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Nature Reviews. Genetics Jul 2023Understanding the consequences of genotype for phenotype (which ranges from molecule-level effects to whole-organism traits) is at the core of genetic diagnostics in... (Review)
Review
Understanding the consequences of genotype for phenotype (which ranges from molecule-level effects to whole-organism traits) is at the core of genetic diagnostics in medicine. Many measures of the deleteriousness of individual alleles exist, but these have limitations for predicting the clinical consequences. Various mechanisms can protect the organism from the adverse effects of functional variants, especially when the variant is paired with a wild type allele. Understanding why some alleles are harmful in the heterozygous state - representing dominant inheritance - but others only with the biallelic presence of pathogenic variants - representing recessive inheritance - is particularly important when faced with the deluge of rare genetic alterations identified by high throughput DNA sequencing. Both awareness of the specific quantitative and/or qualitative effects of individual variants and the elucidation of allelic and non-allelic interactions are essential to optimize genetic diagnosis and counselling.
Topics: Genetics, Medical; Genotype; Phenotype; Mutation; Alleles
PubMed: 36806206
DOI: 10.1038/s41576-023-00574-0 -
Science (New York, N.Y.) Oct 2023Epistasis between genes is traditionally studied with mutations that eliminate protein activity, but most natural genetic variation is in cis-regulatory DNA and...
Epistasis between genes is traditionally studied with mutations that eliminate protein activity, but most natural genetic variation is in cis-regulatory DNA and influences gene expression and function quantitatively. In this study, we used natural and engineered cis-regulatory alleles in a plant stem-cell circuit to systematically evaluate epistatic relationships controlling tomato fruit size. Combining a promoter allelic series with two other loci, we collected over 30,000 phenotypic data points from 46 genotypes to quantify how allele strength transforms epistasis. We revealed a saturating dose-dependent relationship but also allele-specific idiosyncratic interactions, including between alleles driving a step change in fruit size during domestication. Our approach and findings expose an underexplored dimension of epistasis, in which cis-regulatory allelic diversity within gene regulatory networks elicits nonlinear, unpredictable interactions that shape phenotypes.
Topics: Alleles; Epistasis, Genetic; Fruit; Genetic Variation; Genotype; Phenotype; Solanum lycopersicum; Gene Expression Regulation, Plant; Promoter Regions, Genetic; Gene Dosage
PubMed: 37856609
DOI: 10.1126/science.adi5222 -
Genetics in Medicine : Official Journal... Mar 2024Genetic variants at the low end of the penetrance spectrum have historically been challenging to interpret because their high population frequencies exceed the disease...
PURPOSE
Genetic variants at the low end of the penetrance spectrum have historically been challenging to interpret because their high population frequencies exceed the disease prevalence of the associated condition, leading to a lack of clear segregation between the variant and disease. There is currently substantial variation in the classification of these variants, and no formal classification framework has been widely adopted. The Clinical Genome Resource Low Penetrance/Risk Allele Working Group was formed to address these challenges and promote harmonization within the clinical community.
METHODS
The work presented here is the product of internal and community Likert-scaled surveys in combination with expert consensus within the Working Group.
RESULTS
We formally recognize risk alleles and low-penetrance variants as distinct variant classes from those causing highly penetrant disease that require special considerations regarding their clinical classification and reporting. First, we provide a preferred terminology for these variants. Second, we focus on risk alleles and detail considerations for reviewing relevant studies and present a framework for the classification these variants. Finally, we discuss considerations for clinical reporting of risk alleles.
CONCLUSION
These recommendations support harmonized interpretation, classification, and reporting of variants at the low end of the penetrance spectrum.
