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Advanced high-throughput plant phenotyping techniques for genome-wide association studies: A review.Journal of Advanced Research Jan 2022Linking phenotypes and genotypes to identify genetic architectures that regulate important traits is crucial for plant breeding and the development of plant genomics. In... (Review)
Review
Linking phenotypes and genotypes to identify genetic architectures that regulate important traits is crucial for plant breeding and the development of plant genomics. In recent years, genome-wide association studies (GWASs) have been applied extensively to interpret relationships between genes and traits. Successful GWAS application requires comprehensive genomic and phenotypic data from large populations. Although multiple high-throughput DNA sequencing approaches are available for the generation of genomics data, the capacity to generate high-quality phenotypic data is lagging far behind. Traditional methods for plant phenotyping mostly rely on manual measurements, which are laborious, inaccurate, and time-consuming, greatly impairing the acquisition of phenotypic data from large populations. In contrast, high-throughput phenotyping has unique advantages, facilitating rapid, non-destructive, and high-throughput detection, and, in turn, addressing the shortcomings of traditional methods. This review summarizes the current status with regard to the integration of high-throughput phenotyping and GWAS in plants, in addition to discussing the inherent challenges and future prospects. High-throughput phenotyping, which facilitates non-contact and dynamic measurements, has the potential to offer high-quality trait data for GWAS and, in turn, to enhance the unraveling of genetic structures of complex plant traits. In conclusion, high-throughput phenotyping integration with GWAS could facilitate the revealing of coding information in plant genomes.
Topics: Genome, Plant; Genome-Wide Association Study; Genotype; Phenotype; Plant Breeding
PubMed: 35003802
DOI: 10.1016/j.jare.2021.05.002 -
Development and Psychopathology Nov 2012Despite substantial recent advancements in psychiatric genetic research, progress in identifying the genetic basis of anxiety disorders has been limited. We review the... (Review)
Review
Despite substantial recent advancements in psychiatric genetic research, progress in identifying the genetic basis of anxiety disorders has been limited. We review the candidate gene and genome-wide literatures in anxiety, which have made limited progress to date. We discuss several reasons for this hindered progress, including small samples sizes, heterogeneity, complicated comorbidity profiles, and blurred lines between normative and pathological anxiety. To address many of these challenges, we suggest a developmental, multivariate framework that can inform and enhance anxiety phenotypes for genetic research. We review the psychiatric and genetic epidemiological evidence that supports such a framework, including the early onset and chronic course of anxiety disorders, shared genetic risk factors among disorders both within and across time, and developmentally dynamic genetic influences. We propose three strategies for developmentally sensitive phenotyping: examination of early temperamental risk factors, use of latent factors to model underlying anxiety liability, and use of developmental trajectories as phenotypes. Expanding the range of phenotypic approaches will be important for advancing studies of the genetic architecture of anxiety disorders.
Topics: Adolescent; Adolescent Development; Adult; Anxiety Disorders; Child; Child Development; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Phenotype
PubMed: 23062290
DOI: 10.1017/S0954579412000636 -
Briefings in Bioinformatics Sep 2016Phenotypes have gained increased notoriety in the clinical and biological domain owing to their application in numerous areas such as the discovery of disease genes and...
Phenotypes have gained increased notoriety in the clinical and biological domain owing to their application in numerous areas such as the discovery of disease genes and drug targets, phylogenetics and pharmacogenomics. Phenotypes, defined as observable characteristics of organisms, can be seen as one of the bridges that lead to a translation of experimental findings into clinical applications and thereby support 'bench to bedside' efforts. However, to build this translational bridge, a common and universal understanding of phenotypes is required that goes beyond domain-specific definitions. To achieve this ambitious goal, a digital revolution is ongoing that enables the encoding of data in computer-readable formats and the data storage in specialized repositories, ready for integration, enabling translational research. While phenome research is an ongoing endeavor, the true potential hidden in the currently available data still needs to be unlocked, offering exciting opportunities for the forthcoming years. Here, we provide insights into the state-of-the-art in digital phenotyping, by means of representing, acquiring and analyzing phenotype data. In addition, we provide visions of this field for future research work that could enable better applications of phenotype data.
