Person: Arnold, Brian
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Arnold
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Arnold, Brian
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Publication The impact of serotype-specific vaccination on phylodynamic parameters of Streptococcus pneumoniae and the pneumococcal pan-genome(Public Library of Science (PLoS), 2018) Azarian, Taj; Grant, Lindsay R.; Arnold, Brian; Hammitt, Laura L.; Reid, Raymond; Santosham, Mathuram; Weatherholtz, Robert; Goklish, Novalene; Thompson, Claudette; Bentley, Stephen D.; O’Brien, Katherine L.; Hanage, William; Lipsitch, MarcIn the United States, the introduction of the heptavalent pneumococcal conjugate vaccine (PCV) largely eliminated vaccine serotypes (VT); non-vaccine serotypes (NVT) subsequently increased in carriage and disease. Vaccination also disrupts the composition of the pneumococcal pangenome, which includes mobile genetic elements and polymorphic non-capsular antigens important for virulence, transmission, and pneumococcal ecology. Antigenic proteins are of interest for future vaccines; yet, little is known about how the they are affected by PCV use. To investigate the evolutionary impact of vaccination, we assessed recombination, evolution, and pathogen demographic history of 937 pneumococci collected from 1998-2012 among Navajo and White Mountain Apache Native American communities. We analyzed changes in the pneumococcal pangenome, focusing on metabolic loci and 19 polymorphic protein antigens. We found the impact of PCV on the pneumococcal population could be observed in reduced diversity, a smaller pangenome, and changing frequencies of accessory clusters of orthologous groups (COGs). Post-PCV7, diversity rebounded through clonal expansion of NVT lineages and inferred in-migration of two previously unobserved lineages. Accessory COGs frequencies trended toward pre-PCV7 values with increasing time since vaccine introduction. Contemporary frequencies of protein antigen variants are better predicted by pre-PCV7 values (1998-2000) than the preceding period (2006-2008), suggesting balancing selection may have acted in maintaining variant frequencies in this population. Overall, we present the largest genomic analysis of pneumococcal carriage in the United States to date, which includes a snapshot of a true vaccine-naïve community prior to the introduction of PCV7. These data improve our understanding of pneumococcal evolution and emphasize the need to consider pangenome composition when inferring the impact of vaccination and developing future protein-based pneumococcal vaccines.Publication Meiotic Adaptation to Genome Duplication in Arabidopsis arenosa(Elsevier BV, 2013) Yant, Levi; Hollister, J; Wright, K; Arnold, Brian; Higgins, James D.; Franklin, F. Chris H.; Bomblies, KirstenWhole genome duplication (WGD) is a major factor in the evolution of multicellular eukaryotes, yet by doubling the number of homologs, WGD severely challenges reliable chromosome segregation [1, 2, 3], a process conserved across kingdoms [4]. Despite this, numerous genomeduplicated (polyploid) species persist in nature, indicating early problems can be overcome [1, 2]. Little is known about which genes are involved – only one has been molecularly characterized [5]. To gain new insights into the molecular basis of adaptation to polyploidy, we investigated genome-wide patterns of differentiation between natural diploids and tetraploids of Arabidopsis arenosa, an outcrossing relative of A. thaliana [6, 7]. We first show that diploids are not preadapted to polyploid meiosis. We then use a genome scanning approach to show that while polymorphism is extensively shared across ploidy levels, there is strong ploidy-specific differentiation in 39 regions spanning 44 genes. These are discrete, mostly single-gene peaks of sharply elevated differentiation. Among these peaks are eight meiosis genes whose encoded proteins coordinate a specific subset of early meiotic functions, suggesting these genes comprise a polygenic solution to WGD-associated chromosome segregation challenges. Our findings indicate that even conserved meiotic processes can be capable of nimble evolutionary shifts when required.Publication Evolutionary Dynamics of a Multiple-Ploidy System in Arabidopsis Arenosa(2015-05-18) Arnold, Brian; Bomblies, Kirsten; Wakeley, John; Reich, David; Hoekstra, HopiWhole-genome duplication (WGD), which leads to polyploidy, has been implicated in speciation and biological novelty. In plants, many species have experienced historical bouts of WGD or exhibit extant ploidy variation, which is likely representative of an early stage in the evolution of new polyploid lineages. To elucidate the evolutionary dynamics of autopolyploids and species with multiple ploidy levels, I develop population genetic theory in Chapter 2 that I use in Chapter 4 to extract information about the evolutionary history of Arabidopsis arenosa, a European wildflower that has diploid and autotetraploid populations. Chapter 3 involves a separate project exploring the ascertainment bias in restriction site associated DNA sequencing (RADseq). In Chapter 2, I develop coalescent models for autotetraploid species with tetrasomic inheritance and show that the ancestral genetic process in a large population without recombination may be approximated using Kingman’s standard coalescent, with a coalescent effective population size 4N. Using this result, I was able to use existing coalescent simulation programs to show in Chapter 4 that, in A. arenosa, a widespread autotetraploid race arose from a single ancestral population. This autopolyploidization event was not accompanied by immediate reproductive isolation between diploids and tetraploids in this species, as I find evidence of extensive interploidy admixture between diploid and tetraploid populations that are geographically close. To draw these conclusions about population history in Chapter 4, I used a reduced representation genome-sequencing approach based on restriction digestion. However, I was bothered by the possibility that sampling chromosomes based on restriction digestion may introduce a bias in allele frequency estimation due to polymorphisms in restriction sites. To explore the effects of this nonrandom sampling and its sensitivity to different evolutionary parameters, we developed a coalescent-simulation framework in Chapter 3 to mimic the biased recovery of chromosomes in RAdseq experiments. We show that loci with missing haplotypes have estimated diversity statistic values that can deviate dramatically from true values and are also enriched for particular genealogical histories. These results urge caution when applying this technique to make population genetic inferences