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
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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.
Reviewing Editor
- Sarah Cobey, University of Chicago, United States
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).
Version history
- Received: February 22, 2017
- Accepted: July 21, 2017
- Accepted Manuscript published: July 25, 2017 (version 1)
- Version of Record published: August 29, 2017 (version 2)
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.
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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
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- 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.
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- Computational and Systems Biology
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Runs-of-homozygosity (ROH) segments, contiguous homozygous regions in a genome were traditionally linked to families and inbred populations. However, a growing literature suggests that ROHs are ubiquitous in outbred populations. Still, most existing genetic studies of ROH in populations are limited to aggregated ROH content across the genome, which does not offer the resolution for mapping causal loci. This limitation is mainly due to a lack of methods for the efficient identification of shared ROH diplotypes. Here, we present a new method, ROH-DICE (runs-of-homozygous diplotype cluster enumerator), to find large ROH diplotype clusters, sufficiently long ROHs shared by a sufficient number of individuals, in large cohorts. ROH-DICE identified over 1 million ROH diplotypes that span over 100 single nucleotide polymorphisms (SNPs) and are shared by more than 100 UK Biobank participants. Moreover, we found significant associations of clustered ROH diplotypes across the genome with various self-reported diseases, with the strongest associations found between the extended human leukocyte antigen (HLA) region and autoimmune disorders. We found an association between a diplotype covering the homeostatic iron regulator (HFE) gene and hemochromatosis, even though the well-known causal SNP was not directly genotyped or imputed. Using a genome-wide scan, we identified a putative association between carriers of an ROH diplotype in chromosome 4 and an increase in mortality among COVID-19 patients (p-value = 1.82 × 10−11). In summary, our ROH-DICE method, by calling out large ROH diplotypes in a large outbred population, enables further population genetics into the demographic history of large populations. More importantly, our method enables a new genome-wide mapping approach for finding disease-causing loci with multi-marker recessive effects at a population scale.
