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Cell Systems Jan 2021Proteomic technologies now enable the rapid quantification of thousands of proteins across genetically diverse samples. Integration of these data with systems-genetics... (Review)
Review
Proteomic technologies now enable the rapid quantification of thousands of proteins across genetically diverse samples. Integration of these data with systems-genetics analyses is a powerful approach to identify new regulators of economically important or disease-relevant phenotypes in various populations. In this review, we summarize the latest proteomic technologies and discuss technical challenges for their use in population studies. We demonstrate how the analysis of correlation structure and loci mapping can be used to identify genetic factors regulating functional protein networks and complex traits. Finally, we provide an extensive summary of the use of proteome-wide systems genetics throughout fungi, plant, and animal kingdoms and discuss the power of this approach to identify candidate regulators and drug targets in large human consortium studies.
Topics: Humans; Multifactorial Inheritance; Proteome; Proteomics; Research Design
PubMed: 33476553
DOI: 10.1016/j.cels.2020.10.005 -
The New Phytologist Jan 2010The success of the genomics revolution to construct a genetic architecture of a variety of model organisms has placed functional biologists under pressure to show what... (Review)
Review
The success of the genomics revolution to construct a genetic architecture of a variety of model organisms has placed functional biologists under pressure to show what each individual gene does in vivo. Traditionally, this task has fallen on geneticists who systematically perturb gene function and study the consequences. With the advent of large, easily accessible, small-molecule libraries and new methods of chemical synthesis, biologists now have new ways to probe gene function. Often called chemical genetics, this approach involves the screening of compounds that perturb a process of interest. In this scenario, each perturbing chemical is analogous to a specific mutation. Here, we summarize, with specific examples, how chemical genetics is being used in combination with traditional genetics to address problems in plant biology. Because chemical genetics is rooted in genetic analysis, we focus on how chemicals used in combination with genetics can be very powerful in dissecting a process of interest.
Topics: Biochemistry; Genomics; Genotype; Phenotype; Plants; Proteomics
PubMed: 19825020
DOI: 10.1111/j.1469-8137.2009.03045.x -
Biological Psychiatry Jan 2015Virtually all psychiatric traits are genetically complex. This article discusses the genetics of complex traits in psychiatry. The complexity is accounted for by... (Review)
Review
Virtually all psychiatric traits are genetically complex. This article discusses the genetics of complex traits in psychiatry. The complexity is accounted for by numerous factors, including multiple risk alleles, epistasis, and epigenetic effects such as methylation. Risk alleles can individually be common or rare, and can include, for example, single nucleotide polymorphisms and copy number variants that are transmitted or are new mutations, and other kinds of variation. Many different kinds of variation can be important for trait risk, either together in various proportions or as different factors in different subjects. Until more recently, approaches to complex traits were limited, and consequently only a few variants, usually of individually minor effect, were identified. At the present time, a much richer armamentarium exists that includes the routine application of genome-wide association studies and next-generation high-throughput sequencing and the combination of this information with other biologically relevant information, such as expression data. We have also seen the emergence of large meta-analysis and mega-analysis consortia. These developments are extremely important for psychiatric genetics, have advanced the field substantially, and promise formidable gains in the years to come as they are applied more widely.
Topics: Epigenomics; Epistasis, Genetic; Gene-Environment Interaction; Genetic Variation; Genome-Wide Association Study; High-Throughput Nucleotide Sequencing; Humans; Mental Disorders; Pharmacogenetics; Polymorphism, Single Nucleotide
PubMed: 25444161
DOI: 10.1016/j.biopsych.2014.08.005 -
International Journal of Biological... 2009Biology is now entering the new era of systems biology and exerting a growing influence on the future development of various disciplines within life sciences. In early... (Review)
Review
Biology is now entering the new era of systems biology and exerting a growing influence on the future development of various disciplines within life sciences. In early classical and molecular periods of Biology, the theoretical frames of classical and molecular quantitative genetics have been systematically established, respectively. With the new advent of systems biology, there is occurring a paradigm shift in the field of quantitative genetics. Where and how the quantitative genetics would develop after having undergone its classical and molecular periods? This is a difficult question to answer exactly. In this perspective article, the major effort was made to discuss the possible development of quantitative genetics in the systems biology era, and for which there is a high potentiality to develop towards "systems quantitative genetics". In our opinion, the systems quantitative genetics can be defined as a new discipline to address the generalized genetic laws of bioalleles controlling the heritable phenotypes of complex traits following a new dynamic network model. Other issues from quantitative genetic perspective relating to the genetical genomics, the updates of network model, and the future research prospects were also discussed.
