RESUMEN
A century ago experiments with the flowering plant Datura stramonium and the fruit fly Drosophila melanogaster revealed that adding an extra chromosome to a karyotype was much more detrimental than adding a whole set of chromosomes. This phenomenon was referred to as gene balance and has been recapitulated across eukaryotic species. Here, we retrace some developments in this field. Molecular studies suggest that the basis of balance involves stoichiometric relationships of multi-component interactions. This concept has implication for the mechanisms controlling gene expression, genome evolution, sex chromosome evolution/dosage compensation, speciation mechanisms, and the underlying genetics of quantitative traits.
Asunto(s)
Aneuploidia , Evolución Molecular , Regulación de la Expresión Génica , Genoma/genética , Carácter Cuantitativo Heredable , Animales , Datura stramonium/genética , Compensación de Dosificación (Genética) , Drosophila melanogaster/genética , Especiación Genética , Humanos , Cromosomas Sexuales/genéticaRESUMEN
Changes in dosage of part of the genome (aneuploidy) have long been known to produce much more severe phenotypic consequences than changes in the number of whole genomes (ploidy). To examine the basis of these differences, global gene expression in mature leaf tissue for all five trisomies and in diploids, triploids, and tetraploids of Arabidopsis thaliana was studied. The trisomies displayed a greater spread of expression modulation than the ploidy series. In general, expression of genes on the varied chromosome ranged from compensation to dosage effect, whereas genes from the remainder of the genome ranged from no effect to reduced expression approaching the inverse level of chromosomal imbalance (2/3). Genome-wide DNA methylation was examined in each genotype and found to shift most prominently with trisomy 4 but otherwise exhibited little change, indicating that genetic imbalance is generally mechanistically unrelated to DNA methylation. Independent analysis of gene functional classes demonstrated that ribosomal, proteasomal, and gene body methylated genes were less modulated compared with all classes of genes, whereas transcription factors, signal transduction components, and organelle-targeted protein genes were more tightly inversely affected. Comparing transcription factors and their targets in the trisomies and in expression networks revealed considerable discordance, illustrating that altered regulatory stoichiometry is a major contributor to genetic imbalance. Reanalysis of published data on gene expression in disomic yeast and trisomic mouse cells detected similar stoichiometric effects across broad phylogenetic taxa, and indicated that these effects reflect normal gene regulatory processes.
Asunto(s)
Arabidopsis/genética , Cromosomas de las Plantas/genética , Drosophila/genética , Ratones/genética , Aneuploidia , Animales , Cromosomas/genética , Metilación de ADN , Expresión Génica , Poliploidía , Trisomía , Levaduras/genéticaRESUMEN
Genes encoding interacting proteins tend to be co-retained after whole-genome duplication (WGD). The preferential retention after WGD has been explained by the gene balance hypothesis (GBH). However, small-scale duplications could independently occur in the connected gene families. Certain evolutionary strategies might keep the dosage balanced. Here, we examined the gene duplication, interaction and expression patterns of calcineurin B-like (CBL) and CBL-interacting protein kinase (CIPK) gene families to understand the underlying principles. The ratio of the CBL and CIPK gene numbers evolved from 5 : 7 in Physcomitrella to 10 : 26 in Arabidopsis, and retrotransposition, tandem duplication, and WGDs contributed to the expansion. Two pairs of CBLs and six pairs of CIPKs were retained after the α WGD in Arabidopsis, in which specific interaction patterns were identified. In some cases, two retained CBLs (CIPKs) might compete to interact with a sole CIPK (CBL). Results of gene expression analyses indicated that the relatively over-retained duplicates tend to show asymmetric expression, thus avoiding competition. In conclusion, our results suggested that the highly specific interaction, together with the differential gene expression pattern, jointly maintained the balanced dosage for the interacting CBL and CIPK proteins.
