AmplificationTimeR: an R package for timing sequential amplification events.

MOTIVATION: Few methods exist for timing individual amplification events in regions of focal amplification. Current methods are also limited in the copy number states that they are able to time. Here we introduce AmplificationTimeR, a method for timing higher level copy number gains and inferring the most parsimonious order of events for regions that have undergone both single gains and whole genome duplication. Our method is an extension of established approaches for timing genomic gains. RESULTS: We can time more copy number states, and in states covered by other methods our results are comparable to previously published methods. AVAILABILITY AND IMPLEMENTATION: AmplificationTimer is freely available as an R package hosted at https://github.com/Wedge-lab/AmplificationTimeR.

APOBEC3 mutational signatures are associated with extensive and diverse genomic instability across multiple tumour types.

BACKGROUND: The APOBEC3 (apolipoprotein B mRNA editing enzyme catalytic polypeptide 3) family of cytidine deaminases is responsible for two mutational signatures (SBS2 and SBS13) found in cancer genomes. APOBEC3 enzymes are activated in response to viral infection, and have been associated with increased mutation burden and TP53 mutation. In addition to this, it has been suggested that APOBEC3 activity may be responsible for mutations that do not fall into the classical APOBEC3 signatures (SBS2 and SBS13), through generation of double strand breaks.Previous work has mainly focused on the effects of APOBEC3 within individual tumour types using exome sequencing data. Here, we use whole genome sequencing data from 2451 primary tumours from 39 different tumour types in the Pan-Cancer Analysis of Whole Genomes (PCAWG) data set to investigate the relationship between APOBEC3 and genomic instability (GI). RESULTS AND CONCLUSIONS: We found that the number of classical APOBEC3 signature mutations correlates with increased mutation burden across different tumour types. In addition, the number of APOBEC3 mutations is a significant predictor for six different measures of GI. Two GI measures (INDELs attributed to INDEL signatures ID6 and ID8) strongly suggest the occurrence and error prone repair of double strand breaks, and the relationship between APOBEC3 mutations and GI remains when SNVs attributed to kataegis are excluded.We provide evidence that supports a model of cancer genome evolution in which APOBEC3 acts as a causative factor in the development of diverse and widespread genomic instability through the generation of double strand breaks. This has important implications for treatment approaches for cancers that carry APOBEC3 mutations, and challenges the view that APOBECs only act opportunistically at sites of single stranded DNA.

nandb-number and brightness in R with a novel automatic detrending algorithm.

SUMMARY: An R package for performing number and brightness image analysis, with the implementation of a novel automatic detrending algorithm. AVAILABILITY AND IMPLEMENTATION: Available at https://github.com/rorynolan/nandb for all platforms. CONTACT: rnolan@well.ox.ac.uk or spadilla@well.ox.ac.uk. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Author Correction: A dynamic three-step mechanism drives the HIV-1 pre-fusion reaction.

In the version of this article initially published, the label above the top right plot in Fig. 3b (HXB2-Alexa Fluor 488) was incorrect. The correct label is 'HXB2-Alexa Fluor 405'. The error has been corrected in the HTML and PDF versions of the article.

A dynamic three-step mechanism drives the HIV-1 pre-fusion reaction.

Little is known about the intermolecular dynamics and stoichiometry of the interactions of the human immunodeficiency virus type 1 (HIV-1) envelope (Env) protein with its receptors and co-receptors on the host cell surface. Here we analyze time-resolved HIV-1 Env interactions with T-cell surface glycoprotein CD4 (CD4) and C-C chemokine receptor type 5 (CCR5) or C-X-C chemokine receptor type 4 (CXCR4) on the surface of cells, by combining multicolor super-resolution localization microscopy (direct stochastic optical reconstruction microscopy) with fluorescence fluctuation spectroscopy imaging. Utilizing the primary isolate JR-FL and laboratory HXB2 strains, we reveal the time-resolved stoichiometry of CD4 and CCR5 or CXCR4 in the pre-fusion complex with HIV-1 Env. The HIV-1 Env pre-fusion dynamics for both R5- and X4-tropic strains consists of a three-step mechanism, which seems to differ in stoichiometry. Analyses with the monoclonal HIV-1-neutralizing antibody b12 indicate that the mechanism of inhibition differs between JR-FL and HXB2 Env. The molecular insights obtained here identify assemblies of HIV-1 Env with receptors and co-receptors as potential novel targets for inhibitor design.

On the Whereabouts of HIV-1 Cellular Entry and Its Fusion Ports.

HIV-1 disseminates to diverse tissues through different cell types and establishes long-lived reservoirs. The exact cellular compartment where fusion occurs differs depending on the cell type and mode of viral transmission. This implies that HIV-1 may modulate a number of common host cell factors in different cell types. In this review, we evaluate recent advances on the host cell factors that play an important role in HIV-1 entry and fusion. New insights from restriction factors inhibiting virus-cell fusion in vitro may contribute to the development of future therapeutic interventions. Collectively, novel findings underline the need for potent, host-directed therapies that disrupt the earliest stages of the virus life cycle and preclude the emergence of resistant viral variants.