular bases of regulation in this life-threatening bacterium.
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http://dx.doi.org/10.3389/fcimb.2018.00045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5863495PMC
February 2019