Biology subjects

Miller, E. F.

Publications and source records attributed to Miller, E. F..

5 recordsLinked to original sources

bioRxiv2026

The historical domestication of a Clostridium botulinum strain used for the industrial production of botulinum neurotoxin

Laboratory production of botulinum neurotoxin (BoNT) began more than 90 years ago for medical, military, and later pharmaceutical applications, creating one of the longest-running examples of microbial cultivation under sustained human control. A single Clostridium botulinum Group I lineage, Army Hall A (AHA), was established by the U.S. military in 1942 and later gave rise to Hall A-hyper (HAH), the strain widely used for pharmaceutical BoNT production. We analyzed more than 1,000 C. botulinum genomes to identify AHAs closest relatives and to infer the most recent common ancestor (MRCA) shared with its nearest wild lineage. Relative to this MRCA, AHA accumulated nearly 100 genetic changes, including 46 single-nucleotide substitutions, 44 small insertions or deletions, and several large deletions and structural variants that led to the loss of more than 80 genes. A nonsense mutation in mutS generated a hypermutator phenotype that accelerated mutation rates and increased genetic diversity. This event occurred early in the lineages domestication and appears to have facilitated laboratory-adaptive traits, including the lack of sporulation and increased BoNT yield. Competition experiments under standard growth conditions confirmed substantial laboratory adaptation, with AHA exhibiting a strong fitness advantage over a close wild relative. Together, these results reconstruct the genomic trajectory of a bacterium evolving under prolonged human-mediated selection and provide a genome-resolved example of microbial domestication. The findings show how laboratory conditions, industrial selection, and changing mutation rates can jointly shape bacterial evolution, and they offer a general framework for understanding domestication and laboratory adaptation across microbial systems. SignificanceHuman-mediated species domestication has been central to the development of civilization, with well-known examples in plants and animals. Microbes have also been domesticated, often unintentionally and before the advent of modern microbiology. The military and pharmaceutical applications of botulinum neurotoxin led to the sustained cultivation and eventual domestication of a high toxin-producing Clostridium botulinum strain that remains widely used today. We reconstruct the genomic changes along this trajectory and identify a key early mutation that generated a hypermutator phenotype, increasing genetic variation available for human-directed selection. These findings reveal fundamental evolutionary processes shaping bacterial genomes under long-term human control. This genome-resolved example of microbial domestication offers a general framework for understanding laboratory adaptation in both evolutionary and applied microbiology.

microbiology↗

bioRxiv2021

Climate and mountains shaped human ancestral genetic lineages

Extensive sequencing of modern and ancient human genomes has revealed that contemporary populations can be explained as the result of recent mixing of a few distinct ancestral genetic lineages1. But the small number of aDNA samples that predate the Last Glacial Maximum means that the origins of these lineages are not well understood. Here, we circumvent the limited sampling by modelling explicitly the effect of climatic changes and terrain on population demography and migrations through time and space, and show that these factors are sufficient to explain the divergence among ancestral lineages. Our reconstructions show that the sharp separation between African and Eurasian lineages is a consequence of only a few limited periods of connectivity through the arid Arabian peninsula, which acted as the gate out of the Arican continent. The subsequent spread across Eurasia was then mostly shaped by mountain ranges, and to a lesser extent deserts, leading to the split of European and Asians, and the further diversification of these two groups. A high tolerance to cold climates allowed the persistence at high latitudes even during the Last Glacial Maximum, maintaining a pocket in Beringia that led to the later, rapid colonisation of the Americas. The advent of food production was associated with an increase in movement2, but mountains and climate have been shown to still play a major role even in this latter period3,4, affecting the mixing of the ancestral lineages that we have shown to be shaped by those two factors in the first place.

genomics↗

bioRxiv2021

Post-glacial expansion dynamics, not refugial isolation, shaped the genetic structure of a migratory bird, the Yellow Warbler (Setophaga petechia)

