Yale Center for Genome Analysis (YCGA) has been providing cutting-edge next-generation sequencing services using both Illumina short read (SR) and PacBio long read (LR) technologies to support the fundamental research needs of hundreds of Yale and non-Yale NIH-funded investigators. By virtue of its substantial contribution to technology development, breakthrough scientific discoveries, and success in competing for NIH funding, YCGA has emerged as one of the leading genome centers in the world. YCGA has been offering LR sequencing (LRS) services to its users using PacBio RS II system since 2011. During the last 8 years, its use increased by 19-fold, providing more than 1,400 services annually at 80% of the equipment’s capacity. It was used by more than 363 investigators, which resulted in 48 high profile publications. Since February 2019, our RS II system is broken, and repair is prohibitively expensive, hindering our invaluable support to scientific progress. For YCGA to continue to serve the need of its ever-increasing number of users, the current RS II must be replaced with its latest version, the PacBio Sequel II sequencer. Fifty-seven investigators from 6 institutions support our request for funding PacBio Sequel II sequencer, with apt justifications. They propose to use the Sequel II LRS system to study roles of structural variants, full-length transcripts/isoforms, and epigenetic changes in psychiatric, cardiovascular, skin, infectious diseases and cancer. Although Illumina technology is highly successful in detecting single nucleotide variants, its short reads pose several challenges in detecting afore mentioned genetic/epigenetic variations. Studies have shown that unlike its competitor Oxford Nanopore, the PacBio Sequel II provides excellent quality reads with >99.99 % consensus accuracy, which is critical for these applications. Moreover, the requested equipment is cost-effective and has sufficient throughput to support the projects cited in this application and beyond, in supporting the needs of the growing number of investigators wanting to use this cost-effective, cutting-edge technology. The strengths of this proposal include; (1) an efficient and effective centralized facility serving an extremely diverse and productive investigator user base; (2) the extensive experience of the PI (3) the demonstrated ability of YCGA to effectively integrate cutting edge data production and analysis for the benefit of hundreds of Yale and non-Yale researchers, and (4) the extensive infrastructure and expertise that is available to bring the requested instrumentation on-line and to oversee its continuous use. Yale University has made a major investment in capital and institutional talent to build the world-class genomic center that has proven highly successful. The requested instrumentation will leverage the infrastructure to ensure its high value and broad impact on NIH-funded biomedical and basic research within and beyond the Yale community.