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Trends in Ecology & Evolution Aug 2015Phenotypic traits influence species distributions, but ecology lacks established links between multidimensional phenotypes and fitness for predicting species responses... (Review)
Review
Phenotypic traits influence species distributions, but ecology lacks established links between multidimensional phenotypes and fitness for predicting species responses to environmental change. The common focus on single traits rather than multiple trait combinations limits our understanding of their adaptive value, and intraspecific trait covariation has been neglected in ecology despite its importance in evolutionary theory and its likely impact on species distributions. Here, we extend the adaptive landscape framework to ecological sorting of multidimensional phenotypes across environments and discuss how two analytical approaches can be used to quantify fitness as a function of the interaction between the phenotype and the environment. We encourage ecologists to consider how phenotypic integration will constrain species responses to environmental change.
Topics: Adaptation, Biological; Biological Evolution; Environment; Genetic Fitness; Phenotype
PubMed: 26122484
DOI: 10.1016/j.tree.2015.06.003 -
Journal of Paediatrics and Child Health Apr 2015There are many current and evolving tools to assist clinicians in their daily work of phenotyping. In medicine, the term 'phenotype' is usually taken to mean some... (Review)
Review
There are many current and evolving tools to assist clinicians in their daily work of phenotyping. In medicine, the term 'phenotype' is usually taken to mean some deviation from normal morphology, physiology and behaviour. It is ascertained via history, examination and investigations, and a primary aim is diagnosis. Therefore, doctors are, by necessity, expert 'phenotypers'. There is an inherent and partially realised power in phenotypic information that when harnessed can improve patient care. Furthermore, phenotyping developments are increasingly important in an era of rapid advances in genomic technology. Fortunately, there is an expanding network of phenotyping tools that are poised for clinical translation. These tools will preferentially be implemented to mirror clinical workflows and to integrate with advances in genomic and information-sharing technologies. This will synergise with and augment the clinical acumen of medical practitioners. We outline key enablers of the ascertainment, integration and interrogation of clinical phenotype by using genetic diseases, particularly rare ones, as a theme. Successes from the test bed or rare diseases will support approaches to common disease.
Topics: Genetic Diseases, Inborn; Genotype; Humans; Medical History Taking; Phenotype; Physical Examination; Precision Medicine
PubMed: 25109851
DOI: 10.1111/jpc.12705 -
PloS One 2022Previous studies have suggested that gene-environment interactions (GEIs) between a common variant and an environmental factor can influence multiple correlated... (Meta-Analysis)
Meta-Analysis
Previous studies have suggested that gene-environment interactions (GEIs) between a common variant and an environmental factor can influence multiple correlated phenotypes simultaneously, that is, GEI pleiotropy, and that analyzing multiple phenotypes jointly is more powerful than analyzing phenotypes separately by using single-phenotype GEI tests. Methods to test the GEI for rare variants with multiple phenotypes are, however, lacking. In our work, we model the correlation among the GEI effects of a variant on multiple quantitative phenotypes through four kernels and propose four multiphenotype GEI tests for rare variants, which are a test with a homogeneous kernel (Hom-GEI), a test with a heterogeneous kernel (Het-GEI), a test with a projection phenotype kernel (PPK-GEI) and a test with a linear phenotype kernel (LPK-GEI). Through numerical simulations, we show that correlation among phenotypes can enhance the statistical power except for LPK-GEI, which simply combines statistics from single-phenotype GEI tests and ignores the phenotypic correlations. Among almost all considered scenarios, Het-GEI and PPK-GEI are more powerful than Hom-GEI and LPK-GEI. We apply Het-GEI and PPK-GEI in the genome-wide GEI analysis of systolic blood pressure (SBP) and diastolic blood pressure (DBP) in the UK Biobank. We analyze 18,101 genes and find that LEUTX is associated with SBP and DBP (p = 2.20×10-6) through its interaction with hemoglobin. The single-phenotype GEI test and our multiphenotype GEI tests Het-GEI and PPK-GEI are also used to evaluate the gene-hemoglobin interactions for 22 genes that were previously reported to be associated with SBP or DBP in a meta-analysis of genetic main effects. MYO1C shows nominal significance (p < 0.05) by the Het-GEI test. NOS3 shows nominal significance in DBP and MYO1C in both SBP and DBP by the single-phenotype GEI test.
