Identifying the phenotypic effect of nucleotide substitutions in non-coding regions is a recognized challenge in functional genomics and human genetics. Our contribution to these research questions is two-fold: one is the experimental validation of the computational annotations of non-coding variants. We have developed experimental and computational methods for biallelic high-throughput reporter gene assays and electrophoretic mobility gel shift assays (Kalita et al, Bioinformatics, 2017; Kalita et al, 2018, Genome Res). Our second contribution is participation in the development of statistical and computational methods to predict the function of non-coding variants (Wen et al 2015, 2016, 2017). Once we have identified functional non-coding variants in the human genome, we use population genetics analyses to understand their evolutionary relevance (Moyerbrailean et al, 2016, PLoS Genetics).