The Gene Balance Hypothesis: From Classical Genetics to Modern Genomics

Abstract

The concept of genetic balance traces back to the early days of genetics. Additions or subtractions of single chromosomes to the karyotype (aneuploidy) produced greater impacts on the phenotype than whole-genome changes (ploidy). Studies on changes in gene expression in aneuploid and ploidy series revealed a parallel relationship leading to the concept that regulatory genes exhibited a stoichiometric balance, which if upset, would modulate target gene expression. The responsible regulatory genes for these types of effects primarily have been found to be members of signal transduction pathways or transcription factors of various types. Recent studies of retention of selected duplicate genes following diploidization of ancient polyplodization events have found that signal transduction and transcription factors have been preferentially maintained in a dosage-sensitive relationship. In this essay, we review the historical progression of ideas about genetic balance and discuss some challenges in this field for the future. Chromosomal Imbalance. Diagrammatic representation of chromosome variations with the varied chromosome shown in enlarged form. Full or partial monosomics with only one copy of a chromosome or chromosomal segment are usually more severely affected than haploid plants. Trisomic plants with an extra chromosome often show a greater morphological change from the diploid than observed in polyploid plants, such as tetraploids. Secondary trisomics carrying an isochromosome composed of two copies of a chromosome arm show enhanced phenotypic changes for some characteristics typical of the corresponding primary trisomic. When an isochromosome is recovered in an otherwise haploid plant, the imbalance is most severe and results in highly defective plants (Satina et al., 1937). These relationships led to the concept of genetic balance. As this work continued, trisomics were found for all of the possible 12 chromosomes of Datura, but additional forms continued to arise, each with different characteristics. Some of these new forms accentuated a portion of the phenotypic characteristics of the original set of primary trisomics but were missing other changes from the normal diploid. The basis of these forms was revealed to be an extra chromosome that possessed two identical chromosome arms derived from misdivision of the centromere, manifested by a break in the middle of a centromere with fusion of two sister chromatids, to produce mirror image chromosomes (isochromosomes) generated from a single chromosome arm (Belling and Blakeslee, 1924). In these cases, the extra chromosome, called a secondary trisome, would result in a total of four copies of the respective arm, thus providing an explanation for the accentuated partial phenotype compared with the respective trisomic from which it was derived (Figure 1). These results bolstered the concept that a balance of genes was important for the normal phenotype. These and other aneuploid types were summarized in an article entitled “New Jimson Weeds from Old Chromosomes” (Blakeslee, 1934), which cryptically conveys the message that the dosage of chromosomes is important in this case as opposed to genetic variation. Indeed, the more extreme the altered relative dosage of chromosomes, the greater the phenotypic change. This concept is aptly illustrated by the recovery of selected isochromosomes in otherwise haploid plants that had an extreme imbalance and severe phenotype (Satina et al., 1937) (Figure 1). At about the same time as the early studies of Datura were conducted by Blakeslee, Richard Goldschmidt was studying the basis of sex determination in the gypsy moth (Lymantria dispar) (Goldschmidt, 1920). Crosses between different geographic isolates produced progeny that had differing levels of intersexuality, which is a mixture of male and female morphologies. To explain the various results, Goldschmidt hypothesized different male and female factors of varying strengths whose balance was critical for proper sex determination. Within a particular geographic isolate, the sex determination processes are normal, but crosses between different strains produced the intersexual individuals because the various factors had varied in dosage potential between the diverged populations and were no longer matched. In retrospect, this result foreshadowed the concept of Muller-Dobzhansky coevolving gene complexes that interact within a species but cause sterility or inviability in hybrids. In further parallel studies, Calvin Bridges identified a triploid female Drosophila and among her progeny found intersexual flies that possessed a mixture of male and female parts (Bridges, 1925). The karyotype of these intersexual flies was composed of two X chromosomes with an otherwise triploid complement of chromosomes. However, flies with only one X chromosome that were otherwise triploid were male-like in phenotype. Of course, among diploid flies, the males have one X chromosome and the femal