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Proc Natl Acad Sci U S A. Sep 11, 2012; 109(37): 14746–14753.
Published online Aug 20, 2012. doi:  10.1073/pnas.1207726109
PMCID: PMC3443177
Inaugural Article
Genetics

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.

The concept of gene dosage balance arose in the early days of the field of genetics, with the work by Blakeslee et al. (1) using the flowering plant Datura stramonium and the work by Bridges (2) using the fruit fly Drosophila melanogaster. Both studies found that the addition of a single chromosome to a genotype was highly detrimental or lethal, whereas the addition of a complete genome to make a polyploid was viable and resulted in lesser effects on the phenotype. The work on Datura was greatly extended to include four copies of each chromosome arm and multiple whole genomes (3, 4). Subsequently, related principles governing aneuploidy, with some differences, were found throughout eukaryotes (57). More recently, the removal of chromosomes to produce monosomic genotypes shows that there are quite severe phenotypic effects compared with the haploid, which has only one copy of every chromosome (8, 9).

This principle is illustrated in Fig. 1. Maize genotypes were produced that were diploid with one, two, or three doses of representative chromosome arms as well as haploids plus the chromosome arm in question all in a highly similar genetic background. For all three chromosome arms examined, it was clear that addition of a chromosome to the diploid has much less severe effect than addition of a chromosome to a haploid. However, the removal of one of two chromosome arms is also more severe than the reduction in ploidy from diploid to haploid. The doubling of a mere chromosome arm in a haploid leads to a deformity, whereas doubling the whole genome leads to a normal diploid. These comparisons illustrate that the relative dosage of chromosomal segments is critical for normal development and phenotypic characteristics.

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 ...

Extending this relationship to the molecular level, the studies by Birchler (10) and Birchler and Newton (11) found that expression patterns of enzyme and protein levels were modulated more in aneuploid genotypes than with changes in ploidy. The work by Birchler and Newton (11) suggested that a perturbation of stoichiometric relationships of regulatory gene products was a contributor to the effects of genomic imbalance and played a role in these transacting dosage effects on gene expression.

The modulations are both positive and negative depending on the gene, tissue, or chromosomal region studied (11, 12). Although most modulations are within direct or inverse limits between the expression level and the chromosomal dose (Fig. 2), some greater modulations occur. A common dosage effect on gene expression found in aneuploids was an inverse correlation of gene product with the copy number of an unlinked chromosomal region (i.e., an inverse dosage effect) (1012). In other words, monosomics for a particular chromosome arm would modulate the expression of unlinked genes to an upper limit of approximately twofold, whereas the corresponding trisomic would reduce the same gene product to about two-thirds of the amount in the balanced diploid with two copies of all chromosomal regions (Fig. 2). The amount of any one target gene product could be modulated by multiple regions of the genome. This effect is quite common in the data for trisomic segments in other species. including Datura, barley, Arabidopsis, Drosophila, and human trisomic cells (1332). The ability to recover corresponding monosomics in maize facilitated the finding that this effect can be proportional through one, two, and three doses.

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 ...

Furthermore, the combination of a region of the genome that produces an inverse dosage effect on a particular gene product together with the gene encoding that product could result in dosage compensation (Fig. 2). In this case, despite the fact that the gene was varied in one to three copies, the total output realized was more or less constant in the chromosome arm dosage series (10, 11). By dividing the varied chromosome arm into smaller segments and assaying gene expression, the basis of this type of dosage compensation was shown to involve a combination of an inverse dosage effect cancelling a structural gene dosage effect (33). Specifically, the structural gene locus in a smaller segment exhibited a proportional dosage effect, and another region of the larger aneuploid produced an inverse dosage effect. Similar cases of dosage compensation were found for chromosome arm trisomics in Drosophila in the work by Devlin et al. (34). The work by Birchler et al. (35) showed in Drosophila that the basis of this effect also involved the combination of a structural gene dosage effect and an inverse effect operating simultaneously, and it documented the effect on the mRNA level (35). Because an inverse effect may regularly occur on variation of many genomic segments, dosage compensation can also regularly occur when a regulator and a target gene are varied together. The inverse effect can cause compensation of different target genes regardless of the level of activity, because the effect involves a relative stoichiometric relationship of the varied segment to the remainder of the genome, which will be the same for all target genes.

