Exploring the Population Structure, Recombination Landscape, and Pan-Genome of the Global Neisseria meningitidis Population
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Authors
Macalasdair, Neil
Advisors
Trotter, Caroline
Parkhill, Julian
Bentley, Stephen
Date
2021-06-30Awarding Institution
University of Cambridge
Qualification
Doctor of Philosophy (PhD)
Type
Thesis
Metadata
Show full item recordCitation
Macalasdair, N. (2021). Exploring the Population Structure, Recombination Landscape, and Pan-Genome of the Global Neisseria meningitidis Population (Doctoral thesis). https://doi.org/10.17863/CAM.87457
Abstract
Neisseria meningitidis is a gram-negative species of bacteria
which causes meningitis, septicaemia, urethritis, and pneumonia
worldwide. Infections are typically asymptomatic carriage, but
those which cause disease are extremely difficult to treat, leading to a high case-fatality rate. As such, there is considerable
interest in studying N. meningitidis to understand its spread,
what causes development from carriage to invasive disease, and
how its evolution impacts efforts to control the disease. The
latter has been of particular concern in regions where there have
been outbreaks, particularly the ‘meningitis belt’ that spans
from West Africa to East Africa, where there is greater disease
burden and periodic epidemics which can span the region. Due
to difficulties in treatment, the primary method of controlling invasive meningococcal disease is vaccination. Currently, available
vaccines target five of the extant serogroups of N. meningitidis, chosen through study of the serogroups most frequently
found in disease. However, either the replacement of disease
lineages with those of different serogroups or capsular switching
within disease-associated lineages may undermine the success
of mass vaccination efforts and create the need for additional
campaigns. N. meningitidis specifically possesses characteristics
which make vaccine escape likely and unpredictable. The most
important are the adaptions which allow frequent homologous
recombination with other Neisseria. The evolutionary consequences of this sporadic partial chromosomal recombination are not well understood, but the transfer of alleles between distant lineages – including those associated with virulence – has been observed. Another gap in our understanding of bacterial
evolution is in the evolutionary effect of population structure.
Obilgately human-parasitic species such as N. meningitids have
a global distribution and opportunities for rapid migration, and
therefore may have a complex population structure. To study
these problems, I have assembled a collection of over 15,000
whole-genome sequenced N. meningitids isolates from 70 distinct
countries with isolation dates spanning over a hundred years.
These data consist of a mixture of publicly published data, and
three collections of newly sequenced isolates. Using these data,
I determine the global population structure of N. meningitids.
Subsequently, I infer phylogenetic trees for and find patterns of
recombination within major lineages in the global population.
Separately, I also infer and analyse the species-wide pan-genome.
The results of these analyses indicate that N. meningitidis has a
deep well of generally unsampled diversity in an extremely complex population structure which is primarily made up of a few
globally distributed lineages. Within these lineages, population
bottlenecks are a frequent occurrence. The 25 major lineages
differ significantly in both their rates of recombination and the
distribution of recombination across their genomes, but evidence
suggest that most recombination occurs within N. meningitidis.
In a local population, recombination generally acts to reduce
the effect of deleterious mutations, although an example also
exists of recombination acting in concert with positive selection. The pan-genome reveals the extent to which recombination
can disrupt tree-like evolution, with most major lineages containing patterns of relatedness in their accessory gene content
inconsistent with their whole-genome phylogenies. Trends in
the pan-genome indicate that most gene gain is from other N.
meningitidis isolates, but is governed primarily by evolutionary forces and not recombination rate. Together, these results
demonstrate the profound complexity present in the population
structure of N. meningitidis, and distinct evolutionary trends in
individual lineages. This work also underscores the importance
of carriage sampling and the value of a global perspective when studying a globally-distributed species. Further sampling in regions which are under-sampled and ongoing carriage surveillance
will be a crucial part of any long-term efforts to successfully
control the disease through vaccination.
Keywords
Meningitis, Neisseria, Bacteria, Evolution, Recombination, Pangenome
Sponsorship
Wellcome Sanger Institute PhD studentship
Identifiers
This record's DOI: https://doi.org/10.17863/CAM.87457
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