Topics: Humans; Information Storage and Retrieval; Phenotype; Research Design; Translational Research, Biomedical
PubMed: 26420780
DOI: 10.1093/bib/bbv083 -
Advances in Genetics 2016Phenotype is defined as the state of an organism resulting from interactions between genes, environment, disease, molecular mechanisms, and chance. The purpose of the... (Review)
Review
Phenotype is defined as the state of an organism resulting from interactions between genes, environment, disease, molecular mechanisms, and chance. The purpose of the emerging field of phenomics is to systematically determine and measure phenotypes across biology for the sake of understanding. Phenotypes can affect more than one cell type and life stage, so ideal phenotyping would include the state of every cell type within the context of both tissue architecture and the whole organism at each life stage. In medicine, high-resolution anatomic assessment of phenotype is obtained from histology. Histology's interpretative power, codified by Virchow as cellular pathology, is derived from its ability to discern diagnostic and characteristic cellular changes in diseased tissues. Cellular pathology is observed in every major human disease and relies on the ability of histology to detect cellular change in any cell type due to unbiased pan-cellular staining, even in optically opaque tissues. Our laboratory has shown that histology is far more sensitive than stereomicroscopy for detecting phenotypes in zebrafish mutants. Those studies have also shown that more complete sampling, greater consistency in sample orientation, and the inclusion of phenotypes extending over longer length scales would provide greater coverage of common phenotypes. We are developing technical approaches to achieve an ideal detection of cellular pathology using an improved form of X-ray microtomography that retains the strengths and addresses the weaknesses of histology as a screening tool. We are using zebrafish as a vertebrate model based on the overlaps between zebrafish and mammalian tissue architecture, and a body size small enough to allow whole-organism, volumetric imaging at cellular resolution. Automation of whole-organism phenotyping would greatly increase the value of phenomics. Potential societal benefits would include reduction in the cost of drug development, a reduction in the incidence of unexpected severe drug and environmental toxicity, and more rapid elucidation of the contributions of genes and the environment to phenotypes, including the validation of candidate disease alleles identified in population and personal genetics.
Topics: Animals; Environment; Genomics; Humans; Models, Animal; Phenotype; Zebrafish
PubMed: 27503355
DOI: 10.1016/bs.adgen.2016.05.003 -
AMIA ... Annual Symposium Proceedings.... 2022Acute kidney injury (AKI) is a life-threatening and heterogeneous syndrome. Timely and etiology-based personalized treatment is crucial. AKI sub-phenotyping can lead to...
Acute kidney injury (AKI) is a life-threatening and heterogeneous syndrome. Timely and etiology-based personalized treatment is crucial. AKI sub-phenotyping can lead to better understanding of the pathophysiology of AKI and help developing more targeted intervention. Current dimensionality reduction and similarity-based clustering for AKI sub-phenotyping suffer from limited interpretability and specificity. To address these limitations, we propose a pattern mining approach with multiobjective evolutionary algorithm (MOEA) for AKI sub-phenotyping. AKI sub-phenotypes are presented as explicit rules, so no post-hoc explanation is needed. Also, our method can search feature subspace efficiently for minor and highly specific sub-phenotypes. We aimed to discover sub-phenotypes for AKI patients against non-AKI patients (AKI vs non-AKI) and moderate-to-severe AKI patients against mild AKI patients (AKI-2/3 vs AKI-1). We identified 174(178) significant sub-phenotypes with average confidence of 0.33(0.33). Our method can assign patients to a sub-phenotype with higher confidence than k-means clustering, with average improvement of 0.20(0.23).
Topics: Humans; Phenotype; Acute Kidney Injury
PubMed: 37128400
DOI: No ID Found -
Toxicology Jan 2019This study was undertaken to evaluate the use of ontology-based semantic mapping (OS-Mapping) in chemical toxicity assessment. Nineteen chemical-species phenotypic...
