Single-cell atlases of two lophotrochozoan larvae highlight their complex evolutionary histories
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ABSTRACT: Single cell atlases of platyhelminth Müller’s larva and mollusc trochophore larva reveal homologous cell types and phylum specific novelties
Project description:COVID-19, caused by SARS-CoV-2, can result in acute respiratory distress syndrome and multiple-organ failure, but little is known about its pathophysiology. Here, we generated single-cell atlases of 23 lung, 16 kidney, 15 liver and 18 heart COVID-19 autopsy donor tissue samples, and spatial atlases of 14 lung donors. Integrated computational analysis uncovered substantial remodeling in the lung epithelial, immune and stromal compartments, with evidence of multiple paths of failed tissue regeneration, including defective alveolar type 2 differentiation and expansion of myofibroblasts and putative TP63+ intrapulmonary basal-like progenitor cells. Viral RNAs were enriched in mononuclear phagocytic and endothelial lung cells which induced specific host programs. Spatial analysis in lung distinguished inflammatory host responses in lung regions with and without viral RNA. Analysis of the other tissue atlases showed transcriptional alterations in multiple cell types in COVID-19 donor heart tissue, and mapped cell types and genes implicated with disease severity based on COVID-19 GWAS. Our foundational dataset elucidates the biological impact of severe SARS-CoV-2 infection across the body a key step towards new treatments.
Project description:Hybridization plays an important role in the evolution of certain groups of organisms, adaptation to their environments, and diversification of their genomes. The evolutionary histories of such groups are reticulate, and methods for reconstructing them are still in their infancy and have limited applicability. We present a maximum likelihood method for inferring reticulate evolutionary histories while accounting simultaneously for incomplete lineage sorting. Additionally, we propose methods for assessing confidence in the amount of reticulation and the topology of the inferred evolutionary history. Our method obtains accurate estimates of reticulate evolutionary histories on simulated datasets. Furthermore, our method provides support for a hypothesis of a reticulate evolutionary history inferred from a set of house mouse (Mus musculus) genomes. As evidence of hybridization in eukaryotic groups accumulates, it is essential to have methods that infer reticulate evolutionary histories. The work we present here allows for such inference and provides a significant step toward putting phylogenetic networks on par with phylogenetic trees as a model of capturing evolutionary relationships.
Project description:Single-cell data are being generated at an accelerating pace. How best to project data across single-cell atlases is an open problem. We developed a boosted learner that overcomes the greatest challenge with status quo classifiers: low sensitivity, especially when dealing with rare cell types. By comparing novel and published data from distinct scRNA-seq modalities that were acquired from the same tissues, we show that this approach preserves cell-type labels when mapping across diverse platforms.
Project description:Recent studies have documented frequent evolution of clones carrying common cancer mutations in apparently normal tissues, which are implicated in cancer development1-3. However, our knowledge is still missing with regard to what additional driver events take place in what order, before one or more of these clones in normal tissues ultimately evolve to cancer. Here, using phylogenetic analyses of multiple microdissected samples from both cancer and non-cancer lesions, we show unique evolutionary histories of breast cancers harbouring der(1;16), a common driver alteration found in roughly 20% of breast cancers. The approximate timing of early evolutionary events was estimated from the mutation rate measured in normal epithelial cells. In der(1;16)(+) cancers, the derivative chromosome was acquired from early puberty to late adolescence, followed by the emergence of a common ancestor by the patient's early 30s, from which both cancer and non-cancer clones evolved. Replacing the pre-existing mammary epithelium in the following years, these clones occupied a large area within the premenopausal breast tissues by the time of cancer diagnosis. Evolution of multiple independent cancer founders from the non-cancer ancestors was common, contributing to intratumour heterogeneity. The number of driver events did not correlate with histology, suggesting the role of local microenvironments and/or epigenetic driver events. A similar evolutionary pattern was also observed in another case evolving from an AKT1-mutated founder. Taken together, our findings provide new insight into how breast cancer evolves.
