Benefits and Limits of Phasing Alleles for Network Inference of Allopolyploid Complexes.

Accurately reconstructing the reticulate histories of polyploids remains a central challenge for understanding plant evolution. Although phylogenetic networks can provide insights into relationships among polyploid lineages, inferring networks may be hindered by the complexities of homology determination in polyploid taxa. We use simulations to show that phasing alleles from allopolyploid individuals can improve phylogenetic network inference under the multispecies coalescent by obtaining the true network with fewer loci compared to haplotype consensus sequences or sequences with heterozygous bases represented as ambiguity codes. Phased allelic data can also improve divergence time estimates for networks, which is helpful for evaluating allopolyploid speciation hypotheses and proposing mechanisms of speciation. To achieve these outcomes in empirical data, we present a novel pipeline that leverages a recently developed phasing algorithm to reliably phase alleles from polyploids. This pipeline is especially appropriate for target enrichment data, where depth of coverage is typically high enough to phase entire loci. We provide an empirical example in the North American Dryopteris fern complex that demonstrates insights from phased data as well as the challenges of network inference. We establish that our pipeline (PATÉ: Phased Alleles from Target Enrichment data) is capable of recovering a high proportion of phased loci from both diploids and polyploids. These data may improve network estimates compared to using haplotype consensus assemblies by accurately inferring the direction of gene flow, but statistical non-identifiability of phylogenetic networks poses a barrier to inferring the evolutionary history of reticulate complexes.

A first complete phylogenomic hypothesis for diploid blueberries (Vaccinium section Cyanococcus).

PREMISE: The true blueberries (Vaccinium sect. Cyanococcus; Ericaceae), endemic to North America, have been intensively studied for over a century. However, with species estimates ranging from nine to 24 and much confusion regarding species boundaries, this ecologically and economically valuable group remains inadequately understood at a basic evolutionary and taxonomic level. As a first step toward understanding the evolutionary history and taxonomy of this species complex, we present the first phylogenomic hypothesis of the known diploid blueberries. METHODS: We used flow cytometry to verify the ploidy of putative diploid taxa and a target-enrichment approach to obtain a genomic data set for phylogenetic analyses. RESULTS: Despite evidence of gene flow, we found that a primary phylogenetic signal is present. Monophyly for all morphospecies was recovered, with two notable exceptions: one sample of V. boreale was consistently nested in the V. myrtilloides clade and V. caesariense was nested in the V. fuscatum clade. One diploid taxon, Vaccinium pallidum, is implicated as having a homoploid hybrid origin. CONCLUSIONS: This foundational study represents the first attempt to elucidate evolutionary relationships of the true blueberries of North America with a phylogenomic approach and sets the stage for multiple avenues of future study such as a taxonomic revision of the group, the verification of a homoploid hybrid taxon, and the study of polyploid lineages within the context of a diploid phylogeny.

Phylogenomic analyses highlight innovation and introgression in the continental radiations of Fagaceae across the Northern Hemisphere.

Northern Hemisphere forests changed drastically in the early Eocene with the diversification of the oak family (Fagaceae). Cooling climates over the next 20 million years fostered the spread of temperate biomes that became increasingly dominated by oaks and their chestnut relatives. Here we use phylogenomic analyses of nuclear and plastid genomes to investigate the timing and pattern of major macroevolutionary events and ancient genome-wide signatures of hybridization across Fagaceae. Innovation related to seed dispersal is implicated in triggering waves of continental radiations beginning with the rapid diversification of major lineages and resulting in unparalleled transformation of forest dynamics within 15 million years following the K-Pg extinction. We detect introgression at multiple time scales, including ancient events predating the origination of genus-level diversity. As oak lineages moved into newly available temperate habitats in the early Miocene, secondary contact between previously isolated species occurred. This resulted in adaptive introgression, which may have further amplified the diversification of white oaks across Eurasia.

Uncovering the genomic signature of ancient introgression between white oak lineages (Quercus).

