Applying an evolutionary mismatch framework to understand disease susceptibility.

Noncommunicable diseases (NCDs) are on the rise worldwide. Obesity, cardiovascular disease, and type 2 diabetes are among a long list of "lifestyle" diseases that were rare throughout human history but are now common. The evolutionary mismatch hypothesis posits that humans evolved in environments that radically differ from those we currently experience; consequently, traits that were once advantageous may now be "mismatched" and disease causing. At the genetic level, this hypothesis predicts that loci with a history of selection will exhibit "genotype by environment" (GxE) interactions, with different health effects in "ancestral" versus "modern" environments. To identify such loci, we advocate for combining genomic tools in partnership with subsistence-level groups experiencing rapid lifestyle change. In these populations, comparisons of individuals falling on opposite extremes of the "matched" to "mismatched" spectrum are uniquely possible. More broadly, the work we propose will inform our understanding of environmental and genetic risk factors for NCDs across diverse ancestries and cultures.

Characterizing the landscape of gene expression variance in humans.

Gene expression variance has been linked to organismal function and fitness but remains a commonly neglected aspect of molecular research. As a result, we lack a comprehensive understanding of the patterns of transcriptional variance across genes, and how this variance is linked to context-specific gene regulation and gene function. Here, we use 57 large publicly available RNA-seq data sets to investigate the landscape of gene expression variance. These studies cover a wide range of tissues and allowed us to assess if there are consistently more or less variable genes across tissues and data sets and what mechanisms drive these patterns. We show that gene expression variance is broadly similar across tissues and studies, indicating that the pattern of transcriptional variance is consistent. We use this similarity to create both global and within-tissue rankings of variation, which we use to show that function, sequence variation, and gene regulatory signatures contribute to gene expression variance. Low-variance genes are associated with fundamental cell processes and have lower levels of genetic polymorphisms, have higher gene-gene connectivity, and tend to be associated with chromatin states associated with transcription. In contrast, high-variance genes are enriched for genes involved in immune response, environmentally responsive genes, immediate early genes, and are associated with higher levels of polymorphisms. These results show that the pattern of transcriptional variance is not noise. Instead, it is a consistent gene trait that seems to be functionally constrained in human populations. Furthermore, this commonly neglected aspect of molecular phenotypic variation harbors important information to understand complex traits and disease.

Natural selection of immune and metabolic genes associated with health in two lowland Bolivian populations.

A growing body of work has addressed human adaptations to diverse environments using genomic data, but few studies have connected putatively selected alleles to phenotypes, much less among underrepresented populations such as Amerindians. Studies of natural selection and genotype-phenotype relationships in underrepresented populations hold potential to uncover previously undescribed loci underlying evolutionarily and biomedically relevant traits. Here, we worked with the Tsimane and the Moseten, two Amerindian populations inhabiting the Bolivian lowlands. We focused most intensively on the Tsimane, because long-term anthropological work with this group has shown that they have a high burden of both macro and microparasites, as well as minimal cardiometabolic disease or dementia. We therefore generated genome-wide genotype data for Tsimane individuals to study natural selection, and paired this with blood mRNA-seq as well as cardiometabolic and immune biomarker data generated from a larger sample that included both populations. In the Tsimane, we identified 21 regions that are candidates for selective sweeps, as well as 5 immune traits that show evidence for polygenic selection (e.g., C-reactive protein levels and the response to coronaviruses). Genes overlapping candidate regions were strongly enriched for known involvement in immune-related traits, such as abundance of lymphocytes and eosinophils. Importantly, we were also able to draw on extensive phenotype information for the Tsimane and Moseten and link five regions (containing PSD4, MUC21 and MUC22, TOX2, ANXA6, and ABCA1) with biomarkers of immune and metabolic function. Together, our work highlights the utility of pairing evolutionary analyses with anthropological and biomedical data to gain insight into the genetic basis of health-related traits.

Implanted System for Orthostatic Hypotension in Multiple-System Atrophy.

Orthostatic hypotension is a cardinal feature of multiple-system atrophy. The upright posture provokes syncopal episodes that prevent patients from standing and walking for more than brief periods. We implanted a system to restore regulation of blood pressure and enable a patient with multiple-system atrophy to stand and walk after having lost these abilities because of orthostatic hypotension. This system involved epidural electrical stimulation delivered over the thoracic spinal cord with accelerometers that detected changes in body position. (Funded by the Defitech Foundation.).