and helped me tailor analyses in Chapter 4 to accommodate for this particular method of DNA sequencing.Publication Weak Epistasis May Drive Adaptation in Recombining Bacteria(Genetics Society of America, 2018) Arnold, Brian; Gutmann, Michael U.; Grad, Yonatan; Sheppard, Samuel K.; Corander, Jukka; Lipsitch, Marc; Hanage, WilliamThe impact of epistasis on the evolution of multi-locus traits depends on recombination. While sexually reproducing eukaryotes recombine so frequently that epistasis between polymorphisms is not considered to play a large role in short-term adaptation, many bacteria also recombine, some to the degree that their populations are described as "panmictic" or "freely recombining." However, whether this recombination is sufficient to limit the ability of selection to act on epistatic contributions to fitness is unknown. We quantify homologous recombination in five bacterial pathogens and use these parameter estimates in a multilocus model of bacterial evolution with additive and epistatic effects. We find that even for highly recombining species (e.g., Streptococcus pneumoniae or Helicobacter pylori), selection on weak interactions between distant mutations is nearly as efficient as for an asexual species, likely because homologous recombination typically transfers only short segments. However, for strong epistasis, bacterial recombination accelerates selection, with the dynamics dependent on the amount of recombination and the number of loci. Epistasis may thus play an important role in both the short- and long-term adaptive evolution of bacteria, and, unlike in eukaryotes, is not limited to strong effect sizes, closely linked loci, or other conditions that limit the impact of recombination.Publication RADseq underestimates diversity and introduces genealogical biases due to nonrandom haplotype sampling(Wiley Blackwell (Blackwell Publishing), 2013) Arnold, Brian; Corbett-Detig, Russ Brendan; Hartl, Daniel; Bomblies, KirstenReduced representation genome-sequencing approaches based on restriction digestion are enabling large-scale marker generation and facilitating genomic studies in a wide range of model and nonmodel systems. However, sampling chromosomes based on restriction digestion may introduce a bias in allele frequency estimation due to polymorphisms in restriction sites. To explore the effects of this nonrandom sampling and its sensitivity to different evolutionary parameters, we developed a coalescent-simulation framework to mimic the biased recovery of chromosomes in restriction-based short-read sequencing experiments (RADseq). We analysed simulated DNA sequence datasets and compared known values from simulations with those that would be estimated using a RADseq approach from the same samples. We compare these ‘true’ and ‘estimated’ values of commonly used summary statistics, \(\pi\), \(\theta_w\), Tajima's D and \(F_{ST}\). We show that loci with missing haplotypes have estimated summary statistic values that can deviate dramatically from true values and are also enriched for particular genealogical histories. These biases are sensitive to nonequilibrium demography, such as bottlenecks and population expansion. In silico digests with 102 completely sequenced Drosophila melanogaster genomes yielded results similar to our findings from coalescent simulations. Though the potential of RADseq for marker discovery and trait mapping in nonmodel systems remains undisputed, our results urge caution when applying this technique to make population genetic inferences.Publication Genetic Adaptation Associated with Genome-Doubling in Autotetraploid Arabidopsis arenosa(Public Library of Science, 2012) Hollister, Jesse D.; Arnold, Brian; Svedin, Elisabeth; Xue, Katherine; Dilkes, Brian P.; Bomblies, KirstenGenome duplication, which results in polyploidy, is disruptive to fundamental biological processes. Genome duplications occur spontaneously in a range of taxa and problems such as sterility, aneuploidy, and gene expression aberrations are common in newly formed polyploids. In mammals, genome duplication is associated with cancer and spontaneous abortion of embryos. Nevertheless, stable polyploid species occur in both plants and animals. Understanding how natural selection enabled these species to overcome early challenges can provide important insights into the mechanisms by which core cellular functions can adapt to perturbations of the genomic environment. Arabidopsis arenosa includes stable tetraploid populations and is related to well-characterized diploids A. lyrata and A. thaliana. It thus provides a rare opportunity to leverage genomic tools to investigate the genetic basis of polyploid stabilization. We sequenced the genomes of twelve A. arenosa individuals and found signatures suggestive of recent and ongoing selective sweeps throughout the genome. Many of these are at genes implicated in genome maintenance functions, including chromosome cohesion and segregation, DNA repair, homologous recombination, transcriptional regulation, and chromatin structure. Numerous encoded proteins are predicted to interact with one another. For a critical meiosis gene, ASYNAPSIS1, we identified a non-synonymous mutation that is highly differentiated by cytotype, but present as a rare variant in diploid A. arenosa, indicating selection may have acted on standing variation already present in the diploid. Several genes we identified that are implicated in sister chromatid cohesion and segregation are homologous to genes identified in a yeast mutant screen as necessary for survival of polyploid cells, and also implicated in genome instability in human diseases including cancer. This points to commonalities across kingdoms and supports the hypothesis that selection has acted on genes controlling genome integrity in A. arenosa as an adaptive response to genome doubling.Publication Extending Coalescent Theory to Autotetraploids(The Genetics Society of America, 2012) Arnold, Brian; Bomblies, Kirsten; Wakeley, JohnWe develop coalescent models for autotetraploid species with tetrasomic inheritance. We show that the ancestral genetic process in a large population without recombination may be approximated using Kingman’s standard coalescent, with a coalescent effective population size 4N. Numerical results suggest that this approximation is accurate for population sizes on the order of hundreds of individuals. Therefore, existing coalescent simulation programs can be adapted to study population history in autotetraploids simply by interpreting the timescale in units of 4N generations. We also consider the possibility of double reduction, a phenomenon unique to polysomic inheritance, and show that its effects on gene genealogies are similar to partial self-fertilization.