The work by Rabinow et al. (36) tested whether the aneuploid effects on gene expression could be reduced to the action of single genes. Various leaky alleles of the white eye color gene in Drosophila were used as phenotypic reporters to screen for second site modifiers that, when heterozygous, would increase or decrease the expression within a twofold range. The first such mutation found increased the expression of the white eye color gene approximately twofold as a heterozygote and thus, would mimic a monosomic situation on the single gene level. When a small aneuploid region around this gene was present in three copies, the expression of white was reduced to about two-thirds of the normal diploid. In contrast, the eye color of diploid and triploid flies was similar. The introduction of these mutations into a triploid background causes an ~50% increase in expression, thus conforming to an inverse relationship for genomic balance. The effect was first found on the phenotypic level and then documented in some developmental stages on the mRNA level.

The work by Sabl and Birchler (37) surveyed the autosomes of Drosophila for phenotypic dosage-sensitive modifiers of the white eye color gene. Earlier, in studies of X chromosome dosage compensation, the work by Muller (38) described evidence for multiple X-linked dosage-sensitive modifiers of white. In these studies, segments of the genome were found that modulated the expression of white either positively or negatively and illustrated that multiple aneuploid regions could affect the phenotype of a single trait. More regions were found to modulate white negatively compared with those that positively affect white. The work by Birchler (39) found that the dosage of the whole X chromosome produced an inverse dosage effect on the phenotypic expression of white when it was deleted from its normal location on the X chromosome and was present as a transgene on the autosomes, although the up-regulation in normal males with one X chromosome was not a full twofold effect. These phenotypic studies also illustrate the multigenic nature of these modulating effects. However, variation of the whole genome in dosage produces a very similar phenotype in diploid and triploid flies (36), exhibiting little modulation and a proportional expression with ploidy.

The work by Guo and Birchler (12) documented aneuploid modulations of gene expression on the RNA level in maize and found that, in general, the magnitude of modulation was directly or inversely correlated with the degree of genomic imbalance. The work by Guo and Birchler (12) also noted the parallels between the multigenic additive control of quantitative phenotypic traits and the impact of multiple aneuploidies on the same quantitative characteristics. By comparing the effects in the diploid embryo of the maize kernel with the triploid endosperm, it was again found that the magnitude of modulations depended on the deviation of the chromosomal change from the balanced euploid. RNA measurements comparing whole-genome ploidy changes show fewer modulations (40).

The work by Birchler et al. (41) summarized the molecular nature of the known single gene dosage-sensitive modifiers of the white eye color gene in Drosophila that had been recovered over the course of two decades. The collection consisted of transcription factors, chromatin components, and members of signal transduction systems. Several other laboratories noted that transcription factors, tumor suppressor genes, and components of signal transduction are dosage-sensitive (4245). This realization was consistent with the fact that many transcription factors control developmental decisions in Drosophila in a concentration-dependent manner (4651), and the myriad of modifiers of position effect variegation are dosage-sensitive (52). Dosage sensitivity will operate through a cascade of regulatory steps, allowing many connected genes to affect any one process (41).

The gene dosage effects could potentially result simply from a change in concentration of a gene product in the cell, such as the change that occurs with changing the dosage of the most controlling step of biochemical pathways (53). However, there are several theoretical and experimental results that suggest an involvement of relative stoichiometric relationships for many dosage effects. The studies by Veitia (43, 44, 54) modeled the kinetics of assembly of macromolecular complexes to explain how changes in stoichiometry of the component members could produce a dominant phenotypic effect (43). In the context of a multisubunited complex, changing the amount of one subunit can shift the reaction to unproductive subcomplexes and produce a different amount of the complete complex (Fig. 3). The work by Papp et al. (55) examined heterozygous gene KOs in yeast and found a negative correlation between the involvement in macromolecular complexes and fitness. Increased gene copy number to the genome produced a similar effect, and selected co–up-regulation of interactors could correct each other. The work by Papp et al. (55) coined the term balance hypothesis.

