An Eclectic Cast of Cellular Actors Orchestrates Innate Immune Responses in the Mechanisms Driving Obesity and Metabolic Perturbation.

The escalating problem of obesity and its multiple metabolic and cardiovascular complications threatens the health and longevity of humans throughout the world. The cause of obesity and one of its chief complications, insulin resistance, involves the participation of multiple distinct organs and cell types. From the brain to the periphery, cell-intrinsic and intercellular networks converge to stimulate and propagate increases in body mass and adiposity, as well as disturbances of insulin sensitivity. This review focuses on the roles of the cadre of innate immune cells, both those that are resident in metabolic organs and those that are recruited into these organs in response to cues elicited by stressors such as overnutrition and reduced physical activity. Beyond the typical cast of innate immune characters invoked in the mechanisms of metabolic perturbation in these settings, such as neutrophils and monocytes/macrophages, these actors are joined by bone marrow-derived cells, such as eosinophils and mast cells and the intriguing innate lymphoid cells, which are present in the circulation and in metabolic organ depots. Upon high-fat feeding or reduced physical activity, phenotypic modulation of the cast of plastic innate immune cells ensues, leading to the production of mediators that affect inflammation, lipid handling, and metabolic signaling. Furthermore, their consequent interactions with adaptive immune cells, including myriad T-cell and B-cell subsets, compound these complexities. Notably, many of these innate immune cell-elicited signals in overnutrition may be modulated by weight loss, such as that induced by bariatric surgery. Recently, exciting insights into the biology and pathobiology of these cell type-specific niches are being uncovered by state-of-the-art techniques such as single-cell RNA-sequencing. This review considers the evolution of this field of research on innate immunity in obesity and metabolic perturbation, as well as future directions.

Adaptational lag to temperature in valley oak (Quercus lobata) can be mitigated by genome-informed assisted gene flow.

Climate change over the next century is predicted to cause widespread maladaptation in natural systems. This prediction, as well as many sustainable management and conservation practices, assumes that species are adapted to their current climate. However, this assumption is rarely tested. Using a large-scale common garden experiment combined with genome-wide sequencing, we found that valley oak (Quercus lobata), a foundational tree species in California ecosystems, showed a signature of adaptational lag to temperature, with fastest growth rates occurring at cooler temperatures than populations are currently experiencing. Future warming under realistic emissions scenarios was predicted to lead to further maladaptation to temperature and reduction in growth rates for valley oak. We then identified genotypes predicted to grow relatively fast under warmer temperatures and demonstrated that selecting seed sources based on their genotype has the potential to mitigate predicted negative consequences of future climate warming on growth rates in valley oak. These results illustrate that the belief of local adaptation underlying many management and conservation practices, such as using local seed sources for restoration, may not hold for some species. If contemporary adaptational lag is commonplace, we will need new approaches to help alleviate predicted negative consequences of climate warming on natural systems. We present one such approach, "genome-informed assisted gene flow," which optimally matches individuals to future climates based on genotype-phenotype-environment associations.

Distinct Expression and Methylation Patterns for Genes with Different Fates following a Single Whole-Genome Duplication in Flowering Plants.

For most sequenced flowering plants, multiple whole-genome duplications (WGDs) are found. Duplicated genes following WGD often have different fates that can quickly disappear again, be retained for long(er) periods, or subsequently undergo small-scale duplications. However, how different expression, epigenetic regulation, and functional constraints are associated with these different gene fates following a WGD still requires further investigation due to successive WGDs in angiosperms complicating the gene trajectories. In this study, we investigate lotus (Nelumbo nucifera), an angiosperm with a single WGD during the K-pg boundary. Based on improved intraspecific-synteny identification by a chromosome-level assembly, transcriptome, and bisulfite sequencing, we explore not only the fundamental distinctions in genomic features, expression, and methylation patterns of genes with different fates after a WGD but also the factors that shape post-WGD expression divergence and expression bias between duplicates. We found that after a WGD genes that returned to single copies show the highest levels and breadth of expression, gene body methylation, and intron numbers, whereas the long-retained duplicates exhibit the highest degrees of protein-protein interactions and protein lengths and the lowest methylation in gene flanking regions. For those long-retained duplicate pairs, the degree of expression divergence correlates with their sequence divergence, degree in protein-protein interactions, and expression level, whereas their biases in expression level reflecting subgenome dominance are associated with the bias of subgenome fractionation. Overall, our study on the paleopolyploid nature of lotus highlights the impact of different functional constraints on gene fate and duplicate divergence following a single WGD in plant.

Microglia RAGE exacerbates the progression of neurodegeneration within the SOD1G93A murine model of amyotrophic lateral sclerosis in a sex-dependent manner.