Botanists have long recognised interspecific gene flow as a common occurrence within white oaks (Quercus section Quercus). Historical allele exchange, however, has not been fully characterised and the complex genomic signals resulting from the combination of vertical and horizontal gene transmission may confound phylogenetic inference and obscure our ability to accurately infer the deep evolutionary history of oaks. Using anchored enrichment, we obtained a phylogenomic dataset consisting of hundreds of single-copy nuclear loci. Concatenation, species-tree and network analyses were carried out in an attempt to uncover the genomic signal of ancient introgression and infer the divergent phylogenetic topology for the white oak clade. Locus and site-level likelihood comparisons were then conducted to further explore the introgressed signal within our dataset. Historical, intersectional gene flow is suggested to have occurred between an ancestor of the Eurasian Roburoid lineage and Quercus pontica and North American Dumosae and Prinoideae lineages. Despite extensive time past, our approach proved successful in detecting the genomic signature of ancient introgression. Our results, however, highlight the importance of sampling and the use of a plurality of analytical tools and methods to sufficiently explore genomic datasets, uncover this signal, and accurately infer evolutionary history.

Genomic landscape of the global oak phylogeny.

The tree of life is highly reticulate, with the history of population divergence emerging from populations of gene phylogenies that reflect histories of introgression, lineage sorting and divergence. In this study, we investigate global patterns of oak diversity and test the hypothesis that there are regions of the oak genome that are broadly informative about phylogeny. We utilize fossil data and restriction-site associated DNA sequencing (RAD-seq) for 632 individuals representing nearly 250 Quercus species to infer a time-calibrated phylogeny of the world's oaks. We use a reversible-jump Markov chain Monte Carlo method to reconstruct shifts in lineage diversification rates, accounting for among-clade sampling biases. We then map the > 20 000 RAD-seq loci back to an annotated oak genome and investigate genomic distribution of introgression and phylogenetic support across the phylogeny. Oak lineages have diversified among geographic regions, followed by ecological divergence within regions, in the Americas and Eurasia. Roughly 60% of oak diversity traces back to four clades that experienced increases in net diversification, probably in response to climatic transitions or ecological opportunity. The strong support for the phylogeny contrasts with high genomic heterogeneity in phylogenetic signal and introgression. Oaks are phylogenomic mosaics, and their diversity may in fact depend on the gene flow that shapes the oak genome.

Comment on "Eocene Fagaceae from Patagonia and Gondwanan legacy in Asian rainforests".

Wilf et al (Research Articles, 7 June 2019, eaaw5139) claim that Castanopsis evolved in the Southern Hemisphere from where it spread to its modern distribution in Southeast Asia. However, extensive paleobotanical records of Antarctica and Australia lack evidence of any Fagaceae, and molecular patterns indicate shared biogeographic histories of Castanopsis, Castanea, Lithocarpus, and Quercus subgenus Cerris, making the southern route unlikely.

The role of diversification in community assembly of the oaks (Quercus L.) across the continental U.S.

PREMISE OF THE STUDY: Evolutionary and biogeographic history, including past environmental change and diversification processes, are likely to have influenced the expansion, migration, and extinction of populations, creating evolutionary legacy effects that influence regional species pools and the composition of communities. We consider the consequences of the diversification process in shaping trait evolution and assembly of oak-dominated communities throughout the continental United States (U.S.). METHODS: Within the U.S. oaks, we tested for phylogenetic and functional trait patterns at different spatial scales, taking advantage of a dated phylogenomic analysis of American oaks and the U.S. Forest Service (USFS) Forest Inventory and Analysis (FIA). KEY RESULTS: We find (1) phylogenetic overdispersion at small grain sizes throughout the U.S. across all spatial extents and (2) a shift from overdispersion to clustering with increasing grain sizes. Leaf traits have evolved in a convergent manner, and these traits are clustered in communities at all spatial scales, except in the far west, where species with contrasting leaf types co-occur. CONCLUSIONS: Our results support the hypotheses that (1) interspecific interactions were important in parallel adaptive radiation of the genus into a range of habitats across the continent and (2) that the diversification process is a critical driver of community assembly. Functional convergence of complementary species from distinct clades adapted to the same local habitats is a likely mechanism that allows distantly related species to coexist. Our findings contribute to an explanation of the long-term maintenance of high oak diversity and the dominance of the oak genus in North America.

Geographic range velocity and its association with phylogeny and life history traits in North American woody plants.

