Mechanisms of tissue and cell-type specificity in heritable traits and diseases

Hundreds of heritable traits and diseases that are caused by germline aberrations in ubiquitously expressed genes manifest in a remarkably limited number of cell types and tissues across the body. Unravelling mechanisms that govern their tissue-specific manifestations is critical for our understanding of disease aetiologies and may direct efforts to develop treatments. Owing to recent advances in high-throughput technologies and open resources, data and tools are now available to approach this enigmatic phenomenon at large scales, both computationally and experimentally. Here, we discuss the large prevalence of tissue-selective traits and diseases, describe common molecular mechanisms underlying their tissue-selective manifestation and present computational strategies and publicly available resources for elucidating the molecular basis of their genotype-phenotype relationships. The pathology of heritable human traits and diseases often affects a narrow range of tissues, even when causal genes are expressed widely across the body. In this Review, Hekselman and Yeger-Lotem discuss the latest understanding of tissue specificity in human traits and disease, including the diverse underlying molecular mechanisms, experimental and bioinformatics resources to leverage omics data, and implications for understanding disease aetiology.