BACKGROUND: Burgeoning evidence highlights seminal roles for microglia in the pathogenesis of neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). The receptor for advanced glycation end products (RAGE) binds ligands relevant to ALS that accumulate in the diseased spinal cord and RAGE has been previously implicated in the progression of ALS pathology. METHODS: We generated a novel mouse model to temporally delete Ager from microglia in the murine SOD1G93A model of ALS. Microglia Ager deficient SOD1G93A mice and controls were examined for changes in survival, motor function, gliosis, motor neuron numbers, and transcriptomic analyses of lumbar spinal cord. Furthermore, we examined bulk-RNA-sequencing transcriptomic analyses of human ALS cervical spinal cord. RESULTS: Transcriptomic analysis of human cervical spinal cord reveals a range of AGER expression in ALS patients, which was negatively correlated with age at disease onset and death or tracheostomy. The degree of AGER expression related to differential expression of pathways involved in extracellular matrix, lipid metabolism, and intercellular communication. Microglia display increased RAGE immunoreactivity in the spinal cords of high AGER expressing patients and in the SOD1G93A murine model of ALS vs. respective controls. We demonstrate that microglia Ager deletion at the age of symptomatic onset, day 90, in SOD1G93A mice extends survival in male but not female mice. Critically, many of the pathways identified in human ALS patients that accompanied increased AGER expression were significantly ameliorated by microglia Ager deletion in male SOD1G93A mice. CONCLUSIONS: Our results indicate that microglia RAGE disrupts communications with cell types including astrocytes and neurons, intercellular communication pathways that divert microglia from a homeostatic to an inflammatory and tissue-injurious program. In totality, microglia RAGE contributes to the progression of SOD1G93A murine pathology in male mice and may be relevant in human disease.

Landscape genomics of Quercus lobata reveals genes involved in local climate adaptation at multiple spatial scales.

Understanding how the environment shapes genetic variation provides critical insight about the evolution of local adaptation in natural populations. At multiple spatial scales and multiple geographic contexts within a single species, such information could address a number of fundamental questions about the scale of local adaptation and whether or not the same loci are involved at different spatial scales or geographic contexts. We used landscape genomic approaches from three local elevational transects and rangewide sampling to (a) identify genetic variation underlying local adaptation to environmental gradients in the California endemic oak, Quercus lobata; (b) examine whether putatively adaptive SNPs show signatures of selection at multiple spatial scales; and (c) map putatively adaptive variation to assess the scale and pattern of local adaptation. Of over 10 k single-nucleotide polymorphisms (SNPs) generated with genotyping-by-sequencing, we found signatures of natural selection by climate or local environment at over 600 SNPs (536 loci), some at multiple spatial scales across multiple analyses. Candidate SNPs identified with gene-environment tests (LFMM) at the rangewide scale also showed elevated associations with climate variables compared to the background at both rangewide and elevational transect scales with gradient forest analysis. Some loci overlap with those detected in other oak species, raising the question of whether the same loci might be involved in local climate adaptation in different congeneric species that inhabit different geographic contexts. Mapping landscape patterns of adaptive versus background genetic variation identified regions of marked local adaptation and suggests nonlinear association of candidate SNPs and environmental variables. Taken together, our results offer robust evidence for novel candidate genes for local climate adaptation at multiple spatial scales.

Evolutionary lessons from California plant phylogeography.

Phylogeography documents the spatial distribution of genetic lineages that result from demographic processes, such as population expansion, population contraction, and gene movement, shaped by climate fluctuations and the physical landscape. Because most phylogeographic studies have used neutral markers, the role of selection may have been undervalued. In this paper, we contend that plants provide a useful evolutionary lesson about the impact of selection on spatial patterns of neutral genetic variation, when the environment affects which individuals can colonize new sites, and on adaptive genetic variation, when environmental heterogeneity creates divergence at specific loci underlying local adaptation. Specifically, we discuss five characteristics found in plants that intensify the impact of selection: sessile growth form, high reproductive output, leptokurtic dispersal, isolation by environment, and the potential to evolve longevity. Collectively, these traits exacerbate the impact of environment on movement between populations and local selection pressures-both of which influence phylogeographic structure. We illustrate how these unique traits shape these processes with case studies of the California endemic oak, Quercus lobata, and the western North American lichen, Ramalina menziesii Obviously, the lessons we learn from plant traits are not unique to plants, but they highlight the need for future animal, plant, and microbe studies to incorporate its impact. Modern tools that generate genome-wide sequence data are now allowing us to decipher how evolutionary processes affect the spatial distribution of different kinds of genes and also to better model future spatial distribution of species in response to climate change.

Genomic data reveal cryptic lineage diversification and introgression in Californian golden cup oaks (section Protobalanus).

