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Project description:Abstract Proteins operate within dense interconnected networks, where interactions are necessary both for stabilising proteins and enabling them to execute their molecular functions. Remarkably, the protein-protein interaction networks operating within tumour cells continue to function despite widespread genetic perturbations. Previous work has demonstrated that tumour cells tolerate perturbations of paralogs better than perturbations of singleton genes but the mechanistic means by which paralogs tolerate perturbation remain poorly characterised. Here we systematically profile the proteomic response of tumours and tumour cell lines to gene loss. We find many examples of both active compensation, where deletion of one paralog results in increased abundance of another, and collateral loss, where deletion of one paralog results in reduced abundance of another. Active compensation is enriched among sequence-similar paralog pairs that have high protein-protein interaction degree and that are widely conserved across evolution. Active compensation is also significantly more likely to be observed for gene pairs with a known synthetic lethal relationship. Compensating paralogs have more ubiquitination sites, suggesting a role for post-transcriptional control by protein degradation. Our results support a model whereby loss of one gene results in increased protein abundance of its paralog, stabilising the protein-protein interaction network. Consequently, tumour cells become dependent on the paralog for survival, creating potentially targetable vulnerabilities.
2025-05-07 | PXD055643 | Pride
Project description:Structural evolution of the tissue-specific U2AF paralog and alternative splicing factor LS2
| PRJNA657056 | ENA
Project description:Gene duplication enables the emergence of new functions by lowering the general evolutionary pressure. Previous studies have highlighted the role of specific paralog genes during cell differentiation, e.g., in chromatin remodeling complexes. It remains unexplored whether similar mechanisms extend to other biological functions and whether the regulation of paralog genes is conserved across species. Here, we analyze the expression of paralogs across human tissues, during development and neuronal differentiation in fish, rodents and humans. While ~80% of paralog genes are co-regulated, a subset of paralogs shows divergent expression profiles, contributing to variability of protein complexes. We identify 78 substitutions of paralog eggNOG pairs that occur during neuronal differentiation and are conserved across species. Among these, we highlight a substitution between the paralogs Sec23a and Sec23b subunits of the COPII complex. Altering the ratio between these two genes via silencing-RNA knockdown was able to influence neuronal differentiation in different ways. We propose that remodeling of the vesicular transport system via paralog substitutions is an evolutionary conserved mechanism enabling neuronal differentiation.
2022-03-07 | PXD027191 | Pride
Project description:Gene duplication enables the emergence of new functions by lowering the general evolutionary pressure. Previous studies have highlighted the role of specific paralog genes during cell differentiation, e.g., in chromatin remodeling complexes. It remains unexplored whether similar mechanisms extend to other biological functions and whether the regulation of paralog genes is conserved across species. Here, we analyze the expression of paralogs across human tissues, during development and neuronal differentiation in fish, rodents and humans. While ~80% of paralog genes are co-regulated, a subset of paralogs shows divergent expression profiles, contributing to variability of protein complexes. We identify 78 substitutions of paralog eggNOG pairs that occur during neuronal differentiation and are conserved across species. Among these, we highlight a substitution between the paralogs Sec23a and Sec23b subunits of the COPII complex. Altering the ratio between these two genes via silencing-RNA knockdown was able to influence neuronal differentiation in different ways. We propose that remodeling of the vesicular transport system via paralog substitutions is an evolutionary conserved mechanism enabling neuronal differentiation.
2022-03-07 | PXD027195 | Pride
Project description:Gene duplication enables the emergence of new functions by lowering the general evolutionary pressure. Previous studies have highlighted the role of specific paralog genes during cell differentiation, e.g., in chromatin remodeling complexes. It remains unexplored whether similar mechanisms extend to other biological functions and whether the regulation of paralog genes is conserved across species. Here, we analyze the expression of paralogs across human tissues, during development and neuronal differentiation in fish, rodents and humans. While ~80% of paralog genes are co-regulated, a subset of paralogs shows divergent expression profiles, contributing to variability of protein complexes. We identify 78 substitutions of paralog pairs that occur during neuronal differentiation and are conserved across species. Among these, we highlight a substitution between the paralogs Sec23a and Sec23b subunits of the COPII complex. Altering the ratio between these two genes via RNAi-mediated knockdown is sufficient to influence the differentiation of immature neuron. We propose that remodeling of the vesicular transport system via paralog substitutions is an evolutionary conserved mechanism enabling neuronal differentiation.
