Comparative analyses of selection operating on nontranslated intergenic regions of diverse bacterial species

Harry A. Thorpe; Sion C. Bayliss; Laurence D. Hurst; Edward J. Feil

doi:10.1534/genetics.116.195784

Comparative analyses of selection operating on nontranslated intergenic regions of diverse bacterial species

Harry A. Thorpe
, Sion C. Bayliss
, Laurence D. Hurst
, Edward J. Feil^*

^*Corresponding author for this work

Research output: Contribution to journal › Article (Academic Journal) › peer-review

55 Citations (Scopus)

Abstract

Nontranslated intergenic regions (IGRs) compose 10-15% of bacterial genomes, and contain many regulatory elements with key functions. Despite this, there are few systematic studies on the strength and direction of selection operating on IGRs in bacteria using whole-genome sequence data sets. Here we exploit representative whole-genome data sets from six diverse bacterial species: Staphylococcus aureus, Streptococcus pneumoniae, Mycobacterium tuberculosis, Salmonella enterica, Klebsiella pneumoniae, and Escherichia coli. We compare patterns of selection operating on IGRs using two independent methods: the proportion of singleton mutations and the d_I/d_S ratio, where d_I is the number of intergenic SNPs per intergenic site. We find that the strength of purifying selection operating over all intergenic sites is consistently intermediate between that operating on synonymous and nonsynonymous sites. Ribosome binding sites and noncoding RNAs tend to be under stronger selective constraint than promoters and Rho-independent terminators. Strikingly, a clear signal of purifying selection remains even when all these major categories of regulatory elements are excluded, and this constraint is highest immediately upstream of genes. While a paucity of variation means that the data for M. tuberculosis are more equivocal than for the other species, we find strong evidence for positive selection within promoters of this species. This points to a key adaptive role for regulatory changes in this important pathogen. Our study underlines the feasibility and utility of gauging the selective forces operating on bacterial IGRs from whole-genome sequence data, and suggests that our current understanding of the functionality of these sequences is far from complete.

Original language	English
Pages (from-to)	363-376
Number of pages	14
Journal	Genetics
Volume	206
Issue number	1
DOIs	https://doi.org/10.1534/genetics.116.195784
Publication status	Published - May 2017

Bibliographical note

Funding Information:
We are very grateful to Kathie Grant and Tim Dallman of the Gastrointestinal Bacteria Reference Unit at Public Health England for permission to use the Salmonella enterica data. We also thank Adam Eyre-Walker for critical reading of the manuscript and invaluable discussions and acknowledge the anonymous referees for insightful and constructive comments. We are also very grateful to the Medical Research Council-funded Cloud Infrastructure for Microbial Bioinformatics consortium for granting access and support. The Staphylococcus aureus genome sequences were generated as part of a study supported by a grant from the United Kingdom Clinical Research Collaboration Translational Infection Research Initiative and the Medical Research Council (grant number G1000803, held by Sharon Peacock) with contributions from the Biotechnology and Biological Sciences Research Council; the National Institute for Health Research on behalf of the Department of Health; and the Chief Scientist Office of the Scottish Government Health Directorate, on which E.J.F. was a principal investigator and S.C.B. is a postdoctoral researcher. H.A.T. is funded by a University of Bath research studentship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors declare that they have no competing interests.

Publisher Copyright:
© 2017 by the Genetics Society of America.

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Keywords

Bacterial genomics
Intergenic regions (IGRs)
Purifying selection
Whole-genome sequencing

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title = "Comparative analyses of selection operating on nontranslated intergenic regions of diverse bacterial species",

abstract = "Nontranslated intergenic regions (IGRs) compose 10-15\% of bacterial genomes, and contain many regulatory elements with key functions. Despite this, there are few systematic studies on the strength and direction of selection operating on IGRs in bacteria using whole-genome sequence data sets. Here we exploit representative whole-genome data sets from six diverse bacterial species: Staphylococcus aureus, Streptococcus pneumoniae, Mycobacterium tuberculosis, Salmonella enterica, Klebsiella pneumoniae, and Escherichia coli. We compare patterns of selection operating on IGRs using two independent methods: the proportion of singleton mutations and the dI/dS ratio, where dI is the number of intergenic SNPs per intergenic site. We find that the strength of purifying selection operating over all intergenic sites is consistently intermediate between that operating on synonymous and nonsynonymous sites. Ribosome binding sites and noncoding RNAs tend to be under stronger selective constraint than promoters and Rho-independent terminators. Strikingly, a clear signal of purifying selection remains even when all these major categories of regulatory elements are excluded, and this constraint is highest immediately upstream of genes. While a paucity of variation means that the data for M. tuberculosis are more equivocal than for the other species, we find strong evidence for positive selection within promoters of this species. This points to a key adaptive role for regulatory changes in this important pathogen. Our study underlines the feasibility and utility of gauging the selective forces operating on bacterial IGRs from whole-genome sequence data, and suggests that our current understanding of the functionality of these sequences is far from complete.",

keywords = "Bacterial genomics, Intergenic regions (IGRs), Purifying selection, Whole-genome sequencing",

author = "Thorpe, \{Harry A.\} and Bayliss, \{Sion C.\} and Hurst, \{Laurence D.\} and Feil, \{Edward J.\}",

note = "Funding Information: We are very grateful to Kathie Grant and Tim Dallman of the Gastrointestinal Bacteria Reference Unit at Public Health England for permission to use the Salmonella enterica data. We also thank Adam Eyre-Walker for critical reading of the manuscript and invaluable discussions and acknowledge the anonymous referees for insightful and constructive comments. We are also very grateful to the Medical Research Council-funded Cloud Infrastructure for Microbial Bioinformatics consortium for granting access and support. The Staphylococcus aureus genome sequences were generated as part of a study supported by a grant from the United Kingdom Clinical Research Collaboration Translational Infection Research Initiative and the Medical Research Council (grant number G1000803, held by Sharon Peacock) with contributions from the Biotechnology and Biological Sciences Research Council; the National Institute for Health Research on behalf of the Department of Health; and the Chief Scientist Office of the Scottish Government Health Directorate, on which E.J.F. was a principal investigator and S.C.B. is a postdoctoral researcher. H.A.T. is funded by a University of Bath research studentship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors declare that they have no competing interests. Publisher Copyright: {\textcopyright} 2017 by the Genetics Society of America.",