Here we study hybridization, introgression and lineage diversification in the widely distributed canyon live oak (Quercus chrysolepis) and the relict island oak (Q. tomentella), two Californian golden cup oaks with an intriguing biogeographical history. We employed restriction-site-associated DNA sequencing and integrated phylogenomic and population genomic analyses to study hybridization and reconstruct the evolutionary past of these taxa. Our analyses revealed the presence of two cryptic lineages within Q. chrysolepis. One of these lineages shares its most recent common ancestor with Q. tomentella, supporting the paraphyly of Q. chrysolepis. The split of these lineages was estimated to take place during the late Pliocene or the early Pleistocene, a time corresponding well with the common presence of Q. tomentella in the fossil records of continental California. Analyses also revealed historical hybridization among lineages, high introgression from Q. tomentella into Q. chrysolepis in their current area of sympatry, and widespread admixture between the two lineages of Q. chrysolepis in contact zones. Our results support that the two lineages of Q. chrysolepis behave as a single functional species phenotypically and ecologically well differentiated from Q. tomentella, a situation that can be only accommodated considering hybridization and speciation as a continuum with diffuse limits.

RADseq data reveal ancient, but not pervasive, introgression between Californian tree and scrub oak species (Quercus sect. Quercus: Fagaceae).

A long-term debate in evolutionary biology is the extent to which reproductive isolation is a necessary element of speciation. Hybridizing plants in general are cited as evidence against this notion, and oaks specifically have been used as the classic example of species maintenance without reproductive isolation. Here, we use thousands of SNPs generated by RAD sequencing to describe the phylogeny of a set of sympatric white oak species in California and then test whether these species exhibit pervasive interspecific gene exchange. Using RAD sequencing, we first constructed a phylogeny of ten oak species found in California. Our phylogeny revealed that seven scrub oak taxa occur within one clade that diverged from a common ancestor with Q. lobata, that they comprise two subclades, and they are not monophyletic but include the widespread tree oak Q. douglasii. Next, we searched for genomic patterns of allele sharing consistent with gene flow between long-divergent tree oaks with scrub oaks. Specifically, we utilized the D-statistic as well as model-based inference to compare the signature of shared alleles between two focal tree species (Q. lobata and Q. engelmannii) with multiple scrub species within the two subclades. We found that introgression is not equally pervasive between sympatric tree and scrub oak species. Instead, gene flow commonly occurs from scrub oaks to recently sympatric Q. engelmannii, but less so from scrub oaks to long-sympatric Q. lobata. This case study illustrates the influence of ancient introgression and impact of reproductive isolating mechanisms in preventing indiscriminate interspecific gene exchange.

Assessment of shared alleles in drought-associated candidate genes among southern California white oak species (Quercus sect. Quercus).

BACKGROUND: Hybridization and introgression are common phenomena among oak species. These processes can be beneficial by introducing favorable genetic variants across species (adaptive introgression). Given that drought is an important stress, impacting physiological and morphological variation and limiting distributions, our goal was to identify drought-related genes that might exhibit patterns of introgression influenced by natural selection. Using RNAseq, we sequenced whole transcriptomes of 24 individuals from three oaks in southern California: (Quercus engelmannii, Quercus berberidifolia, Quercus cornelius-mulleri) and identified genetic variants to estimate admixture rates of all variants and those in drought genes. RESULTS: We found 398,042 variants across all loci and 4352 variants in 139 drought candidate genes. STRUCTURE analysis of all variants revealed the majority of our samples were assignable to a single species, but with several highly admixed individuals. When using drought-associated variants, the same individuals exhibited less admixture and their allele frequencies were more polarized between Engelmann and scrub oaks than when using the total gene set. These findings are consistent with the hypothesis that selection may act differently on functional genes, such as drought-associated genes, and point to candidate genes that are suggestive of divergent selection among species maintaining adaptive differences. For example, the drought genes that showed the strongest bias against engelmannii-fixed oak variants in scrub oaks were related to sugar transporter, coumarate-coA ligases, glutathione S-conjugation, and stress response. CONCLUSION: This pilot study illustrates that whole transcriptomes of individuals will provide useful data for identifying functional genes that contribute to adaptive divergence among hybridizing species.

Impacts of human-induced environmental disturbances on hybridization between two ecologically differentiated Californian oak species.

Natural hybridization, which can be involved in local adaptation and in speciation processes, has been linked to different sources of anthropogenic disturbance. Here, we use genotypic data to study range-wide patterns of genetic admixture between the serpentine-soil specialist leather oak (Quercus durata) and the widespread Californian scrub oak (Quercus berberidifolia). First, we estimated hybridization rates and the direction of gene flow. Second, we tested the hypothesis that genetic admixture increases with different sources of environmental disturbance, namely anthropogenic destruction of natural habitats and wildfire frequency estimated from long-term records of fire occurrence. Our analyses indicate considerable rates of hybridization (> 25%), asymmetric gene flow from Q. durata into Q. berberidifolia, and a higher occurrence of hybrids in areas where both species live in close parapatry. In accordance with the environmental disturbance hypothesis, we found that genetic admixture increases with wildfire frequency, but we did not find a significant effect of other sources of human-induced habitat alteration (urbanization, land clearing for agriculture) or a suite of ecological factors (climate, elevation, soil type). Our findings highlight that wildfires constitute an important source of environmental disturbance, promoting hybridization between two ecologically well-differentiated native species.