During the glacial periods of the Pleistocene, swathes of the Northern Hemisphere were covered by ice sheets, tundra, and permafrost, leaving large areas uninhabitable for temperate and boreal species. The glacial refugia paradigm proposes that, during glaciations, species living in the Northern Hemisphere were forced southwards, forming isolated populations that persisted in disjunct regions known as refugia. According to this hypothesis, as ice sheets retreated, species recolonised the continent from these glacial refugia, and the mixing of these lineages is responsible for modern patterns of genetic diversity. An alternative hypothesis is that complex genetic patterns could also arise simply from heterogenous post-glacial expansion dynamics, without separate refugia. Both mitochondrial and genomic data from the North American yellow warbler (Setophaga petechia) shows the presence of an eastern and western clade, a pattern often ascribed to the presence of two refugia. However, species distribution modelling (SDM) of the past range of this species fails to identify obvious refugia during the Last Glacial Maximum. Using a climate-informed spatial genetic modelling (CISGeM) framework, which allows us to integrate knowledge of past geographic ranges based on SDM, we reconstructed past population sizes, range expansions, and likely recolonisation dynamics of this species, generating spatially and temporally explicit demographic reconstructions. The model captures the empirical genetic structure despite including only a single, large glacial refugium. The observed contemporary population structure was generated during the expansion dynamics after the glaciation and is due to unbalanced rates of northward advance to the east and west linked to the melting of the icesheets. Thus, modern population structure in this species is consistent with expansion dynamics, and refugial isolation is not required to explain it, highlighting the importance of explicitly testing drivers of geographic structure. Significance statementPatterns of population differentiation in many species have often been attributed to the mixing of isolates from distinct refugia that formed during periods of glaciation, when range fragmentation was likely. By formally bringing together multiple lines of evidence, we demonstrate that the patterns of genetic diversity seen across the range of the yellow warbler (Setophaga petechia) were not the result of multiple isolated refugia. Instead, asymmetric expansion from a single cohesive range generated the observed patterns; the expansions asymmetry was due to the uneven melting of the icesheets over time. Thus, we demonstrate the importance of reconstructing species range dynamics when trying to explain patterns of genetic differentiation.

evolutionary biology↗

bioRxiv2020

mtDNAcombine: tools to combine sequences from multiple studies

Today an unprecedented amount of genetic sequence data is stored in publicly available repositories. For decades now, mitochondrial DNA (mtDNA) has been the workhorse of genetic studies, and as a result, there is a large volume of mtDNA data available in these repositories for a wide range of species. Indeed, whilst whole genome sequencing is an exciting prospect for the future, for most non-model organisms classical markers such as mtDNA remain widely used. By compiling existing data from multiple original studies, it is possible to build powerful new datasets capable of exploring many questions in ecology, evolution and conservation biology. One key question that these data can help inform is what happened in a species demographic past. However, compiling data in this manner is not trivial, there are many complexities associated with data extraction, data quality and data handling. Here we present the mtDNAcombine package, a collection of tools developed to manage some of the major decisions associated with handling multi-study sequence data with a particular focus on preparing mtDNA data for Bayesian Skyline Plot demographic reconstructions.

bioinformatics↗

bioRxiv2019

mtDNA-based reconstructions of change in effective population sizes of Holarctic birds do not agree with their reconstructed range sizes based on paleoclimates

During the Quaternary, large climate oscillations had profound impacts on the distribution, demography and diversity of species globally. Birds offer a special opportunity for studying these impacts because surveys of geographical distributions, publicly-available genetic sequence data, and the existence of species with adaptations to life in structurally different habitats, permit large-scale comparative analyses. We use Bayesian Skyline Plot (BSP) analysis of mitochondrial DNA to reconstruct profiles depicting how effective population size (Ne) may have changed over time, focussing on variation in the effect of the last deglaciation among 102 Holarctic species. Only 3 species showed a decline in Ne since the Last Glacial Maximum (LGM) and 7 showed no sizeable change, whilst 92 profiles revealed an increase in Ne. Using bioclimatic Species Distribution Models (SDMs), we also estimated changes in species potential range extent since the LGM. Whilst most modelled ranges also increased, we found no correlation across species between the magnitude of change in range size and change in Ne. The lack of correlation between SDM and BSP reconstructions could not be reconciled even when range shifts were considered. We suggest the lack of agreement between these measures might be linked to changes in population densities which can be independent of range changes. We caution that interpreting either SDM or BSPs independently is problematic and potentially misleading. Additionally, we found that Ne of wetland species tended to increase later than species from terrestrial habitats, possibly reflecting a delayed increase in the extent of this habitat type after the LGM.

evolutionary biology↗