Protein under-wrapping causes dosage sensitivity and decreases gene duplicability.
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ABSTRACT:
SUBMITTER: Liang H
PROVIDER: S-EPMC2211539 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The evolutionary process leading to the fixation of newly duplicated genes is not well understood. It was recently proposed that the fixation of duplicate genes is frequently driven by positive selection for increased gene dosage (i.e., the gene dosage hypothesis), because haploinsufficient genes were reported to have more paralogs than haplosufficient genes in the human genome. However, the previous analysis incorrectly assumed that the presence of dominant abnormal alleles of a human gene means that the gene is haploinsufficient, ignoring the fact that many dominant abnormal alleles arise from gain-of-function mutations. Here we show in both humans and yeast that haploinsufficient genes generally do not duplicate more frequently than haplosufficient genes. Yeast haploinsufficient genes do exhibit enhanced retention after whole-genome duplication compared to haplosufficient genes if they encode members of stable protein complexes, but the same phenomenon is absent if the genes do not encode protein complex members, suggesting that the dosage balance effect rather than the dosage effect is the underlying cause of the phenomenon. On the basis of these and other results, we conclude that selection for higher gene dosage does not play a major role in driving the fixation of duplication genes.
| S-EPMC2516101 | biostudies-literature
Project description:Whereas the rate of gene duplication is relatively high, only certain duplications survive the filter of natural selection and can contribute to genome evolution. However, the reasons why certain genes can be retained after duplication whereas others cannot remain largely unknown. Many proteins contain intrinsically disordered regions (IDRs), whose structures fluctuate between alternative conformational states. Due to their high flexibility, IDRs often enable protein-protein interactions and are the target of post-translational modifications. Intrinsically disordered proteins (IDPs) have characteristics that might either stimulate or hamper the retention of their encoding genes after duplication. On the one hand, IDRs may enable functional diversification, thus promoting duplicate retention. On the other hand, increased IDP availability is expected to result in deleterious unspecific interactions. Here, we interrogate the proteomes of human, Drosophila melanogaster, Caenorhabditis elegans, Saccharomyces cerevisiae, Arabidopsis thaliana and Escherichia coli, in order to ascertain the impact of protein intrinsic disorder on gene duplicability. We show that, in general, proteins encoded by duplicated genes tend to be less disordered than those encoded by singletons. The only exception is proteins encoded by ohnologs, which tend to be more disordered than those encoded by singletons or genes resulting from small-scale duplications. Our results indicate that duplication of genes encoding IDPs outside the context of whole-genome duplication (WGD) is often deleterious, but that IDRs facilitate retention of duplicates in the context of WGD. We discuss the potential evolutionary implications of our results.
| S-EPMC5737077 | biostudies-literature
Project description:Duplications of genes encoding highly connected and essential proteins are selected against in several species but not in human, where duplicated genes encode highly connected proteins. To understand when and how gene duplicability changed in evolution, we compare gene and network properties in four species (Escherichia coli, yeast, fly, and human) that are representative of the increase in evolutionary complexity, defined as progressive growth in the number of genes, cells, and cell types. We find that the origin and conservation of a gene significantly correlates with the properties of the encoded protein in the protein-protein interaction network. All four species preserve a core of singleton and central hubs that originated early in evolution, are highly conserved, and accomplish basic biological functions. Another group of hubs appeared in metazoans and duplicated in vertebrates, mostly through vertebrate-specific whole genome duplication. Such recent and duplicated hubs are frequently targets of microRNAs and show tissue-selective expression, suggesting that these are alternative mechanisms to control their dosage. Our study shows how networks modified during evolution and contributes to explaining the occurrence of somatic genetic diseases, such as cancer, in terms of network perturbations.
| S-EPMC3072358 | biostudies-literature
Project description:It has previously been reported that protein complexity (i.e. number of subunits in a protein complex) is negatively correlated to gene duplicability in yeast as well as in humans. However, unlike in yeast, protein connectivity in a protein-protein interaction network has a positive correlation with gene duplicability in human genes. In the present study, we have analyzed 1732 human and 1269 yeast proteins that are present both in a protein-protein interaction network as well as in a protein complex network. In the human case, we observed that both protein connectivity and protein complexity complement each other in a mutually exclusive manner over gene duplicability in a positive direction. Analysis of human haploinsufficient proteins and large protein complexes (complex size >10) shows that when protein connectivity does not have any direct association with gene duplicability, there exists a positive correlation between gene duplicability and protein complexity. The same trend, however, is not found in case of yeast, where both protein connectivity and protein complexity independently guide gene duplicability in the negative direction. We conclude that the higher rate of duplication of human genes may be attributed to organismal complexity either by increasing connectivity in the protein-protein interaction network or by increasing protein complexity.
| S-EPMC2955712 | biostudies-literature
Project description:BackgroundA prerequisite for a duplication to spread through and persist in a given population is retaining expression of both gene copies. Yet changing a gene's dosage is frequently detrimental to fitness. Consequently, dosage-sensitive genes are less likely to duplicate. However, in cases where the level of gene product is controlled, via negative feedback, by its own abundance, an increase in gene copy number can in principle be decoupled from an increase in protein while both copies remain expressed. Using data from the transcriptional networks of E. coli and S. cerevisiae, we test the hypothesis that genes under negative auto-regulation show enhanced duplicability.ResultsControlling for several known correlates of duplicability, we find no statistically significant support in either E. coli or S. cerevisiae that transcription factors under negative auto-regulation hold a duplicability advantage over transcription factors with no auto-regulation.ConclusionBased on the analysis of transcriptional networks in E. coli and S. cerevisiae, there is no evidence that negative auto-regulation has contributed, on a genome-wide scale, to the variability in gene family sizes in these species.