Topics: Humans; Alleles; Genetic Variation; Penetrance; Gene Frequency
PubMed: 38054408
DOI: 10.1016/j.gim.2023.101036 -
Biomolecules Aug 2023The STIM family of proteins plays a crucial role in a plethora of cellular functions through the regulation of store-operated Ca entry (SOCE) and, thus, intracellular... (Review)
Review
The STIM family of proteins plays a crucial role in a plethora of cellular functions through the regulation of store-operated Ca entry (SOCE) and, thus, intracellular calcium homeostasis. The two members of the mammalian STIM family, STIM1 and STIM2, are transmembrane proteins that act as Ca sensors in the endoplasmic reticulum (ER) and, upon Ca store discharge, interact with and activate the Orai/CRACs in the plasma membrane. Dysregulation of Ca signaling leads to the pathogenesis of a variety of human diseases, including neurodegenerative disorders, cardiovascular diseases, cancer, and immune disorders. Therefore, understanding the mechanisms underlying Ca signaling pathways is crucial for developing therapeutic strategies targeting these diseases. This review focuses on several rare conditions associated with STIM1 mutations that lead to either gain- or loss-of-function, characterized by myopathy, hematological and immunological disorders, among others, and due to abnormal activation of CRACs. In addition, we summarize the current evidence concerning STIM2 allele duplication and deletion associated with language, intellectual, and developmental delay, recurrent pulmonary infections, microcephaly, facial dimorphism, limb anomalies, hypogonadism, and congenital heart defects.
Topics: Animals; Humans; Alleles; Body Fluids; Cardiovascular Diseases; Cell Membrane; Endoplasmic Reticulum; Mammals
PubMed: 37759684
DOI: 10.3390/biom13091284 -
Nature Communications Aug 2023Despite large sequencing and data sharing efforts, previously characterized pathogenic variants only account for a fraction of Mendelian disease patients, which...
Despite large sequencing and data sharing efforts, previously characterized pathogenic variants only account for a fraction of Mendelian disease patients, which highlights the need for accurate identification and interpretation of novel variants. In a large Mendelian cohort of 4577 molecularly characterized families, numerous scenarios in which variant identification and interpretation can be challenging are encountered. We describe categories of challenges that cover the phenotype (e.g. novel allelic disorders), pedigree structure (e.g. imprinting disorders masquerading as autosomal recessive phenotypes), positional mapping (e.g. double recombination events abrogating candidate autozygous intervals), gene (e.g. novel gene-disease assertion) and variant (e.g. complex compound inheritance). Overall, we estimate a probability of 34.3% for encountering at least one of these challenges. Importantly, our data show that by only addressing non-sequencing-based challenges, around 71% increase in the diagnostic yield can be expected. Indeed, by applying these lessons to a cohort of 314 cases with negative clinical exome or genome reports, we could identify the likely causal variant in 54.5%. Our work highlights the need to have a thorough approach to undiagnosed diseases by considering a wide range of challenges rather than a narrow focus on sequencing technologies. It is hoped that by sharing this experience, the yield of undiagnosed disease programs globally can be improved.
Topics: Alleles; Causality; Exome; Hope; Information Dissemination
PubMed: 37644014
DOI: 10.1038/s41467-023-40909-3 -
Animal Genetics Dec 2023Half a century ago, a seminal article on the hitchhiking effect by Smith and Haigh inaugurated the concept of the selection signature. Selective sweeps are characterised... (Review)
Review
Half a century ago, a seminal article on the hitchhiking effect by Smith and Haigh inaugurated the concept of the selection signature. Selective sweeps are characterised by the rapid spread of an advantageous genetic variant through a population and hence play an important role in shaping evolution and research on genetic diversity. The process by which a beneficial allele arises and becomes fixed in a population, leading to a increase in the frequency of other linked alleles, is known as genetic hitchhiking or genetic draft. Kimura's neutral theory and hitchhiking theory are complementary, with Kimura's neutral evolution as the 'null model' and positive selection as the 'signal'. Both are widely accepted in evolution, especially with genomics enabling precise measurements. Significant advances in genomic technologies, such as next-generation sequencing, high-density SNP arrays and powerful bioinformatics tools, have made it possible to systematically investigate selection signatures in a variety of species. Although the history of selection signatures is relatively recent, progress has been made in the last two decades, owing to the increasing availability of large-scale genomic data and the development of computational methods. In this review, we embark on a journey through the history of research on selective sweeps, ranging from early theoretical work to recent empirical studies that utilise genomic data.
Topics: Animals; Selection, Genetic; Models, Genetic; Alleles; Computational Biology; Genomics; Genetics, Population
PubMed: 37710403
DOI: 10.1111/age.13355 -
Developmental Cell Nov 2023The zebrafish is amenable to a variety of genetic approaches. However, lack of conditional deletion alleles limits stage- or cell-specific gene knockout. Here, we...
