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Nature Papers Examine Factors Affecting Mutation Detection, Map of Development, Sequencer Performance

An examination of how aspects of the sequencing and analysis process can influence efforts to detect cancer mutations in clinical samples is reported in Nature Biotechnology this week, highlighting the need for reproducibility and accuracy in precision oncology. While the falling costs of next-generation sequencing have led to a rise in the technology's use in the clinic, no bulk sequencing study has yet addressed the effects of cross-site reproducibility or weighed the biological, technical, and computational factors that influence variant identification. An international team led by scientists from the US Food and Drug Administration and Fudan University interrogated somatic mutations in paired tumor/normal cell lines to identify factors affecting detection reproducibility and accuracy at six different centers. Using both whole-genome sequencing and whole-exome sequencing, the investigators evaluated the reproducibility of different sample types with varying input amounts, tumor purity, and multiple library construction protocols, followed by processing with nine bioinformatics pipelines. They find that read coverage and callers affected both WGS and WES reproducibility, but WES performance was influenced by insert fragment size, genomic copy content, and the global imbalance score. "Because these samples were prepared from a pair of well-characterized, renewable tumor/normal cell lines from the same donor, our results can serve as a reference for the NGS research community when performing benchmarking studies for the development of new NGS products, assays, and informatics tools," the study's authors write. They also provide recommendations regarding DNA fragmentation for WES runs, selection of NGS platforms, and bioinformatics tools based on the nature of available biosamples and study objectives. Such recommendations, they say, can improve the reproducibility and accuracy of NGS for cancer mutation detection.

An overview of the Human Developmental Cell Atlas (HDCA), which aims to create a comprehensive map of cells during development as part of the Human Cell Atlas, is presented in this week's Nature. Like the Human Genome Project, the HDCA will integrate the output from a growing community of scientists who are mapping human development into a unified atlas, the members of the project write. The investigators describe their early milestones and their use of human stem-cell-derived cultures, organoids, and animal models to inform the HDCA, especially for prenatal tissues that are hard to acquire. They also set out future plans and describe the challenges facing the initiative.

A study benchmarking the performance of common sequencing instruments is published in Nature Biotechnology this week by members of the Association of Biomolecular Resource Facilities. The study focuses on a range of instruments including ones from Illumina, Thermo Fisher Scientific, Pacific Biosciences, and Oxford Nanopore using human and bacterial reference DNA samples. "This study serves as a benchmark for current genomics technologies, as well as a resource to inform experimental design and next-generation sequencing variant calling," the researchers write.