Asunto(s)
Arabidopsis , Proteínas de Plantas , Arabidopsis/genética , Arabidopsis/metabolismo , Proteínas de Unión al Calcio/genética , Duplicación de Gen , Proteínas de Plantas/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismoRESUMEN
Retention or loss of paralogs following duplication correlates strongly with the function of the gene and whether the gene was duplicated by whole-genome duplication (WGD) or by small-scale duplication. Selection on relative gene dosage (to maintain proper stoichiometry among interacting proteins) has been invoked to explain these patterns of duplicate gene retention and loss. In order for gene dosage to be visible to natural selection, there must necessarily be a correlation between gene copy number and gene expression level (transcript abundance), but this has rarely been examined. We used RNA-Seq data from seven Glycine subgenus Glycine species (three recently formed allotetraploids and their four diploid progenitors) to determine if expression patterns and gene dosage responses at the level of transcription are consistent with selection on relative gene dosage. As predicted, metabolic pathways and gene ontologies that are putatively dosage-sensitive based on duplication history exhibited reduced expression variance across species, and more coordinated expression responses to recent WGD, relative to putatively dosage-insensitive networks. We conclude that selection on relative dosage has played an important role in shaping gene networks in Glycine.
Asunto(s)
Diploidia , Dosificación de Gen , Regulación de la Expresión Génica de las Plantas , Glycine max/genética , Poliploidía , Duplicación de Gen , Ontología de Genes , Redes Reguladoras de Genes , Genes de PlantasRESUMEN
Global analysis of gene expression via RNA sequencing was conducted for trisomics for the left arm of chromosome 2 (2L) and compared with the normal genotype. The predominant response of genes on 2L was dosage compensation in that similar expression occurred in the trisomic compared with the diploid control. However, the male and female trisomic/normal expression ratio distributions for 2L genes differed in that females also showed a strong peak of genes with increased expression and males showed a peak of reduced expression relative to the opposite sex. For genes in other autosomal regions, the predominant response to trisomy was reduced expression to the inverse of the altered chromosomal dosage (2/3), but a minor peak of increased expression in females and further reduced expression in males were also found, illustrating a sexual dimorphism for the response to aneuploidy. Moreover, genes with sex-biased expression as revealed by comparing amounts in normal males and females showed responses of greater magnitude to trisomy 2L, suggesting that the genes involved in dosage-sensitive aneuploid effects also influence sex-biased expression. Each autosomal chromosome arm responded to 2L trisomy similarly, but the ratio distributions for X-linked genes were distinct in both sexes, illustrating an X chromosome-specific response to aneuploidy.
Asunto(s)
Compensación de Dosificación (Genética)/genética , Drosophila/genética , Evolución Molecular , Caracteres Sexuales , Trisomía , Cromosoma X/genética , Animales , Drosophila/metabolismo , Femenino , Ontología de Genes , Larva/metabolismo , Masculino , Modelos Genéticos , Análisis de Secuencia de ARNRESUMEN
The gene balance hypothesis proposes that selection acts on the dosage (i.e. copy number) of genes within dosage-sensitive portions of networks, pathways, and protein complexes to maintain balanced stoichiometry of interacting proteins, because perturbations to stoichiometric balance can result in reduced fitness. This selection has been called dosage balance selection. Dosage balance selection is also hypothesized to constrain expression responses to dosage changes, making dosage-sensitive genes (those encoding members of interacting proteins) experience more similar expression changes. In allopolyploids, where whole-genome duplication involves hybridization of diverged lineages, organisms often experience homoeologous exchanges that recombine, duplicate, and delete homoeologous regions of the genome and alter the expression of homoeologous gene pairs. Although the gene balance hypothesis makes predictions about the expression response to homoeologous exchanges, they have not been empirically tested. We used genomic and transcriptomic data from 6 resynthesized, isogenic Brassica napus lines over 10 generations to identify homoeologous exchanges, analyzed expression responses, and tested for patterns of genomic imbalance. Groups of dosage-sensitive genes had less variable expression responses to homoeologous exchanges than dosage-insensitive genes, a sign that their relative dosage is constrained. This difference was absent for homoeologous pairs whose expression was biased toward the B. napus A subgenome. Finally, the expression response to homoeologous exchanges was more variable than the response to whole-genome duplication, suggesting homoeologous exchanges create genomic imbalance. These findings expand our knowledge of the impact of dosage balance selection on genome evolution and potentially connect patterns in polyploid genomes over time, from homoeolog expression bias to duplicate gene retention.
