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Non-genetic and genetic rewiring underlie adaptation to hypomorphic alleles of an essential gene.

ABSTRACT: Adaptive evolution to cellular stress is a process implicated in a wide range of biological and clinical phenomena. Two major routes of adaptation have been identified: non-genetic changes, which allow expression of different phenotypes in novel environments, and genetic variation achieved by selection of fitter phenotypes. While these processes are broadly accepted, their temporal and epistatic features in the context of cellular evolution and emerging drug resistance are contentious. In this manuscript, we generated hypomorphic alleles of the essential nuclear pore complex (NPC) gene NUP58. By dissecting early and long-term mechanisms of adaptation in independent clones, we observed that early physiological adaptation correlated with transcriptome rewiring and upregulation of genes known to interact with the NPC; long-term adaptation and fitness recovery instead occurred via focal amplification of NUP58 and restoration of mutant protein expression. These data support the concept that early phenotypic plasticity allows later acquisition of genetic adaptations to a specific impairment. We propose this approach as a genetic model to mimic targeted drug therapy in human cells and to dissect mechanisms of adaptation.

SUBMITTER: Targa A

PROVIDER: S-EPMC8561638 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Phenotypic plasticity and genetic rewiring underlie adaptation in response to hypomorphic alleles of an essential gene

Project description:Adaptive evolution in response to cellular stress is a critical process implicated in a wide range of core biological and clinical phenomena. Two major routes of adaptation have been identified: non-genetic cellular plasticity, which allows expression of different phenotypes in novel environments, and genetic variation achieved by selection of fitter phenotypes. While these processes are now broadly accepted, their temporal and epistatic features in the context of cellular evolution and emerging drug resistance are contentious. In this manuscript, we generated hypomorphic alleles of the essential nuclear pore complex (NPC) gene NUP58. By dissecting both early and long-term mechanisms of adaptation in independent clones, we observed that early physiological adaptation correlated with transcriptome rewiring and upregulation of genes known to interact with the NPC. In contrast, long-term adaptation and fitness recovery occurred via focal amplification of NUP58 and restoration of mutant protein expression. These data support the concept that plasticity-mediated and genetic routes can co-exist to enable cellular evolution, with early flexibility of phenotype allowing later acquisition of genetic adaptations to a specific impairment. We propose this approach as a genetic model to mimic targeted drug therapy in human cells and dissection of early and late adaptation. Targeting both mechanisms in parallel may reduce the emergence of drug resistance

2021-10-14 | GSE161061 | GEO

TMT-MS2_cellular adaptation to hypomorphic alleles of essential gene NUP58

Project description:Adaptive evolution in response to cellular stress is a critical process implicated in a wide range of core biological and clinical phenomena. Two major routes of adaptation have been identified: non-genetic cellular plasticity, which allows expression of different phenotypes in novel environments, and genetic variation achieved by selection of fitter phenotypes. While these processes are now broadly accepted, their temporal and epistatic features in the context of cellular evolution and emerging drug resistance are contentious. In this project, we generated hypomorphic alleles of the essential nuclear pore complex (NPC) gene NUP58. By dissecting both early and long-term mechanisms of adaptation in independent clones, we observed that early physiological adaptation correlated with transcriptome rewiring and upregulation of genes known to interact with the NPC. In contrast, long-term adaptation and fitness recovery occurred via focal amplification of NUP58 and restoration of mutant protein expression. These data support the concept that plasticity-mediated and genetic routes can co-exist to enable cellular evolution, with early flexibility of phenotype allowing later acquisition of genetic adaptations to a specific impairment. We propose this approach as a genetic model to mimic targeted drug therapy in human cells and to dissect early and late mechanisms of adaptation. Targeting both mechanisms in parallel may reduce the emergence of drug resistance.

2021-11-02 | PXD022255 | Pride

Phenotypic plasticity and genetic rewiring underlie adaptation in response to hypomorphic alleles of an essential gene

Project description:Phenotypic plasticity and genetic rewiring underlie adaptation in response to hypomorphic alleles of an essential gene

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Global coordination in adaptation to gene rewiring.

