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Functional Diversification, Redundancy, and Epistasis among Paralogs of the Drosophila melanogaster Obp50a-d Gene Cluster.

ABSTRACT: Large multigene families, such as the insect odorant-binding proteins (OBPs), are thought to arise through functional diversification after repeated gene duplications. Whereas many OBPs function in chemoreception, members of this family are also expressed in tissues outside chemosensory organs. Paralogs of the Obp50 gene cluster are expressed in metabolic and male reproductive tissues, but their functions and interrelationships remain unknown. Here, we report the genetic dissection of four members of the Obp50 cluster, which are in close physical proximity without intervening genes. We used CRISPR technology to excise the entire cluster while introducing a PhiC31 reintegration site to reinsert constructs in which different combinations of the constituent Obp genes were either intact or rendered inactive. We performed whole transcriptome sequencing and assessed sexually dimorphic changes in transcript abundances (transcriptional niches) associated with each gene-edited genotype. Using this approach, we were able to estimate redundancy, additivity, diversification, and epistasis among Obp50 paralogs. We analyzed the effects of gene editing of this cluster on organismal phenotypes and found a significant skewing of sex ratios attributable to Obp50a, and sex-specific effects on starvation stress resistance attributable to Obp50d. Thus, there is functional diversification within the Obp50 cluster with Obp50a contributing to development and Obp50d to stress resistance. The deletion-reinsertion approach we applied to the Obp50 cluster provides a general paradigm for the genetic dissection of paralogs of multigene families.

SUBMITTER: Johnstun JA

PROVIDER: S-EPMC8097280 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Functional Diversification, Redundancy and Epistasis among Paralogs of the Drosophila melanogaster Obp50a-d Gene Cluster

Project description:Large multigene families, such as the insect odorant binding proteins (OBPs), are thought to arise through functional diversification after repeated gene duplications. Whereas many OBPs function in chemoreception, members of this family are also expressed in tissues outside chemosensory organs. Paralogs of the Obp50 gene cluster are expressed in metabolic and male reproductive tissues, but their functions and interrelationships remain unknown. Here, we report the genetic dissection of four members of the Obp50 cluster, which are in close physical proximity without intervening genes. We used CRISPR technology to excise the entire cluster while introducing a PhiC31 re-integration site to reinsert constructs in which different combinations of the constituent Obp genes were either intact or rendered inactive. We performed whole transcriptome sequencing and assessed sexually dimorphic changes in transcript abundances (“transcriptional niches”) associated with each gene-edited genotype. Using this approach, we were able to estimate redundancy, additivity, diversification, and epistasis among Obp50 paralogs. We analyzed the effects of gene editing of this cluster on organismal phenotypes and found a significant skewing of sex ratios attributable to Obp50a, and sex-specific effects on starvation stress resistance attributable to Obp50d. Thus there is functional diversification within the Obp50 cluster with Obp50a contributing to development and Obp50d to stress resistance. The deletion-reinsertion approach we applied to the Obp50 cluster provides a general paradigm for the genetic dissection of paralogs of multigene families.

2021-05-12 | GSE159393 | GEO

Functional Diversification, Redundancy and Epistasis among Paralogs of the Drosophila melanogaster Obp50a-d Gene Cluster

Project description:Functional Diversification, Redundancy and Epistasis among Paralogs of the Drosophila melanogaster Obp50a-d Gene Cluster

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Mitochondrial-Y chromosome epistasis in <i>Drosophila melanogaster</i>.

Project description:The coordination between mitochondrial and nuclear genes is crucial to eukaryotic organisms. Predicting the nature of these epistatic interactions can be difficult because of the transmission asymmetry of the genes involved. While autosomes and X-linked genes are transmitted through both sexes, genes on the Y chromosome and in the mitochondrial genome are uniparentally transmitted through males and females, respectively. Here, we generate 36 otherwise isogenic Drosophila melanogaster strains differing only in the geographical origin of their mitochondrial genome and Y chromosome, to experimentally examine the effects of the uniparentally inherited parts of the genome, as well as their interaction, in males. We assay longevity and gene expression through RNA-sequencing. We detect an important role for both mitochondrial and Y-linked genes, as well as extensive mitochondrial-Y chromosome epistasis. In particular, genes involved in male reproduction appear to be especially sensitive to such interactions, and variation on the Y chromosome is associated with differences in longevity. Despite these interactions, we find no evidence that the mitochondrial genome and Y chromosome are co-adapted within a geographical region. Overall, our study demonstrates a key role for the uniparentally inherited parts of the genome for male biology, but also that mito-nuclear interactions are complex and not easily predicted from simple transmission asymmetries.

