The advent of next-generation sequencing (NGS) is revolutionizing biology and medicine and is rapidly becoming a standard tool for investigation. Recognizing the tremendous potential of NGS, Yale University establish the Yale Center for Genome Analysis (YCGA) in 2009. YCGA has led the development of a new genome center model, focusing on a centralized facility with the highest standards of innovation, data production and analysis, but which is open access to the community rather than having projects selected by an oversight group. This scalable model has provided broad access to NGS, which has spurred innovation and eliminated barriers to experimentation by new users. By virtue of its substantial contribution to technology development for data production and analysis, accompanied by high profile scientific discoveries and success in competing for NIH funding, YCGA has emerged as one of the leading genome centers in the country. High-performance computation is indispensable for NGS operation. YCGA produces an average of more than 30 terabases of sequence data per month, necessitating infrastructure for data storage, analysis and interpretation. YCGA’s current dedicated HPC instrumentation has served more than 1,000 users from 327 institutions/departments as well as many non-Yale investigators, and is making an enormous contribution to biomedicine (since 2015 published >500 research articles including, >70 publications in Science, Nature, Cell, N Engl J Med) reporting new genes contributing to autism, cardiovascular disease, cancer, and congenital diseases of the heart and brain, as well as fundamental advances in understanding of enhancer function, mechanisms of microRNA formation, and mechanisms of evolutionary change. YCGA's dedicated compute cluster and storage is predominantly 6 years old and near the end of its productive life. This architecture must be replaced and upgraded if YCGA is to continue to serve its users. The requested HPC instrumentation will increase computational capacity to match growing demand, will greatly improve data storage and networking, and will reduce the power and cooling requirements. The strengths of this proposal include; (1) an efficient and effective centralized facility serving an extremely diverse, large and productive mostly NIH funded investigator user base; (2) the demonstrated ability of YCGA to effectively integrate cutting edge data production and analysis for the benefit of hundreds of NIH funded Yale and non-Yale researchers, (3) and the extensive infrastructure and expertise that is available to bring the requested instrumentation online and to oversee its continuous use. Yale University has made a major investment in capital and institutional talent to build a first-rate infrastructure that has proven highly successful. The requested instrumentation will be highly leveraged upon this existing infrastructure ensuring that it will be of high value and broad impact on NIH supported biomedical and bas...