ABSTRACT
The UK Biobank genotyped about 500k participants using Applied Biosystems Axiom microarrays. Participants were subsequently sequenced by the UK Biobank Exome Sequencing Consortium. Axiom genotyping was highly accurate in comparison to sequencing results, for almost 100,000 variants both directly genotyped on the UK Biobank Axiom array and via whole exome sequencing. However, in a study using the exome sequencing results of the first 50k individuals as reference (truth), it was observed that the positive predictive value (PPV) decreased along with the number of heterozygous array calls per variant. We developed a novel addition to the genotyping algorithm, Rare Heterozygous Adjusted (RHA), to significantly improve PPV in variants with minor allele frequency below 0.01%. The improvement in PPV was roughly equal when comparing to the exome sequencing of 50k individuals, or to the more recent ~200k individuals. Sensitivity was higher in the 200k data. The improved calling algorithm, along with enhanced quality control of array probesets, significantly improved the positive predictive value and the sensitivity of array data, making it suitable for the detection of ultra-rare variants.
Subject(s)
Exome , High-Throughput Nucleotide Sequencing , Humans , Genotype , High-Throughput Nucleotide Sequencing/methods , Retrospective Studies , Biological Specimen Banks , Polymorphism, Single Nucleotide , Algorithms , United KingdomABSTRACT
Physics-based simulation is needed to understand the function of biological structures and can be applied across a wide range of scales, from molecules to organisms. Simbios (the National Center for Physics-Based Simulation of Biological Structures, http://www.simbios.stanford.edu/) is one of seven NIH-supported National Centers for Biomedical Computation. This article provides an overview of the mission and achievements of Simbios, and describes its place within systems biology. Understanding the interactions between various parts of a biological system and integrating this information to understand how biological systems function is the goal of systems biology. Many important biological systems comprise complex structural systems whose components interact through the exchange of physical forces, and whose movement and function is dictated by those forces. In particular, systems that are made of multiple identifiable components that move relative to one another in a constrained manner are multibody systems. Simbios' focus is creating methods for their simulation. Simbios is also investigating the biomechanical forces that govern fluid flow through deformable vessels, a central problem in cardiovascular dynamics. In this application, the system is governed by the interplay of classical forces, but the motion is distributed smoothly through the materials and fluids, requiring the use of continuum methods. In addition to the research aims, Simbios is working to disseminate information, software and other resources relevant to biological systems in motion.
ABSTRACT
We present a computational method that predicts a pathway of residues that mediate protein allosteric communication. The pathway is predicted using only a combination of distance constraints between contiguous residues and evolutionary data. We applied this analysis to find pathways of conserved residues connecting the myosin ATP binding site to the lever arm. These pathway residues may mediate the allosteric communication that couples ATP hydrolysis to the lever arm recovery stroke. Having examined pre-stroke conformations of Dictyostelium, scallop, and chicken myosin II as well as Dictyostelium myosin I, we observed a conserved pathway traversing switch II and the relay helix, which is consistent with the understood need for allosteric communication in this conformation. We also examined post-rigor and rigor conformations across several myosin species. Although initial residues of these paths are more heterogeneous, all but one of these paths traverse a consistent set of relay helix residues to reach the beginning of the lever arm. We discuss our results in the context of structural elements and reported mutational experiments, which substantiate the significance of the pre-stroke pathways. Our method provides a simple, computationally efficient means of predicting a set of residues that mediate allosteric communication. We provide a refined, downloadable application and source code (on https://simtk.org) to share this tool with the wider community (https://simtk.org/home/allopathfinder).
