Congratulations to Dr. Noah Zaitlen on a new R01 titled, "Rarely Common: Uncovering the dominant role of rare variants in the genetic architecture of complex human traits". The vast majority of human mutations have minor allele frequencies (MAF) under 1%, with the plurality observed only once (i.e., “singletons”). While Mendelian diseases are predominantly caused by rare alleles, the cumulative contribution of rare variants to produce complex phenotypes remains hotly debated. In this proposal, they (Hernandez, Ahituv, Torgerson, Zaitlen) will perform high-throughput functional validation of ultrarare variants on human gene expression. They will model how the genetic architecture of gene expression varies across tissues and across populations (with an emphasis on understudied minority populations). They will then expand our inference to complex diseases to improve the utility of genetics in biomedical studies across diverse populations.