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 ...

In molecular terms, dosage imbalance can be illustrated with the heuristic example of the trimeric factor A-B-A. If its assembly follows a random pathway, allowing the formation of intermediate species AB and BA before assembly of the complete A-B-A trimer, a decrease in the concentration of A can lead to a reduction of ABA yield. This result is the case, because at some point in the assembly reaction, A will become limiting during the production of AB and BA that will not yield trimers (Fig. 3). Subunit B will be limiting at low concentration but in excess, will cause a reduction in the ABA yield (43). Examples of this relationship have been noted (56). Thus, both positive and negative effects on the ABA yield will depend on the relative amount of B to A (57). This example illustrates that the relative amount of subunits entering the assembly reaction of a complex can affect the amount of functional product, which can have downstream genetic consequences.

The work by Liang et al. (58) compared the degree of protein underwrapping to the occurrence of gene duplicability across taxa. Protein underwrapping is the property of proteins to be penetrated by water molecules. With increasing protein–protein interactions, a greater level of underwrapping can be tolerated, because such interactions stabilize the relevant proteins. There is an overall negative correlation between the degree of underwrapping and the ability to survive as a gene duplicate in a wide range of taxa from bacteria to humans. This result suggests that, with a greater number of protein–protein interactions involved with macromolecular complexes, there are increasing negative fitness consequences of single gene duplication, which manifests as a stoichiometric imbalance.

The work by Schuster-Böckler et al. (59) examined this issue in a different manner. Using a protein domain database, a negative correlation was found between the number of protein–protein interaction domains that were present in a protein and its ability to be maintained as a copy number variant (CNV) in human populations. Also, the dosage-sensitive genes exhibited less expression variation among tissues and among individuals for the same tissue. These results also support the hypothesis that changing the stoichiometry of components of macromolecular complexes or the interactome will produce a dominant phenotypic effect that affects fitness.

The work by Lemos et al. (60) showed that the number of interactions of a protein (i.e., its connectivity) constrains genetic variation of its expression in yeast and fruit fly populations. Namely, they reported a negative correlation between the variation of gene expression and the number of protein–protein interactions. Moreover, the degree of expression variation among genes encoding interactors was smaller than the degree of expression variation of random gene pairs. Finally, the levels of expression of interactors displayed a positive correlation across strains.

Gene Balance Hypothesis

The experimental and theoretical findings involved with gene balance that are described above were formulated from phenotypic data, gene expression patterns in dosage manipulations, and identification of their underlying basis in dosage-sensitive regulatory genes. Connections were then made to interacting members of multisubunit complexes and their kinetics and mode of assembly. The principle can also be stated in reverse. The stoichiometry of members of multisubunit complexes can affect the amount of functional complete product, which in turn, affects patterns of gene expression (if the complex is regulatory) and ultimately, the phenotype and evolutionary fitness. Clearly, there are complicated processes involved in these steps that will impact the outcome, but the bulk of the data suggests this generalization, which has implications as outlined below.

Implications for Evolutionary Genomics

From a different perspective, the field of evolutionary genomics came to the realization that sequenced genomes, such as yeast and Arabidopsis, revealed the remnants of ancient whole-genome duplications (WGD) (6168). After these tetraploidization events, many genes were lost in a return to diploidy but in a nonrandom fashion depending on function. The classes of genes remaining for longer periods from the WGD were revealed to be those classes involved with macromolecular complexes in general, which include the ribosome (69) and proteasome and of note for the discussion here, transcription factors and components of signal transduction pathways (64, 7074). These classes of genes were similar to the dosage-sensitive modifiers of the white eye color gene in Drosophila (41). The implication is that deletion of one member of a duplicate pair of these classes would have a negative fitness effect and be selected against. Thus, the duplicate pair would be retained for longer periods of evolutionary time than other gene classes. The retained genes, in fact, show evidence of purifying selection in both duplicates (66, 75), which is consistent with a selection of maintenance of the stoichiometric relationship. The studies by Birchler et al. (53) and Freeling and Thomas (72) noted the relationship of these evolutionary results to classical studies of genomic balance, in that variation of part of the genome is more detrimental than variation of the whole genome.

