Gene Expression in <italic toggle="yes">Leishmania</italic> Is Regulated Predominantly by Gene Dosage

ABSTRACT Leishmania tropica, a unicellular eukaryotic parasite present in North and East Africa, the Middle East, and the Indian subcontinent, has been linked to large outbreaks of cutaneous leishmaniasis in displaced populations in Iraq, Jordan, and Syria. Here, we report the genome sequence of thi...

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Autores principales:	Stefano A. Iantorno, Caroline Durrant, Asis Khan, Mandy J. Sanders, Stephen M. Beverley, Wesley C. Warren, Matthew Berriman, David L. Sacks, James A. Cotton, Michael E. Grigg
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2017
Materias:	CNV Leishmania RNA-seq gene dosage gene expression Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/3b56349811ae4170ad5d58be0a235158
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spelling	oai:doaj.org-article:3b56349811ae4170ad5d58be0a2351582021-11-15T15:51:51ZGene Expression in <italic toggle="yes">Leishmania</italic> Is Regulated Predominantly by Gene Dosage10.1128/mBio.01393-172150-7511https://doaj.org/article/3b56349811ae4170ad5d58be0a2351582017-11-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01393-17https://doaj.org/toc/2150-7511ABSTRACT Leishmania tropica, a unicellular eukaryotic parasite present in North and East Africa, the Middle East, and the Indian subcontinent, has been linked to large outbreaks of cutaneous leishmaniasis in displaced populations in Iraq, Jordan, and Syria. Here, we report the genome sequence of this pathogen and 7,863 identified protein-coding genes, and we show that the majority of clinical isolates possess high levels of allelic diversity, genetic admixture, heterozygosity, and extensive aneuploidy. By utilizing paired genome-wide high-throughput DNA sequencing (DNA-seq) with RNA-seq, we found that gene dosage, at the level of individual genes or chromosomal “somy” (a general term covering disomy, trisomy, tetrasomy, etc.), accounted for greater than 85% of total gene expression variation in genes with a 2-fold or greater change in expression. High gene copy number variation (CNV) among membrane-bound transporters, a class of proteins previously implicated in drug resistance, was found for the most highly differentially expressed genes. Our results suggest that gene dosage is an adaptive trait that confers phenotypic plasticity among natural Leishmania populations by rapid down- or upregulation of transporter proteins to limit the effects of environmental stresses, such as drug selection. IMPORTANCE Leishmania is a genus of unicellular eukaryotic parasites that is responsible for a spectrum of human diseases that range from cutaneous leishmaniasis (CL) and mucocutaneous leishmaniasis (MCL) to life-threatening visceral leishmaniasis (VL). Developmental and strain-specific gene expression is largely thought to be due to mRNA message stability or posttranscriptional regulatory networks for this species, whose genome is organized into polycistronic gene clusters in the absence of promoter-mediated regulation of transcription initiation of nuclear genes. Genetic hybridization has been demonstrated to yield dramatic structural genomic variation, but whether such changes in gene dosage impact gene expression has not been formally investigated. Here we show that the predominant mechanism determining transcript abundance differences (>85%) in Leishmania tropica is that of gene dosage at the level of individual genes or chromosomal somy.Stefano A. IantornoCaroline DurrantAsis KhanMandy J. SandersStephen M. BeverleyWesley C. WarrenMatthew BerrimanDavid L. SacksJames A. CottonMichael E. GriggAmerican Society for MicrobiologyarticleCNVLeishmaniaRNA-seqgene dosagegene expressionMicrobiologyQR1-502ENmBio, Vol 8, Iss 5 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	CNV Leishmania RNA-seq gene dosage gene expression Microbiology QR1-502
spellingShingle	CNV Leishmania RNA-seq gene dosage gene expression Microbiology QR1-502 Stefano A. Iantorno Caroline Durrant Asis Khan Mandy J. Sanders Stephen M. Beverley Wesley C. Warren Matthew Berriman David L. Sacks James A. Cotton Michael E. Grigg Gene Expression in <italic toggle="yes">Leishmania</italic> Is Regulated Predominantly by Gene Dosage
description	ABSTRACT Leishmania tropica, a unicellular eukaryotic parasite present in North and East Africa, the Middle East, and the Indian subcontinent, has been linked to large outbreaks of cutaneous leishmaniasis in displaced populations in Iraq, Jordan, and Syria. Here, we report the genome sequence of this pathogen and 7,863 identified protein-coding genes, and we show that the majority of clinical isolates possess high levels of allelic diversity, genetic admixture, heterozygosity, and extensive aneuploidy. By utilizing paired genome-wide high-throughput DNA sequencing (DNA-seq) with RNA-seq, we found that gene dosage, at the level of individual genes or chromosomal “somy” (a general term covering disomy, trisomy, tetrasomy, etc.), accounted for greater than 85% of total gene expression variation in genes with a 2-fold or greater change in expression. High gene copy number variation (CNV) among membrane-bound transporters, a class of proteins previously implicated in drug resistance, was found for the most highly differentially expressed genes. Our results suggest that gene dosage is an adaptive trait that confers phenotypic plasticity among natural Leishmania populations by rapid down- or upregulation of transporter proteins to limit the effects of environmental stresses, such as drug selection. IMPORTANCE Leishmania is a genus of unicellular eukaryotic parasites that is responsible for a spectrum of human diseases that range from cutaneous leishmaniasis (CL) and mucocutaneous leishmaniasis (MCL) to life-threatening visceral leishmaniasis (VL). Developmental and strain-specific gene expression is largely thought to be due to mRNA message stability or posttranscriptional regulatory networks for this species, whose genome is organized into polycistronic gene clusters in the absence of promoter-mediated regulation of transcription initiation of nuclear genes. Genetic hybridization has been demonstrated to yield dramatic structural genomic variation, but whether such changes in gene dosage impact gene expression has not been formally investigated. Here we show that the predominant mechanism determining transcript abundance differences (>85%) in Leishmania tropica is that of gene dosage at the level of individual genes or chromosomal somy.
format	article
author	Stefano A. Iantorno Caroline Durrant Asis Khan Mandy J. Sanders Stephen M. Beverley Wesley C. Warren Matthew Berriman David L. Sacks James A. Cotton Michael E. Grigg
author_facet	Stefano A. Iantorno Caroline Durrant Asis Khan Mandy J. Sanders Stephen M. Beverley Wesley C. Warren Matthew Berriman David L. Sacks James A. Cotton Michael E. Grigg
author_sort	Stefano A. Iantorno
title	Gene Expression in <italic toggle="yes">Leishmania</italic> Is Regulated Predominantly by Gene Dosage
title_short	Gene Expression in <italic toggle="yes">Leishmania</italic> Is Regulated Predominantly by Gene Dosage
title_full	Gene Expression in <italic toggle="yes">Leishmania</italic> Is Regulated Predominantly by Gene Dosage
title_fullStr	Gene Expression in <italic toggle="yes">Leishmania</italic> Is Regulated Predominantly by Gene Dosage
title_full_unstemmed	Gene Expression in <italic toggle="yes">Leishmania</italic> Is Regulated Predominantly by Gene Dosage
title_sort	gene expression in <italic toggle="yes">leishmania</italic> is regulated predominantly by gene dosage
publisher	American Society for Microbiology
publishDate	2017
url	https://doaj.org/article/3b56349811ae4170ad5d58be0a235158
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Gene Expression in <italic toggle="yes">Leishmania</italic> Is Regulated Predominantly by Gene Dosage

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