Multiple merger genealogies in outbreaks ofMycobacterium tuberculosis

Abstract

The Kingman coalescent and its developments are often considered among the most important advances in population genetics of the last decades. Demographic inference based on the coalescent theory has been used to reconstruct the population dynamics and evolutionary history of several species, including Mycobacterium tuberculosis (MTB), an important human pathogen causing tuberculosis. One key assumption of Kingman's coalescent is that the number of descendants of different individuals does not vary strongly, and violating this assumption could lead to severe biases caused by model misspecification. Individual lineages of MTB are expected to vary strongly in reproductive success because 1) MTB is potentially under constant selection due to the pressure of the host immune system, 2) MTB undergoes repeated population bottlenecks when it transmits from one host to another, and 3) some hosts show much higher transmission rates compared to the average ("super-spreaders").Here we used an Approximate Bayesian Computation approach to test whether multiple merger coalescents (MMC), a class of models that allow for large variation in offspring sizes, are more adequate models to study MTB populations. We considered eleven publicly available whole genome sequence data sets sampled from MTB local populations and outbreaks and found that MMC had a better fit compared to the Kingman coalescent for nine of the eleven data sets. These results indicate that the neutral model for analyzing MTB outbreaks, and potentially the outbreaks of other pathogens, should be reassessed, and that past findings based on the Kingman coalescent need to be revisited.

Sweepstakes reproductive success via pervasive and recurrent selective sweeps

“…It is also the first time multiple merger coalescent models based on neutral evolution and selection are contrasted. Previously, two neutral Λ-coalescents have been compared to data of outbreaks of the tuberculosis bacterium and used the Bolthausen-Sznitman coalescent ( α = 1) to model rapid selection (Menardo et al, 2019) Our findings have repercussions for and give impetus to further theoretical development of multiple merger coalescents, particularly for multiple merger coalescent models of strong selection.…”

“…This mode of reproduction characterizes many annual plants, a myriad of insects, and vertebrates such as the Pacific salmon ( Oncorhynchus ) and the Arctic cod ( Boreogadus saida ), a close relative of the Atlantic cod. We further posit that sweepstakes may be the mode of reproduction of viruses (Timm and Yin, 2012) as inferred from overdispersion of offspring distribution from superspreader individuals and events (Endo et al, 2020), some cancer cells (Kato et al, 2017), and various bacteria (Wright and Vetsigian, 2019; Menardo et al, 2019; Ypma et al, 2013). Fungi and plant pathogens, which cause extensive crop losses of great economic importance (Pimentel et al, 2000), may also reproduce by sweepstakes.…”

How do monomorphic bacteria evolve? The Mycobacterium tuberculosis complex and the awkward population genetics of extreme clonality

“…Several studies have shown that non-neutral processes confound demographic inference and should not simply be assumed away. Recombination (Hedge and Wilson, 2014), population structure (Heller et al, 2013), sampling design, gene conversion, and selection (Lapierre et al, 2016), as well as the skewness of reproductive success (Menardo et al, 2021a) all create spurious signs of population size changes. As observed by Lapierre et al, 2016, such methodological biases might explain why population size trajectories look suspiciously similar for a wide range of species.…”

“…Recently, progeny skew was brought up as a neglected aspect of MTBC evolution with potentially significant effects on genetic diversity (Morales-Arce et al, 2020) and population genetic inference (Menardo et al, 2021a). Progeny skew refers to the unequal distribution of offspring among parental individuals in a population.…”

The within-host evolution of antimicrobial resistance in Mycobacterium tuberculosis

“…forces that all reduce the observed genetic diversity present) result in an underestimation of MTBC mutation rates within-host when using evolutionary frameworks centered around the Wright–Fisher model. Use of evolutionary models that take clonality and skewed progeny distributions into account, such as multiple-merger coalescent theory (Menardo, Gagneux and Freund 2020 ; Morales‐Arce et al . 2020 ), may allow for a better estimate of MTBC genetic diversity production, including testing whether different MTBC genetic backgrounds indeed have different mutation rates.…”