Diverse environmental perturbations reveal the evolution and context-dependency of genetic effects on gene expression levels.

There is increasing appreciation that, in addition to being shaped by an individual's genotype and environment, most complex traits are also determined by poorly understood interactions between these two factors. So-called "genotype × environment" (G×E) interactions remain difficult to map at the organismal level but can be uncovered using molecular phenotypes. To do so at large scale, we used TM3'seq to profile transcriptomes across 12 cellular environments in 544 immortalized B cell lines from the 1000 Genomes Project. We mapped the genetic basis of gene expression levels across environments and revealed a context-dependent genetic architecture: The average heritability of gene expression levels increased in treatment relative to control conditions, and on average, each treatment revealed new expression quantitative trait loci (eQTLs) at 11% of genes. Across our experiments, 22% of all identified eQTLs were context-dependent, and this group was enriched for trait- and disease-associated loci. Further, evolutionary analyses suggested that positive selection has shaped G×E loci involved in responding to immune challenges and hormones but not to man-made chemicals. We hypothesize that this reflects a reduced opportunity for selection to act on responses to molecules recently introduced into human environments. Together, our work highlights the importance of considering an exposure's evolutionary history when studying and interpreting G×E interactions, and provides new insight into the evolutionary mechanisms that maintain G×E loci in human populations.

Determinants of microbiome composition: Insights from free-ranging hybrid zebras (Equus quagga × grevyi).

The composition of mammalian gut microbiomes is highly conserved within species, yet the mechanisms by which microbiome composition is transmitted and maintained within lineages of wild animals remain unclear. Mutually compatible hypotheses exist, including that microbiome fidelity results from inherited dietary habits, shared environmental exposure, morphophysiological filtering and/or maternal effects. Interspecific hybrids are a promising system in which to interrogate the determinants of microbiome composition because hybrids can decouple traits and processes that are otherwise co-inherited in their parent species. We used a population of free-living hybrid zebras (Equus quagga × grevyi) in Kenya to evaluate the roles of these four mechanisms in regulating microbiome composition. We analysed faecal DNA for both the trnL-P6 and the 16S rRNA V4 region to characterize the diets and microbiomes of the hybrid zebra and of their parent species, plains zebra (E. quagga) and Grevy's zebra (E. grevyi). We found that both diet and microbiome composition clustered by species, and that hybrid diets and microbiomes were largely nested within those of the maternal species, plains zebra. Hybrid microbiomes were less variable than those of either parent species where they co-occurred. Diet and microbiome composition were strongly correlated, although the strength of this correlation varied between species. These patterns are most consistent with the maternal-effects hypothesis, somewhat consistent with the diet hypothesis, and largely inconsistent with the environmental-sourcing and morphophysiological-filtering hypotheses. Maternal transmittance likely operates in conjunction with inherited feeding habits to conserve microbiome composition within species.

Vibrational Circular Dichroism of a Chiral Triplet Nitrene Investigated Under Matrix-Isolation Conditions in Parahydrogen.

Vibrational circular dichroism (VCD) spectra of chiral high-spin organic radicals are expected to show a strong intensity enhancement and are thought to be difficult to predict using state-of-the-art theoretical methods. Herein we show that the chiral triplet nitrene obtained from photochemical cleavage of N2 from enantiopure 2-azido-9H-fluorenol does not feature extraordinarily strong intensities and that the experimental spectra match nicely with calculated ones. Thereby, this study demonstrates the general feasibility of studies on chiral high-spin organics by matrix-isolation VCD.

Deep Brain Stimulation Improves Parkinson's Disease-Associated Pain by Decreasing Spinal Nociception.

Dopamine exerts antinociceptive effects on pain in PD at cortical and spinal levels, whereas only cortical effects have been described for DBS, so far. By assessing the nociceptive flexion reflex (NFR) threshold at medication on, and DBS ON and OFF in two patients, we showed that DBS additionally decreases spinal nociception.

Ancestral polymorphisms shape the adaptive radiation of Metrosideros across the Hawaiian Islands.

