Human inbreeding has decreased in time through the Holocene

The history of human inbreeding is controversial. In particular, how the development of sedentary and/or agricultural societies may have influenced overall inbreeding levels is unclear. Here we present an approach for reliable estimation of runs of homozygosity (ROH) in genomes with ≥3x mean sequence coverage across >1 million SNPs, and apply this to 411 ancient Eurasian genomes from the last 15,000 years. We show that the frequency of inbreeding, as measured by ROH, has decreased over time. The strongest effect is associated with the Neolithic transition, but the trend has since continued, indicating a population size effect on inbreeding prevalence. We further show that most inbreeding in our historical sample can be attributed to small population size instead of consanguinity. We observed singular cases of high consanguinity only among members of farming societies

The XMM-Newton serendipitous survey: VIII. the first XMM-Newton serendipitous source catalogue from overlapping observations

Context. XMM-Newton has observed the X-ray sky since early 2000. The XMM-Newton Survey Science Centre Consortium has published catalogues of X-ray and ultraviolet sources found serendipitously in the individual observations. This series is now augmented by a catalogue dedicated to X-ray sources detected in spatially overlapping XMM-Newton observations. Aims. The aim of this catalogue is to explore repeatedly observed sky regions. It thus makes use of the long(er) effective exposure time per sky area and offers the opportunity to investigate long-term flux variability directly through the source-detection process. Methods. A new standardised strategy for simultaneous source detection on multiple observations was introduced, including an adaptive-smoothing method to describe the image background. It was coded as a new task within the XMM-Newton Science Analysis System and used to compile a catalogue of sources from 434 stacks comprising 1789 overlapping XMM-Newton observations that entered the 3XMM-DR7 catalogue, have a low background and full-frame readout of all EPIC cameras. Results. The first stacked catalogue is called 3XMM-DR7s. It contains 71 951 unique sources with positions and parameters such as fluxes, hardness ratios, quality estimates, and information on inter-observation variability, directly derived from a simultaneous fit. Source parameters are calculated for the stack and for each contributing observation. About 15% of the sources are new with respect to 3XMM-DR7. Through stacked source detection, the parameters of repeatedly observed sources are determined with higher accuracy than in the individual observations. The method is more sensitive to faint sources and tends to produce fewer spurious detections. Conclusions. With this first stacked catalogue we demonstrate the feasibility and benefit of the approach. It supplements the large data base of XMM-Newton detections with additional, in particular faint, sources and adds variability information. In the future, the catalogue will be expanded to larger samples and continued within the series of serendipitous XMM-Newton source catalogues.FJC acknowledges financial support through grant AYA2015-64346-C2-1P (MINECO/FEDER) and MTC through grant ESP2016-76683-C3-1R (MINECO/FEDER

Many non-equivalent realizations of the associahedron

Hohlweg and Lange (2007) and Santos (2004, unpublished) have found two different ways of constructing exponential families of realizations of the n-dimensional associahedron with normal vectors in {0,1,-1}^n, generalizing the constructions of Loday (2004) and Chapoton-Fomin-Zelevinsky (2002). We classify the associahedra obtained by these constructions modulo linear equivalence of their normal fans and show, in particular, that the only realization that can be obtained with both methods is the Chapoton-Fomin-Zelevinsky (2002) associahedron. For the Hohlweg-Lange associahedra our classification is a priori coarser than the classification up to isometry of normal fans, by Bergeron-Hohlweg-Lange-Thomas (2009). However, both yield the same classes. As a consequence, we get that two Hohlweg-Lange associahedra have linearly equivalent normal fans if and only if they are isometric. The Santos construction, which produces an even larger family of associahedra, appears here in print for the first time. Apart of describing it in detail we relate it with the c-cluster complexes and the denominator fans in cluster algebras of type A. A third classical construction of the associahedron, as the secondary polytope of a convex n-gon (Gelfand-Kapranov-Zelevinsky, 1990), is shown to never produce a normal fan linearly equivalent to any of the other two constructions.Comment: 30 pages, 13 figure

Plasma miRNA profile at COVID-19 onset predicts severity status and mortality

BACKGROUND: MicroRNAs (miRNAs) have a crucial role in regulating immune response against infectious diseases, showing changes early in disease onset and before the detection of the pathogen. Thus, we aimed to analyze the plasma miRNA profile at COVID-19 onset to identify miRNAs as early prognostic biomarkers of severity and survival. METHODS AND RESULTS: Plasma miRNome of 96 COVID-19 patients that developed asymptomatic/mild, moderate and severe disease was sequenced together with a group of healthy controls. Plasma immune-related biomarkers were also assessed. COVID-19 patients showed 200 significant differentially expressed (SDE) miRNAs concerning healthy controls, with upregulated putative targets of SARS-CoV-2, and inflammatory miRNAs. Among COVID-19 patients, 75 SDE miRNAs were observed in asymptomatic/mild compared to symptomatic patients, which were involved in platelet aggregation and cytokine pathways, among others. Moreover, 137 SDE miRNAs were identified between severe and moderate patients, where miRNAs targeting the SARS CoV-2 genome were the most strongly disrupted. Finally, we constructed a mortality predictive risk score (miRNA-MRS) with ten miRNAs. Patients with higher values had a higher risk of 90-days mortality (hazard ratio = 4.60; p-value < 0.001). Besides, the discriminant power of miRNA-MRS was significantly higher than the observed for age and gender (AUROC = 0.970 vs. 0.881; p = 0.042). CONCLUSIONS: SARS-CoV-2 infection deeply disturbs the plasma miRNome from an early stage of COVID-19, making miRNAs highly valuable as early predictors of severity and mortality

Are Reduced Levels of Coagulation Proteins Upon Admission Linked to COVID-19 Severity and Mortality?