A corollary of this concept is that segmental genomic duplications that include genes encoding members of macromolecular complexes would be underrepresented in genomes, because they would alter the stoichiometry of interacting genes. Studies in yeast, Arabidopsis, rice, poplar, and mammals (64, 67, 7680) reveal that this is the case. Furthermore, the study of copy number polymorphisms indicates an underrepresentation of CNVs of genes that are heavily connected in the interactome (8183). Thus, there are complementary patterns of classes of genes for those that are selected to survive longer after WGD vs. those that can survive in populations as segmental or CNVs.

For these relationships to occur, there must be a reasonable correlation between gene copy number and protein level expression. There are little data available on this point in multicellular organisms on the whole-genome level, but the work by Springer et al. (84) examined this point in baker’s yeast. By studying a collection of heterozygous gene KOs, the protein quantities were determined. In this study, only 5% of genes had little to no correlation between functional gene copy number and encoded protein abundance. For 80% of genes, there was a strong correlation between copy number and protein quantity. The role of protein degradation in the context of genomic balance has not been investigated.

The retention of some classes of genes for longer evolutionary periods than others is unlikely to be because of divergence of function or expression in most cases. There are several reasons for this conclusion. First, after WGDs, most duplicates eventually become reduced back to the singleton state. If the duplicates had diverged and acquired novel functions (neofunctionalization) or split functions (subfunctionalization) as the basis of longer retention, the remaining member of the pair would need to back-mutate to regain all functions, which is highly improbable. Second, as noted, the spectrum of genes generally found in segmental duplications is complementary to the spectrum retained after WGD. This circumstance is not predicted by the divergence hypothesis. Indeed, duplication by whole genome or segments would provide an equal opportunity for divergence, which does not explain the observed pattern (74). Despite these considerations, we do note that a subset of duplicate genes has certainly changed or split their functions as an important aspect of evolution when considering all classes of genes (85). The longer retention of duplicate pairs after WGD through gene balance might allow greater periods of evolutionary time to provide the opportunity for gradual divergence of dosage-sensitive genes, among them being those genes with critical regulatory functions. Also, over evolutionary time, the relative constraints on duplicate genes can shift to absolute constraints (86).

The eventual deterioration of the duplicate state of members of macromolecular complexes can be attributed to several factors recognized at present. First, for several cases of allopolyploidy, there is an overall difference in gene expression contributed by one or the other genome present (8791). When the two genomes are examined for the fraction of genes removed over evolutionary time, the genome with lesser expression has suffered a greater number of deletions (87, 9294). Deletion of a member of a balanced set of duplicates from the lesser expressed genome would be expected to have fewer detrimental effects than deletion for the more highly expressed genome. If there are insufficient detrimental effects of the deletion event on reproductive fitness, there will be no selection against it. Second, to the extent that there is an imperfect relationship of gene copy number and the encoded protein abundance in the cell, some deletions would be of little consequence. An intertwined consideration is that deletion of critical downstream target genes of transcription factors and signal transduction components might eventually modulate how the quantity of the regulatory complex is effective. Third, the role of microRNAs in affecting genomic balance is unknown but potentially important in terms of modulating the expression of transcription factors, because microRNAs can operate in a dosage-sensitive manner (95). Indeed, microRNAs from duplicate genomes in the grass family are preferentially retained from both genomes (96, 97) after WGD events, presumably because of their impact on the amount of regulatory proteins. Fourth, different subunits of a complex might have different magnitudes of dosage sensitivity, and also, selection on one member of the complex might affect the others (98). Modeling of the kinetics and mode of complex formation illustrates that changing the concentration of each subunit can behave differently (57). Also, the penetrance and expressivity of variants of highly connected gene products might affect their evolutionary outcome.