Topics: Computational Biology; Genomics; Molecular Biology; Systems Biology
PubMed: 19173038
DOI: 10.7150/ijbs.5.161 -
Methods in Molecular Biology (Clifton,... 2022Genetic ancestry inference can be used to stratify patient cohorts and to model pharmacogenomic variation within and between populations. We provide a detailed guide to...
Genetic ancestry inference can be used to stratify patient cohorts and to model pharmacogenomic variation within and between populations. We provide a detailed guide to genetic ancestry inference using genome-wide genetic variant datasets, with an emphasis on two widely used techniques: principal components analysis (PCA) and ADMIXTURE analysis. PCA can be used for patient stratification and categorical ancestry inference, whereas ADMIXTURE is used to characterize genetic ancestry as a continuous variable. Visualization methods are critical for the interpretation of genetic ancestry inference methods, and we provide instructions for how the results of PCA and ADMIXTURE can be effectively visualized.
Topics: Genetic Techniques; Genetics, Population; Humans; Pharmacogenetics; Polymorphism, Single Nucleotide; Population Groups; Principal Component Analysis
PubMed: 36068478
DOI: 10.1007/978-1-0716-2573-6_21 -
Drug Metabolism Reviews 2008A brief history of human genetics and genomics is provided, comparing recent progress in those fields with that in pharmacogenetics and pharmacogenomics, which are... (Review)
Review
A brief history of human genetics and genomics is provided, comparing recent progress in those fields with that in pharmacogenetics and pharmacogenomics, which are subsets of genetics and genomics, respectively. Sequencing of the entire human genome, the mapping of common haplotypes of single-nucleotide polymorphisms (SNPs), and cost-effective genotyping technologies leading to genome-wide association (GWA) studies - have combined convincingly in the past several years to demonstrate the requirements needed to separate true associations from the plethora of false positives. While research in human genetics has moved from monogenic to oligogenic to complex diseases, its pharmacogenetics branch has followed, usually a few years behind. The continuous discoveries, even today, of new surprises about our genome cause us to question reviews declaring that "personalized medicine is almost here" or that "individualized drug therapy will soon be a reality." As summarized herein, numerous reasons exist to show that an "unequivocal genotype" or even an "unequivocal phenotype" is virtually impossible to achieve in current limited-size studies of human populations. This problem (of insufficiently stringent criteria) leads to a decrease in statistical power and, consequently, equivocal interpretation of most genotype-phenotype association studies. It remains unclear whether personalized medicine or individualized drug therapy will ever be achievable by means of DNA testing alone.
Topics: Biotransformation; Databases, Genetic; Drug-Related Side Effects and Adverse Reactions; Epigenesis, Genetic; Genetic Predisposition to Disease; Genetic Testing; Genetics, Medical; Genome, Human; Genomics; Genotype; History, 19th Century; History, 20th Century; History, 21st Century; Human Genome Project; Humans; Linkage Disequilibrium; Molecular Biology; Multifactorial Inheritance; Patient Selection; Pharmaceutical Preparations; Pharmacogenetics; Phenotype; Polymorphism, Single Nucleotide
PubMed: 18464043
DOI: 10.1080/03602530801952864 -
Current Psychiatry Reports Oct 2018The purpose of this review is to contextualize findings from the first 25 years of PTSD genetics research, focusing on the most robust findings and interpreting results... (Review)
Review
PURPOSE OF REVIEW
The purpose of this review is to contextualize findings from the first 25 years of PTSD genetics research, focusing on the most robust findings and interpreting results in light of principles that have emerged from modern genetics studies.
RECENT FINDINGS
Genome-wide association studies (GWAS) encompassing tens of thousands of participants enabled the first molecular genetic heritability and genetic correlation estimates for PTSD in 2017. In 2018, highly promising loci for PTSD were reported, including variants in and near the CAMKV, KANSL1, and TCF4 genes. Twin studies from 25 years ago established that PTSD is genetically influenced and foreshadowed the molecular genetic findings of today. Discoveries that were impossible with smaller studies have been achieved via collaborative/team-science efforts. Most promisingly, individual genomic loci offer entirely novel clues about PTSD etiology, providing the raw material for transformative discoveries, and the future of PTSD research is bright.
Topics: Genetic Predisposition to Disease; Genetic Research; Genome-Wide Association Study; Genomics; Humans; Stress Disorders, Post-Traumatic
PubMed: 30350223
DOI: 10.1007/s11920-018-0980-1 -
Trends in Genetics : TIG Mar 2021Interrogation of disease-relevant cellular and molecular traits exhibited by genetically diverse cell populations enables in vitro systems genetics approaches for... (Review)
Review
Interrogation of disease-relevant cellular and molecular traits exhibited by genetically diverse cell populations enables in vitro systems genetics approaches for uncovering the basic properties of cellular function and identity. Primary cells, stem cells, and organoids derived from genetically diverse mouse strains, such as Collaborative Cross and Diversity Outbred populations, offer the opportunity for parallel in vitro/in vivo screening. These panels provide genetic resolution for variant discovery and functional characterization, as well as disease modeling and in vivo validation capabilities. Here we review mouse cellular systems genetics approaches for characterizing the influence of genetic variation on signaling networks and phenotypic diversity, and we discuss approaches for data integration and cross-species validation.