The geographic ranges of taxa change in response to environmental conditions. Yet whether rates of range movement (biotic velocities) are phylogenetically conserved is not well known. Phylogenetic conservatism of biotic velocities could reflect similarities among related lineages in climatic tolerances and dispersal-associated traits. We assess whether late Quaternary biotic velocities were phylogenetically conserved and whether they correlate with climatic tolerances and dispersal-associated traits. We used phylogenetic regression and nonparametric correlation to evaluate associations between biotic velocities, dispersal-associated traits, and climatic tolerances for 28 woody plant genera and subgenera in North America. The velocities with which woody plant taxa shifted their core geographic range limits were positively correlated from time step to time step between 16 and 7 ka. The strength of this correlation weakened after 7 ka as the pace of climate change slowed. Dispersal-associated traits and climatic tolerances were not associated with biotic velocities. Although the biotic velocities of some genera were consistently fast and others consistently slow, biotic velocities were not phylogenetically conserved. The rapid late Quaternary range shifts of plants lacking traits that facilitate frequent long-distance dispersal has long been noted (i.e., Reid's Paradox). Our results are consistent with this paradox and show that it remains robust when phylogenetic information is taken into account. The lack of association between biotic velocities, dispersal-associated traits, and climatic tolerances may reflect several, nonmutually exclusive processes, including rare long-distance dispersal, biotic interactions, and cryptic refugia. Because late Quaternary biotic velocities were decoupled from dispersal-associated traits, trait data for genera and subgenera cannot be used to predict longer-term (millennial-scale) floristic responses to climate change.

Pervasive migration across rainforest and sandy coastal plain Aechmea nudicaulis (Bromeliaceae) populations despite contrasting environmental conditions.

Understanding the colonization of extreme marginal habitats and the relative roles of space and environment in maintaining peripheral populations remains challenging. Here, we leverage a system of pairs of rainforest and sandy coastal plain communities that allow us to decouple spatial and environmental effects in the population structure and migration rates of the bromeliad Aechmea nudicaulis. Structure and gene flow between populations were estimated from Bayesian clustering and coalescent-based migration models applied to chloroplast sequence and nuclear microsatellite data. Contrary to our initial expectation, the sharp environmental gradient between rainforest and sandy plains does not seem to have affected the colonization and migration dynamics in A. nudicaulis. Our analyses uncover pervasive gene flow between neighbouring habitats in both chloroplast and nuclear data despite the striking differences in environmental conditions. This result is consistent with a scenario of repeated colonization of the sandy coastal plains from forest populations through seed dispersal, as well as the maintenance of gene flow between habitats through pollination. We also recovered a broad north/south population structure that has been found in other Atlantic rainforest groups and possibly reflects older phylogeographic dynamics.

Sympatric parallel diversification of major oak clades in the Americas and the origins of Mexican species diversity.

Oaks (Quercus, Fagaceae) are the dominant tree genus of North America in species number and biomass, and Mexico is a global center of oak diversity. Understanding the origins of oak diversity is key to understanding biodiversity of northern temperate forests. A phylogenetic study of biogeography, niche evolution and diversification patterns in Quercus was performed using 300 samples, 146 species. Next-generation sequencing data were generated using the restriction-site associated DNA (RAD-seq) method. A time-calibrated maximum likelihood phylogeny was inferred and analyzed with bioclimatic, soils, and leaf habit data to reconstruct the biogeographic and evolutionary history of the American oaks. Our highly resolved phylogeny demonstrates sympatric parallel diversification in climatic niche, leaf habit, and diversification rates. The two major American oak clades arose in what is now the boreal zone and radiated, in parallel, from eastern North America into Mexico and Central America. Oaks adapted rapidly to niche transitions. The Mexican oaks are particularly numerous, not because Mexico is a center of origin, but because of high rates of lineage diversification associated with high rates of evolution along moisture gradients and between the evergreen and deciduous leaf habits. Sympatric parallel diversification in the oaks has shaped the diversity of North American forests.

Phylogeny and biogeography of East Asian evergreen oaks (Quercus section Cyclobalanopsis; Fagaceae): Insights into the Cenozoic history of evergreen broad-leaved forests in subtropical Asia.

The evolutionary history of Quercus section Cyclobalanopsis, a dominant lineage in East Asian evergreen broadleaved forests (EBLFs), has not been comprehensively studied using molecular tools. In this study, we reconstruct the first comprehensive phylogeny of this lineage using a genomic approach (restriction-site associated DNA sequencing, RAD-seq), sampling 35 of the ca. 90 species currently recognized, representing all main morphological groups of section Cyclobalanopsis. In addition, 10 other species of Quercus and two outgroups were also sampled. Divergence times were estimated using a relaxed clock model and two fossil calibrations. Ancestral areas and dispersal routes were inferred using statistical dispersal-vicariance analysis and the dispersal-extinction-cladogenesis (DEC) model. The phylogeny of Quercus section Cyclobalanopsis demonstrates the section to be monophyletic, comprising two main lineages and six subclades that are well supported by anatomical traits. Biogeographical reconstructions indicate that the wide northern hemisphere distribution of Quercus was disrupted in the Late Eocene, leading to the main extant groups at about 33 Ma. The earliest divergences in section Cyclobalanopsis correspond to the phased uplift of the Himalayas and lateral extrusion of Indochina at the transition of the Oligocene and Miocene, where the highest rate of diversification occurred in the late Miocene. Dispersal from Sino-Himalaya and the Palaeotropics to Sino-Japan in the Miocene was facilitated by the increased intensity of East Asian summer monsoons and by the Middle Miocene Climatic Optimum. Our results highlight the importance of climatic changes and Indo-Eurasian collision-induced tectonic activities from the Neogene onward to the spatial-temporal diversification patterns of Asian EBLF lineages.