Implications for Chromosomal-Level Evolution

Genomic balance phenomena at the chromosomal level have been experimentally observed in polyploid plant species. Common wheat is an allopolyploid consisting of three genomes, each composed of seven chromosomes for a total of 21 homolog pairs. The work by Sears (99) generated a series of monosomics with only one copy of each homolog. In addition, because of the multiple genomes, the work by Sears (99) was also able to produce nullisomics for each homolog (i.e., having no copy of a chromosome). This condition is possible in wheat, because there are two other similar genomes present that provide the genes that are missing in the nullisomic. Each nullisomic has a characteristic detrimental phenotype. However, Sears (99) constructed plants that carried four copies of a related (homeologous) chromosome and was able to partially correct the abnormality associated with each nullisomic. These constructs were referred to as compensating nullisomic–tetrasomic lines.

This type of effect has been found to rebalance the genome in newly formed cases of whole-genome duplication (100). In resynthesized allotetraploid Brassica napus, chromosome segregation was not faithful in the first few generations, which produced many lineages exhibiting aneuploidy. With continuation through additional generations, the chromosome number resolved to the number typical of the balanced genome. However, when the chromosomes were examined using a karyotyping method that allows one to distinguish all chromosomes, many lineages were found in which four chromosomes from one diploid progenitor were present but no chromosomes from the other; also, there were equally balanced cases of three chromosomes of one genome and one chromosome of the other genome. In other words, compensating aneuploids were resolved that were similar to the experimentally derived cases in wheat.

A natural case of a rebalancing allopolyploid has been described for the genus Tragopogon (101). Newly formed allotetraploids have been documented in recent time because of the introduction of one contributing species to North America from Europe. Different cases of allopolyploid formation exhibit varying numbers of chromosomes from one diploid progenitor or the other, but they seldom have more than four of each chromosome, thus maintaining a genomic balance. The shift in the chromosomal complement between genomes might have an impact on the resolution of the WGD in divergent lineages because of different genetic variants being fixed on different chromosomes. This finding illustrates how genomic balance at this level might influence the evolutionary trajectory.

Implications for Human Disease

Although the concept of gene balance has been considered as a basis of aneuploidy syndromes, dosage sensitivity of the responsible genes would also impact other human medical conditions. There can be abnormal phenotypes that arise from the absence of one allele at a given locus (i.e., one-half of the normal amount of gene product is not sufficient to ensure a normal phenotype). This phenomenon is called haploinsufficiency when compatible with survival of the individual or haplolethality when it leads to death. There is a myriad of human genetic conditions involving mutations of transcription factors and signal transduction components that leads to haploinsufficiency (42, 43, 102).

The work by Pessia et al. (103) noted that the expression of genes encoding components of macromolecular complexes on the mammalian X chromosome is similar to the expression of autosomal genes encoding other members of the same complexes, suggesting selection to maintain their relative stoichiometry despite a difference in dosage between the X chromosome and the autosomes. The work by Pessia et al. (103) also suggested that X inactivation in female mammals evolved as a mechanism to maintain this similar relative expression. Pessia et al. (103) postulated the potential contribution of dosage-sensitive genes to X chromosomal aneuploid syndromes.

The work by Berger et al. (104) summarized the evidence that partial inactivation of tumor suppressor genes (very often by somatic mutation) can contribute to cancer development. The amount of a particular product of a tumor suppressor gene is critical. Indeed, null alleles of tumor suppressor genes as heterozygotes can condition tumorigenesis in the context of stoichiometric complexes. Moreover, a particular allele may have differing effects in different backgrounds, which might be a reflection of altered expression of the gene of interest or the relationship of its gene product levels to other interacting gene products in the cell.