Project description:Gene rewiring is a common evolutionary phenomenon in nature that may lead to extinction for living organisms. Recent studies on synthetic biology demonstrate that cells can survive genetic rewiring. This survival (adaptation) is often linked to the stochastic expression of rewired genes with random transcriptional changes. However, the probability of adaptation and the underlying common principles are not clear. We performed a systematic survey of an assortment of gene-rewired Escherichia coli strains to address these questions. Three different cell fates, designated good survivors, poor survivors and failures, were observed when the strains starved. Large fluctuations in the expression of the rewired gene were commonly observed with increasing cell size, but these changes were insufficient for adaptation. Cooperative reorganizations in the corresponding operon and genome-wide gene expression largely contributed to the final success. Transcriptome reorganizations that generally showed high-dimensional dynamic changes were restricted within a one-dimensional trajectory for adaptation to gene rewiring, indicating a general path directed toward cellular plasticity for a successful cell fate. This finding of global coordination supports a mechanism of stochastic adaptation and provides novel insights into the design and application of complex genetic or metabolic networks.

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Novel Hypomorphic Alleles of the Mouse Tyrosinase Gene Induced by CRISPR-Cas9 Nucleases Cause Non-Albino Pigmentation Phenotypes.

Project description:Tyrosinase is a key enzyme in melanin biosynthesis. Mutations in the gene encoding tyrosinase (Tyr) cause oculocutaneous albinism (OCA1) in humans. Alleles of the Tyr gene have been useful in studying pigment biology and coat color formation. Over 100 different Tyr alleles have been reported in mice, of which ?24% are spontaneous mutations, ?60% are radiation-induced, and the remaining alleles were obtained by chemical mutagenesis and gene targeting. Therefore, most mutations were random and could not be predicted a priori. Using the CRISPR-Cas9 system, we targeted two distinct regions of exon 1 to induce pigmentation changes and used an in vivo visual phenotype along with heteroduplex mobility assays (HMA) as readouts of CRISPR-Cas9 activity. Most of the mutant alleles result in complete loss of tyrosinase activity leading to an albino phenotype. In this study, we describe two novel in-frame deletion alleles of Tyr, dhoosara (Sanskrit for gray) and chandana (Sanskrit for sandalwood). These alleles are hypomorphic and show lighter pigmentation phenotypes of the body and eyes. This study demonstrates the utility of CRISPR-Cas9 system in generating domain-specific in-frame deletions and helps gain further insights into structure-function of Tyr gene.

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Autosomal Dominant Polycystic Kidney Disease: Presence of Hypomorphic Alleles in <i>PKD1</i> Gene.

Project description:Autosomal dominant polycystic kidney disease is characterized by multiple cysts in both kidneys manifesting in adult life. In general, the disorder is caused by a pathogenic variant in one allele of PKD1 or PKD2 genes, while the other allele is normal. Pathogenic variants in both the alleles are rare and have variable phenotypes, from lethal or perinatal presentation to a mild form in later adulthood, depending on the type of variant. Here, we describe a proband with two variants (p.Thr1773Ile and p.Ala1871Thr in trans) in PKD1 gene, who presented with disease at age 24 years. Both the parents and one brother had a variant in one allele, the other being wild type only and had normal ultrasound findings. Segregation studies suggest that both the variants may act as "hypomorphic" or "incompletely penetrant" alleles and acting together resulted in haploinsufficiency of protein PC1 in renal cells, leading to cystogenesis in the proband. The consequences of the presence of two hypomorphic variants have been poorly documented in literature. We reviewed the few published cases having two hypomorphic variants and the data conform to the conclusions that we reached by study of the family described. It is emphasized that to resolve the significance of suspected hypomorphic variants, segregation studies in the parents and siblings are essential.

| S-EPMC6309388 | biostudies-literature

Hypomorphic temperature-sensitive alleles of NSDHL cause CK syndrome.