Some of the most spectacular adaptive radiations begin with founder populations on remote islands. How genetically limited founder populations give rise to the striking phenotypic and ecological diversity characteristic of adaptive radiations is a paradox of evolutionary biology. We conducted an evolutionary genomics analysis of genus Metrosideros, a landscape-dominant, incipient adaptive radiation of woody plants that spans a striking range of phenotypes and environments across the Hawaiian Islands. Using nanopore-sequencing, we created a chromosome-level genome assembly for Metrosideros polymorpha var. incana and analyzed whole-genome sequences of 131 individuals from 11 taxa sampled across the islands. Demographic modeling and population genomics analyses suggested that Hawaiian Metrosideros originated from a single colonization event and subsequently spread across the archipelago following the formation of new islands. The evolutionary history of Hawaiian Metrosideros shows evidence of extensive reticulation associated with significant sharing of ancestral variation between taxa and secondarily with admixture. Taking advantage of the highly contiguous genome assembly, we investigated the genomic architecture underlying the adaptive radiation and discovered that divergent selection drove the formation of differentiation outliers in paired taxa representing early stages of speciation/divergence. Analysis of the evolutionary origins of the outlier single nucleotide polymorphisms (SNPs) showed enrichment for ancestral variations under divergent selection. Our findings suggest that Hawaiian Metrosideros possesses an unexpectedly rich pool of ancestral genetic variation, and the reassortment of these variations has fueled the island adaptive radiation.

No fitness cost entailed by type VI secretion system synthesis, assembly, contraction, or disassembly in enteroaggregative Escherichia coli.

IMPORTANCE: Bacteria use weapons to deliver effectors into target cells. One of these weapons, the type VI secretion system (T6SS), assembles a contractile tail acting as a spring to propel a toxin-loaded needle. Due to its size and mechanism of action, the T6SS was intuitively thought to be energetically costly. Here, using a combination of mutants and growth measurements in liquid medium, on plates, and in competition experiments, we show that the T6SS does not entail a growth cost to enteroaggregative Escherichia coli.

Isomer-Specific Heavy-Atom Tunneling in the Ring Expansion of Fluorenylazirines.

The photolysis of 2-azidofluorene in solid argon at 3 K results in the formation of 2-fluorenylnitrene. The nitrene undergoes subsequent rearrangements to two isomeric didehydroazepines (ketenimines) which differ in the position of the N atom in the seven-membered ring. The rearrangement of the nitrene to the didehydroazepines proceeds in a two-step process. The first step is a photochemical rearrangement to form the corresponding isomeric benzazirines A and B. The second step is the opening of the three-membered rings of A and B to form the isomeric didehydroazepines. While benzazirine A could easily be detected, isomer B was not observed, despite the corresponding didehydroazepine being formed in the matrix. Further experiments revealed that A rearranges to the didehydroazepine via heavy-atom tunneling. Semiquantitative estimations based on DFT calculations confirm that A should undergo a tunneling rearrangement with tunneling rates on the order of the experimentally observed rates. In contrast, estimations for B suggest that for this isomer the tunneling rates should be much larger, resulting in lifetimes too short to be observable under the conditions of matrix isolation. These experiments demonstrate the influence of position isomerism on quantum tunneling rates.

GC-FTICR mass spectrometry with dopant assisted atmospheric pressure photoionization: application to the characterization of plastic pyrolysis oil.

Pyrolysis is a promising way to convert plastic waste into valuable resources. However, for downstream upgrading processes, many undesirable species, such as conjugated diolefins or heteroatom-containing compounds, can be generated during this pyrolysis. In-depth chemical characterization is therefore required to improve conversion and valorization. Because of the high molecular diversity found in these samples, advanced analytical instrumentation is needed to provide accurate and complete characterization. Generally, direct infusion Fourier transform mass spectrometry is used to gather information at the molecular level, but it has the disadvantage of limited structural insights. To overcome this drawback, gas chromatography has been coupled to Fourier transform ion cyclotron resonance mass spectrometry. By taking advantage of soft atmospheric pressure photoionization, which preserves molecular information, and the use of different dopants (pyrrole, toluene, and benzene), selective ionization of different chemical families was achieved. Differences in the ionization energy of the dopants will only allow the ionization of the molecules of the pyrolysis oil which have lower ionization energy, or which are accessible via specific chemical ionization pathways. With a selective focus on hydrocarbon species and especially hydrocarbon species having a double bond equivalent (DBE) value of 2, pyrrole is prone to better ionize low-mass molecules with lower retention times compared to the dopant benzene, which allowed better ionization of high-mass molecules with higher retention times. The toluene dopant presented the advantage of ionizing both low and high mass molecules.

