Fig. 1.

Various types of dosage sensitivity. Dosage sensitivity can be due to any of several different mechanisms. a For some proteins there is a minimum amount of active product required for normal function (haploinsufficiency). A hemizygous deletion or other loss of function allele will reduce the amount of active product below the threshold for functionality. b Some proteins form inappropriate interactions at high concentration, such as protein aggregation. These aggregates may themselves be toxic, or may phenocopy a deletion by removing the proteins from availability. c Dosage-balanced genes have constrained relative stoichiometry, for example the ratio of gp6 protein to gp7 protein in phage HK97 must be correct in order to achieve correct protein complex assembly. If gp6 is present in excess it preferentially forms large homomers, thus becoming unavailable to form the complex with gp7. d A simplified, hypothetical example of concentration-dependent activity based on the splicing of pyruvate kinase M, where the concentration of the splicing regulator determines its location of binding, which in turn determines which isoform is produced. Panel d is a modified from [25]