Background: The link between coagulation system disorders and COVID-19 has not yet been fully elucidated. Aim: Evaluating the association of non-previously reported coagulation proteins with COVID-19 severity and mortality. Design: Cross-sectional study of 134 COVID-19 patients recruited at admission and classified according to the highest COVID-19 severity reached (asymptomatic/mild, moderate, or severe) and 16 healthy control individuals. Methods: Coagulation proteins levels (antithrombin, prothrombin, factor_XI, factor_XII, and factor_XIII) and CRP were measured in plasma by the ProcartaPlex Panel (Invitrogen) multiplex immunoassay upon diagnosis. Results: We found higher levels of antithrombin, prothrombin, factor XI, factor XII, and factor XIII in asymptomatic/mild and moderate COVID-19 patients compared to healthy individuals. Interestingly, decreased levels of antithrombin and factors XI, XII, and XIII were observed in those patients who eventually developed severe illness. Additionally, survival models showed us that patients with lower levels of these coagulation proteins had an increased risk of death. Conclusion: COVID-19 provokes early increments of some specific coagulation proteins in most patients. However, lower levels of these proteins at diagnosis might "paradoxically" imply a higher risk of progression to severe disease and COVID-19-related mortality.This study was supported by grants from Instituto de Salud Carlos III [ISCIII; Grant Number COV20/1144 (MPY224/20) to AF-R/MJ-S]. AF-R, MJ-S, and MR are Miguel Servet researchers supported and funded by ISCIII (Grant Numbers: CP14CIII/00010 to AF-R, CP17CIII/00007 to MJ-S, and CP19CIII/00002 to MR).S

Metabolic Profiling at COVID-19 Onset Shows Disease Severity and Sex-Specific Dysregulation

Background: metabolic changes through SARS-CoV-2 infection has been reported but not fully comprehended. This metabolic dysregulation affects multiple organs during COVID-19 and its early detection can be used as a prognosis marker of severity. Therefore, we aimed to characterize metabolic and cytokine profile at COVID-19 onset and its relationship with disease severity to identify metabolic profiles predicting disease progression. Material and methods: we performed a retrospective cross-sectional study in 123 COVID-19 patients which were stratified as asymptomatic/mild, moderate and severe according to the highest COVID-19 severity status, and a group of healthy controls. We performed an untargeted plasma metabolic profiling (gas chromatography and capillary electrophoresis-mass spectrometry (GC and CE-MS)) and cytokine evaluation. Results: After data filtering and identification we observed 105 metabolites dysregulated (66 GC-MS and 40 CE-MS) which shown different expression patterns for each COVID-19 severity status. These metabolites belonged to different metabolic pathways including amino acid, energy, and nitrogen metabolism among others. Severity-specific metabolic dysregulation was observed, as an increased transformation of L-tryptophan into L-kynurenine. Thus, metabolic profiling at hospital admission differentiate between severe and moderate patients in the later phase of worse evolution. Several plasma pro-inflammatory biomarkers showed significant correlation with deregulated metabolites, specially with L-kynurenine and L-tryptophan. Finally, we describe a strong sex-related dysregulation of metabolites, cytokines and chemokines between severe and moderate patients. In conclusion, metabolic profiling of COVID-19 patients at disease onset is a powerful tool to unravel the SARS-CoV-2 molecular pathogenesis. Conclusions: This technique makes it possible to identify metabolic phenoconversion that predicts disease progression and explains the pronounced pathogenesis differences between sexes.This study was supported by grants from Instituto de Salud Carlos III (ISCIII; grant number COV20/1144 (MPY224/20) to AF-R/MJ-S). The study was also funded by CIBER - Consorcio Centro de Investigación Biomédica en Red - (CB 2021; CB21/13/00044), Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación and Unión Europea - NextGenerationEU. AF-R and MJ-S are Miguel Servet researchers supported and funded by ISCIII (grant numbers: CP14CIII/00010 to AFR and CP17CIII/00007 to MJ-S). Universidad Alfonso X el Sabio, grant number 1.013.005S

The Role of Inbreeding in the Extinction of a European Royal Dynasty

The kings of the Spanish Habsburg dynasty (1516–1700) frequently married close relatives in such a way that uncle-niece, first cousins and other consanguineous unions were prevalent in that dynasty. In the historical literature, it has been suggested that inbreeding was a major cause responsible for the extinction of the dynasty when the king Charles II, physically and mentally disabled, died in 1700 and no children were born from his two marriages, but this hypothesis has not been examined from a genetic perspective. In this article, this hypothesis is checked by computing the inbreeding coefficient (F) of the Spanish Habsburg kings from an extended pedigree up to 16 generations in depth and involving more than 3,000 individuals. The inbreeding coefficient of the Spanish Habsburg kings increased strongly along generations from 0.025 for king Philip I, the founder of the dynasty, to 0.254 for Charles II and several members of the dynasty had inbreeding coefficients higher than 0.20. In addition to inbreeding due to unions between close relatives, ancestral inbreeding from multiple remote ancestors makes a substantial contribution to the inbreeding coefficient of most kings. A statistically significant inbreeding depression for survival to 10 years is detected in the progenies of the Spanish Habsburg kings. The results indicate that inbreeding at the level of first cousin (F = 0.0625) exerted an adverse effect on survival of 17.8%±12.3. It is speculated that the simultaneous occurrence in Charles II (F = 0.254) of two different genetic disorders: combined pituitary hormone deficiency and distal renal tubular acidosis, determined by recessive alleles at two unlinked loci, could explain most of the complex clinical profile of this king, including his impotence/infertility which in last instance led to the extinction of the dynasty