Drosophila melanogaster microbiome is shaped by strict filtering and neutrality along a latitudinal cline.

Microbiomes affect many aspects of host biology, but the eco-evolutionary forces that shape their diversity in natural populations remain poorly understood. Geographical gradients, such as latitudinal clines, generate predictable patterns in biodiversity at macroecological scales, but whether these macroscale processes apply to host-microbiome interactions is an open question. To address this question, we sampled the microbiomes of 13 natural populations of Drosophila melanogaster along a latitudinal cline in the eastern United States. The microbiomes were surprisingly consistent across the cline, as latitude did not predict either alpha or beta diversity. Only a narrow taxonomic range of bacteria were present in all microbiomes, indicating that strict taxonomic filtering by the host and neutral ecological dynamics are the primary factors shaping the fly microbiome. Our findings reveal the complexity of eco-evolutionary interactions shaping microbial variation in D. melanogaster and highlight the need for additional sampling of the microbiomes in natural populations along environmental gradients.

Visualization and identification of single meteoritic organic molecules by atomic force microscopy.

Using high-resolution atomic force microscopy (AFM) with CO-functionalized tips, we atomically resolved individual molecules from Murchison meteorite samples. We analyzed powdered Murchison meteorite material directly, as well as processed extracts that we prepared to facilitate characterization by AFM. From the untreated Murchison sample, we resolved very few molecules, as the sample contained mostly small molecules that could not be identified by AFM. By contrast, using a procedure based on several trituration and extraction steps with organic solvents, we isolated a fraction enriched in larger organic compounds. The treatment increased the fraction of molecules that could be resolved by AFM, allowing us to identify organic constituents and molecular moieties, such as polycyclic aromatic hydrocarbons and aliphatic chains. The AFM measurements are complemented by high-resolution mass spectrometry analysis of Murchison fractions. We provide a proof of principle that AFM can be used to image and identify individual organic molecules from meteorites and propose a method for extracting and preparing meteorite samples for their investigation by AFM. We discuss the challenges and prospects of this approach to study extraterrestrial samples based on single-molecule identification.

Meta-analysis suggests the microbiome responds to Evolve and Resequence experiments in Drosophila melanogaster.

BACKGROUND: Experimental evolution has a long history of uncovering fundamental insights into evolutionary processes, but has largely neglected one underappreciated component--the microbiome. As eukaryotic hosts evolve, the microbiome may also respond to selection. However, the microbial contribution to host evolution remains poorly understood. Here, we re-analyzed genomic data to characterize the metagenomes from ten Evolve and Resequence (E&R) experiments in Drosophila melanogaster to determine how the microbiome changed in response to host selection. RESULTS: Bacterial diversity was significantly different in 5/10 studies, primarily in traits associated with metabolism or immunity. Duration of selection did not significantly influence bacterial diversity, highlighting the importance of associations with specific host traits. CONCLUSIONS: Our genomic re-analysis suggests the microbiome often responds to host selection; thus, the microbiome may contribute to the response of Drosophila in E&R experiments. We outline important considerations for incorporating the microbiome into E&R experiments. The E&R approach may provide critical insights into host-microbiome interactions and fundamental insight into the genomic basis of adaptation.

Structural analysis of petroporphyrins from asphaltene by trapped ion mobility coupled with Fourier transform ion cyclotron resonance mass spectrometry.

