Stanford MoTrPAC Bioinformatics Center

摘要 控制SARS-CoV-2感染和相关致病过程需要了解宿主和 病毒遗传因素决定了疾病的结局。这项研究旨在描述基因组流行病学的特征 严重急性呼吸综合征冠状病毒2型(SARS冠状病毒2，或SARS-CoV-2)，并定义宿主 基因对病毒感染结局的影响。我们将对1000名新冠肺炎阳性的人进行全基因组测序 斯坦福卫生保健中心的患者作为这项研究的一部分。斯坦福大学医院和诊所有 试行了一种强大且可重复的下一代测序试验，用于病毒和宿主基因组的联合检测。 对ICU患者的319个鼻拭子样本和15件淡黄色大衣的初步试验表明，我们能够 提取、测序和分析所有鼻拭子上的低通宿主基因组和RNAseq数据。在这些棉签中， 我们能够从180个基因组中获得完整的病毒基因组序列。319寄主的遗传谱系分析 基因组显示，拉美裔/拉丁裔、太平洋岛民和其他高危人群的比例过高， 重述我们和其他人在案例中看到的种族差距。在这个项目中，我们将按顺序 额外样本使我们的新冠肺炎阳性样本总数达到1,000个，包括住院患者、门诊患者、 重病和危重病人。我们将在未来12个月内扩大这个项目的规模，并跟踪感染、严重、 危重和康复患者，以表征疾病严重程度从轻微到严重的多组学特征 病得很重。这将通过两个目标来实现。第一个目标集中在宿主基因测序上， NP拭子，我们希望在那里恢复足够的遗传物质来表征宿主基因组到高 归责质量。我们还将表征宿主的遗传祖先和背景多基因风险分数 一系列相关的特征。一组100个同时期的新冠肺炎阴性样本也将被测序为 治疗人群中背景血统的对照和比较。同时，我们将收集DTC 从不同的人群样本中获得遗传数据。我们的第二个目标是病毒基因组数据 从NP拭子中提取的。我们将充分描述每个样本中SARS-CoV-2基因组的特征 有可能，并在拭子样本中检测到混合感染。我们的目标是了解病毒的检测极限 技术、对复制病毒动力学的影响以及SARS-CoV-2的选择性剪接特征 基因组在感染过程中的变化。完成这里列出的目标将是下一代的试点 可用于监测北加州SARS-CoV-2宿主和病毒遗传学的测序 在世界各地复制。这对于第二波的准备和检测联合感染至关重要。 在感染SARS-CoV-2的人中，并对紧急跟踪 2020年下半年及以后的大流行。

ABSTRACT Control of SARS-CoV-2 infection and related pathogenic processes requires an understanding of how host and viral genetics factors drive disease outcome. The study is designed to characterize the genomic epidemiology of severe acute respiratory syndrome coronavirus 2 (SARS coronavirus 2, or SARS-CoV-2) and define host genetic effects on the outcome of viral infection. We will whole-genome sequence 1,000 COVID-19 positive patients at Stanford Health Care as part of this research study. Stanford University Hospitals and Clinics has piloted a robust and reproducible next-generation sequencing assay for joint viral and host genome detection. An initial pilot of 319 nasal swab samples and 15 Buffy coats from ICU patients demonstrates we are able to extract, sequence and analyze low pass host genomes and RNAseq data on all nasal swabs. Of these swabs, we were able to obtain full viral genome sequences from 180. Genetic ancestry analysis of the 319 host genomes shows overrepresentation of Hispanic/Latinos, Pacific Islanders, and other at-risk populations, recapitulating the ethnic disparity we and others have seen among cases. In this project, we will sequence additional samples to bring our total to 1,000 COVID-19 positive samples including inpatient, outpatient, severe, and critically ill patients. We will scale this project over the next 12 months and follow infected, severe, critical, and recovered patients to characterize the multiomic profile of disease severity from mild to severe to critically ill. This will be accomplished through two Aims. The first aim focuses on host genetic sequencing from NP swabs where we expect to recover sufficient genetic material to characterize the host genome to high imputation quality. We will also characterize host genetic ancestry and background polygenic risk score for a host of related traits. A set of 100 contemporaneous COVID-19 negative samples will also be sequenced as controls and comparison for background ancestry in the treatment population. In parallel we will collect DTC derived genetic data from a diverse population sample. Our second aim focuses on the virus genome data obtained from NP swabs. We will fully characterize as much of the SARS-CoV-2 genome per sample as possible and detect co-infections in the swab sample. Our goal is to understand the limit of detection for the technology, impact on reproducing viral dynamics, and characterizing alternative splicing in the SARS-CoV-2 genome over the time course of infection. Completion of the Aims outlined here will pilot Next Generation Sequencing for surveillance of SARS-CoV-2 host and viral genetics in Northern California that can be replicated across the world. This is critical for preparedness of a second wave and detecting co-infections among those infected with SARS-CoV-2 and contributes significantly to the emergency tracking of the pandemic during the second half of 2020 and beyond.