Gene duplication and the environmental regulation of physiology and development.
Ontology highlight
ABSTRACT:
SUBMITTER: Gibbs DC
PROVIDER: S-EPMC4201434 | biostudies-literature | 2014 Jun
REPOSITORIES: biostudies-literature
Publications
Gene duplication and the environmental regulation of physiology and development.
Gibbs David C DC Donohue Kathleen K
Ecology and evolution 20140506 11
When different life stages have different environmental tolerances, development needs to be regulated so that each life stage experiences environmental conditions that are suitable for it, if fitness is to be maintained. Restricting the timing of developmental transitions to occur under specific combinations of environmental conditions is therefore adaptively important. However, impeding development can itself incur demographic and fitness costs. How do organisms regulate development and physiol ...[more]
Similar Datasets
Project description:BackgroundCopy number variants (CNVs) linked to genes involved in nervous system development or function are often associated with neuropsychiatric disease. While CNVs involving deletions generally cause severe and highly penetrant patient phenotypes, CNVs leading to duplications tend instead to exhibit widely variable and less penetrant phenotypic expressivity among affected individuals. CNVs located on chromosome 15q13.3 affecting the alpha-7 nicotinic acetylcholine receptor subunit (CHRNA7) gene contribute to multiple neuropsychiatric disorders with highly variable penetrance. However, the basis of such differential penetrance remains uncharacterized. Here, we generated induced pluripotent stem cell (iPSC) models from first-degree relatives with a 15q13.3 duplication and analyzed their cellular phenotypes to uncover a basis for the dissimilar phenotypic expressivity.ResultsThe first-degree relatives studied included a boy with autism and emotional dysregulation (the affected proband-AP) and his clinically unaffected mother (UM), with comparison to unrelated control models lacking this duplication. Potential contributors to neuropsychiatric impairment were modeled in iPSC-derived cortical excitatory and inhibitory neurons. The AP-derived model uniquely exhibited disruptions of cellular physiology and neurodevelopment not observed in either the UM or unrelated controls. These included enhanced neural progenitor proliferation but impaired neuronal differentiation, maturation, and migration, and increased endoplasmic reticulum (ER) stress. Both the neuronal migration deficit and elevated ER stress could be selectively rescued by different pharmacologic agents. Neuronal gene expression was also dysregulated in the AP, including reduced expression of genes related to behavior, psychological disorders, neuritogenesis, neuronal migration, and Wnt, axonal guidance, and GABA receptor signaling. The UM model instead exhibited upregulated expression of genes in many of these same pathways, suggesting that molecular compensation could have contributed to the lack of neurodevelopmental phenotypes in this model. However, both AP- and UM-derived neurons exhibited shared alterations of neuronal function, including increased action potential firing and elevated cholinergic activity, consistent with increased homomeric CHRNA7 channel activity.ConclusionsThese data define both diagnosis-associated cellular phenotypes and shared functional anomalies related to CHRNA7 duplication that may contribute to variable phenotypic penetrance in individuals with 15q13.3 duplication. The capacity for pharmacological agents to rescue some neurodevelopmental anomalies associated with diagnosis suggests avenues for intervention for carriers of this duplication and other CNVs that cause related disorders.