Asunto(s)
Brassica napus , Brassica napus/genética , Genoma de Planta , Poliploidía , Perfilación de la Expresión Génica , TranscriptomaRESUMEN
Whole-genome duplication is widespread in plant evolutionary history and is followed by nonrandom gene loss to return to a diploid state. Across multiple angiosperm species, the retained genes tend to be dosage-sensitive regulatory genes such as transcription factors, yet data for younger polyploid species is sparse. Here, we analyzed the retention, expression, and genetic variation in transcription factors in the recent allohexaploid bread wheat (Triticum aestivum L.). By comparing diploid, tetraploid, and hexaploid wheat, we found that, following each of two hybridization and whole-genome duplication events, the proportion of transcription factors in the genome increased. Transcription factors were preferentially retained over other genes as homoeologous groups in tetraploid and hexaploid wheat. Across cultivars, transcription factor homoeologs contained fewer deleterious missense mutations than nontranscription factors, suggesting that transcription factors are maintained as three functional homoeologs in hexaploid wheat populations. Transcription factor homoeologs were more strongly coexpressed than nontranscription factors, indicating conservation of function between homoeologs. We found that the B3, MADS-M-type, and NAC transcription factor families were less likely to have three homoeologs present than other families, which was associated with low expression levels and high levels of tandem duplication. Together, our results show that transcription factors are preferentially retained in polyploid wheat genomes although there is variation between families. Knocking out one transcription factor homoeolog to alter gene dosage, using TILLING or CRISPR, could generate new phenotypes for wheat breeding.
Asunto(s)
Factores de Transcripción , Triticum , Regulación de la Expresión Génica de las Plantas , Genoma de Planta , Fitomejoramiento , Poliploidía , Tetraploidía , Factores de Transcripción/genética , Triticum/genéticaRESUMEN
Dosage effects in plants are caused by changes in the copy number of chromosomes, segments of chromosomes, or multiples of individual genes. Genes often exhibit a dosage effect in which the amount of product is closely correlated with the number of copies present. However, when larger segments of chromosomes are varied, there are trans-acting effects across the genome that are unleashed that modulate gene expression in cascading effects. These appear to be mediated by the stoichiometric relationship of gene regulatory machineries. There are both positive and negative modulations of target gene expression, but the latter is the plurality effect. When this inverse effect is combined with a dosage effect, compensation for a gene can occur in which its expression is similar to the normal diploid regardless of the change in chromosomal dosage. In contrast, changing the whole genome in a polyploidy series has fewer relative effects as the stoichiometric relationship is not disrupted. Together, these observations suggest that the stoichiometry of gene regulation is important as a reflection of the mode of assembly of the individual subunits involved in the effective regulatory macromolecular complexes. This principle has implications for gene expression mechanisms, quantitative trait genetics, and the evolution of genes depending on the mode of duplication, either segmentally or via whole-genome duplication.
Asunto(s)
Epigénesis Genética/genética , Dosificación de Gen/genética , Plantas/genética , Aneuploidia , Cromosomas de las Plantas/genética , Epigenómica/métodos , Expresión Génica/genética , Regulación de la Expresión Génica/genética , Frecuencia de los Genes/genética , Genoma de Planta/genética , Fenotipo , Poliploidía , Carácter Cuantitativo HeredableRESUMEN
Aneuploidy has profound effects on an organism, typically more so than polyploidy, and the basis of this contrast is not fully understood. A dosage series of the maize long arm of chromosome 1 (1L) was used to compare relative global gene expression in different types and degrees of aneuploidy to gain insights into how the magnitude of genomic imbalance as well as hypoploidy affects global gene expression. While previously available methods require a selective examination of specific genes, RNA sequencing provides a whole-genome view of gene expression in aneuploids. Most studies of global aneuploidy effects have concentrated on individual types of aneuploids because multiple dose aneuploidies of the same genomic region are difficult to produce in most model genetic organisms. The genetic toolkit of maize allows the examination of multiple ploidies and 1-4 doses of chromosome arms. Thus, a detailed examination of expression changes both on the varied chromosome arms and elsewhere in the genome is possible, in both hypoploids and hyperploids, compared with euploid controls. Previous studies observed the inverse trans effect, in which genes not varied in DNA dosage were expressed in a negative relationship to the varied chromosomal region. This response was also the major type of changes found globally in this study. Many genes varied in dosage showed proportional expression changes, though some were seen to be partly or fully dosage compensated. It was also found that the effects of aneuploidy were progressive, with more severe aneuploids producing effects of greater magnitude.
