Agafonov, O. | bioRxiv Science

bioRxiv2020

Accuracy and efficiency of germline variant calling pipelines for human genome data

Advances in next-generation sequencing technology has enabled whole genome sequencing (WGS) to be widely used for identification of causal variants in a spectrum of genetic-related disorders, and provided new insight into how genetic polymorphisms affect disease phenotypes. The development of different bioinformatics pipelines has continuously improved the variant analysis of WGS data, however there is a necessity for a systematic performance comparison of these pipelines to provide guidance on the application of WGS-based scientific and clinical genomics. In this study, we evaluated the performance of three variant calling pipelines (GATK, DRAGEN and DeepVariant) using Genome in a Bottle Consortium, "synthetic-diploid" and simulated WGS datasets. DRAGEN and DeepVariant show a better accuracy in SNPs and indels calling, with no significant differences in their F1-score. DRAGEN platform offers accuracy, flexibility and a highly-efficient running speed, and therefore superior advantage in the analysis of WGS data on a large scale. The combination of DRAGEN and DeepVariant also provides a good balance of accuracy and efficiency as an alternative solution for germline variant detection in further applications. Our results facilitate the standardization of benchmarking analysis of bioinformatics pipelines for reliable variant detection, which is critical in genetics-based medical research and clinical application.

bioinformatics↗

bioRxiv2018

Homeostatic Controllers Compensating for Growth and Perturbations

Cells and organisms have developed homeostatic mechanisms to maintain internal stabilities which protect them against a changing environment. How cellular growth and homeostasis interact is still not well understood, but of increasing interest to the synthetic and molecular biology community where molecular control circuits are sought and tried to maintain homeostasis that opposes the diluting effects of cell growth. In this paper we describe the performance of four negative feedback (inflow) controllers, which, for different observed growth laws (time-dependent increase in the cellular volume V) are able to compensate for various time-dependent removals of the controlled variable A. The four implementations of integral control are based on zero-order, first-order autocatalytic, second-order (antithetic), and derepressing inhibition kinetics. All controllers behave ideal in the sense that they for step-wise perturbations in V and A are able to drive the controlled variable precisely back to the controllers theoretical set-point [Formula] The applied increase in cellular volume includes linear, exponential and saturating growth and reflect experimentally observed growth laws of single cell organisms and other cell types. During the increase in V, additional linear or exponential time-dependent perturbations which remove A are applied, and controllers are tested with respect to their ability to compensate for both the increase in volume V and the applied perturbations removing A. Our results show that the way how integral control is kinetically implemented and the structure of the negative feedback loop are essential determinants of a controllers performance. The results provide a ranking between the four tested controller types. Considering exponential volume increases together with an exponentially increasing removal rate of A controllers based on derepression kinetics perform best, but break down when the control-inhibitors concentration gets too low. The first-order autocatalytic controller is able to defend time-dependent exponential growth and removals in A, but generally with a certain offset below its theoretical set-point [Formula] The controllers based on zero-order and second-order (antithetic) integral feedback can only manage linear increases in V and removals in A, in dependence of the controllers aggressiveness. Our results provide a theoretical basis what controller kinetics are needed in order to compensate for different growth laws.

biophysics↗