Molecular characterization of compounds present in highly complex mixtures such as petroleum is proving to be one of the main analytical challenges. Heavy fractions, such as asphaltenes, exhibit immense molecular and isomeric complexity. Fourier transform ion cyclotron resonance mass spectrometry (FTICR MS) with its unequalled resolving power, mass accuracy and dynamic range can address the isobaric complexity. Nevertheless, isomers remain largely inaccessible. Therefore, another dimension of separation is required. Recently, ion mobility mass spectrometry has revealed great potential for isomer description. In this study, the combination of trapped ion mobility and Fourier transform ion cyclotron resonance mass spectrometry (TIMS-FTICR) is used to obtain information on the structural features and isomeric diversity of vanadium petroporphyrins present in heavy petroleum fractions. The ion mobility spectra provided information on the isomeric diversity of the different classes of porphyrins. The determination of the collision cross section (CCS) from the peak apex allows us to hypothesize about the structural aspects of the petroleum molecules. In addition, the ion mobility signal full width at half maximum (FWHM) was used as a measure for isomeric diversity. Finally, theoretical CCS determinations were conducted first on core structures and then on alkylated petroporphyrins taking advantage of the linear correlation between the CCS and the alkylation level. This allowed the proposal of putative structures in agreement with the experimental results. The authors believe that the presented workflow will be useful for the structural prediction of real unknowns in highly complex mixtures.

Correlated optical and electrical analyses of inhomogeneous core/shell InGaN/GaN nanowire light emitting diodes.

The performance of core-shell InGaN/GaN nanowire (NW) light emitting diodes (LEDs) can be limited by wire-to-wire electrical inhomogeneities. Here we investigate an array of core-shell InGaN/GaN NWs which are morphologically identical, but present electrical dissimilarities in order to understand how the nanoscale phenomena observed in individual NWs affect the working performance of the whole array. The LED shows a low number of NWs (∼20%) producing electroluminescence under operating conditions. This is related to a presence of a potential barrier at the interface between the NW core and the radially grown n-doped layer, which differently affects the electrical properties of the NWs although they are morphologically identical. The impact of the potential barrier on the performance of the NW array is investigated by correlating multi-scanning techniques, namely electron beam induced current microscopy, electroluminescence mapping and cathodoluminescence analysis. It is found that the main cause of inhomogeneity in the array is related to a non-optimized charge injection into the active region, which can be overcome by changing the contact architecture so that the electrons become injected directly in the n-doped underlayer. The LED with so-called 'front-n-contacting' is developed leading to an increase of the yield of emitting NWs from 20% to 65%.

Heavy-Atom Tunneling in Semibullvalenes: How Driving Force, Substituents, and Environment Influence the Tunneling Rates.

Invited for the cover of this issue are the groups of Elsa Sanchez-Garcia and Wolfram Sander at the Universität Duisburg-Essen and the Ruhr-Universität Bochum. The image depicts the ideas skillfully visualized by Markus Henkel on the shift in equilibrium induced by isotopic labelling. Read the full text of the article at 10.1002/chem.202001202.

Heavy-Atom Tunneling in Semibullvalenes: How Driving Force, Substituents, and Environment Influence the Tunneling Rates.

The Cope rearrangement of selectively deuterated isotopomers of 1,5-dimethylsemibullvalene 2 a and 3,7-dicyano-1,5-dimethylsemibullvalene 2 b were studied in cryogenic matrices. In both semibullvalenes the Cope rearrangement is governed by heavy-atom tunneling. The driving force for the rearrangements is the small difference in the zero-point vibrational energies of the isotopomers. To evaluate the effect of the driving force on the tunneling probability in 2 a and 2 b, two different pairs of isotopomers were studied for each of the semibullvalenes. The reaction rates for the rearrangement of 2 b in cryogenic matrices were found to be smaller than the ones of 2 a under similar conditions, whereas differences in the driving force do not influence the rates. Small curvature tunneling (SCT) calculations suggest that the reduced tunneling rate of 2 b compared to that of 2 a results from a change in the shape of the potential energy barrier. The tunneling probability of the semibullvalenes strongly depends on the matrix environment; however, for 2 a in a qualitatively different way than for 2 b.

Complex movement disorder in a patient with heterozygous YY1 mutation (Gabriele-de Vries syndrome).

YY1 mutations cause Gabriele-de Vries syndrome, a recently described condition involving cognitive impairment, facial dysmorphism and intrauterine growth restriction. Movement disorders were reported in 5/10 cases of the original series, but no detailed description was provided. Here we present a 21-year-old woman with a mild intellectual deficit, facial dysmorphism and a complex movement disorder including an action tremor, cerebellar ataxia, dystonia, and partial ocular apraxia as the presenting and most striking feature. Whole-exome sequencing revealed a novel heterozygous de novo mutation in YY1 [NM: 003403.4 (YY1): c.907 T > C; p.(Cys303Arg)], classified as pathogenic according to the ACMG guidelines.