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T1 - Comparative analyses of selection operating on nontranslated intergenic regions of diverse bacterial species

AU - Thorpe, Harry A.

AU - Bayliss, Sion C.

AU - Hurst, Laurence D.

AU - Feil, Edward J.

N1 - Funding Information: We are very grateful to Kathie Grant and Tim Dallman of the Gastrointestinal Bacteria Reference Unit at Public Health England for permission to use the Salmonella enterica data. We also thank Adam Eyre-Walker for critical reading of the manuscript and invaluable discussions and acknowledge the anonymous referees for insightful and constructive comments. We are also very grateful to the Medical Research Council-funded Cloud Infrastructure for Microbial Bioinformatics consortium for granting access and support. The Staphylococcus aureus genome sequences were generated as part of a study supported by a grant from the United Kingdom Clinical Research Collaboration Translational Infection Research Initiative and the Medical Research Council (grant number G1000803, held by Sharon Peacock) with contributions from the Biotechnology and Biological Sciences Research Council; the National Institute for Health Research on behalf of the Department of Health; and the Chief Scientist Office of the Scottish Government Health Directorate, on which E.J.F. was a principal investigator and S.C.B. is a postdoctoral researcher. H.A.T. is funded by a University of Bath research studentship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors declare that they have no competing interests. Publisher Copyright: © 2017 by the Genetics Society of America.

PY - 2017/5

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N2 - Nontranslated intergenic regions (IGRs) compose 10-15% of bacterial genomes, and contain many regulatory elements with key functions. Despite this, there are few systematic studies on the strength and direction of selection operating on IGRs in bacteria using whole-genome sequence data sets. Here we exploit representative whole-genome data sets from six diverse bacterial species: Staphylococcus aureus, Streptococcus pneumoniae, Mycobacterium tuberculosis, Salmonella enterica, Klebsiella pneumoniae, and Escherichia coli. We compare patterns of selection operating on IGRs using two independent methods: the proportion of singleton mutations and the dI/dS ratio, where dI is the number of intergenic SNPs per intergenic site. We find that the strength of purifying selection operating over all intergenic sites is consistently intermediate between that operating on synonymous and nonsynonymous sites. Ribosome binding sites and noncoding RNAs tend to be under stronger selective constraint than promoters and Rho-independent terminators. Strikingly, a clear signal of purifying selection remains even when all these major categories of regulatory elements are excluded, and this constraint is highest immediately upstream of genes. While a paucity of variation means that the data for M. tuberculosis are more equivocal than for the other species, we find strong evidence for positive selection within promoters of this species. This points to a key adaptive role for regulatory changes in this important pathogen. Our study underlines the feasibility and utility of gauging the selective forces operating on bacterial IGRs from whole-genome sequence data, and suggests that our current understanding of the functionality of these sequences is far from complete.

AB - Nontranslated intergenic regions (IGRs) compose 10-15% of bacterial genomes, and contain many regulatory elements with key functions. Despite this, there are few systematic studies on the strength and direction of selection operating on IGRs in bacteria using whole-genome sequence data sets. Here we exploit representative whole-genome data sets from six diverse bacterial species: Staphylococcus aureus, Streptococcus pneumoniae, Mycobacterium tuberculosis, Salmonella enterica, Klebsiella pneumoniae, and Escherichia coli. We compare patterns of selection operating on IGRs using two independent methods: the proportion of singleton mutations and the dI/dS ratio, where dI is the number of intergenic SNPs per intergenic site. We find that the strength of purifying selection operating over all intergenic sites is consistently intermediate between that operating on synonymous and nonsynonymous sites. Ribosome binding sites and noncoding RNAs tend to be under stronger selective constraint than promoters and Rho-independent terminators. Strikingly, a clear signal of purifying selection remains even when all these major categories of regulatory elements are excluded, and this constraint is highest immediately upstream of genes. While a paucity of variation means that the data for M. tuberculosis are more equivocal than for the other species, we find strong evidence for positive selection within promoters of this species. This points to a key adaptive role for regulatory changes in this important pathogen. Our study underlines the feasibility and utility of gauging the selective forces operating on bacterial IGRs from whole-genome sequence data, and suggests that our current understanding of the functionality of these sequences is far from complete.

KW - Bacterial genomics

KW - Intergenic regions (IGRs)

KW - Purifying selection

KW - Whole-genome sequencing

UR - https://www.scopus.com/pages/publications/85020736816

U2 - 10.1534/genetics.116.195784

DO - 10.1534/genetics.116.195784

M3 - Article (Academic Journal)

C2 - 28280056

AN - SCOPUS:85020736816

SN - 0016-6731

VL - 206

SP - 363

EP - 376

JO - Genetics

JF - Genetics

IS - 1

ER -

Comparative analyses of selection operating on nontranslated intergenic regions of diverse bacterial species

Abstract

Bibliographical note

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Keywords

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