PaperPlayer biorxiv bioinformatics

Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.09.15.298281v1?rss=1

Authors: Shevtsova, N. A., Ha, N. T., Rybak, I. A., Dougherty, K. J.

Abstract:

The mechanisms involved in generation of rhythmic locomotor activity in the mammalian spinal cord remain poorly understood. These mechanisms supposedly rely on both intrinsic properties of constituting neurons and interactions between them. A subset of Shox2 neurons was found to contribute to generation of spinal locomotor activity. The preceding study (Ha and Dougherty, 2018) revealed the presence of bidirectional electrical coupling between these neurons in neonatal spinal cords, which can be critically involved in neuronal synchronization and generation of populational bursting. Gap junctional connections found between functionally-related Shox2 interneurons decrease with age, possibly being replaced by increasing interactions through chemical synapses. Here, we developed a computational model of a population of these neurons sparsely connected by electrical or/and chemical synapses and investigated the dependence of frequency of populational bursting on the type and strength of neuronal interconnections. The model provides important insights into the mechanisms of the locomotor rhythm generation.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.09.16.299453v1?rss=1

Authors: Staritzbichler, R., Sarti, E., Yaklich, E., Stamm, M., Aleksandrova, A., Khafizov, K., Forrest, L. R.

Abstract:

The alignment of primary sequences is a fundamental step in the analysis of protein structure, function, and evolution. Integral membrane proteins pose a significant challenge for such sequence alignment approaches, because their evolutionary relationships can be very remote, and because a high content of hydrophobic amino acids reduces their complexity. Frequently, biochemical or biophysical data is available that informs the optimum alignment, for example, indicating specific positions that share common functional or structural roles. Currently, if those positions are not correctly aligned by a standard pairwise alignment procedure, the incorporation of such information into the alignment is typically addressed in an ad hoc manner, with manual adjustments. However, such modifications are problematic because they reduce the robustness and reproducibility of the alignment. An alternative approach is the use of restraints, or anchors, to incorporate such position-matching explicitly during alignment. Here we introduce position anchoring in the alignment tool AlignMe as an aid to pairwise sequence alignment of membrane proteins. Applying this approach to realistic scenarios involving distantly-related and low complexity sequences, we illustrate how the addition of even a single anchor can dramatically improve the accuracy of the alignments, while maintaining the reproducibility and rigor of the overall alignment.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.09.16.299495v1?rss=1

Authors: Hart, R., Prlic, A.

Abstract:

Motivation Access to biological sequence data, such as genome, transcript, or protein sequence, is at the core of many bioinformatics analysis workflows. The National Center for Biotechnology Information (NCBI), Ensembl, and other sequence database maintainers provide methods to access sequences through network connections. For many users, the convenience and currency of remotely managed data are compelling, and the network latency is non-consequential. However, for high-throughput and clinical applications, local sequence collections are essential for performance, stability, privacy, and reproducibility. Results Here we describe SeqRepo, a novel system for building a local, high-performance, non-redundant collection of biological sequences. SeqRepo enables clients to use primary database identifiers and several digests to identify sequences and sequence alises. SeqRepo provides a native Python interface and a REST interface, which can run locally and enables access from other programming languages. SeqRepo also provides an alternative REST interface based on the GA4GH refget protocol. SeqRepo provides fast random access to sequence slices. We provide results that demonstrate that a local SeqRepo sequence collection yields significant performance benefits of up to 1300-fold over remote sequence collections. In our use case for a variant validation and normalization pipeline, SeqRepo improved throughput 50-fold relative to use with remote sequences. SeqRepo may be used with any species or sequence type. Regular snapshots of Human sequence collections are available. It is often convenient or necessary to use a computed digest as a sequence identifier. For example, a digest-based identifier may be used to refer to proprietary reference genomes or segments of a graph genome, for which conventional identifiers will not be available. Here we also introduce a convention for the application of the SHA-512 hashing algorithm with Base64 encoding to generate URL-safe identifiers. This convention, sha512t24u, combines a fast digest mechanism with a space-efficient representation that can be used for any object. Our report includes an analysis of timing and collision probabilities for sha512t24u. SeqRepo enables clients to use sha512t24u as identifiers, thereby seamlessly integrating public and private sequence sets. Availability SeqRepo is released under the Apache License 2.0 and is available on github and PyPi. Docker images and database snapshots are also available. See https://github.com/biocommons/biocommons.seqrepo .