This study was undertaken to evaluate the use of ontology-based semantic mapping (OS-Mapping) in chemical toxicity assessment. Nineteen chemical-species phenotypic profiles (CSPPs) were constructed by ontologically annotating the toxicity responses reported in more than seven hundred published studies of ten chemicals on six vertebrate species. The CSPPs were semantically compared to more than 29,000 publicly available phenotypic profiles of genes, KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways, and diseases based on a cross-species phenotype ontology. OS-Mapping was shown to differentiate chemical toxicities among themselves as well as within and across species. It also revealed cases of chemical by species interactions. In addition to confirming similar MOAs (mechanisms of action) for a few chemicals, OS-Mapping also generated novel insights into the MOAs underlying some seemingly different, yet phenotypically similar, classes of chemicals. The nature of a unified cross-species phenotype ontology and its representation of diverse knowledge domains allowed the construction of a complete phenotypic continuum for the 17α-ethynylestradiol_fathead minnow across the biological levels of organization, which complemented a similar one derived from the Comparative Toxicogenomics Database but based primarily on 17α-ethynylestradiol-induced molecular phenotypes. Overall, OS-Mapping has been demonstrated to offer a powerful approach to help bridge the gap between the molecular and non-molecular phenotypes of chemicals characterized by using high throughput or traditional omics methods and their apical endpoints of greater regulatory relevance, which are typically phenotypes found at the higher levels of biological organization. OS-Mapping also enables comparative toxicity assessment among chemicals, both within and across species. Furthermore, the semantic analysis of phenotypes can reveal additional novel MOAs for some well-known chemicals and discover candidate MOAs for chemicals that are less molecularly characterized. A full phenotypic continuum based on OS-Mapping will also be conducive to the future development of adverse outcome pathways. As phenomics continues to advance and the ontological annotation of literature becomes more automated, the power of OS-Mapping will be further enhanced.
Topics: Animals; Biological Ontologies; Fishes; Hazardous Substances; Humans; Mice; Phenotype; Rats; Risk Assessment; Semantics
PubMed: 30468866
DOI: 10.1016/j.tox.2018.11.005 -
American Journal of Human Genetics Jan 2023Although genomic research has predominantly relied on phenotypic ascertainment of individuals affected with heritable disease, the falling costs of sequencing allow... (Review)
Review
Although genomic research has predominantly relied on phenotypic ascertainment of individuals affected with heritable disease, the falling costs of sequencing allow consideration of genomic ascertainment and reverse phenotyping (the ascertainment of individuals with specific genomic variants and subsequent evaluation of physical characteristics). In this research modality, the scientific question is inverted: investigators gather individuals with a genomic variant and test the hypothesis that there is an associated phenotype via targeted phenotypic evaluations. Genomic ascertainment research is thus a model of predictive genomic medicine and genomic screening. Here, we provide our experience implementing this research method. We describe the infrastructure we developed to perform reverse phenotyping studies, including aggregating a super-cohort of sequenced individuals who consented to recontact for genomic ascertainment research. We assessed 13 studies completed at the National Institutes of Health (NIH) that piloted our reverse phenotyping approach. The studies can be broadly categorized as (1) facilitating novel genotype-disease associations, (2) expanding the phenotypic spectra, or (3) demonstrating ex vivo functional mechanisms of disease. We highlight three examples of reverse phenotyping studies in detail and describe how using a targeted reverse phenotyping approach (as opposed to phenotypic ascertainment or clinical informatics approaches) was crucial to the conclusions reached. Finally, we propose a framework and address challenges to building collaborative genomic ascertainment research programs at other institutions. Our goal is for more researchers to take advantage of this approach, which will expand our understanding of the predictive capability of genomic medicine and increase the opportunity to mitigate genomic disease.
Topics: Phenotype; Genotype; Genome; Genomics; Medical Informatics
PubMed: 36608682
DOI: 10.1016/j.ajhg.2022.12.004 -
Current Opinion in Genetics &... Dec 2013More than 150 years after Mendel discovered the laws of heredity, the genetic architecture of phenotypic variation remains elusive. Here, we discuss recent progress in... (Review)
Review
More than 150 years after Mendel discovered the laws of heredity, the genetic architecture of phenotypic variation remains elusive. Here, we discuss recent progress in deciphering how genotypes map onto phenotypes, sources of genetic complexity, and how model organisms are illuminating general principles about the relationship between genetic and phenotypic variation. Moreover, we highlight insights gleaned from large-scale sequencing studies in humans, and how this knowledge informs outstanding questions about the genetic architecture of quantitative traits and complex diseases. Finally, we articulate how the confluence of technologies enabling whole-genome sequencing, comprehensive phenotyping, and high-throughput functional assays of polymorphisms will facilitate a more principled and mechanistic understanding of the genetic architecture of phenotypic variation.