Topics: Epistasis, Genetic; Gene-Environment Interaction; Models, Genetic; Phenotype
PubMed: 36223383
DOI: 10.1371/journal.pone.0275929 -
BioEssays : News and Reviews in... Sep 2022Evolutionary biology is paying increasing attention to the mechanisms that enable phenotypic plasticity, evolvability, and extra-genetic inheritance. Yet, there is a...
Evolutionary biology is paying increasing attention to the mechanisms that enable phenotypic plasticity, evolvability, and extra-genetic inheritance. Yet, there is a concern that these phenomena remain insufficiently integrated within evolutionary theory. Understanding their evolutionary implications would require focusing on phenotypes and their variation, but this does not always fit well with the prevalent genetic representation of evolution that screens off developmental mechanisms. Here, we instead use development as a starting point, and represent it in a way that allows genetic, environmental and epigenetic sources of phenotypic variation to be independent. We show why this representation helps to understand the evolutionary consequences of both genetic and non-genetic phenotype determinants, and discuss how this approach can instigate future areas of empirical and theoretical research.
Topics: Adaptation, Physiological; Biological Evolution; Genetic Variation; Genotype; Phenotype
PubMed: 35863907
DOI: 10.1002/bies.202100225 -
Trends in Cell Biology Jun 2024Non-genetic alterations can produce changes in a cell's phenotype. In cancer, these phenomena can influence a cell's fitness by conferring access to heritable,... (Review)
Review
Non-genetic alterations can produce changes in a cell's phenotype. In cancer, these phenomena can influence a cell's fitness by conferring access to heritable, beneficial phenotypes. Herein, we argue that current discussions of 'phenotypic plasticity' in cancer evolution ignore a salient feature of the original definition: namely, that it occurs in response to an environmental change. We suggest 'phenotypic noise' be used to distinguish non-genetic changes in phenotype that occur independently from the environment. We discuss the conceptual and methodological techniques used to identify these phenomena during cancer evolution. We propose that the distinction will guide efforts to define mechanisms of phenotype change, accelerate translational work to manipulate phenotypes through treatment, and, ultimately, improve patient outcomes.
Topics: Animals; Humans; Cell Plasticity; Neoplasms; Phenotype; Evolution, Molecular
PubMed: 37968225
DOI: 10.1016/j.tcb.2023.10.002 -
Annual Review of Pharmacology and... Jan 2024Pharmacogenomics (PGx) enables personalized treatment for the prediction of drug response and to avoid adverse drug reactions. Currently, PGx mainly relies on the... (Review)
Review
Pharmacogenomics (PGx) enables personalized treatment for the prediction of drug response and to avoid adverse drug reactions. Currently, PGx mainly relies on the genetic information of absorption, distribution, metabolism, and excretion (ADME) targets such as drug-metabolizing enzymes or transporters to predict differences in the patient's phenotype. However, there is evidence that the phenotype-genotype concordance is limited. Thus, we discuss different phenotyping strategies using exogenous xenobiotics (e.g., drug cocktails) or endogenous compounds for phenotype prediction. In particular, minimally invasive approaches focusing on liquid biopsies offer great potential to preemptively determine metabolic and transport capacities. Early studies indicate that ADME phenotyping using exosomes released from the liver is reliable. In addition, pharmacometric modeling and artificial intelligence improve phenotype prediction. However, further prospective studies are needed to demonstrate the clinical utility of individualized treatment based on phenotyping strategies, not only relying on genetics. The present review summarizes current knowledge and limitations.
Topics: Humans; Artificial Intelligence; Genotype; Biomarkers; Phenotype; Drug-Related Side Effects and Adverse Reactions
PubMed: 37585662
DOI: 10.1146/annurev-pharmtox-032023-121106 -
Mammalian Genome : Official Journal of... Oct 2015New sequencing technologies have ushered in a new era for diagnosis and discovery of new causative mutations for rare diseases. However, the sheer numbers of candidate... (Review)
Review
New sequencing technologies have ushered in a new era for diagnosis and discovery of new causative mutations for rare diseases. However, the sheer numbers of candidate variants that require interpretation in an exome or genomic analysis are still a challenging prospect. A powerful approach is the comparison of the patient's set of phenotypes (phenotypic profile) to known phenotypic profiles caused by mutations in orthologous genes associated with these variants. The most abundant source of relevant data for this task is available through the efforts of the Mouse Genome Informatics group and the International Mouse Phenotyping Consortium. In this review, we highlight the challenges in comparing human clinical phenotypes with mouse phenotypes and some of the solutions that have been developed by members of the Monarch Initiative. These tools allow the identification of mouse models for known disease-gene associations that may otherwise have been overlooked as well as candidate genes may be prioritized for novel associations. The culmination of these efforts is the Exomiser software package that allows clinical researchers to analyse patient exomes in the context of variant frequency and predicted pathogenicity as well the phenotypic similarity of the patient to any given candidate orthologous gene.
