Prof. LI Xin's group from the Shanghai Institute of Nutrition and Health of the Chinese Academy of Sciences constructed a gene dosage constraint map from large human transcriptome biobanks. The dosage map uncovers a mechanistic link between Mendelian inheritance and homeostasis of biological systems. The study was published in American Journal of Human Genetics on August 23. 

Why Mendelian diseases have dominant vs. recessive modes is a long-standing question in genetics. A comprehensive understanding of gene dosage constraint is critical in answering this question. Previous knowledge of dosage constraint was mainly based on loss-of-function mutations or copy number variations in human populations, which is underpowered due to ultra-rareness of such mutations.   

Prof. LI's group draw insights from widespread transcriptome (RNA) variation among human populations and utilize cis-regulatory variants (which instruct the transcription of DNA to RNA) to construct an RNA based map of gene dosage sensitivity (named MoDs) across human tissues. This new map more directly reflects dosage constraints of genes under physiological conditions.   

Based on the new dosage map, the group further explored functional implications of dosage constraints, and discovered that negative feedback for maintaining homeostasis is the major force shaping dosage sensitivity. Genes differ in dosage sensitivity because of their different roles in negative feedback axes where signaling genes (transcription factor, protein kinase, ion-channel and cellular machinery) are dosage sensitive, while effector genes (metabolic enzyme, transporter, cytokine and receptor) are dosage tolerant.   

MoDs can help better understand pathogenic modes of inheritance (dominance vs. recessiveness), and infer which tissues may be affected by a genetic mutation. By identifying effector vs. signaling components along negative feedback axes, MoDs can further inform underlying homeostasis mechanism of human diseases and guide the development of effective therapeutics.