Project description:CK syndrome (CKS) is an X-linked recessive intellectual disability syndrome characterized by dysmorphism, cortical brain malformations, and an asthenic build. Through an X chromosome single-nucleotide variant scan in the first reported family, we identified linkage to a 5 Mb region on Xq28. Sequencing of this region detected a segregating 3 bp deletion (c.696_698del [p.Lys232del]) in exon 7 of NAD(P) dependent steroid dehydrogenase-like (NSDHL), a gene that encodes an enzyme in the cholesterol biosynthesis pathway. We also found that males with intellectual disability in another reported family with an NSDHL mutation (c.1098 dup [p.Arg367SerfsX33]) have CKS. These two mutations, which alter protein folding, show temperature-sensitive protein stability and complementation in Erg26-deficient yeast. As described for the allelic disorder CHILD syndrome, cells and cerebrospinal fluid from CKS patients have increased methyl sterol levels. We hypothesize that methyl sterol accumulation, not only cholesterol deficiency, causes CKS, given that cerebrospinal fluid cholesterol, plasma cholesterol, and plasma 24S-hydroxycholesterol levels are normal in males with CKS. In summary, CKS expands the spectrum of cholesterol-related disorders and insight into the role of cholesterol in human development.

| S-EPMC2997364 | biostudies-literature

EDA gene mutations underlie non-syndromic oligodontia.

Project description:Recent studies have detected mutations in the EDA gene, previously identified as causing X-linked hypohidrotic ectodermal dysplasia (XLHED), in two families with X-linked non-syndromic hypodontia. Notably, all affected males in both families exhibited isolated oligodontia, while almost all female carriers showed a milder or normal phenotype. We hypothesized that the EDA gene could be responsible for sporadic non-syndromic oligodontia in affected males. In this study, we examined 15 unrelated males with non-syndromic oligodontia. Three novel EDA mutations (p.Ala259Glu, p. Arg289Cys, and p.Arg334His) were identified in four individuals (27%). A genetic defect in the EDA gene could result in non-syndromic oligodontia in affected males.

| S-EPMC3317984 | biostudies-literature

Non-coding RNAs underlie genetic predisposition to breast cancer.

Project description:BACKGROUND:Genetic variants identified through genome-wide association studies (GWAS) are predominantly non-coding and typically attributed to altered regulatory elements such as enhancers and promoters. However, the contribution of non-coding RNAs to complex traits is not clear. RESULTS:Using targeted RNA sequencing, we systematically annotated multi-exonic non-coding RNA (mencRNA) genes transcribed from 1.5-Mb intervals surrounding 139 breast cancer GWAS signals and assessed their contribution to breast cancer risk. We identify more than 4000 mencRNA genes and show their expression distinguishes normal breast tissue from tumors and different breast cancer subtypes. Importantly, breast cancer risk variants, identified through genetic fine-mapping, are significantly enriched in mencRNA exons, but not the promoters or introns. eQTL analyses identify mencRNAs whose expression is associated with risk variants. Furthermore, chromatin interaction data identify hundreds of mencRNA promoters that loop to regions that contain breast cancer risk variants. CONCLUSIONS:We have compiled the largest catalog of breast cancer-associated mencRNAs to date and provide evidence that modulation of mencRNAs by GWAS variants may provide an alternative mechanism underlying complex traits.

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Project description:Mitogen-activated protein kinases (MAPKs) have a number of targets which they regulate at transcriptional and post-translational levels to mediate specific responses. The yeast Hog1 MAPK is essential for cell survival under hyperosmotic conditions and it plays multiple roles in gene expression, metabolic regulation, signal fidelity and cell cycle regulation. Here we describe essential and non-essential roles of Hog1 using engineered yeast cells in which osmoadaptation was reconstituted in a Hog1-independent manner. We rewired Hog1-dependent osmotic stress-induced gene expression under the control of Fus3/Kss1 MAPKs, which are activated upon osmostress via crosstalk in hog1Δ cells. This approach revealed that osmotic up-regulation of only two Hog1-dependent glycerol biosynthesis genes, GPD1 and GPP2, is sufficient for successful osmoadaptation. Moreover, some of the previously described Hog1-dependent mechanisms appeared to be dispensable for osmoadaptation in the engineered cells. These results suggest that the number of essential MAPK functions may be significantly smaller than anticipated and that knockout approaches may lead to over-interpretation of phenotypic data.

| S-EPMC3986706 | biostudies-literature

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