| S-EPMC2739200 | biostudies-literature
Project description:Sequencing technology is increasingly demonstrating the impact of genomic copy number variation (CNV) on phenotypes. Opposing variation in growth, head size, cognition and behaviour is known to result from deletions and reciprocal duplications of some genomic regions. We propose normative inversion of face shape, opposing difference from a matched norm, as a basis for investigating the effects of gene dosage on craniofacial development. We use dense surface modelling techniques to match any face (or part of a face) to a facial norm of unaffected individuals of matched age, sex and ethnicity and then we reverse the individual's face shape differences from the matched norm to produce the normative inversion. We demonstrate for five genomic regions, 4p16.3, 7q11.23, 11p15, 16p13.3 and 17p11.2, that such inversion for individuals with a duplication or (epi)-mutation produces facial forms remarkably similar to those associated with a deletion or opposite (epi-)mutation of the same region, and vice versa. The ability to visualise and quantify face shape effects of gene dosage is of major benefit for determining whether a CNV is the cause of the phenotype of an individual and for predicting reciprocal consequences. It enables face shape to be used as a relatively simple and inexpensive functional analysis of the gene(s) involved.
| S-EPMC4148161 | biostudies-literature
Project description: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.
| S-EPMC3443177 | biostudies-other
Project description:BackgroundLateral gene transfer is a major force in microbial evolution and a great source of genetic innovation in prokaryotes. Protein complexity has been claimed to be a barrier for gene transfer, due to either the inability of a new gene's encoded protein to become a subunit of an existing complex (lack of positive selection), or from a harmful effect exerted by the newcomer on native protein assemblages (negative selection).ResultsWe tested these scenarios using data from the model prokaryote Escherichia coli. Surprisingly, the data did not support an inverse link between membership in protein complexes and gene transfer. As the complexity hypothesis, in its strictest sense, seemed valid only to essential complexes, we broadened its scope to include connectivity in general. Transferred genes are found to be less involved in protein-protein interactions, outside stable complexes, and this is especially true for genes recently transferred to the E. coli genome. Thus, subsequent to transfer, new genes probably integrate slowly into existing protein-interaction networks. We show that a low duplicability of a gene is linked to a lower chance of being horizontally transferred. Notably, many essential genes in E. coli are conserved as singletons across multiple related genomes, have high connectivity and a highly vertical phylogenetic signal.ConclusionHigh complexity and connectivity generally do not impede gene transfer. However, essential genes that exhibit low duplicability and high connectivity do exhibit mostly vertical descent.
| S-EPMC2374987 | biostudies-literature
Project description:Noncoding sequence contains pathogenic mutations. Yet, compared with mutations in protein-coding sequence, pathogenic regulatory mutations are notoriously difficult to recognize. Most fundamentally, we are not yet adept at recognizing the sequence stretches in the human genome that are most important in regulating the expression of genes. For this reason, it is difficult to apply to the regulatory regions the same kinds of analytical paradigms that are being successfully applied to identify mutations among protein-coding regions that influence risk. To determine whether dosage sensitive genes have distinct patterns among their noncoding sequence, we present two primary approaches that focus solely on a gene's proximal noncoding regulatory sequence. The first approach is a regulatory sequence analogue of the recently introduced residual variation intolerance score (RVIS), termed noncoding RVIS, or ncRVIS. The ncRVIS compares observed and predicted levels of standing variation in the regulatory sequence of human genes. The second approach, termed ncGERP, reflects the phylogenetic conservation of a gene's regulatory sequence using GERP++. We assess how well these two approaches correlate with four gene lists that use different ways to identify genes known or likely to cause disease through changes in expression: 1) genes that are known to cause disease through haploinsufficiency, 2) genes curated as dosage sensitive in ClinGen's Genome Dosage Map, 3) genes judged likely to be under purifying selection for mutations that change expression levels because they are statistically depleted of loss-of-function variants in the general population, and 4) genes judged unlikely to cause disease based on the presence of copy number variants in the general population. We find that both noncoding scores are highly predictive of dosage sensitivity using any of these criteria. In a similar way to ncGERP, we assess two ensemble-based predictors of regional noncoding importance, ncCADD and ncGWAVA, and find both scores are significantly predictive of human dosage sensitive genes and appear to carry information beyond conservation, as assessed by ncGERP. These results highlight that the intolerance of noncoding sequence stretches in the human genome can provide a critical complementary tool to other genome annotation approaches to help identify the parts of the human genome increasingly likely to harbor mutations that influence risk of disease.
| S-EPMC4557908 | biostudies-literature
Project description:The 'balance hypothesis' predicts that non-stoichiometric variations in concentrations of proteins participating in complexes should be deleterious. As a corollary, heterozygous deletions and overexpression of protein complex members should have measurable fitness effects. However, genome-wide studies of heterozygous deletions in Saccharomyces cerevisiae and overexpression have been unable to unambiguously relate complex membership to dosage sensitivity. We test the hypothesis that it is not complex membership alone but rather the topology of interactions within a complex that is a predictor of dosage sensitivity. We develop a model that uses the law of mass action to consider how complex formation might be affected by varying protein concentrations given a protein's topological positioning within the complex. Although we find little evidence for combinatorial inhibition of complex formation playing a major role in overexpression phenotypes, consistent with previous results, we show significant correlations between predicted sensitivity of complex formation to protein concentrations and both heterozygous deletion fitness and protein abundance noise levels. Our model suggests a mechanism for dosage sensitivity and provides testable predictions for the effect of alterations in protein abundance noise.
| S-EPMC2671925 | biostudies-literature