Asunto(s)
Aneuploidia , Dosificación de Gen/genética , Genoma de Planta/genética , Zea mays/genética , Regulación de la Expresión Génica de las Plantas/genéticaRESUMEN
The role of genomic balance in accumulating species hybrid incompatibilities is discussed. Aneuploidy has been shown to produce more global modulations than polyploidy with the responsible genes being transcription factors and signaling components involved in molecular complexes, illustrating a stoichiometric component to gene expression. Genomic imbalance is usually detrimental to the organism and in many cases results in lethality. Here, it is proposed that once gene flow is prevented between or within populations by various speciation initiating processes, the stoichiometric relationship of members of macromolecular complexes can change via compensatory drift with the eventual result of newly established functional balances. However, when these new relationships are brought together in interspecific hybrids, detrimental consequences will occur. We suggest that these detrimental interactions contribute to hybrid incompatibilities.
RESUMEN
The TEL2, TTI1, and TTI2 proteins are co-chaperones for heat shock protein 90 (HSP90) to regulate the protein folding and maturation of phosphatidylinositol 3-kinase-related kinases (PIKKs). Referred to as the TTT complex, the genes that encode them are highly conserved from man to maize. TTT complex and PIKK genes exist mostly as single copy genes in organisms where they have been characterized. Members of this interacting protein network in maize were identified and synteny analyses were performed to study their evolution. Similar to other species, there is only one copy of each of these genes in maize which was due to a loss of the duplicated copy created by ancient allotetraploidy. Moreover, the retained copies of the TTT complex and the PIKK genes tolerated extensive retrotransposon insertion in their introns that resulted in increased gene lengths and gene body methylation, without apparent effect in normal gene expression and function. The results raise an interesting question on whether the reversion to single copy was due to selection against deleterious unbalanced gene duplications between members of the complex as predicted by the gene balance hypothesis, or due to neutral loss of extra copies. Uneven alteration of dosage either by adding extra copies or modulating gene expression of complex members is being proposed as a means to investigate whether the data supports the gene balance hypothesis or not.
RESUMEN
While most mutations are recessive, variants that affect quantitative traits are largely semi-dominant in their action making hybrids between divergent genotypes intermediate. In parallel, changes in chromosomal dosage (aneuploidy) for multiple regions of the genome modulate quantitative characters. We have previously argued that these observations are a reflection of a common process, originating from the more or less subtle effects of changes in dosage on the action of multi-subunit regulatory machineries. Kinetic analyses that vary the amount of one subunit of a complex while holding others constant do not always predict a linear response for the production of the whole. Indeed, in many instances, strong non-linear effects are expected. Here, we advocate that these kinetic observations and predictions should be incorporated into quantitative genetics thought.
Asunto(s)
Genoma de Planta , Carácter Cuantitativo Heredable , Patrón de Herencia/genética , Cinética , Modelos Genéticos , FenotipoRESUMEN
Crosses between plants at different ploidy levels will often result in failure of endosperm development. The basis of this phenomenon has been attributed to parental gene imprinting of genes involved with endosperm development but a review of the data from maize indicates a dosage interaction between the contributions of the female gametophyte and the primary endosperm nucleus to early endosperm development. However, it is noted that parental imprinting is a non-mutational means that can alter dosage sensitive factors and therefore can contribute to this effect. Operationally, the genes determining ploidy hybridization barrier would qualify for Dobzhansky-Muller incompatibilities that prevent gene flow between species.
RESUMEN
A common modulation of gene expression in aneuploids is an inverse correlation of the monitored gene with the dosage of another segment of the genome. Such effects can be reduced to the action of single genes. One gene previously found to modulate leaky alleles of the white eye color gene in Drosophila is Inverse regulator-a (Inr-a). Heterozygotes of mutations increase the expression of white about 2-fold, and trisomic regions surrounding the gene reduce the expression to about two-thirds of the normal diploid level. Further cytological definition of the location of this gene on the second chromosome led to a candidate pre-mRNA cleavege complex II protein (Pcf11) as the only gene in the remaining region whose mutations exhibit recessive lethality as do alleles of Inr-a. The product of Pcf11 has been implicated in transcriptional initiation, elongation, and termination reactions. Four mutant alleles showed molecular lesions predicted to lead to nonfunctional products of Pcf11. The identification of the molecular lesion of Inr-a provides insight into the basis of this common aneuploidy effect.