Phylogenomics reveals a complex evolutionary history of lobed-leaf white oaks in western North America.

Species within the genus Quercus (oak) hybridize in complex patterns that have yet to be fully explored with phylogenomic data. Analyses to date have recovered reasonable divergent patterns, suggesting that the impact of introgression may not always be obvious in inferred oak phylogenies. We explore this phenomenon using RADseq data for 136 samples representing 54 oak species by conducting phylogenetic analyses designed to distinguish signals of lineage diversification and hybridization, focusing on the lobed-leaf species Quercus gambelii, Q. lobata, and Q. garryana in the context of a broad sampling of allied white oaks (Quercus section Quercus), and particularly the midwestern Q. macrocarpa. We demonstrate that historical introgressive hybridization between once sympatric species affects phylogeny estimation. Historical range expansion during periods of favorable climate likely explains our observations; analyses support genetic exchange between ancestral populations of Q. gambelii and Q. macrocarpa. We conclude that the genomic consequences of introgression caused the attraction of distant lineages in phylogenetic tree space, and that introgressive and divergent signals can be disentangled to produce a robust estimate of the phylogenetic history of the species.

A genetic legacy of introgression confounds phylogeny and biogeography in oaks.

Oaks (Quercus L.) have long been suspected to hybridize in nature, and widespread genetic exchange between morphologically defined species is well documented in two- to six-species systems, but the phylogenetic consequences of hybridization in oaks have never been demonstrated in a phylogenetically diverse sample. Here, we present phylogenomic analyses of a ca 30 Myr clade that strongly support morphologically defined species and the resolution of novel clades of white oaks; however, historical hybridization across clade boundaries is detectable and, undiagnosed, would obscure the imprint of biogeographic history in the phylogeny. Phylogenetic estimation from restriction-site-associated DNA sequencing data for 156 individuals representing 81 species supports two successive intercontinental disjunctions of white oaks: an early vicariance between the Eurasian and American white oaks, and a second, independent radiation represented by two relictual species. A suite of subsampled and partitioned analyses, however, supports a more recent divergence of the Eurasian white oaks from within the American white oaks and suggests that historic introgression between the Eurasian white oaks and a now-relictual lineage biases concatenated phylogenetic estimates. We demonstrate how divergence and reticulation both influence our understanding of the timing and nature of diversification and global colonization in these ecologically and economically important taxa.

A time and a place for everything: phylogenetic history and geography as joint predictors of oak plastome phylogeny.

Owing to high rates of introgressive hybridization, the plastid genome is poorly suited to fine-scale DNA barcoding and phylogenetic studies of the oak genus (Quercus, Fagaceae). At the tips of the oak plastome phylogeny, recent gene migration and reticulation generally cause topology to reflect geographic structure, while deeper branches reflect lineage divergence. In this study, we quantify the simple and partial effects of geographic proximity and nucleome-inferred phylogenetic history on oak plastome phylogeny at different evolutionary scales. Our study compares pairwise phylogenetic distances based on complete plastome sequences, pairwise phylogenetic distances from nuclear restriction site-associated DNA sequences (RADseq), and pairwise geographic distances for 34 individuals of the white oak clade representing 24 North American and Eurasian species. Within the North American white oak clade alone, phylogenetic history has essentially no effect on plastome variation, while geography explains 11%-21% of plastome phylogenetic variance. However, across multiple continents and clades, phylogeny predicts 30%-41% of plastome variation, geography 3%-41%. Tipwise attenuation of phylogenetic informativeness in the plastome means that in practical terms, plastome data has little use in solving phylogenetic questions, but can still be a useful barcoding or phylogenetic marker for resolving questions among major clades.

