UCSF

Background: Genome-wide association studies have identified numerous disease-associated variants, but a vast majority are located in non-coding regions, making it challenging to understand their functional impact. This complexity necessitates new techniques to identify causal variants in non-coding regions and elucidate their specific cellular contexts and mechanisms of action. Here we present work i) examining mutations that create nullomers in the human genome to explore its potential utility in identifying pathogenic mutations and ii) a single-cell multi-omic study identifying the transcriptome and regulome of the human and mouse hypothalamus to identify regulatory regions of obesity-associated variants.Methods: (i) We generated all possible mutations of the human genome that can lead to emergence of a nullomer, and examine where in the genome they emerge. (ii) We apply single-cell RNA and ATAC sequencing to adult hypothalamus samples. Results and Conclusions: (i) Our findings highlight CpG hypermutability and methylated cytosines as key elements leading to resurfacing of nullomers in individuals. We also showcase that nullomers can have applications in disease annotation and pathogenic variant identification. (ii) We identified regulatory elements of hypothalamus cell types and mapped obesity-associated variants to cell-type specific peaks. We validated these regions to be enhancers using CRISPR editing and CRISPRi.