| S-EPMC8317352 | biostudies-literature
Project description:Aim To identify genes which are differentially expressed between calcicoles and non- calcicoles. Background Grasslands on the calcareous soils of chalk and other limestones are among the most species-rich plant communities in Europe (Rodwell 1991 et seq.). They have experienced huge losses and remain vulnerable to such impacts as neglect of traditional management, agricultural improvement and global changes in climate, nitrogen depositions and ozone levels. Our understanding of the physiological characteristics of calcicoles and calcifuges remains limited. A detailed understanding of the genetic basis of the mechanisms that enable calcicoles to thrive on calcareous soils is essential to enable us to predict how these plant communities and their constituent species will be affected by environmental change and how the biodiversity of these ecosystems can be sustained.At Lancaster we have been studying calcicole-calcifuge physiology, with particular reference to Ca2+-tolerance, for over fifteen years. Recently, our research has focused on the regulation of apoplastic Ca2+ in Arabidospsis thaliana. We have compared the response of two ecotypes of A. thaliana, the non-calcicole ecotype Columbia (Col-4) and the calcicole ecotype Cal-0, which is a genetically uniform line from an original population collected by Ratcliffe from a rocky limestone slope in 1954, to rhizospheric Ca2+. Our results show that Cal-0, exhibits a markedly higher tolerance to growth on high rhizospheric Ca2+ compared to Col-4.Our hypothesis is that adaptation to a calcareous environment will be reflected in altered gene expression. To test this hypothesis we will grow Col-4 and Cal-0 at low (1 mM) and high (12.5 mM) rhizospheric Ca2+ and compare the patterns of gene expression by microarray analysis. In the first instance, to eliminate any differences in gene expression between the Cal-0 and Col-4 ecotypes, we will compare RNA that will be extracted using the Qiagen RNEasy kits, from plants grown at 16 hour day lengths and will be harvested after 30 days of growth on sand watered with 0.5 X Long Ashton solution containing 1 mM CaCl2. Experimenter name = Bev Abram Experimenter phone = 01524 65201ext93524 Experimenter fax = 01524 843854 Experimenter address = Biological Sciences Experimenter address = Lancaster University Experimenter address = Bailrigg Experimenter address = Lancaster Experimenter zip/postal_code = LA1 4YQ Experimenter country = UK Keywords: strain_or_line_design
2007-01-08 | GSE5728 | GEO
Project description:The purpose of this set of arrays is to provide a third replicate to use in data analysis addition to the 2 previous replicates for all samples already generated on this project. Our hypothesis is that adaptation to a calcareous environment will be reflected in altered gene expression including genes encoding transporters, ion channels, transcription factors, etc. To test this hypothesis we grew a laboratory non-calcicole (Col-4) and a laboratory calcicole (Cal-0) ecotypes of A. thaliana at low (1 mM) and high (12.5 mM) rhizospheric Ca2+ and compare the patterns of gene expression by microarray analysis. We then collected from the wild, a putative calcicole ecotype (Elland)and a putative non-calcicole (Penicuik) and grew both at low (1 mM) and high (12.5 mM) rhizospheric Ca2+ and compared expression profiles to the laboratory ecotypes. Experimenter name = Bev Abram Experimenter phone = 01524 592931 Experimenter address = Dept Biological Sciences Experimenter address = Lancaster University Experimenter address = Bailrigg Experimenter address = Lancaster Experimenter zip/postal_code = LA1 4YQ Experimenter country = UK Keywords: growth_condition_design; strain_or_line_design
2006-08-15 | GSE5523 | GEO
Project description:Primary outcome(s): Development of Gene - Environmental interaction risk score methodology and Gene - Environmental Risk Score (GERS) of colorectal cancer;Development of high risk criteria that could be applied final GERS prediction model
Study Design: Observational Study Model : Cohort, Time Perspective : Other(Prospective+Retrospective), Enrollment : 270000, Biospecimen Retention : Collect & Archive- Sample with DNA, Biospecimen Description : whole blood, serum, urine
| 2509007 | ecrin-mdr-crc
Project description:Social environmental conditions, particularly the experience of social adversity, have long been connected with health and mortality in humans and other social mammals. Efforts to identify the physiological basis for these effects have historically focused on their neurological, endocrinological, and immunological consequences. Recently, this search has been extended to understanding the role of gene regulation in sensing, mediating, and determining susceptibility to social environmental variation. Studies in laboratory rodents, captive primates, and human populations have revealed correlations between social conditions and the regulation of a large number of genes, some of which are likely causal. Gene expression responses to the social environment are, in turn, mediated by a set of underlying regulatory mechanisms, of which epigenetic marks are the best studied to date. Importantly, a number of genes involved in the response to the social environment are also associated with susceptibility to other external stressors, as well as certain diseases. Hence, gene regulatory studies are a promising avenue for understanding, and potentially developing strategies to address, the effects of social adversity on health.