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Mitochondrial - Y Chromosome Epistasis in Drosophila melanogaster

Project description:We generate 36 otherwise isogenic Drosophila melanogaster strains differing only in the geographical origin of their mitochondrial genome and Y chromosome to experimentally examine the effects of the uniparentaly inherited parts of the genome, as well as their interaction, in males. We assay gene expression through RNA-sequencing and detect an important role for both mitochondrial and Y-linked genes, as well as extensive mitochondrial-Y chromosome epistasis.

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High-resolution protein interaction map of the Drosophila melanogaster p38 mitogen-activated protein kinases reveals limited functional redundancy.

Project description:Functional redundancy is a pivotal mechanism that supports the robustness of biological systems at a molecular, cellular, and organismal level. The extensive prevalence of redundancy in molecular networks has been highlighted by recent systems biology studies; however, a detailed mechanistic understanding of redundant functions in specific signaling modules is often missing. We used affinity purification of protein complexes coupled to tandem mass spectrometry to generate a high-resolution protein interaction map of the three homologous p38 mitogen-activated protein kinases (MAPKs) in Drosophila and assessed the utility of such a map in defining the extent of common and unique functions. We found a correlation between the depth of integration of individual p38 kinases into the protein interaction network and their functional significance in cultured cells and in vivo. Based on these data, we propose a central role of p38b in the Drosophila p38 signaling module, with p38a and p38c playing more peripheral, auxiliary roles. We also present the first in vivo evidence demonstrating that an evolutionarily conserved complex of p38b with glycogen synthase links stress sensing to metabolic adaptation.

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Accelerated inbreeding depression suggests synergistic epistasis for deleterious mutations in Drosophila melanogaster.

Project description:Epistasis may have important consequences for a number of issues in quantitative genetics and evolutionary biology. In particular, synergistic epistasis for deleterious alleles is relevant to the mutation load paradox and the evolution of sex and recombination. Some studies have shown evidence of synergistic epistasis for spontaneous or induced deleterious mutations appearing in mutation-accumulation experiments. However, many newly arising mutations may not actually be segregating in natural populations because of the erasing action of natural selection. A demonstration of synergistic epistasis for naturally segregating alleles can be achieved by means of inbreeding depression studies, as deleterious recessive allelic effects are exposed in inbred lines. Nevertheless, evidence of epistasis from these studies is scarce and controversial. In this paper, we report the results of two independent inbreeding experiments carried out with two different populations of Drosophila melanogaster. The results show a consistent accelerated inbreeding depression for fitness, suggesting synergistic epistasis among deleterious alleles. We also performed computer simulations assuming different possible models of epistasis and mutational parameters for fitness, finding some of them to be compatible with the results observed. Our results suggest that synergistic epistasis for deleterious mutations not only occurs among newly arisen spontaneous or induced mutations, but also among segregating alleles in natural populations.

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Functional significance of isoform diversification in the protocadherin gamma gene cluster.

Project description:The mammalian Protocadherin (Pcdh) alpha, beta, and gamma gene clusters encode a large family of cadherin-like transmembrane proteins that are differentially expressed in individual neurons. The 22 isoforms of the Pcdhg gene cluster are diversified into A-, B-, and C-types, and the C-type isoforms differ from all other clustered Pcdhs in sequence and expression. Here, we show that mice lacking the three C-type isoforms are phenotypically indistinguishable from the Pcdhg null mutants, displaying virtually identical cellular and synaptic alterations resulting from neuronal apoptosis. By contrast, mice lacking three A-type isoforms exhibit no detectable phenotypes. Remarkably, however, genetically blocking apoptosis rescues the neonatal lethality of the C-type isoform knockouts, but not that of the Pcdhg null mutants. We conclude that the role of the Pcdhg gene cluster in neuronal survival is primarily, if not specifically, mediated by its C-type isoforms, whereas a separate role essential for postnatal development, likely in neuronal wiring, requires isoform diversity.

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Fitness Assays Reveal Incomplete Functional Redundancy of the HoxA1 and HoxB1 Paralogs of Mice.

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