Gene balance hypothesis: connecting issues of dosage sensitivity across biological disciplines

Abstract

We summarize, in this review, the evidence that genomic balance influences gene expression, quantitative traits, dosage compensation, aneuploid syndromes, population dynamics of copy number variants and differential evolutionary fate of genes after partial or whole-genome duplication. Gene balance effects are hypothesized to result from stoichiometric differences among members of macromolecular complexes, the interactome, and signaling pathways. The implications of gene balance are discussed.

Fig. 1.

Effect of genomic imbalance on quantitative phenotypic characteristics in maize. (A) From left to right, this series of plants is haploid, haploid plus the long arm of chromosome 1 (1L), one copy of 1L, two copies of 1L, and three copies of 1L in an otherwise diploid background. (B and C) Analogous genotypes for the short arm of chromosomes 5 (5S) and 9 (9S), respectively. A meter stick is included for scale. These examples include one of the longer (1L) and one of the shorter (9S) chromosome arms in the maize genome and illustrate that similar imbalance phenomena occur for all tested arms. The addition of a chromosome arm to a haploid plant produces a much greater impact on the phenotype than adding the same arm to an otherwise diploid plant, illustrating the concept of genomic balance. Dosage manipulation of chromosome arms is made using translocations with the supernumerary B chromosome (10, 11), and haploids are produced using an inducer line (12). The dosage and ploidy were determined by metaphase chromosome spreads of root tips, and then, the classified seedlings were grown into plants in the greenhouse. Photographs by Fangpu Han.

Fig. 2.

Diagrammatic representation of the types of effects observed for gene expression in aneuploids. The x axis depicts the chromosomal dosage. The y axis depicts the percentage of expression in the aneuploid compared with the diploid. (A) A gene dosage effect occurs when the structural gene produces a proportional amount of product to its copy number. (B) There are also direct transacting effects, in which a gene is modulated in expression in direct correlation with a different chromosomal dosage. (C) Another transacting modulation is the inverse dosage effect, in which the expression of a target gene is inversely correlated with the dosage of another chromosomal region. (D) Dosage compensation occurs when the expression of a structural gene does not change with its dosage. Dosage compensation results when an inverse dosage effect of an aneuploid region includes, among its target genes, those genes that are also on the varied chromosome. The two effects, structural gene and inverse, combined together cancel to produce nearly equal expression in all chromosomal doses. Modified from Birchler (13).

Fig. 3.

Heuristic examples of stoichiometric imbalance in the context of a trimer A-B-A. For simplicity, we consider that the assembly of ABA is random and irreversible. (A) Normal condition with a particular stoichiometric balance between the molar amounts of A and B. (B) Halving the amount of monomer A leads to a decrease of trimer yield, because there is not enough of A to complete the reaction. (C) Increasing the relative amount of B leads to a decrease of ABA for the same reasons. The molar ratio of each condition is indicated.