| S-EPMC3809334 | biostudies-literature
Project description:Copy number variants at chromosome 15q13.3 contribute to liability for multiple intellectual and developmental disabilities (IDDs) including Autism Spectrum Disorder (ASD). Individuals with duplications of this interval, which includes the gene CHRNA7, have IDDs with variable penetrance. However, the basis of such differential affectation remains uncharacterized.Methods: Induced pluripotent stem cell (iPSC) models were generated from two first degree relatives with the same 15q13.3 duplication, a boy with distinct features of autism and emotional dysregulation (the affected proband, AP) and his clinically unaffected mother (the UM). These models were compared to unrelated control subjects lacking this duplication (UC, male and female). iPSC-derived neural progenitors and cortical neuroids consisting of cortical excitatory and inhibitory neurons were used to model potential contributors to neuropsychiatric impairment. Results: The AP-derived model uniquely exhibited disruptions of cellular physiology and neurodevelopment not observed in either the UM or in unrelated male and female controls. These included enhanced neural progenitor proliferation but impaired neuronal differentiation, maturation, and migration, and increased endoplasmic reticulum (ER) stress in neural progenitors. Both the AP’s neuronal migration deficit and elevated ER stress could be selectively rescued by different pharmacologic agents. Neuronal gene expression was also specifically dysregulated in the AP, including altered expression of genes related to behavior, psychological disorders, neuritogenesis, neuronal migration, and WNT signaling. By contrast with these AP-specific phenotypes, both the AP- and UM-derived neurons exhibited shared alterations of neuronal function, including elevated cholinergic activity consistent with increased homomeric CHRNA7 channel activity.Conclusion: Together, these data define both affectation-specific phenotypes seen only in the AP, as well as abnormalities observed in both individuals with CHRNA7 duplication, the AP and UM, but not in UC-derived neurons. This is, to our knowledge, the first study to use a human stem cell-based platform to study the basis of variable affectation in cases of 15q13.3 duplication at the cellular, molecular, and functional levels. This work suggests potential approaches for suppressing abnormal neurodevelopment or physiology that may contribute to severity of affectation in this proband. Some of these AP-specific neurodevelopmental anomalies, or the functional anomalies observed in both 15q13.3 duplication carriers (the AP and UM), could also contribute to the differential phenotypic penetrance seen in other individuals with 15q13.3 duplication.
2021-06-07 | GSE143908 | GEO
Project description:Across taxa, circadian control of physiology and behavior arises from cell-autonomous oscillations in gene expression, governed by a networks of so-called 'clock genes', collectively forming transcription-translation feedback loops. In modern vertebrates, these networks contain multiple copies of clock gene family members, which arose through whole genome duplication (WGD) events during evolutionary history. It remains unclear to what extent multiple copies of clock gene family members are functionally redundant or have allowed for functional diversification. We addressed this problem through an analysis of clock gene expression in the Atlantic salmon, a representative of the salmonids, a group which has undergone at least 4 rounds of WGD since the base of the vertebrate lineage, giving an unusually large complement of clock genes. By comparing expression patterns across multiple tissues, and during development, we present evidence for gene- and tissue-specific divergence in expression patterns, consistent with functional diversification of clock gene duplicates. In contrast to mammals, we found no evidence for coupling between cortisol and circadian gene expression, but cortisol mediated non-circadian regulated expression of a subset of clock genes in the salmon gill was evident. This regulation is linked to changes in gill function necessary for the transition from fresh- to sea-water in anadromous fish. Overall, this analysis emphasises the potential for a richly diversified clock gene network to serve a mixture of circadian and non-circadian functions in vertebrate groups with complex genomes.
| S-EPMC7575087 | biostudies-literature
Project description:Coexpression of genes within a functional module can be conserved at great evolutionary distances, whereas the associated regulatory mechanisms can substantially diverge. For example, ribosomal protein (RP) genes are tightly coexpressed in Saccharomyces cerevisiae, but the cis and trans factors associated with them are surprisingly diverged across Ascomycota fungi. Little is known, however, about the functional impact of such changes on actual expression levels or about the selective pressures that affect them. Here, we address this question in the context of the evolution of the regulation of RP gene expression by using a comparative genomics approach together with cross-species functional assays. We show that an activator (Ifh1) and a repressor (Crf1) that control RP gene regulation in normal and stress conditions in S. cerevisiae are derived from the duplication and subsequent specialization of a single ancestral protein. We provide evidence that this regulatory innovation coincides with the duplication of RP genes in a whole-genome duplication (WGD) event and may have been important for tighter control of higher levels of RP transcripts. We find that subsequent loss of the derived repressor led to the loss of a stress-dependent repression of RPs in the fungal pathogen Candida glabrata. Our comparative computational and experimental approach shows how gene duplication can constrain and drive regulatory evolution and provides a general strategy for reconstructing the evolutionary trajectory of gene regulation across species.