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.09.16.299339v1?rss=1

Authors: Zhu, J., Ren, H., Zhong, H., Li, X., Zou, Y., Han, M., Li, M., Madsen, L., Kristiansen, K., Xiao, L.

Abstract:

High-quality and comprehensive reference gene catalogs are essential for metagenomic research. The rather low diversity of samples used to construct existing catalogs of mouse gut metagenomes limits the size and numbers of identified genes in existing catalogs. We therefore established an expanded gene catalog of genes in the mouse gut metagenomes (EMGC) containing >5.8 million genes by integrating 88 newly sequenced samples, 86 mouse-gut-related bacterial genomes and 3 existing gene catalogs. EMGC increases the number on non-redundant genes by more than one million genes compared to the so far most extensive catalog. More than 50% of the genes in EMGC were taxonomically assigned and 30% were functionally annotated. 902 Metagenomic species (MGS) assigned to 122 taxa are identified based on the EMGC. The EMGC-based analysis of samples from groups of mice originating from different animal providers, housing laboratories and genetic strains substantiated that diet is a major contributor to differences in composition and functional potential of the gut microbiota irrespective of differences in environment and genetic background. We envisage that EMGC will serve as an efficient and resource-saving reference dataset for future metagenomic studies in mice.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.09.14.296970v1?rss=1

Authors: Alm, E. J., Dai, C. L., Zhao, S., Lu, Z., evans, e.

Abstract:

An individual's microbiome consists of a diverse set of bacterial strains that encode rich information on its colonization and evolutionary history. Here, we introduce a versatile and straightforward reference-based strain tracking approach (StrainTrack) that determines whether distinct metagenomes carry closely-related strains based on gene presence and absence profiles. We show that StrainTrack can predict whether two metagenomes originate from the same donor via counting the number of species sharing closely-related strains, achieving >96% specificity, and ~100% sensitivity. When applied to the metagenomes of adult twins in the TwinsUK registry, we identify six cases of closely-related strains carried by both twins, potentially over decades of colonization.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.09.14.296418v1?rss=1

Authors: Conard, A. M., Goodman, N., Hu, Y., Perrimon, N., Singh, R., Lawrence, C., Larschan, E.

Abstract:

Uncovering how transcription factors (TFs) regulate their targets at the DNA, RNA and protein levels over time is critical to define gene regulatory networks (GRNs) in normal and diseased states. RNA-seq has become a standard method to measure gene regulation using an established set of analysis steps. However, none of the currently available pipeline methods for interpreting ordered genomic data (in time or space) use time series models to assign cause and effect relationships within GRNs, are adaptive to diverse experimental designs, or enable user interpretation through a web-based platform. Furthermore, methods which integrate ordered RNA-seq data with transcription factor binding data are urgently needed. Here, we present TIMEOR (Trajectory Inference and Mechanism Exploration with Omics data in R), the first web-based and adaptive time series multi-omics pipeline method which infers the relationship between gene regulatory events across time. TIMEOR addresses the critical need for methods to predict causal regulatory mechanism networks between TFs from time series multi-omics data. We used TIMEOR to identify a new link between insulin stimulation and the circadian rhythm cycle. TIMEOR is available at https://github.com/ashleymaeconard/TIMEOR.git.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.09.14.296590v1?rss=1

Authors: Chang, C.-H., Yeung, D., Spicer, V., Krokhin, O. V., Ishihama, Y.

Abstract:

The contribution of peptide amino-acid sequence to collision cross-section values (CCS) has been investigated using a dataset of ~134,000 peptides of four different charge states (1+ to 4+). The migration data was acquired using a two-dimensional LC/trapped ion mobility spectrometry/quadrupole/time-of-flight MS analysis of HeLa cell digests created using 7 different proteases and was converted to CCS values. Following the previously reported modeling approaches using intrinsic size parameters (ISP), we extended this methodology to encode the position of individual residues within a peptide sequence. A generalized prediction model was built by dividing the dataset into 8 groups (four charges for both tryptic/non-tryptic peptides). Position dependent ISPs were independently optimized for the eight subsets of peptides, resulting in prediction accuracy of ~0.981 for the entire population of peptides. We find that ion mobility is strongly affected by the peptide's ability to solvate the positively charged sites. Internal positioning of polar residues and proline leads to decreased CCS values as they improve charge solvation; conversely, this ability decreases with increasing peptide charge due to electrostatic repulsion. Furthermore, higher helical propensity and peptide hydrophobicity result in preferential formation of extended structures with higher than predicted CCS values. Finally, acidic/basic residues exhibit position dependent ISP behaviour consistent with electrostatic interaction with the peptide macro-dipole, which affects the peptide helicity.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.09.14.293522v1?rss=1

Authors: Briand, S., Dessimoz, C., El-Mabrouk, N., Nevers, Y.