2022-03-07 | PXD027387 | Pride
Project description:Ribosomes have long been thought of as homogeneous macromolecular machines, but recent evidence suggests they are heterogeneous and could be specialised to regulate translation. Here, we have isolated ribosomal complexes and characterised their protein content across 4 tissues of Drosophila melanogaster via TMT-MS. We find that testes and ovaries contain the most heterogeneous ribosome populations, which occurs through a combination of ribosomal protein paralog-enrichment and ribosomal protein paralog-switching. We have also solved structures of ribosomes isolated from tissues by cryo-EM, revealing differences in precise ribosomal arrangement for testis and ovary 80S ribosomes. Differences in the amino acid composition of paralog pairs and their localisation on the ribosome exterior indicate paralog-switching could alter the ribosome surface, enabling different proteins to regulate translation. One testis-specific paralog-switching pair is also found in humans, suggesting this is a conserved site of ribosome heterogeneity. Overall, this work allows us to propose that mRNA translation might be regulated in the gonads through ribosome heterogeneity, providing a potential means of ribosome specialisation.
2021-07-22 | PXD026227 | Pride
Project description:CRISPR knockout screens have accelerated the discovery of important cancer genetic dependencies. However, traditional CRISPR-Cas9 screens are limited in their ability to assay the function of redundant or duplicated genes. Paralogs in multi-gene families constitute two-thirds of the protein-coding genome, so this blind spot is the rule, not the exception. To overcome the limitations of single gene CRISPR knockout screens, we developed paired guide RNAs for Paralog gENetic interaction mapping (pgPEN), a pooled CRISPR/Cas9 approach which targets over a thousand duplicated human paralogs in single knockout and double knockout configurations. We applied pgPEN to two cell lineages and discovered that over 10% of human paralogs exhibit synthetic lethality in at least one cellular context. We recovered known synthetic lethal paralogs such as MAP2K1/MAP2K2, important drug targets such as CDK4/CDK6, and numerous other synthetic lethal pairs such as CCNL1/CCNL2. In addition, we identified ten tumor suppressive paralog pairs whose compound loss promotes cell growth. These findings identify a large number of previously unidentified essential gene families and nominate new druggable targets for oncology drug discovery.
2021-08-31 | GSE178179 | GEO
Project description:Discovery of synthetic lethal and tumor suppressive paralog pairs in the human genome
| PRJNA737515 | ENA
Project description:Evolutionary outcomes depend not only on the selective forces acting upon a species, but also on the genetic background. However, large timescales and uncertain historical selection pressures can make it difficult to discern such important background differences between species. Experimental evolution is one tool to compare evolutionary potential of known genotypes in a controlled environment. Here we utilized a highly reproducible evolutionary adaptation in Saccharomyces cerevisiae to investigate whether experimental evolution of other yeast species would select for similar adaptive mutations. We evolved populations of S. cerevisiae, S. paradoxus, S. mikatae, S. uvarum, and interspecific hybrids between S. uvarum and S. cerevisiae for 200-500 generations in sulfate-limited continuous culture. Wild-type S. cerevisiae cultures invariably amplify the high affinity sulfate transporter gene, SUL1. However, while amplification of the SUL1 locus was detected in S. paradoxus and S. mikatae populations, S. uvarum cultures instead selected for amplification of the paralog, SUL2. We measured the relative fitness of strains bearing deletions and amplifications of both SUL genes from different species, confirming that, converse to S. cerevisiae, S. uvarum SUL2 contributes more to fitness in sulfate limitation than S. uvarum SUL1. By measuring the fitness and gene expression of chimeric promoter-ORF constructs, we were able to delineate the cause of this differential fitness effect primarily to the promoter of S. uvarum SUL1. Our data show evidence of differential sub-functionalization among the sulfur transporters across Saccharomyces species through recent changes in noncoding sequence. Furthermore, these results show a clear example of how such background differences due to paralog divergence can drive changes in genome evolution.
2016-09-30 | GSE87401 | GEO