PhysiMeSS - a new physiCell addon for extracellular matrix modelling

The extracellular matrix, composed of macromolecules like collagen fibres, provides structural support to cells and acts as a barrier that metastatic cells degrade to spread beyond the primary tumour. While agent-based frameworks, such as PhysiCell, can simulate the spatial dynamics of tumour evolution, they only implement cells as circles (2D) or spheres (3D). To model the extracellular matrix as a network of fibres, we require a new type of agent represented by line segments (2D) or cylinders (3D). Here, we present PhysiMeSS, an addon of PhysiCell, introducing a new agent type to describe fibres and their physical interactions with cells and other fibres. PhysiMeSS implementation is available at https://github.com/PhysiMeSS/PhysiMeSS and in the official PhysiCell repository. We provide examples describing the possibilities of this framework. This tool may help tackle important biological questions, such as diseases linked to dysregulation of the extracellular matrix or the processes leading to cancer metastasis

Modeling the extracellular matrix in cell migration and morphogenesis:a guide for the curious biologist

The extracellular matrix (ECM) is a highly complex structure through which biochemical and mechanical signals are transmitted. In processes of cell migration, the ECM also acts as a scaffold, providing structural support to cells as well as points of potential attachment. Although the ECM is a well-studied structure, its role in many biological processes remains difficult to investigate comprehensively due to its complexity and structural variation within an organism. In tandem with experiments, mathematical models are helpful in refining and testing hypotheses, generating predictions, and exploring conditions outside the scope of experiments. Such models can be combined and calibrated with in vivo and in vitro data to identify critical cell-ECM interactions that drive developmental and homeostatic processes, or the progression of diseases. In this review, we focus on mathematical and computational models of the ECM in processes such as cell migration including cancer metastasis, and in tissue structure and morphogenesis. By highlighting the predictive power of these models, we aim to help bridge the gap between experimental and computational approaches to studying the ECM and to provide guidance on selecting an appropriate model framework to complement corresponding experimental studies

Evidence of Polygenic Adaptation to High Altitude from Tibetan and Sherpa Genomes

Although Tibetans and Sherpa present several physiological adjustments evolved to cope with selective pressures imposed by the high-altitude environment, especially hypobaric hypoxia, few selective sweeps at a limited number of hypoxia related genes were confirmed by multiple genomic studies. Nevertheless, variants at these loci were found to be associated only with downregulation of the erythropoietic cascade, which represents an indirect aspect of the considered adaptive phenotype. Accordingly, the genetic basis of Tibetan/Sherpa adaptive traits remains to be fully elucidated, in part due to limitations of selection scans implemented so far and mostly relying on the hard sweep model.In order to overcome this issue, we used whole-genome sequence data and several selection statistics as input for gene network analyses aimed at testing for the occurrence of polygenic adaptation in these high-altitude Himalayan populations. Being able to detect also subtle genomic signatures ascribable to weak positive selection at multiple genes of the same functional subnetwork, this approach allowed us to infer adaptive evolution at loci individually showing small effect sizes, but belonging to highly interconnected biological pathways overall involved in angiogenetic processes.Therefore, these findings pinpointed a series of selective events neglected so far, which likely contributed to the augmented tissue blood perfusion observed in Tibetans and Sherpa, thus uncovering the genetic determinants of a key biological mechanism that underlies their adaptation to high altitude

Complex interplay between neutral and adaptive evolution shaped differential genomic background and disease susceptibility along the Italian peninsula

The Italian peninsula has long represented a natural hub for human migrations across the Mediterranean area, being involved in several prehistoric and historical population movements. Coupled with a patchy environmental landscape entailing different ecological/cultural selective pressures, this might have produced peculiar patterns of population structure and local adaptations responsible for heterogeneous genomic background of present-day Italians. To disentangle this complex scenario, genome-wide data from 780 Italian individuals were generated and set into the context of European/Mediterranean genomic diversity by comparison with genotypes from 50 populations. To maximize possibility of pinpointing functional genomic regions that have played adaptive roles during Italian natural history, our survey included also ∼250,000 exomic markers and ∼20,000 coding/regulatory variants with well-established clinical relevance. This enabled fine-grained dissection of Italian population structure through the identification of clusters of genetically homogeneous provinces and of genomic regions underlying their local adaptations. Description of such patterns disclosed crucial implications for understanding differential susceptibility to some inflammatory/autoimmune disorders, coronary artery disease and type 2 diabetes of diverse Italian subpopulations, suggesting the evolutionary causes that made some of them particularly exposed to the metabolic and immune challenges imposed by dietary and lifestyle shifts that involved western societies in the last centuries

WebMaBoSS: A Web Interface for Simulating Boolean Models Stochastically

International audienceWebMaBoSS is an easy-to-use web interface for conversion, storage, simulation and analysis of Boolean models that allows to get insight from these models without any specific knowledge of modeling or coding. It relies on an existing software, MaBoSS, which simulates Boolean models using a stochastic approach: it applies continuous time Markov processes over the Boolean network. It was initially built to fill the gap between Boolean and continuous formalisms, i.e., providing semi-quantitative results using a simple representation with a minimum number of parameters to fit. The goal of WebMaBoSS is to simplify the use and the analysis of Boolean models coping with two main issues: 1) the simulation of Boolean models of intracellular processes with MaBoSS, or any modeling tool, may appear as non-intuitive for non-experts; 2) the simulation of already-published models available in current model databases (e.g., Cell Collective, BioModels) may require some extra steps to ensure compatibility with modeling tools such as MaBoSS. With WebMaBoSS, new models can be created or imported directly from existing databases. They can then be simulated, modified and stored in personal folders. Model simulations are performed easily, results visualized interactively, and figures can be exported in a preferred format. Extensive model analyses such as mutant screening or parameter sensitivity can also be performed. For all these tasks, results are stored and can be subsequently filtered to look for specific outputs