| S-EPMC2851827 | biostudies-other
Project description:BackgroundSleep disturbances in autism spectrum disorder (ASD) represent a common and vexing comorbidity. Clinical heterogeneity amongst these warrants studies of the mechanisms associated with specific genetic etiologies. Duplications of 15q11.2-13.1 (Dup15q syndrome) are highly penetrant for neurodevelopmental disorders (NDDs) such as intellectual disability and ASD, as well as sleep disturbances. Genes in the 15q region, particularly UBE3A and a cluster of GABAA receptor genes, are critical for neural development, synaptic protein synthesis and degradation, and inhibitory neurotransmission. During awake electroencephalography (EEG), children with Dup15q syndrome demonstrate increased beta band oscillations (12-30 Hz) that likely reflect aberrant GABAergic neurotransmission. Healthy sleep rhythms, necessary for robust cognitive development, are also highly dependent on GABAergic neurotransmission. We therefore hypothesized that sleep physiology would be abnormal in children with Dup15q syndrome.MethodsTo test the hypothesis that elevated beta oscillations persist in sleep in Dup15q syndrome and that NREM sleep rhythms would be disrupted, we computed: (1) beta power, (2) spindle density, and (3) percentage of slow-wave sleep (SWS) in overnight sleep EEG recordings from a cohort of children with Dup15q syndrome (n = 15) and compared them to age-matched neurotypical children (n = 12).ResultsChildren with Dup15q syndrome showed abnormal sleep physiology with elevated beta power, reduced spindle density, and reduced or absent SWS compared to age-matched neurotypical controls.LimitationsThis study relied on clinical EEG where sleep staging was not available. However, considering that clinical polysomnograms are challenging to collect in this population, the ability to quantify these biomarkers on clinical EEG-routinely ordered for epilepsy monitoring-opens the door for larger-scale studies. While comparable to other human studies in rare genetic disorders, a larger sample would allow for examination of the role of seizure severity, medications, and developmental age that may impact sleep physiology.ConclusionsWe have identified three quantitative EEG biomarkers of sleep disruption in Dup15q syndrome, a genetic condition highly penetrant for ASD. Insights from this study not only promote a greater mechanistic understanding of the pathophysiology defining Dup15q syndrome, but also lay the foundation for studies that investigate the association between sleep and cognition. Abnormal sleep physiology may undermine healthy cognitive development and may serve as a quantifiable and modifiable target for behavioral and pharmacological interventions.
| S-EPMC8336244 | biostudies-literature
Project description:Changes in cis-regulatory regions are thought to play a major role in the genetic basis of adaptation. However, few studies have linked cis-regulatory variation with adaptation in natural populations. Here, using a combination of exome and RNA-seq data, we performed expression quantitative trait locus (eQTL) mapping and allele-specific expression analyses to study the genetic architecture of regulatory variation in wild house mice (Mus musculus domesticus) using individuals from five populations collected along a latitudinal cline in eastern North America. Mice in this transect showed clinal patterns of variation in several traits, including body mass. Mice were larger in more northern latitudes, in accordance with Bergmann's rule. We identified 17 genes where cis-eQTLs were clinal outliers and for which expression level was correlated with latitude. Among these clinal outliers, we identified two genes (Adam17 and Bcat2) with cis-eQTLs that were associated with adaptive body mass variation and for which expression is correlated with body mass both within and between populations. Finally, we performed a weighted gene co-expression network analysis (WGCNA) to identify expression modules associated with measures of body size variation in these mice. These findings demonstrate the power of combining gene expression data with scans for selection to identify genes involved in adaptive phenotypic evolution, and also provide strong evidence for cis-regulatory elements as essential loci of environmental adaptation in natural populations.
| S-EPMC6211637 | biostudies-literature