Most cancers are associated with a highly aneuploid state involving many changes in the chromosomal constitution of the cells (105). Interestingly, cancerous cells are highly proliferative (106), which contrasts the cellular and organismal detrimental aneuploid phenotypes described above. No studies have directly addressed the issue of stoichiometric effects in cancer cells in the context of regulatory balance and whether the aneuploid condition optimizes the dosage relationship of a subset of regulatory factors in a manner that would relieve the otherwise detrimental effects of altered segmental dosage.

Implications for Quantitative Traits

Another tenet of the gene balance hypothesis is that quantitative traits will be affected by many loci that exhibit dosage effects (107). The parallels between the genetic control of quantitative traits and the effect of multiple aneuploidies on any particular phenotypic characteristic were noted in the work by Guo and Birchler (12), and also, they are illustrated in Fig. 1. Because many dosage modifiers affect any one phenotypic characteristic, variation in these genes would be expected to affect quantitative traits. The identification of the molecular basis of several quantitative trait loci indicates that transcription factors and signal transduction components are major contributors (108111). Transgene-generated dosage series of such candidates confirm the dosage sensitivity (112). Human height illustrates that a quantitative trait can be affected by a large number of genes. Genome-wide association studies have documented at least 180 genes that can affect this trait (113). Nevertheless, the variation in any one population is a small fraction of the mean height. A large number of genes has also been found to affect any particular trait in experiments involving inbred lines of maize and Drosophila that would, however, detect effects of variants in both dosage-sensitive and -insensitive genes (114, 115).

Another consequence of genomic balance is that there will be highly multigenic subtle variation that can allow selection in many directions using standing variation. In animal and plant breeding, when hard selection is applied to a population, traits can readily be shifted by subtle measures over time. The work by Darwin (116) highlighted the diversity of pigeons and dogs as examples in which artificial selection had produced a wide variety of forms within one species. An example in which the underlying genetics has been examined involves the Illinois high and low oil selection in maize (117). Starting with an open-pollinated population, selection was applied for increased and decreased oil content in the kernels. Both types of selection respond well and have not shown a plateau over many decades. Reversal of the direction of selection responds equally well. A determination of the genetic differences between high and low oil lines indicated a multigenic difference of at least 50 genes with additive effects (117).

With subtle standing variation in many regulatory genes that could impact a particular quantitative trait, the potential exists for natural selection to change the phenotype to significant extremes, although through gradual steps. If the standing subtle variation in dosage-balanced regulatory genes is neutral, the status quo will be maintained, which as the work by Williams (118) pointed out, is a major aspect of evolution. However, if a selection pressure on a trait arises because of changing conditions and is strong enough to overcome any detrimental aspects of a potential shift in the stiochiometries of interacting gene products, the potential for extreme changes in the phenotype in a gradual stepwise manner is present if the pressure continues over generations. Epistasis, in which one gene affects the manifestation of another, is also likely to impact this process as well as an interaction between dosage-sensitive and qualitative variants.

The evolutionary overretention of highly connected genes after WGD and underrepresentation among CNVs in populations suggest that a mere 25% change in quantity of gene product is usually selected against for these gene classes. Also, the fact that CNVs in humans cause recognizable detrimental clinical conditions (119) illustrates that changes of gene product quantity in this range impact the phenotype. These results have implications for the fate of natural variants that do not involve gene copy number change but alter the expression level in other ways. An analogy can be made to genes that mimic aneuploid syndromes, in that changes in quantity of gene products will be detrimental. Thus, mutations that change the quantity of a balanced gene product in this range will likely be selected against. Only more subtle changes can remain neutral or nearly neutral. Thus, the transacting regulatory variation affecting a particular trait is likely to be multigenic but with each variant being of small magnitude because of these selective dosage constraints.