Topics: Gene-Environment Interaction; Genetic Predisposition to Disease; Genetic Variation; Genome-Wide Association Study; Genotype; Humans; Models, Genetic; Phenotype; Quantitative Trait Loci
PubMed: 24287334
DOI: 10.1016/j.gde.2013.10.008 -
Journal of Neurodevelopmental Disorders Feb 2023Recurrent gene dosage disorders impart substantial risk for psychopathology. Yet, understanding that risk is hampered by complex presentations that challenge classical...
BACKGROUND
Recurrent gene dosage disorders impart substantial risk for psychopathology. Yet, understanding that risk is hampered by complex presentations that challenge classical diagnostic systems. Here, we present a suite of generalizable analytic approaches for parsing this clinical complexity, which we illustrate through application to XYY syndrome.
METHOD
We gathered high-dimensional measures of psychopathology in 64 XYY individuals and 60 XY controls, plus additional interviewer-based diagnostic data in the XYY group. We provide the first comprehensive diagnostic description of psychiatric morbidity in XYY syndrome and show how diagnostic morbidity relates to functioning, subthreshold symptoms, and ascertainment bias. We then map behavioral vulnerabilities and resilience across 67 behavioral dimensions before borrowing techniques from network science to resolve the mesoscale architecture of these dimensions and links to observable functional outcomes.
RESULTS
Carriage of an extra Y-chromosome increases risk for diverse psychiatric diagnoses, with clinically impactful subthreshold symptomatology. Highest rates are seen for neurodevelopmental and affective disorders. A lower bound of < 25% of carriers are free of any diagnosis. Dimensional analysis of 67 scales details the profile of psychopathology in XYY, which survives control for ascertainment bias, specifies attentional and social domains as the most impacted, and refutes stigmatizing historical associations between XYY and violence. Network modeling compresses all measured symptom scales into 8 modules with dissociable links to cognitive ability, adaptive function, and caregiver strain. Hub modules offer efficient proxies for the full symptom network.
CONCLUSIONS
This study parses the complex behavioral phenotype of XYY syndrome by applying new and generalizable analytic approaches for analysis of deep-phenotypic psychiatric data in neurogenetic disorders.
Topics: Humans; Male; XYY Karyotype; Sex Chromosome Disorders; Cognition; Phenotype
PubMed: 36803654
DOI: 10.1186/s11689-023-09476-y -
Philosophical Transactions of the Royal... Feb 2010Metazoan life cycles can be complex in different ways. A number of diverse phenotypes and reproductive events can sequentially occur along the cycle, and at certain... (Review)
Review
Metazoan life cycles can be complex in different ways. A number of diverse phenotypes and reproductive events can sequentially occur along the cycle, and at certain stages a variety of developmental and reproductive options can be available to the animal, the choice among which depends on a combination of organismal and environmental conditions. We hypothesize that a diversity of phenotypes arranged in developmental sequence throughout an animal's life cycle may have evolved by genetic assimilation of alternative phenotypes originally triggered by environmental cues. This is supported by similarities between the developmental mechanisms mediating phenotype change and alternative phenotype determination during ontogeny and the common ecological condition that favour both forms of phenotypic variation. The comparison of transcription profiles from different developmental stages throughout a complex life cycle with those from alternative phenotypes in closely related polyphenic animals is expected to offer critical evidence upon which to evaluate our hypothesis.
Topics: Animals; Biological Evolution; Cell Differentiation; Ecosystem; Environment; Growth and Development; Life Cycle Stages; Models, Biological; Phenotype
PubMed: 20083638
DOI: 10.1098/rstb.2009.0268