Topics: Animals; Computational Biology; Databases, Genetic; Disease Models, Animal; Exome; Genetic Diseases, Inborn; Genomics; Humans; Mice; Mutation; Phenotype
PubMed: 26092691
DOI: 10.1007/s00335-015-9577-8 -
Philosophical Transactions of the Royal... Jul 2022Identifying the general principles by which genotypes are converted into phenotypes remains a challenge in the post-genomic era. We still lack a predictive understanding... (Review)
Review
Identifying the general principles by which genotypes are converted into phenotypes remains a challenge in the post-genomic era. We still lack a predictive understanding of how genes shape interactions among cells and tissues in response to signalling and environmental cues, and hence how regulatory networks generate the phenotypic variation required for adaptive evolution. Here, we discuss how techniques borrowed from synthetic biology may facilitate a systematic exploration of evolvability across biological scales. Synthetic approaches permit controlled manipulation of both endogenous and fully engineered systems, providing a flexible platform for investigating causal mechanisms . Combining synthetic approaches with multi-level phenotyping (phenomics) will supply a detailed, quantitative characterization of how internal and external stimuli shape the morphology and behaviour of living organisms. We advocate integrating high-throughput experimental data with mathematical and computational techniques from a variety of disciplines in order to pursue a comprehensive theory of evolution. This article is part of the theme issue 'Genetic basis of adaptation and speciation: from loci to causative mutations'.
Topics: Adaptation, Physiological; Animals; Genome; Genomics; Phenotype; Synthetic Biology
PubMed: 35634925
DOI: 10.1098/rstb.2020.0517 -
Mammalian Genome : Official Journal of... Jun 2019The International Mouse Phenotyping Consortium (IMPC) continues to expand the catalogue of mammalian gene function by conducting genome and phenome-wide phenotyping on... (Review)
Review
The International Mouse Phenotyping Consortium (IMPC) continues to expand the catalogue of mammalian gene function by conducting genome and phenome-wide phenotyping on knockout mouse lines. The extensive and standardized phenotype screens allow the identification of new potential models for human disease through cross-species comparison by computing the similarity between the phenotypes observed in the mutant mice and the human phenotypes associated to their orthologous loci in Mendelian disease. Here, we present an update on the novel disease models available from the most recent data release (DR10.0), with 5861 mouse genes fully or partially phenotyped and a total number of 69,982 phenotype calls reported. With approximately one-third of human Mendelian genes with orthologous null mouse phenotypes described, the range of available models relevant for human diseases keeps increasing. Among the breadth of new data, we identify previously uncharacterized disease genes in the mouse and additional phenotypes for genes with existing mutant lines mimicking the associated disorder. The automated and unbiased discovery of relevant models for all types of rare diseases implemented by the IMPC constitutes a powerful tool for human genetics and precision medicine.
Topics: Animals; Disease Models, Animal; Genome; Humans; Mice; Mice, Knockout; Phenotype; Precision Medicine
PubMed: 31127358
DOI: 10.1007/s00335-019-09804-5 -
Current Opinion in Microbiology Aug 2023How microbes interact with their environment and how the complex interplay of their genes enables them to survive and thrive under stress is a fundamental question in... (Review)
Review
How microbes interact with their environment and how the complex interplay of their genes enables them to survive and thrive under stress is a fundamental question in microbial system biology, which is also important from a public health perspective. Large-scale studies of gene-gene, gene-drug, and drug-drug interactions have proven to be powerful tools for elucidating gene function and functional modules in the cell. Approaches that systematically quantify phenotypes in libraries of microbial strains with genome-wide genetic perturbations are crucial for progress in this area. Here, we review recent advances in this field, and point out applications to the study of gene-drug interactions. We highlight newly developed techniques for the rapid generation of genome-wide mutant libraries and the high-throughput measurement of more complex phenotypes and other observables, such as cell morphology or thermal stability of the proteome.
Topics: Phenotype; Genome
PubMed: 37276805
DOI: 10.1016/j.mib.2023.102333