A novel founder MYO15A frameshift duplication is the major cause of genetic hearing loss in Oman

The increased risk for autosomal recessive disorders is one of the most well-known medical implications of consanguinity. In the Sultanate of Oman, a country characterized by one of the highest rates of consanguineous marriages worldwide, prevalence of genetic hearing loss (GHL) is estimated to be 6/10\u2009000. Families of GHL patients have higher consanguinity rates than the general Omani population, indicating a major role for recessive forms. Mutations in GJB2, the most commonly mutated GHL gene, have been sporadically described. We collected 97 DNA samples of GHL probands, affected/unaffected siblings and parents from 26 Omani consanguineous families. Analyzing a first family by whole-exome sequencing, we identified a novel homozygous frameshift duplication (c.1171_1177dupGCCATCT) in MYO15A, the gene linked to the deafness locus DFNB3. This duplication was then found in a total of 8/26 (28%) families, within a 849\u2009kb founder haplotype. Reconstruction of haplotype structure at MYO15A surrounding genomic regions indicated that the founder haplotype branched out in the past two to three centuries from a haplotype present worldwide. The MYO15A duplication emerges as the major cause of GHL in Oman. These findings have major implications for the design of GHL diagnosis and prevention policies in Oma

Gut microbiota composition in Himalayan and Andean populations and its relationship with diet, lifestyle and adaptation to the high-altitude environment

Human populations living at high altitude evolved a number of biological adjustments to cope with a challenging environment characterised especially by reduced oxygen availability and limited nutritional resources. This condition may also affect their gut microbiota composition. Here, we explored the impact of exposure to such selective pressures on human gut microbiota by considering different ethnic groups living at variable degrees of altitude: the high-altitude Sherpa and low-altitude Tamang populations from Nepal, the high-altitude Aymara population from Bolivia, as well as a low-altitude cohort of European ancestry, used as control. We thus observed microbial profiles common to the Sherpa and Aymara, but absent in the low-altitude cohorts, which may contribute to the achievement of adaptation to high-altitude lifestyle and nutritional conditions. The collected evidences suggest that microbial signatures associated to these rural populations may enhance metabolic functions able to supply essential compounds useful for the host to cope with high altitude-related physiological changes and energy demand. Therefore, these results add another valuable piece of the puzzle to the understanding of the beneficial effects of symbiosis between microbes and their human host even from an evolutionary perspective

Ancient and recent admixture layers in Sicily and Southern Italy trace multiple migration routes along the Mediterranean

The Mediterranean shores stretching between Sicily, Southern Italy and the Southern Balkans witnessed a long series of migration processes and cultural exchanges. Accordingly, present-day population diversity is composed by multiple genetic layers, which make the deciphering of different ancestral and historical contributes particularly challenging. We address this issue by genotyping 511 samples from 23 populations of Sicily, Southern Italy, Greece and Albania with the Illumina GenoChip Array, also including new samples from Albanian- and Greek-speaking ethno-linguistic minorities of Southern Italy. Our results reveal a shared Mediterranean genetic continuity, extending from Sicily to Cyprus, where Southern Italian populations appear genetically closer to Greek-speaking islands than to continental Greece. Besides a predominant Neolithic background, we identify traces of Post-Neolithic Levantine- and Caucasus-related ancestries, compatible with maritime Bronze-Age migrations. We argue that these results may have important implications in the cultural history of Europe, such as in the diffusion of some Indo-European languages. Instead, recent historical expansions from North-Eastern Europe account for the observed differentiation of present-day continental Southern Balkan groups. Patterns of IBD-sharing directly reconnect Albanian-speaking Arbereshe with a recent Balkan-source origin, while Greek-speaking communities of Southern Italy cluster with their Italian-speaking neighbours suggesting a long-term history of presence in Southern Italy

The genetic legacy of the Yaghnobis: A witness of an ancient Eurasian ancestry in the historically reshuffled central Asian gene pool

Objectives: The Yaghnobis are an ethno-linguistic minority historically settled along the Yaghnob River in the Upper-Zarafshan Valley in Tajikistan. They speak a language of Old Sogdian origin, which is the only present-day witness of the Lingua Franca used along the Silk Road in Late Antiquity. The aim of this study was to reconstruct the genetic history of this community in order to shed light on its isolation and genetic ancestry within the Euro-Asiatic context. Materials and Methods: A total of 100 DNA samples were collected in the Yaghnob and Matcha Valleys during several expeditions and their mitochondrial, Y-chromosome and autosomal genome-wide variation were compared with that from a large set of modern and ancient Euro-Asiatic samples. Results: Findings from uniparental markers highlighted the long-term isolation of the Yaghnobis. Mitochondrial DNA ancestry traced an ancient link with Middle Eastern populations, whereas Y-chromosome legacy showed more tight relationships with Central Asians. Admixture, outgroup-f3, and D-statistics computed on autosomal variation corroborated Y-chromosome evidence, pointing respectively to low Anatolian Neolithic and high Steppe ancestry proportions in Yaghnobis, and to their closer affinity with Tajiks than to Iranians. Discussion: Although the Yaghnobis do not show evident signs of recent admixture, they could be considered a modern proxy for the source of gene flow for many Central Asian and Middle Eastern groups. Accordingly, they seem to retain a peculiar genomic ancestry probably ascribable to an ancient gene pool originally wide spread across a vast area and subsequently reshuffled by distinct demographic events occurred in Middle East and Central Asia