A look at the preparation and utility of organic pentafluorosulfanyl-containing compounds is presented. Topics discussed include the chemistry of aliphatic SF5 compounds and access to aromatic SF5 ...compounds.
The sensitivity of massively-parallel sequencing has confirmed that most cancers are oligoclonal, with subpopulations of neoplastic cells harboring distinct mutations. A fine resolution view of this ...clonal architecture provides insight into tumor heterogeneity, evolution, and treatment response, all of which may have clinical implications. Single tumor analysis already contributes to understanding these phenomena. However, cryptic subclones are frequently revealed by additional patient samples (e.g., collected at relapse or following treatment), indicating that accurately characterizing a tumor requires analyzing multiple samples from the same patient. To address this need, we present SciClone, a computational method that identifies the number and genetic composition of subclones by analyzing the variant allele frequencies of somatic mutations. We use it to detect subclones in acute myeloid leukemia and breast cancer samples that, though present at disease onset, are not evident from a single primary tumor sample. By doing so, we can track tumor evolution and identify the spatial origins of cells resisting therapy.
TP53 mutated acute myeloid leukemia (AML) responds poorly to chemotherapy and has a short overall survival rate with a median of 5–9 months. Poor outcomes in TP53 mutated AML following chemotherapy ...have been observed and treatment options remain limited, although the presence of TP53 mutations alone should not be a barrier to therapy. Decitabine is emerging as an alternative treatment option for patients with TP53 mutated AML, although the agent has not been associated with deep molecular remissions and requires additional consolidation. The clinical and genomic characteristics of TP53 mutated AML are reviewed in this paper.
Structured populations, and replicated zones of contact between species, are an ideal opportunity to study regions of the genome with unusual levels of differentiation; and these can illuminate the ...genomic architecture of species isolation, and the spread of adaptive alleles across species ranges. Here, we investigated the effects of gene flow on divergence and adaptation in the Mytilus complex of species, including replicated parental populations in quite distant geographical locations. We used target enrichment sequencing of 1269 contigs of a few kb each, including some genes of known function, to infer gene genealogies at a small chromosomal scale. We show that geography is an important determinant of the genomewide patterns of introgression in Mytilus and that gene flow between different species, with contiguous ranges, explained up to half of the intraspecific outliers. This suggests that local introgression is both widespread and tends to affect larger chromosomal regions than purely intraspecific processes. We argue that this situation might be common, and this implies that genome scans should always consider the possibility of introgression from sister species, unsampled differentiated backgrounds, or even extinct relatives, for example Neanderthals in humans. The hypothesis that reticulate evolution over long periods of time contributes widely to adaptation, and to the spatial and genomic reorganization of genetic backgrounds, needs to be more widely considered to make better sense of genome scans.
Intracellular endosymbiotic bacteria are found in many terrestrial arthropods and have a profound influence on host biology. A basic question about these symbionts is why they infect the hosts that ...they do, but estimating symbiont incidence (the proportion of potential host species that are actually infected) is complicated by dynamic or low prevalence infections. We develop a maximum-likelihood approach to estimating incidence, and testing hypotheses about its variation. We apply our method to a database of screens for bacterial symbionts, containing more than 3600 distinct arthropod species and more than 150 000 individual arthropods. After accounting for sampling bias, we estimate that 52% (CIs: 48–57) of arthropod species are infected with Wolbachia, 24% (CIs: 20–42) with Rickettsia and 13% (CIs: 13–55) with Cardinium. We then show that these differences stem from the significantly reduced incidence of Rickettsia and Cardinium in most hexapod orders, which might be explained by evolutionary differences in the arthropod immune response. Finally, we test the prediction that symbiont incidence should be higher in speciose host clades. But while some groups do show a trend for more infection in species-rich families, the correlations are generally weak and inconsistent. These results argue against a major role for parasitic symbionts in driving arthropod diversification.
Emerging viral diseases are often the product of a host shift, where a pathogen jumps from its original host into a novel species. Phylogenetic studies show that host shifts are a frequent event in ...the evolution of most pathogens, but why pathogens successfully jump between some host species but not others is only just becoming clear. The susceptibility of potential new hosts can vary enormously, with close relatives of the natural host typically being the most susceptible. Often, pathogens must adapt to successfully infect a novel host, for example by evolving to use different cell surface receptors, to escape the immune response, or to ensure they are transmitted by the new host. In viruses there are often limited molecular solutions to achieve this, and the same sequence changes are often seen each time a virus infects a particular host. These changes may come at a cost to other aspects of the pathogen's fitness, and this may sometimes prevent host shifts from occurring. Here we examine how these evolutionary factors affect patterns of host shifts and disease emergence.
Research aimed at understanding the geographic context of evolutionary histories is burgeoning across biological disciplines. Recent endeavors attempt to interpret contemporaneous genetic variation ...in the light of increasingly detailed geographical and environmental observations. Such interest has promoted the development of phylogeographic inference techniques that explicitly aim to integrate such heterogeneous data. One promising development involves reconstructing phylogeographic history on a continuous landscape. Here, we present a Bayesian statistical approach to infer continuous phylogeographic diffusion using random walk models while simultaneously reconstructing the evolutionary history in time from molecular sequence data. Moreover, by accommodating branch-specific variation in dispersal rates, we relax the most restrictive assumption of the standard Brownian diffusion process and demonstrate increased statistical efficiency in spatial reconstructions of overdispersed random walks by analyzing both simulated and real viral genetic data. We further illustrate how drawing inference about summary statistics from a fully specified stochastic process over both sequence evolution and spatial movement reveals important characteristics of a rabies epidemic. Together with recent advances in discrete phylogeographic inference, the continuous model developments furnish a flexible statistical framework for biogeographical reconstructions that is easily expanded upon to accommodate various landscape genetic features.
It is now common for population geneticists to estimate FST for a large number of loci across the genome, before testing for selected loci as being outliers to the FST distribution. One surprising ...result of such FST scans is the often high proportion (>1% and sometimes >10%) of outliers detected, and this is often interpreted as evidence for pervasive local adaptation. In this issue of Molecular Ecolog, Fourcade et al. () observe that a particularly high rate of FST outliers has often been found in river organisms, such as fishes or damselflies, despite there being no obvious reason why selection should affect a larger proportion of the genomes of these organisms. Using computer simulations, Fourcade et al. () show that the strong correlation in co‐ancestry produced in long one‐dimensional landscapes (such as rivers, valleys, peninsulas, oceanic ridges or coastlines) greatly increases the neutral variance in FST, especially when the landscape is further reticulated into fractal networks. As a consequence, outlier tests have a high rate of false positives, unless this correlation can be taken into account. Fourcade et al.'s study highlights an extreme case of the general problem, first noticed by Robertson (,b) and Nei & Maruyama (), that correlated co‐ancestry inflates the neutral variance in FST when compared to its expectation under an island model of population structure. Similar warnings about the validity of outlier tests have appeared regularly since then but have not been widely cited in the recent genomics literature. We further emphasize that FST outliers can arise in many different ways and that outlier tests are not designed for situations where the genetic architecture of local adaptation involves many loci.
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