Project description:In humans, three genes--ADRB1, ADRB2 and ADRB3--encode beta-adrenoreceptors (ADRB); these molecules mediate the action of catecholamines in multiple tissues and play pivotal roles in cardiovascular, respiratory, metabolic, and immunological functions. Genetic variants in ADRB genes have been associated with widespread diseases and conditions, but inconsistent results have often been obtained. Here, we addressed the recent evolutionary history of ADRB genes in human populations. Although ADRB1 is neutrally evolving, most tests rejected neutral evolution for ADRB2 in European, African, and Asian population samples. Analysis of inferred haplotypes for ADRB2 revealed three major clades with a coalescence time of 1-1.5 million years, suggesting that the gene is either subjected to balancing selection or undergoing a selective sweep. Haplotype analysis also revealed ethnicity-specific differences. Additionally, we observed significant deviations from Hardy-Weinberg equilibrium (HWE) for ADRB2 genotypes in distinct European cohorts; HWE deviation depends on sex (only females are in disequilibrium), and genotypes displaying maximum and minimum relative fitness differ across population samples, suggesting a complex situation possibly involving epistasis or maternal selection. Overall, our data indicate that future association studies involving ADRB2 will benefit from taking into account ethnicity-specific haplotype distributions and sex-based effects. With respect to ADRB3, our data indicate that the gene has been subjected to a selective sweep in African populations, the Trp64 variant possibly representing the selection target. Given the previous association of the ancestral ADRB3 Arg64 allele with obesity and type 2 diabetes, dietary adaptations might represent the underlying selective force.
Project description:Individual heterogeneity in life history shapes eco-evolutionary processes, and unobserved heterogeneity can affect demographic outputs characterising life history and population dynamical properties. Demographic frameworks like matrix models or integral projection models represent powerful approaches to disentangle mechanisms linking individual life histories and population-level processes. Recent developments have provided important steps towards their application to study eco-evolutionary dynamics, but so far individual heterogeneity has largely been ignored. Here, we present a general demographic framework that incorporates individual heterogeneity in a flexible way, by separating static and dynamic traits (discrete or continuous). First, we apply the framework to derive the consequences of ignoring heterogeneity for a range of widely used demographic outputs. A general conclusion is that besides the long-term growth rate lambda, all parameters can be affected. Second, we discuss how the framework can help advance current demographic models of eco-evolutionary dynamics, by incorporating individual heterogeneity. For both applications numerical examples are provided, including an empirical example for pike. For instance, we demonstrate that predicted demographic responses to climate warming can be reversed by increased heritability. We discuss how applications of this demographic framework incorporating individual heterogeneity can help answer key biological questions that require a detailed understanding of eco-evolutionary dynamics.
Project description:Phylogenetic trees for the four extant species of African hominoids are presented, based on mtDNA control region-1 sequences from 1,158 unique haplotypes. We include 83 new haplotypes of western chimpanzees and bonobos. Phylogenetic analysis of this enlarged database, which takes intraspecific geographic variability into account, reveals different patterns of evolution among species and great heterogeneity in species-level variation. Several chimpanzee and bonobo clades (and even single social groups) have retained substantially more mitochondrial variation than is seen in the entire human species. Among the 811 human haplotypes, those that branch off early are predominantly but not exclusively African. Neighbor joining trees provide strong evidence that eastern chimpanzee and human clades have experienced reduced effective population sizes, the latter apparently since the Homo sapiens-neanderthalensis split. Application of topiary pruning resolves ambiguities in the phylogenetic tree that are attributable to homoplasies in the data set. The diverse patterns of mtDNA sequence variation seen in today's hominoid taxa probably reflect historical differences in ecological plasticity, female-biased dispersal, range fragmentation over differing periods of time, and competition among social groups. These results are relevant to the origin of zoonotic diseases, including HIV-1, and call into question some aspects of the current taxonomic treatment and conservation management of gorillas and chimpanzees.