Topics: Animals; Gene Regulatory Networks; Genetic Variation; Genetics; Genomics; Genotype; Mice; Quantitative Trait Loci; Signal Transduction; Systems Biology
PubMed: 33010949
DOI: 10.1016/j.tig.2020.09.007 -
Genetics Jul 2017With a century-old history of fundamental discoveries, the fruit fly has long been a favored experimental organism for a wide range of scientific inquiries. But is not... (Review)
Review
With a century-old history of fundamental discoveries, the fruit fly has long been a favored experimental organism for a wide range of scientific inquiries. But is not a "legacy" model organism; technical and intellectual innovations continue to revitalize fly research and drive advances in our understanding of conserved mechanisms of animal biology. Here, we provide an overview of this "ecosystem" and discuss how to address emerging challenges to ensure its continued productivity. researchers are fortunate to have a sophisticated and ever-growing toolkit for the analysis of gene function. Access to these tools depends upon continued support for both physical and informational resources. Uncertainty regarding stable support for bioinformatic databases is a particular concern, at a time when there is the need to make the vast knowledge of functional biology provided by this model animal accessible to scientists studying other organisms. Communication and advocacy efforts will promote appreciation of the value of the fly in delivering biomedically important insights. Well-tended traditions of large-scale tool development, open sharing of reagents, and community engagement provide a strong basis for coordinated and proactive initiatives to improve the fly research ecosystem. Overall, there has never been a better time to be a fly pusher.
Topics: Animals; Drosophila; Genetic Techniques; Genetics; Models, Animal; Workforce
PubMed: 28684603
DOI: 10.1534/genetics.117.202390 -
Journal of Translational Medicine Jan 2022The identification of pathogenic variant in patients with thoracic aortic aneurysms and dissections (TAAD) was previously found to be a significant indicator pointing to...
Good performance of the criteria of American College of Medical Genetics and Genomics/Association for Molecular Pathology in prediction of pathogenicity of genetic variants causing thoracic aortic aneurysms and dissections.
BACKGROUND
The identification of pathogenic variant in patients with thoracic aortic aneurysms and dissections (TAAD) was previously found to be a significant indicator pointing to earlier need for surgical intervention. In order to evaluate available methods for classifying identified genetic variants we have compared the event-free survival in a cohort of TAAD patients classified as genotype-positive versus genotype-negative by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG-AMP) criteria or by ClinVar database.
METHODS
We analyzed previously unreported cohort of 132 patients tested in the routine clinical setting for genetic variants in a custom panel of 30 genes associated with TAAD or the TruSight Cardio commercial panel of 174 genes associated with cardiac disease. The identified variants were classified using VarSome platform. Kaplan-Meier survival curves were constructed to compare the event-free survival between probands defined as 'genotype-positive' and 'genotype-negative' using different classifications in order to compare their performance.
RESULTS
Out of 107 rare variants found, 12 were classified as pathogenic/likely pathogenic by ClinVar, 38 were predicted to be pathogenic/likely pathogenic by ACMG. Variant pathogenicity as assessed by ACMG criteria was a strong predictor of event free survival (event free survival at 50 years 83% vs. 50%, for genotype positive patients vs. reference, respectively, p = 0.00096). The performance of ACMG criteria was similar to that of ClinVar (event free survival at 50 years 87% vs. 50%, for genotype positive patients vs. reference, respectively p = 0.023) but independent from it as shown by analysing variants with no ClinVar record (event free survival at 50 years 80% vs. 50%, p = 0.0039). Variants classified as VUS by ACMG criteria or ClinVar did not affect event-free survival. TAAD specific custom gene panel performed similar to the larger universal cardiac panel.
CONCLUSIONS
In our cohort of unrelated TAAD patients ACMG classification tool available at VarSome was useful in assessing pathogenicity of novel genetic variants. Gene panel containing the established genes associated with the highest risk of hereditary TAAD (ACTA1, COL3A1, FBN1, MYH11, SMAD3, TGFB2, TGFBR1, TGFBR2, MYLK) was sufficient to identify prevailing majority of variants most likely to be causative of the disease.
Topics: Aortic Aneurysm, Thoracic; Genetic Testing; Genetic Variation; Genetics, Medical; Genomics; Humans; Pathology, Molecular; United States; Virulence
PubMed: 35078481
DOI: 10.1186/s12967-022-03251-8