The zebrafish is amenable to a variety of genetic approaches. However, lack of conditional deletion alleles limits stage- or cell-specific gene knockout. Here, we applied an existing protocol to establish a floxed allele for gata2a but failed to do so due to off-target integration and incomplete knockin. To address these problems, we applied simultaneous co-targeting with Cas12a to insert loxP sites in cis, together with transgenic counterscreening and comprehensive molecular analysis, to identify off-target insertions and confirm targeted knockins. We subsequently used our approach to establish endogenously floxed alleles of foxc1a, rasa1a, and ruvbl1, each in a single generation. We demonstrate the utility of these alleles by verifying Cre-dependent deletion, which yielded expected phenotypes in each case. Finally, we used the floxed gata2a allele to demonstrate an endothelial autonomous requirement in lymphatic valve development. Together, our results provide a framework for routine generation and application of endogenously floxed alleles in zebrafish.
Topics: Mice; Animals; Mice, Knockout; Zebrafish; Alleles; Integrases; Gene Knockout Techniques
PubMed: 37633272
DOI: 10.1016/j.devcel.2023.07.022 -
Trends in Genetics : TIG Apr 2024Dominance is usually considered a constant value that describes the relative difference in fitness or phenotype between heterozygotes and the average of homozygotes at a... (Review)
Review
Dominance is usually considered a constant value that describes the relative difference in fitness or phenotype between heterozygotes and the average of homozygotes at a focal polymorphic locus. However, the observed dominance can vary with the genetic background of the focal locus. Here, alleles at other loci modify the observed phenotype through position effects or dominance modifiers that are sometimes associated with pathogen resistance, lineage, sex, or mating type. Theoretical models have illustrated how variable dominance appears in the context of multi-locus interaction (epistasis). Here, we review empirical evidence for variable dominance and how the observed patterns may be captured by proposed epistatic models. We highlight how integrating epistasis and dominance is crucial for comprehensively understanding adaptation and speciation.
Topics: Models, Genetic; Heterozygote; Phenotype; Homozygote; Alleles; Epistasis, Genetic
PubMed: 38453542
DOI: 10.1016/j.tig.2023.12.003 -
Biochemistry. Biokhimiia Jan 2024The review discusses the mechanisms of monoallelic expression, such as genomic imprinting, in which gene transcription depends on the parental origin of the allele, and... (Review)
Review
The review discusses the mechanisms of monoallelic expression, such as genomic imprinting, in which gene transcription depends on the parental origin of the allele, and random monoallelic transcription. Data on the regulation of gene activity in the imprinted regions are summarized with a particular focus on the areas controlling imprinting and factors influencing the variability of the imprintome. The prospects of studies of the monoallelic expression are discussed.
Topics: Genomic Imprinting; DNA Methylation; Alleles
PubMed: 38467547
DOI: 10.1134/S000629792401005X -
HLA Jul 2023Genetic variation in the MICA and MICB genes located within the major histocompatibility complex region has been reported to be associated with transplantation outcome...
Genetic variation in the MICA and MICB genes located within the major histocompatibility complex region has been reported to be associated with transplantation outcome and susceptibility to autoimmune diseases and infections. Only limited data of polymorphism in these genes in different populations are available. We here report allelic variation at 2-field resolution and the haplotypes of the MICA and MICB genes in Finland (n = 1032 individuals), a north European population with historical bottleneck and founder effects. Altogether 24 MICA and 18 MICB alleles were found, forming 70 estimated MICA-MICB haplotypes. As compared to other populations frequency differences were found, for example, MICA*010:01 was found to be at an allele frequency of 0.133 in Finland which is higher than in other European populations (0.021-0.077), but close to Asian populations (0.151-0.220). Three novel alleles with amino acid change are described. The results demonstrate a relatively high level of polymorphism and population differences in MICA and MICB allele distribution.
Topics: Humans; Alleles; Histocompatibility Antigens Class I; Finland; Polymorphism, Genetic; Gene Frequency; Haplotypes
PubMed: 36919857
DOI: 10.1111/tan.15023