Phylogenomic inferences from reference-mapped and de novo assembled short-read sequence data using RADseq sequencing of California white oaks (Quercus section Quercus).

The emergence of next generation sequencing has increased by several orders of magnitude the amount of data available for phylogenetics. Reduced representation approaches, such as restriction-sited associated DNA sequencing (RADseq), have proven useful for phylogenetic studies of non-model species at a wide range of phylogenetic depths. However, analysis of these datasets is not uniform and we know little about the potential benefits and drawbacks of de novo assembly versus assembly by mapping to a reference genome. Using RADseq data for 83 oak samples representing 16 taxa, we identified variants via three pipelines: mapping sequence reads to a recently published draft genome of Quercus lobata, and de novo assembly under two sets of locus filters. For each pipeline, we inferred the maximum likelihood phylogeny. All pipelines produced similar trees, with minor shifts in relationships within well-supported clades, despite the fact that they yielded different numbers of loci (68 000 - 111 000 loci) and different degrees of overlap with the reference genome. We conclude that both the reference-aligned and de novo assembly pipelines yield reliable results, and that advantages and disadvantages of these approaches pertain mainly to downstream uses of RADseq data, not to phylogenetic inference per se.

Whole-genome duplication and molecular evolution in Cornus L. (Cornaceae) - Insights from transcriptome sequences.

The pattern and rate of genome evolution have profound consequences in organismal evolution. Whole-genome duplication (WGD), or polyploidy, has been recognized as an important evolutionary mechanism of plant diversification. However, in non-model plants the molecular signals of genome duplications have remained largely unexplored. High-throughput transcriptome data from next-generation sequencing have set the stage for novel investigations of genome evolution using new bioinformatic and methodological tools in a phylogenetic framework. Here we compare ten de novo-assembled transcriptomes representing the major lineages of the angiosperm genus Cornus (dogwood) and relevant outgroups using a customized pipeline for analyses. Using three distinct approaches, molecular dating of orthologous genes, analyses of the distribution of synonymous substitutions between paralogous genes, and examination of substitution rates through time, we detected a shared WGD event in the late Cretaceous across all taxa sampled. The inferred doubling event coincides temporally with the paleoclimatic changes associated with the initial divergence of the genus into three major lineages. Analyses also showed an acceleration of rates of molecular evolution after WGD. The highest rates of molecular evolution were observed in the transcriptome of the herbaceous lineage, C. canadensis, a species commonly found at higher latitudes, including the Arctic. Our study demonstrates the value of transcriptome data for understanding genome evolution in closely related species. The results suggest dramatic increase in sea surface temperature in the late Cretaceous may have contributed to the evolution and diversification of flowering plants.

The evolution and diversification of the red oaks of the California Floristic Province (Quercus section Lobatae, series Agrifoliae).

PREMISE OF THE STUDY: The California Floristic Province (CA-FP) is a unique and diverse region of floral endemism, yet the timing and nature of divergence and diversification of many lineages remain underexplored. We seek to elucidate the evolutionary history of the red oaks of the CA-FP, the Agrifoliae. METHODS: We collected PstI-associated RAD-seq data as well as morphometrics from individuals of the four species across their ranges, including varieties and hybrids. Phylogeny and divergence times were estimated. We analyzed morphological differentiation in over 70 plants using PCA and assessed species delimitation and admixture using genotype clustering analysis in over 40 plants. KEY RESULTS: We find that the Agrifoliae are monophyletic and sister to all other red oak species. Within the Agrifoliae, all species are supported, with Quercus kelloggii sister to a clade of subevergreen taxa: (Quercus agrifolia - (Q. parvula + Q. wislizeni)). Molecular and morphometric analyses are equivocal for named varieties. Notably, Q. parvula var. tamalpaisensis appears to be part of a hybrid swarm between Q. parvula and Q. wislizeni. Dating estimates were concordant with previous hypotheses and geological evidence, with diversification occurring between 10 and 20 million years ago. CONCLUSIONS: The Agrifoliae represent a geographically discrete, early-diverging red oak lineage that diversified during the period of drying and warming associated with Sierran uplift during the middle Miocene. Molecular differentiation within the clade supports the current taxonomy, including an east-west species level pattern (Q. parvula and Q. wislizeni) and north-south intraspecific patterns to some degree, although the latter require additional study.

Phylogeny and biogeography of the American live oaks (Quercus subsection Virentes): a genomic and population genetics approach.