Abstract:

Comparing trees is a basic task for many purposes, and especially in phylogeny where different tree reconstruction tools may lead to different trees, likely representing contradictory evolutionary information. While a large variety of pairwise measures of similarity or dissimilarity have been developed for comparing trees with no information on internal nodes, very few measures have been designed for node labeled trees, which is for instance the case of reconciled gene trees. Recently, we proposed a formulation of the Labeled Robinson Foulds (LRF) edit distance with edge extensions, edge contractions between identically labeled nodes, and node label flips. However, this distance (the size of a most parsimonious path of such events transforming one node-labeled tree into the other) proved difficult to compute, in particular, because "good" edges, i.e. edges present in the two trees, may have to be contracted. Here, we report on a different formulation of the LRF edit distance --- based on node insertion, deletion, and label substitution --- comparing two node-labeled trees, which we show can be computed in linear time. The new formulation also maintains other desirable properties: being a metric, reducing to Robinson Foulds for unlabeled trees, and maintaining an intuitive interpretation. The new distance is computable for an arbitrary number of label types, thus making it useful for applications involving not only speciations and duplications, but also horizontal gene transfers and further events associated with the internal nodes of the tree. To illustrate the utility of the new distance, we use it to study the impact of taxon sampling on labeled gene tree inference and conclude that denser taxon sampling yields better trees.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.09.14.296392v1?rss=1

Authors: Sabban, S. S.

Abstract:

Due to the increased hygienic life style of the developed world allergy is an increasing disease. Once allergy develops, sufferers are permanently trapped in a hyper immune response that makes them sensitive to innocuous substances. This paper discusses the strategy and protocol employed which designed proteins displaying a human IgE motif very close in proximity to the IgE's Fc{epsilon}RI receptor binding site. The motif of interest was the FG motif and it was excised and grafted onto the protein scaffold 1YN3. The new structure (scaffold + motif) was fixed-backbone sequence designed around the motif to find an amino acid sequence that would fold to the designed structure correctly. Ten computationally designed proteins showed successful folding when simulated using the AbinitioRelax folding simulation and the IgE epitope was clearly displayed in its native three dimensional structure in all of them. Such a designed protein has the potential to be used as a pan anti-allergy vaccine by guiding the immune system towards developing antibodies against this strategic location on the body's own IgE molecule, thus neutralising it and presumably permanently shutting down a major aspect of the Th2 immune pathway.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.09.14.296939v1?rss=1

Authors: Freyman, W. A., McManus, K. F., Shringarpure, S. S., Jewett, E. M., Bryc, K., Auton, A.

Abstract:

Estimating the genomic location and length of identical-by-descent (IBD) segments among individuals is a crucial step in many genetic analyses. However, the exponential growth in the size of biobank and direct-to-consumer (DTC) genetic data sets makes accurate IBD inference a significant computational challenge. Here we present the templated positional Burrows-Wheeler transform (TPBWT) to make fast IBD estimates robust to haplotype and phasing errors. Using haplotype data simulated over pedigrees with realistic genotyping and phasing errors we show that the TPBWT outperforms other state-of-the-art IBD inference algorithms in terms of speed and accuracy. For each phase-aware method, we explore the false positive and false negative rates of inferring IBD by segment length and characterize the types of error commonly found. Additionally we compare the performance of the TPBWT against a widely used phase-free IBD inference approach that is robust to phasing errors. We introduce both in-sample and out-of-sample TPBWT-based IBD inference algorithms and demonstrate their computational efficiency on massive-scale datasets with millions of samples. Furthermore we describe a binary file format for TPBWT-compressed haplotypes that results in fast and efficient out-of-sample IBD computes against very large cohort panels. Finally, we demonstrate the utility of the TPBWT in a brief empirical analysis exploring geographic patterns of haplotype sharing within Mexico. Hierarchical clustering of IBD shared across regions within Mexico reveals the geographic structure of Mexico's rich genetic diversity. Our software implementation of the TPBWT is freely available in the code repository https://github.com/23andMe/phasedibd.

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