Genome-wide identification of lineage and locus specific variation associated with pneumococcal carriage duration
- Wellcome Trust Sanger Institute, United Kingdom
- Imperial College London, United Kingdom
- University College London, United Kingdom
- Mahidol University, Thailand
- Wellcome Trust Sanger Centre, United Kingdom
- Angkor Hospital for Children, Cambodia
Abstract
Streptococcus pneumoniae is a leading cause of invasive disease in infants, especially in low-income settings. Asymptomatic carriage in the nasopharynx is a prerequisite for disease, but variability in its duration is currently only understood at the serotype level. Here we developed a model to calculate the duration of carriage episodes from longitudinal swab data, and combined these results with whole genome sequence data. We estimated that pneumococcal genomic variation accounted for 63% of the phenotype variation, whereas the host traits considered here (age and previous carriage) accounted for less than 5%. We further partitioned this heritability into both lineage and locus effects, and quantified the amount attributable to the largest sources of variation in carriage duration: serotype (17%), drug-resistance (9%) and other significant locus effects (7%). A pan-genome-wide association study identified prophage sequences as being associated with decreased carriage duration independent of serotype, potentially by disruption of the competence mechanism. These findings support theoretical models of pneumococcal competition and antibiotic resistance.
Data availability
-
Dense genomic sampling identifies highways of pneumococcal recombinationPublicly available in the NCBI Sequencing Read Archive (SRA) under study accessions ERP000435, ERP000483, ERP000485, ERP000487, ERP000598 and ERP000599.
Article and author information
Author details
Nicholas J Croucher
Funding
Wellcome (98051)
- John A Lees
- Julian Parkhill
- Stephen D Bentley
Medical Research Council (1365620)
- John A Lees
Royal Society (104169/Z/14/Z)
- Nicholas J Croucher
Royal Society (104169/Z/14/Z)
- Nicholas J Croucher
Wellcome (083735/Z/07/Z)
- Paul Turner
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: Written informed consent was obtained from the mothers prior to study enrolment. Ethical approval was granted by the ethics committees of the Faculty of Tropical Medicine, Mahidol University, Thailand (MUTM-2009-306) and Oxford University, UK (OXTREC-031-06).
Copyright
© 2017, Lees et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 3,590
- views
-
- 536
- downloads
-
- 89
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Genome-wide identification of lineage and locus specific variation associated with pneumococcal carriage duration
eLife 6:e26255.
https://doi.org/10.7554/eLife.26255
Further reading
-
- Medicine
- Microbiology and Infectious Disease
- Epidemiology and Global Health
- Immunology and Inflammation
eLife has published articles on a wide range of infectious diseases, including COVID-19, influenza, tuberculosis, HIV/AIDS, malaria and typhoid fever.
-
- Computational and Systems Biology
- Genetics and Genomics
Untranslated regions (UTRs) contain crucial regulatory elements for RNA stability, translation and localization, so their integrity is indispensable for gene expression. Approximately 3.7% of genetic variants associated with diseases occur in UTRs, yet a comprehensive understanding of UTR variant functions remains limited due to inefficient experimental and computational assessment methods. To systematically evaluate the effects of UTR variants on RNA stability, we established a massively parallel reporter assay on 6555 UTR variants reported in human disease databases. We examined the RNA degradation patterns mediated by the UTR library in two cell lines, and then applied LASSO regression to model the influential regulators of RNA stability. We found that UA dinucleotides and UA-rich motifs are the most prominent destabilizing element. Gain of UA dinucleotide outlined mutant UTRs with reduced stability. Studies on endogenous transcripts indicate that high UA-dinucleotide ratios in UTRs promote RNA degradation. Conversely, elevated GC content and protein binding on UA dinucleotides protect high-UA RNA from degradation. Further analysis reveals polarized roles of UA-dinucleotide-binding proteins in RNA protection and degradation. Furthermore, the UA-dinucleotide ratio of both UTRs is a common characteristic of genes in innate immune response pathways, implying a coordinated stability regulation through UTRs at the transcriptomic level. We also demonstrate that stability-altering UTRs are associated with changes in biobank-based health indices, underscoring the importance of precise UTR regulation for wellness. Our study highlights the importance of RNA stability regulation through UTR primary sequences, paving the way for further exploration of their implications in gene networks and precision medicine.
