Leveraging biochemical reactions to unravel functional impacts of cancer somatic variants affecting protein interaction interfaces [version 3; peer review: 2 approved]

Background: Considering protein mutations in their biological context is essential for understanding their functional impact, interpretation of high-dimensional datasets and development of effective targeted therapies in personalized medicine. Methods: We combined the curated knowledge of biochemical reactions from Reactome with the analysis of interaction-mediating 3D interfaces from Mechismo. In addition, we provided a software tool for users to explore and browse the analysis results in a multi-scale perspective starting from pathways and reactions to protein-protein interactions and protein 3D structures. Results: We analyzed somatic mutations from TCGA, revealing several significantly impacted reactions and pathways in specific cancer types. We found examples of genes not yet listed as oncodrivers, whose rare mutations were predicted to affect cancer processes similarly to known oncodrivers. Some identified processes lack any known oncodrivers, which suggests potentially new cancer-related processes (e.g. complement cascade reactions). Furthermore, we found that mutations perturbing certain processes are significantly associated with distinct phenotypes (i.e. survival time) in specific cancer types (e.g. PIK3CA centered pathways in LGG and UCEC cancer types), suggesting the translational potential of our approach for patient stratification. Our analysis also uncovered several druggable processes (e.g. GPCR signalling pathways) containing enriched reactions, providing support for new off-label therapeutic options. Conclusions: In summary, we have established a multi-scale approach to study genetic variants based on protein-protein interaction 3D structures. Our approach is different from previously published studies in its focus on biochemical reactions and can be applied to other data types (e.g. post-translational modifications) collected for many types of disease

Spatially resolved star formation and inside-out quenching in the TNG50 simulation and 3D-HST observations

We compare the star-forming main sequence (SFMS) of galaxies – both integrated and resolved on 1 kpc scales – between the high-resolution TNG50 simulation of IllustrisTNG and observations from the 3D-HST slitless spectroscopic survey at z ∼ 1. Contrasting integrated star formation rates (SFRs), we find that the slope and normalization of the star-forming main sequence in TNG50 are quantitatively consistent with values derived by fitting observations from 3D-HST with the Prospector Bayesian inference framework. The previous offsets of 0.2–1 dex between observed and simulated main-sequence normalizations are resolved when using the updated masses and SFRs from Prospector. The scatter is generically smaller in TNG50 than in 3D-HST for more massive galaxies with M*> 1010 M⊙, by ∼10–40 per cent, after accounting for observational uncertainties. When comparing resolved star formation, we also find good agreement between TNG50 and 3D-HST: average specific star formation rate (sSFR) radial profiles of galaxies at all masses and radii below, on, and above the SFMS are similar in both normalization and shape. Most noteworthy, massive galaxies with M*> 1010.5 M⊙, which have fallen below the SFMS due to ongoing quenching, exhibit a clear central SFR suppression, in both TNG50 and 3D-HST. In contrast, the original Illustris simulation and a variant TNG run without black hole kinetic wind feedback, do not reproduce the central SFR profile suppression seen in data. In TNG, inside-out quenching is due to the supermassive black hole (SMBH) feedback model operating at low accretion rates

A crowdsourced analysis to identify ab initio molecular signatures predictive of susceptibility to viral infection

The response to respiratory viruses varies substantially between individuals, and there are currently no known molecular predictors from the early stages of infection. Here we conduct a community-based analysis to determine whether pre- or early post-exposure molecular factors could predict physiologic responses to viral exposure. Using peripheral blood gene expression profiles collected from healthy subjects prior to exposure to one of four respiratory viruses (H1N1, H3N2, Rhinovirus, and RSV), as well as up to 24 h following exposure, we find that it is possible to construct models predictive of symptomatic response using profiles even prior to viral exposure. Analysis of predictive gene features reveal little overlap among models; however, in aggregate, these genes are enriched for common pathways. Heme metabolism, the most significantly enriched pathway, is associated with a higher risk of developing symptoms following viral exposure. This study demonstrates that pre-exposure molecular predictors can be identified and improves our understanding of the mechanisms of response to respiratory viruses

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

A crowdsourced analysis to identify ab initio molecular signatures predictive of susceptibility to viral infection

The response to respiratory viruses varies substantially between individuals, and there are currently no known molecular predictors from the early stages of infection. Here we conduct a community-based analysis to determine whether pre- or early post-exposure molecular factors could predict physiologic responses to viral exposure. Using peripheral blood gene expression profiles collected from healthy subjects prior to exposure to one of four respiratory viruses (H1N1, H3N2, Rhinovirus, and RSV), as well as up to 24 h following exposure, we find that it is possible to construct models predictive of symptomatic response using profiles even prior to viral exposure. Analysis of predictive gene features reveal little overlap among models; however, in aggregate, these genes are enriched for common pathways. Heme metabolism, the most significantly enriched pathway, is associated with a higher risk of developing symptoms following viral exposure. This study demonstrates that pre-exposure molecular predictors can be identified and improves our understanding of the mechanisms of response to respiratory viruses

A Method for Reference-Free Genome Assembly Quality Assessment

How to assess the quality of a genome assembly without the help of a reference sequence is an open question. Only a few techniques are currently used in the literature and each has obvious bias. An additional method, restriction enzyme associated DNA (RAD) marker alignment, is proposed here. With high enough density, this method should be able to assess the quality of de novo assemblies without the biases of current methods. With the growing ambition to sequence new genomes and the accelerating ability to do so cost effectively, methods to assess the quality of reference-free genome assemblies will become increasingly important. In addition to the existing methods of EST and conserved sequence alignment, RAD marker alignment may contribute to this effort

joshuaburkhart/FIOncoNet: Initial Pre-Release

using network comparison techniques to understand oncogenic mutation