A simple principle concerning the robustness of protein complex activity to changes in gene expression

Semple, Jennifer I.; Vavouri, Tanya; Lehner, Ben

doi:10.1186/1752-0509-2-1

Cited by 86 publications

(103 citation statements)

References 24 publications

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“…Following polyploidization, balanced gene loss operates to maintain equitable dosage among functionally related loci participating in protein complexes. Similarly, studies in yeast have revealed that dosagesensitive genes are more likely to encode subunits of protein complexes (4,52), further indicating the strong selective pressure to maintain the stoichiometric interdependence of multiple gene products that form a single functioning macromolecule (43). In humans, dosage imbalance of interacting proteins has been hypothesized to predispose to disease (53).…”

Section: Discussionmentioning

confidence: 99%

Concerted copy number variation balances ribosomal DNA dosage in human and mouse genomes

Gibbons

Branco

Godinho

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

179

176

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Tandemly repeated ribosomal DNA (rDNA) arrays are among the most evolutionary dynamic loci of eukaryotic genomes. The loci code for essential cellular components, yet exhibit extensive copy number (CN) variation within and between species. CN might be partly determined by the requirement of dosage balance between the 5S and 45S rDNA arrays. The arrays are nonhomologous, physically unlinked in mammals, and encode functionally interdependent RNA components of the ribosome. Here we show that the 5S and 45S rDNA arrays exhibit concerted CN variation (cCNV). Despite 5S and 45S rDNA elements residing on different chromosomes and lacking sequence similarity, cCNV between these loci is strong, evolutionarily conserved in humans and mice, and manifested across individual genotypes in natural populations and pedigrees. Finally, we observe that bisphenol A induces rapid and parallel modulation of 5S and 45S rDNA CN. Our observations reveal a novel mode of genome variation, indicate that natural selection contributed to the evolution and conservation of cCNV, and support the hypothesis that 5S CN is partly determined by the requirement of dosage balance with the 45S rDNA array. We suggest that human disease variation might be traced to disrupted rDNA dosage balance in the genome.nucleolus | ribosome | gene dosage balance | concerted evolution | bisphenol A R epeated gene arrays have provided unique challenges to genetic and genome analyses, and have remained among the most elusive components of eukaryotic genomes (1, 2). Tandemly repeated loci of high copy number (CN) are labile, evolutionary dynamic, often subjected to concerted evolution of DNA sequences, and display abundant CN variation that emerges from high rates of repeat expansion and contraction (1). Moreover, natural selection contributes to the determination of gene CN, shaping rapid gene amplification in cancer, balanced gene loss after whole genome duplication, and optimal gene CN in locally adapted populations (3-5). For example, higher CN of the amylase gene is present in populations with starch-rich diets across organisms as diverse as humans, dogs, and fungi (3, 6, 7). Remarkably, gene CN may also be developmentally amplified in specific tissues to ensure rates of transcription in genes with high transcriptional demands (8,9). This is the case, for instance, of the chorion genes in Drosophila, which are amplified up to 80 fold in ovarian cells (10).The ribosomal DNA (rDNA) arrays display substantial CN variation within and between species (2, 11-16). The variation is functionally relevant with rDNA CN polymorphism modifying chromatin states and gene expression across the genome in humans and flies (17)(18)(19). In mammals, the rDNA arrays are dispersed across several chromosomes, and encode the four rRNAs that account for more than 60% of all transcription in the cell (20,21). Transcription of rDNA loci varies with cell and tissue type and is epigenetically regulated with allelic specificity (22, 23). The four rRNAs are indispensable structural and catalyti...

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Section: Discussionmentioning

confidence: 99%

Concerted copy number variation balances ribosomal DNA dosage in human and mouse genomes

Gibbons

Branco

Godinho

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

179

176

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“…A potentially relevant point is that proteins with oligomerization potential can also be costly, providing the substrate for well-known human disorders involving inappropriate protein aggregates (e.g., Alzheimer’s and Parkinson’s diseases) (16), and more generally encouraging deleterious promiscuous protein-protein interactions when overexpressed (99, 104). This fine line between adaptive complexity and pathology encourages the hypothesis that the evolutionary roots of numerous protein-protein interactions may simply reside in their initial roles as compensating mechanisms for mild structural defects of monomeric proteins (25).…”

Section: Protein Structure and Complex Cellular Adaptationsmentioning

confidence: 99%

The Repatterning of Eukaryotic Genomes by Random Genetic Drift

Lynch

Bobay

Catania

et al. 2011

Annu. Rev. Genom. Hum. Genet.

121

132

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Recent observations on rates of mutation, recombination, and random genetic drift highlight the dramatic ways in which fundamental evolutionary processes vary across the divide between unicellular microbes and multicellular eukaryotes. Moreover, population-genetic theory suggests that the range of variation in these parameters is sufficient to explain the evolutionary diversification of many aspects of genome size and gene structure found among phylogenetic lineages. Most notably, large eukaryotic organisms that experience elevated magnitudes of random genetic drift are susceptible to the passive accumulation of mutationally hazardous DNA that would otherwise be eliminated by efficient selection. Substantial evidence also suggests that variation in the population-genetic environment influences patterns of protein evolution, with the emergence of certain kinds of amino-acid substitutions and protein-protein complexes only being possible in populations with relatively small effective sizes. These observations imply that the ultimate origins of many of the major genomic and proteomic disparities between prokaryotes and eukaryotes and among eukaryotic lineages have been molded as much by intrinsic variation in the genetic and cellular features of species as by external ecological forces.

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“…Second, unless a newly emerging dimer has a symmetric interface and the correct subunit orientation, concatenations into indefinite filaments can arise. Numerous human disorders are known to result from inappropriate protein aggregation (11), and highly expressed proteins are especially vulnerable to promiscuous interactions (12,13). Third, in diploid species, some dimerizing mutations may have deleterious effects in heterozygous individuals as a consequence of heterotypic complexation, a process that can greatly reduce the probability of establishment of the dimerizing allele (10).…”

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confidence: 99%

Evolutionary diversification of the multimeric states of proteins

Lynch

2013

Proc. Natl. Acad. Sci. U.S.A.

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Significance Rather than operating as single units, most proteins assemble as multimers, usually with all subunits derived from the same gene. In contrast to patterns of gene structure and genome organization, which typically exhibit substantial increases in complexity from unicellular to multicellular organisms, the structural complexity of orthologous proteins appears roughly constant over the tree of life. The interfaces of multimers also often shift dramatically over evolutionary time. To explain these observations, a model is presented for the stochastic origin of variation in the multimeric states of proteins via the joint processes of mutation, random genetic drift, and constant directional selection.

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A simple principle concerning the robustness of protein complex activity to changes in gene expression

Cited by 86 publications

References 24 publications

Concerted copy number variation balances ribosomal DNA dosage in human and mouse genomes

Concerted copy number variation balances ribosomal DNA dosage in human and mouse genomes

The Repatterning of Eukaryotic Genomes by Random Genetic Drift

Evolutionary diversification of the multimeric states of proteins

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