Indeed, results of mutation accumulation studies conducted in nematodes (120) and fruit flies (121) suggest constraints on regulatory modulations. In experiments in which mutations were allowed to accumulate in lineages for many generations and then global gene expression studies conducted and compared with the progenitor state or related species, the changes in expression of largest magnitude involved individual target genes, whereas the global transcriptional patterns of gene expression were more or less maintained. These studies suggest that the apparent regulatory variation, as opposed to individual target gene expression, is more constrained. In other studies of cis and trans variation, cis variation for a target gene varies to greater magnitude than trans regulatory variation, which is, however, multigenic if the variation is great enough to be detected (122134). The multigenic low-magnitude transacting effects on gene expression, the mutation accumulation results, and the finding that members of protein complexes that exhibit dosage effects have limited variation form a consistent set of observations suggesting that there is a generalized constraint on regulatory variation. These considerations are also consistent with the phenotypic effects of aneuploidy as illustrated in Fig. 1, in which no genotype differs from the balanced state by more than a twofold dosage but nevertheless, can condition rather detrimental effects. Modulations at this magnitude, and even below, will likely be selected against because of the negative effects of altered regulatory balance.

In eukaryotic organisms with a primarily diploid phase, new mutations that arise will be present in a heterozygous condition. In this state, they will not be subject to selection unless they have some degree of dominance. Strictly recessive mutations are only available for selection in the homozygous state. This situation for recessive mutations is usually restricted to small populations in which the new alleles can change in frequency by random drift. However, for mutations in genes involved with dosage-sensitive interactions, they will produce a semidominance. If the change in amount of gene product caused by the new allele is detrimental, it will be selected against. As noted above for preferentially retained genes from WGD, there is, indeed, evidence for purifying selection. However, if a change in quantity confers a reproductively adaptive state, it can spread through the population because of the partial dominance.

The role of epigenetic variation in dosage balance has not been explored. Epigenetic effects can change the function of an allele or gene without changing the nucleotide sequence (135). Epigenetically silenced alleles have been documented, and these alleles can be inherited over generations (136). Parental imprinting of alleles, in which the history of an allele will determine whether it is expressed or not, creates a critical dosage effect for the encoded gene product. If the silencing mechanism is defective and the usually silent allele is expressed, detrimental effects result. This fact illustrates that a quantitative change in gene product of twofold is critical. The driving evolutionary force for uniparental expression is likely to be a nonmutational means to modulate the amount of gene product (137).

Concluding Remarks

In the synthesis described in this article, it is postulated that alterations of the stoichiometric balance of members of macromolecular complexes will affect the assembly of the whole. By extension, gene dosage balance also operates in the context of signal transduction (54, 111). This stoichiometric principle has implications for the control of gene expression and the constraints on variation for various regulatory genes. In turn, these consequences will affect developmental processes and thus, modulate quantitative traits, providing at least a partial explanation for their multigenic inheritance. The dosage effects will contribute to the molecular basis of aneuploid syndromes and the phenotypic manifestations of CNV on the single gene level. Within populations, this principle governs the fate of natural variants that alter the quantity of regulatory molecules as well as the actual gene number. The evolutionary consequence of gene dosage balance impacts the differential retention of classes of genes depending on whether they are duplicated by WGD or segmentally. Subtle variations can exist for the multitude of regulatory genes, which have the potential to affect any one trait. With the appropriate strong selection in one direction, gradual accumulation of variants contributing to more phenotypic extremes than the progenitor can occur. With the gene balance hypothesis, an initial synthesis is proposed for findings in the realm of biophysics, gene expression, chromosome biology, quantitative traits, and evolutionary biology.

Acknowledgments

Maya Benavides, Zhi Gao, and Fangpu Han classified the plants shown in Fig. 1 and produced the photographs. We thank Patrick Edger, Chris Pires, Bernardo Lemos, and Kathleen Newton for comments. J.A.B. thanks many former associates who contributed to the cited work. Research related to this topic has been supported by National Institutes of Health Grant R01GM068042. R.A.V. is supported by the Centre National de la Recherche Scientifique, the University Paris VII, the Institut Universitaire de France, La Ligue National Contre le Cancer (Comité de Paris), and the Groupement d’entreprises françaises dans la lutte contre le cancer (GEFLUC).

Footnotes

The authors declare no conflict of interest.

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