Stanford MoTrPAC Bioinformatics Center

摘要 控制SARS-CoV-2感染和相关的致病过程需要了解宿主和 病毒遗传学因素驱动疾病结果。该研究旨在描述基因组流行病学特征， 严重急性呼吸道综合征冠状病毒2（SARS冠状病毒2，或SARS-CoV-2），并定义宿主 基因对病毒感染结果的影响我们将全基因组测序1,000个COVID-19阳性 患者在斯坦福大学卫生保健作为这项研究的一部分。斯坦福大学医院和诊所 试验了一种用于病毒和宿主基因组联合检测的稳健且可重复的下一代测序检测方法。 来自ICU患者的319份鼻拭子样本和15份血沉棕黄层的初步试验表明，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。在这些拭子中， 我们获得了180个病毒的全基因组序列319宿主的遗传谱系分析 基因组显示，西班牙裔/拉丁美洲人、太平洋岛民和其他高危人群的比例过高， 这是我们和其他人在病例中看到的种族差异。在这个项目中，我们将 额外的样本，使我们的总数达到1,000个COVID-19阳性样本，包括住院，门诊， 重症和危重症患者。我们将在未来12个月内扩大这个项目，并跟踪感染，严重， 危重和康复患者，以描述疾病严重程度从轻度到重度到重度的多组学特征 病危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， NP拭子，我们希望从中回收足够的遗传物质，以表征宿主基因组， 估算质量。我们还将描述宿主遗传祖先和背景多基因风险评分， 一系列相关的特征一组100个同期COVID-19阴性样本也将被测序， 对照和治疗人群背景血统的比较。同时，我们将收集DTC 从不同的人口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拭子中获得。我们将充分表征每个样本的SARS-CoV-2基因组， 并检测拭子样本中的合并感染。我们的目标是了解检测极限的 技术，对复制病毒动力学的影响，以及表征SARS-CoV-2中的选择性剪接 基因组在感染过程中的变化。完成这里概述的目标将试点下一代 在北方加州监测SARS-CoV-2宿主和病毒遗传学的测序， 在世界各地复制。这对于防备第二波疫情和检测合并感染至关重要 在那些感染了SARS-CoV-2的人中， 于二零二零年下半年及以后期间，疫情持续。

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.