PROJECT SUMMARY The Baylor College of Medicine Genomic Center for Infectious Diseases (GCID) proposal seeks to provide a comprehensive, large scale genomics program for NIAID with the goal of enhancing our understanding of host and microbiome interactions related to infectious disease genomics. In this TMC-GCID renewal proposal, the Sequencing Analysis and Resource Dissemination (SARD) Core will deliver most cost effective and efficient ways to generate high quality metagenomic and transcriptomic data, and genome assemblies for the four TMC- GCID research projects: Bacteria, Virus, Fungi, and Parasite. The SARD Core brings together sequencing and analytical expertise in human genetics and large-scale genomics from the Human Genome Sequencing Center (HGSC) with microbial, viral, and metagenomics experience from the Alkek Center for Metagenomics and Microbiome Research (CMMR). Large heterogeneous datasets will be generated, evaluated, and characterized using new and proven sequencing and analytical methods to further our understanding of how polymorphisms (host or microbe) contribute to mechanisms of pathogenesis. Advances in high-throughput next generation sequencing (NGS) such as the development of viral capture enrichment pipelines, host RNA-Seq have facilitated studies of the microbiome and host susceptibility genetics. Advances in long-read sequencing contribute to higher quality full-length parasite and bacterial genome assemblies; the bacterial reference genome datasets have facilitated establishment of competitive infection studies (SUMMIT) among closely related strains. New approaches, such as single cell RNA sequencing, have enabled a more discrete examination of the cellular response to infection and the transduction of signals from an infected cell to adjacent cells. In the current proposal, we will continue to advance the existing NGS applications, while also leveraging new sequencing technologies such as PacBio Revio to deliver long read assemblies at lower cost, support MAS-ISO-seq to deliver full-length transcripts and isoforms. The Oxford Nanopore (ONT) platform will enable novel sequencing applications for low biomass samples (e.g. ONT Adaptive sampling). While new sequencing platforms (e.g. Element AVITI) or new methodology, e.g. MERFISH for single cell spatial transcriptomics and the antibody- based Olink platform for targeted protein profiling, will be evaluated for their use across our research projects. Multiple cost reduction strategies are also proposed. The SARD Core will be responsible for supporting the program by managing sample tracking via LIMS, data management, data analysis and data dissemination and focus on bioinformatic tool developments that seek to optimize existing protocols, as well as create new workflows in response to new sequencing technologies and molecular techniques. All resulting data and tools will be made available to the wider GCID and NIAID scientific community.