The nature and timing of evolution of niche differentiation among closely related species remains an important question in ecology and evolution. The American live oak clade, Virentes, which spans the unglaciated temperate and tropical regions of North America and Mesoamerica, provides an instructive system in which to examine speciation and niche evolution. We generated a fossil-calibrated phylogeny of Virentes using RADseq data to estimate divergence times and used nuclear microsatellites, chloroplast sequences and an intron region of nitrate reductase (NIA-i3) to examine genetic diversity within species, rates of gene flow among species and ancestral population size of disjunct sister species. Transitions in functional and morphological traits associated with ecological and climatic niche axes were examined across the phylogeny. We found the Virentes to be monophyletic with three subclades, including a southwest clade, a southeastern US clade and a Central American/Cuban clade. Despite high leaf morphological variation within species and transpecific chloroplast haplotypes, RADseq and nuclear SSR data showed genetic coherence of species. We estimated a crown date for Virentes of 11 Ma and implicated the formation of the Sea of Cortés in a speciation event ~5 Ma. Tree height at maturity, associated with fire tolerance, differs among the sympatric species, while freezing tolerance appears to have diverged repeatedly across the tropical-temperate divide. Sympatric species thus show evidence of ecological niche differentiation but share climatic niches, while allopatric and parapatric species conserve ecological niches, but diverge in climatic niches. The mode of speciation and/or degree of co-occurrence may thus influence which niche axis plants diverge along.

Biogeographic analysis of the woody plants of the Southern Appalachians: Implications for the origins of a regional flora.

PREMISE OF THE STUDY: We investigated the origins of 252 Southern Appalachian woody species representing 158 clades to analyze larger patterns of biogeographic connectivity around the northern hemisphere. We tested biogeographic hypotheses regarding the timing of species disjunctions to eastern Asia and among areas of North America. METHODS: We delimited species into biogeographically informative clades, compiled sister-area data, and generated graphic representations of area connections across clades. We calculated taxon diversity within clades and plotted divergence times. KEY RESULTS: Of the total taxon diversity, 45% were distributed among 25 North American endemic clades. Sister taxa within eastern North America and eastern Asia were proportionally equal in frequency, accounting for over 50% of the sister-area connections. At increasing phylogenetic depth, connections to the Old World dominated. Divergence times for 65 clades with intercontinental disjunctions were continuous, whereas 11 intracontinental disjunctions to western North America and nine to eastern Mexico were temporally congruent. CONCLUSIONS: Over one third of the clades have likely undergone speciation within the region of eastern North America. The biogeographic pattern for the region is asymmetric, consisting of mostly mixed-aged, low-diversity clades connecting to the Old World, and a minority of New World clades. Divergence time data suggest that climate change in the Late Miocene to Early Pliocene generated disjunct patterns within North America. Continuous splitting times during the last 45 million years support the hypothesis that widespread distributions formed repeatedly during favorable periods, with serial cooling trends producing pseudocongruent area disjunctions between eastern North America and eastern Asia.

A randomized phase 2 study comparing two doses of delafloxacin with tigecycline in adults with complicated skin and skin-structure infections.

BACKGROUND: A randomized, double-blind, multicenter trial was done to compare two doses of delafloxacin with tigecycline in patients with various complicated skin and skin-structure infections (wound infections following surgery, trauma, burns, or animal/insect bites, abscesses, and cellulitis). METHODS: Patients were randomized 1:1:1 to receive delafloxacin 300mg intravenous (IV) every 12h, delafloxacin 450mg IV every 12h, or tigecycline 100mg IV×1, followed by 50mg IV every 12h; randomization was stratified by infection type. Duration of therapy was 5-14 days. The primary efficacy analysis, performed on the clinically evaluable (CE) population at the test-of-cure (TOC) visit (14-21 days after the final dose of study drug), compared clinical response rates in the delafloxacin and tigecycline arms. Clinical response rates in the two delafloxacin arms were also compared. RESULTS: Among CE patients, clinical cure rates at TOC visit were similar in the delafloxacin and tigecycline arms (94.3%, 92.5%, and 91.2%, respectively in delafloxacin 300-mg, delafloxacin 450-mg, and tigecycline arms). Overall, the most frequent adverse events were nausea, vomiting, and diarrhea; the 300-mg delafloxacin arm was the best-tolerated regimen. CONCLUSIONS: Delafloxacin was similarly effective as tigecycline for a variety of complicated skin and skin-structure infections and was well tolerated. (Clinicaltrials.gov NCT 0719810).