Michael J. Sanderson’s research while affiliated with University of Massachusetts Chan Medical School and other places

BALB/c and C57BL/6 mouse strains are widely used as animal model in studies of respiratory diseases, such as asthma. Asthma is characterized by airway hyperresponsiveness, which is eventually resulted from the excessive airway smooth muscle (ASM) contraction mediated by Ca²⁺ oscillations in ASM cells. It is reported that BALB/c mice have inherently higher airway responsiveness, but show no different contractive response of tracheal ring as compared to C57BL/6 mice. However, whether the different airway responsiveness is due to the different extents of small airway contraction, and what’s underlying mechanism remains unknown. Here, we assess agonist-induced small airway contraction and Ca²⁺ oscillations in ASM cells between BALB/c and C57BL/6 mice by using precision-cut lung slices (PCLS). We found that BALB/c mice showed an intrinsically stronger extent of small airway narrowing and faster Ca²⁺ oscillations in ASM cells in response to agonists. These differences were associated with a higher magnitude of Ca²⁺ influx via store-operated Ca²⁺ entry (SOCE), as a result of increased expression of SOCE components (STIM1, Orai1) in the ASM cells of small airway of BALB/c mice. An established mathematical model and experimental results suggested that the increased SOC current could result in increased agonist-induced Ca²⁺ oscillations. Therefore, the inherently higher SOC underlies the increased Ca²⁺ oscillation frequency in ASM cells and stronger small airway contraction in BALB/c mice, thus higher airway responsiveness in BALB/c than C57BL/6 mouse strain.

We present an improved genome assembly of the saguaro cactus ( Carnegiea gigantea (Engelm.) Britton & Rose), obtained by incorporating long-read PacBio data to the existing short reads. The assembly improves in terms of total size, contiguity, and accuracy, allowing to extend the range of sequence analyses beyond the single-gene scale. Consequently, the assembly is 16% larger and has 20% more genes, expanding the resources for a neglected yet very remarkable plant family such as Cactaceae. Species taxonomy Eukaryota; Viridiplantae; Streptophyta; Streptophytina; Embryophyta; Tracheophyta; Euphyllophyta; Spermatophyta; Magnoliopsida; Mesangiospermae; eudicotyledons; Gunneridae; Pentapetalae; Caryophyllales; Cactineae; Cactaceae; Cactoideae; Echinocereeae; Carnegiea gigantea (Engelm.) Britton & Rose) (also known as saguaro cactus) (NCBI txid: 171969).

Reconstructing accurate historical relationships within a species poses numerous challenges, not least in many plant groups in which gene flow is high enough to extend well beyond species boundaries. Nonetheless, the extent of tree-like history within a species is an empirical question on which it is now possible to bring large amounts of genome sequence to bear. We assess phylogenetic structure across the geographic range of the saguaro cactus, an emblematic member of Cactaceae, a clade known for extensive hybridization and porous species boundaries. Using 200 Gb of whole genome resequencing data from 20 individuals sampled from 10 localities, we assembled two data sets comprising 150,000 biallelic single nucleotide polymorphisms (SNPs) from protein coding sequences. From these we inferred within-species trees and evaluated their significance and robustness using five qualitatively different inference methods. Despite the low sequence diversity, large census population sizes, and presence of wide-ranging pollen and seed dispersal agents, phylogenetic trees were well resolved and highly consistent across both data sets and all methods. We inferred that the most likely root, based on marginal likelihood comparisons, is to the east and south of the region of highest genetic diversity, which lies along the coast of the Gulf of California in Sonora, Mexico. Together with striking decreases in marginal likelihood found to the north, this supports hypotheses that saguaro's current range reflects post-glacial expansion from the refugia in the south of its range. We conclude with observations about practical and theoretical issues raised by phylogenomic data sets within species, in which SNP-based methods must be used rather than gene tree methods that are widely used when sequence divergence is higher. These include computational scalability, inference of gene flow, and proper assessment of statistical support in the presence of linkage effects.

The plastid genomes of photosynthetic green plants have largely maintained conserved gene content and order as well as structure over hundreds of millions of years of evolution. Several plant lineages, however, have departed from this conservation and contain many plastome structural rearrangements, which have been associated with an abundance of repeated sequences both overall and near rearrangement endpoints. We sequenced the plastomes of 25 taxa of Astragalus L. (Fabaceae), a large genus in the inverted repeat–lacking clade of legumes, to gain a greater understanding of the connection between repeats and plastome inversions. We found plastome repeat structure has a strong phylogenetic signal among these closely related taxa mostly in the New World clade of Astragalus called Neo-Astragalus. Taxa without inversions also do not differ substantially in their overall repeat structure from four taxa each with one large-scale inversion. For two taxa with inversion endpoints between the same pairs of genes, differences in their exact endpoints indicate the inversions occurred independently. Our proposed mechanism for inversion formation suggests the short inverted repeats now found near the endpoints of the four inversions may be there as a result of these inversions rather than their cause. The longer inverted repeats now near endpoints may have allowed the inversions first mediated by shorter microhomologous sequences to propagate, something that should be considered in explaining how any plastome rearrangement becomes fixed regardless of the mechanism of initial formation.

