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 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 the Kingman 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 and of antibiotic treatment, 2) MTB undergoes repeated population bottlenecks when it transmits from one host to the next, 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 reproductive success among lineages, are more appropriate models to study MTB populations. We considered eleven publicly available whole genome sequence data sets sampled from local MTB populations and outbreaks, and found that MMC had a better fit compared to the Kingman coalescent for ten of the eleven data sets. These results indicate that the null model for analyzing MTB outbreaks should be reassessed, and that past findings based on the Kingman coalescent need to be revisited.

Genealogical structure changes as range expansions transition from pushed to pulled

“…This framework can be used to infer the importance of density feedback in growth and dispersal or to predict evolution during range expansions. Furthermore, our work provides a generic explanation for the skewed genealoobserved in empirical studies (11,84). Previously, such genealogies were attributed to either very strong selection or sweepstakes reproduction, both of which could be less common than range expansions.…”

“…For example, many studies have analyzed the effects of time-dependent population sizes and spatial structure on the coalescent (2,17). Despite providing better fits to the data, this generalized Kingman coalescent does not capture some of the qualitative features of empirical genealogiesnamely, the existence of multiple mergers in the genealogical trees (11,18).…”

“…Importantly, the Kingman coalescent contains only pairwise mergers between lineages. However, several studies have attempted to test these predictions directly in real populations and found significant deviations (8)(9)(10)(11).…”

Interpreting the pervasive observation of U-shaped Site Frequency Spectra

“…Our method should thus still be able to detect multiple merger signals even if caused by processes that lead to another MMC. Assessing further which MMC models are best fitting for biological populations could be informative [MGF20]. In this regard, our inference approach is based on computing E ( T i ) from Eq.…”

Multiple-merger genealogies -- models, consequences, inference

“…infecting very many other patients, which could be modelled as a multiple-merger genealogy. With Menardo and Gagneux, I investigated in [41] whether indeed classes of Λ-n-coalescents fit better to the data than Kingman's n-coalescent with exponential growth. We considered 11 publicly available data sets and performed model selection using the ABC approach described above.…”