Phylogenetic trees from real-world data often include short edges with very few substitutions per site, which can lead to partially resolved trees and poor accuracy. Theory indicates that the number of sites needed to accurately reconstruct a fully resolved tree grows at a rate proportional to the inverse square of the length of the shortest edge. However, when inferred trees are partially resolved due to short edges, “accuracy” should be defined as the rate of discovering false splits (clades on a rooted tree) relative to the actual number found. Thus, accuracy can be high even if short edges are common. Specifically, in a “near-perfect” parameter space in which trees are large, the tree length ξ (the sum of all edge lengths) is small, and rate variation is minimal, the expected false positive rate is less than ξ∕3; the exact value depends on tree shape and sequence length. This expected false positive rate is far below the false negative rate for small ξ and often well below 5% even when some assumptions are relaxed. We show this result analytically for maximum parsimony and explore its extension to maximum likelihood using theory and simulations. For hypothesis testing, we show that measures of split “support” that rely on bootstrap resampling consistently imply weaker support than that implied by the false positive rates in near-perfect trees. The near-perfect parameter space closely fits several empirical studies of human virus diversification during outbreaks and epidemics, including Ebolavirus, Zika virus, and SARS-CoV-2, reflecting low substitution rates relative to high transmission/sampling rates in these viruses.

A bstract Phylogenetic trees from real-world data often include short edges with very few substitutions per site, which can lead to partially resolved trees and poor accuracy. Theory indicates that the number of sites needed to accurately reconstruct a fully resolved tree grows at a rate proportional to the inverse square of the length of the shortest edge. However, when inferred trees are partially resolved due to short edges, “accuracy” should be defined as the rate of discovering false splits (clades on a rooted tree) relative to the actual number found. Thus, accuracy can be high even if short edges are common. Specifically, in a “near-perfect” parameter space in which trees are large, the tree length ξ (the sum of all edge lengths), is small, and rate variation is minimal, the expected false positive rate is less than ξ /3; the exact value depends on tree shape and sequence length. This expected false positive rate is far below the false negative rate for small ξ and often well below 5% even when some assumptions are relaxed. We show this result analytically for maximum parsimony and explore its extension to maximum likelihood using theory and simulations. For hypothesis testing, we show that measures of split “support” that rely on bootstrap resampling consistently imply weaker support than that implied by the false positive rates in near-perfect trees. The near-perfect parameter space closely fits several empirical studies of human virus diversification during outbreaks and epidemics, including Ebolavirus, Zika virus, and SARS-CoV-2, reflecting low substitution rates relative to high transmission/sampling rates in these viruses.

Coordination of cellular activity is vital to multicellular function and intercellular Ca²⁺ waves may serve as a signaling mechanism to coordinate localized cellular responses. Intercellular Ca²⁺ waves occur in a diversity of cell types and are initiated by a variety of stimuli. These Ca²⁺ waves propagate by the diffusion of an internal or external messenger. The major internal second messengers are inositol trisphosphate (IP3) and Ca²⁺, which reach adjacent cells via gap junctions to propagate Ca²⁺ waves by Ca²⁺-induced Ca²⁺ release from the endoplasmic reticulum via IP3 or ryanodine receptors. External messengers, including adenosine triphosphate and glutamate, are released by vesicular discharge or via hemi-channels of gap junctions or pannexins to stimulate G-protein-coupled receptors of nearby cells to initiate intracellular Ca²⁺ increases. Ca²⁺ waves are limited in size when the messenger is generated only by the initiating cell but more extensive when messenger production is regenerative in participating cells.

A bstract Genome sequence data are routinely being used to infer phylogenetic history within and between closely related diploid species, but few tree inference methods are specifically tailored to diploid genotype data. Here we re-examine the method of “polymorphism parsimony” (Inger 1967; Farris 1978; Felsenstein 1979), originally introduced to study morphological characters and chromosome inversion polymorphisms, to evaluate its utility for unphased diploid genotype data in large scale phylogenomic data sets. We show that it is equivalent to inferring species trees by minimizing deep coalescences—assuming an infinite sites model. Two potential advantages of this approach are scalability and estimation of a rooted tree. As with some other single nucleotide polymorphism (SNP) based methods, it requires thinning of data sets to statistically independent sites, and we describe a genotype-based test for phylogenetic independence. To evaluate this approach in genome scale data, we construct intraspecific phylogenies for 10 populations of the saguaro cactus using 200 Gbp of resequencing data, and then use these methods to test whether the population with highest genetic diversity corresponds to the root of the genotype trees. Results were highly congruent with the (unrooted) trees obtained using SVDquartets, a scalable alternative method of phylogenomic inference.

A bstract Terraces in phylogenetic tree space are sets of trees with identical optimality scores for a given data set, arising from missing data. These were first described for multilocus phylogenetic data sets in the context of maximum parsimony inference and maximum likelihood inference under certain model assumptions. Here we show how the mathematical properties that lead to terraces extend to gene tree - species tree problems in which the gene trees are incomplete. Inference of species trees from either sets of gene family trees subject to duplication and loss, or allele trees subject to incomplete lineage sorting, can exhibit terraces in their solution space. First, we show conditions that lead to a new kind of terrace, which stems from subtree operations that appear in reconciliation problems for incomplete trees. Then we characterize when terraces of both types can occur when the optimality criterion for tree search is based on duplication, loss or deep coalescence scores. Finally, we examine the impact of assumptions about the causes of losses: whether they are due to imperfect sampling or true evolutionary deletion.