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Background: Although previous observational studies have shown an association between venous thromboembolism (VTE) and atrial fibrillation (AF), the underlying causal relationship between them remains uncertain. Methods and results: This two-sample bidirectional Mendelian randomization (MR) analysis was performed to investigate the causal relationship between VTE and AF. The VTE dataset were obtained from FinnGen, including 9,176 cases and 209,616 controls. Meanwhile a genome-wide association study (GWAS) of 60,620 individuals with AF and 970,216 control subjects identified genetic variations associated with AF. The principal MR analytic approach used in this study is the inverse-variance weighting (IVW) method. Furthermore, we performed complementary MR analyses, including the MR-Egger, Weighted median (WM), and Weighted Mode. MR pleiotropy residual sum was applied to identify pleiotropy. The MR analysis showed suggestive causal associations between VTE and the risk of AF (p = 0.0245, OR [95%CI]: 1.027 [1.003, 1.051]). The reverse MR analysis found that genetic susceptibility to AF was not significantly associated with VTE, as determined by the IVW method (p = 0.7773). The robustness of these findings was corroborated through MR sensitivity analyses. Conclusions: There is a unidirectional causal relationship between VTE and AF, meaning that VTE is a causal risk factor for AF, whereas no effect of AF on VTE was identified. [ABSTRACT FROM AUTHOR]

Psoriasis is a chronic inflammatory skin disorder with multiple causes, including genetic and environmental factors. Despite advances in treatment, there remains a need to identify novel therapeutic targets. A Mendelian randomization (MR) analysis was conducted to identify therapeutic targets for psoriasis. Data on cis-expression quantitative trait loci were obtained from the eQTLGen Consortium (n = 31,684). Summary statistics for psoriasis (outcome) were sourced from the GWAS Catalog with a sample size of 484,598, including 5,427 cases and 479,171 controls. Colocalization analysis was used to assess whether psoriasis risk and gene expression were driven by shared single nucleotide polymorphisms. Drug prediction and molecular docking were utilized to validate the pharmacological value of the drug targets. The MR analysis found that 81 drug targets were significantly associated, and two (TYK2 and PRSS36) were supported by colocalization analysis (PP.H4 > 0.80). Phenome-wide association studies did not show any associations with other traits at the gene level. Biologically, these genes were closely related to immune function. Molecular docking revealed strong binding with drugs and proteins, as supported by available structural data. This study validated TYK2 as a drug target for psoriasis, in line with its existing clinical use, including the development of decucravacitinib. PRSS36 is a potential novel target requiring further investigation. [ABSTRACT FROM AUTHOR]

Background: Although various aspects of cisplatin resistance have been studied, the impact of genetic variations still needs to be explored. Aim: This study aimed to investigate the impact of cisplatin on meningiomas using a two-sample Mendelian randomization (MR) approach, employing genetic variants associated with cisplatin use as instrumental variables. Method: We conducted a two-sample MR analysis using genome-wide association study (GWAS) data. Instrumental variables were derived from single-nucleotide polymorphisms (SNPs) associated with meningioma to estimate the causal relationship with cisplatin resistance. Sensitivity analyses were performed to confirm the findings. Results: Genetic predisposition to meningioma significantly increased the risk of cisplatin resistance (odds ratio (OR): 1.63; 95% confidence interval (CI) 1.44–1.85, P < 0.05). Sensitivity analyses supported the causal link. Conclusion: This MR study suggests that genetic predisposition to meningioma increases susceptibility to cisplatin resistance. Further research is needed to uncover the mechanisms behind these causal effects. [ABSTRACT FROM AUTHOR]

Objectives: Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease with an unsatisfactory state of treatment. We aim to explore novel targets for SLE from a genetic standpoint. Methods: Cis-expression quantitative trait loci (eQTLs) for whole blood from 31,684 samples provided by the eQTLGen Consortium as well as two large SLE cohorts were utilized for screening and validating genes causally associated with SLE. Colocalization analysis was employed to further investigate whether changes in the expression of risk genes, as indicated by GWAS signals, influence the occurrence and development of SLE. Targets identified for drug development were evaluated for potential side effects using a phenome-wide association study (PheWAS). Based on the multiple databases, we explored the interactions between drugs and genes for drug prediction and the assessment of current medications. Results: The analysis comprised 5427 druggable genes in total. The two-sample Mendelian randomization (MR) in the discovery phase identified 20 genes causally associated with SLE and validated 8 genes in the replication phase. Colocalization analysis ultimately identified five genes (BLK, HIST1H3H, HSPA1A, IL12A, NEU1) with PPH4 > 0.8. PheWAS further indicated that drugs acting on BLK and IL12A are less likely to have potential side effects, while HSPA1A and NEU1 were associated with other traits. Four genes (BLK, HSPA1A, IL12A, NEU1) have been targeted for drug development in autoimmune diseases and other conditions. Conclusions:.This study identified five genes as therapeutic targets for SLE. Repurposing and developing drugs targeting these genes is anticipated to improve the existing treatment state for SLE. Key Points • We identified five gene targets of priority for the treatment of SLE, with BLK and IL12A indicating fewer side effects. • Among the existing drugs that target these candidate genes, Ustekinumab, Ebdarokimab, and Briakinumab (targeting the IL12 gene) and CD24FC (targeting HSPA1A) may potentially be repurposed for the treatment of SLE. [ABSTRACT FROM AUTHOR]

This article offers a close examination of a small selection of pedigrees taken from German Mendelian and eugenic scholarship of the 1920s and 1930s. It examines the procedures that became customary for presenting data on human inherited pathologies, as well as the frequent changes in the information content of those charts. Relevant biographical and genealogical data was removed, and important indications regarding the diagnostic methods applied by the investigating scholar were lost, as soon as a pedigree was charted or reproduced. Data on healthy individuals was condensed, leading to an emphasis on the hereditary burden of pathological traits. At times, healthy individuals were entirely omitted, as were exogenous martial partners. These modifications paved the way for further theoretical amendments, including the addition of 'carrier' status to chosen individuals along the pedigree. With this addition, these pedigrees changed their ontological status, from empirical records of human reproduction to partially hypothetical illustrations of Mendelian theory itself. This process was complemented by the representation of theoretical genetic models in the format of a human pedigree. A comparison to practices of charting pedigrees still common today suggests that the processes hereby revealed are far from exceptional. In line with the ideas put forward by Ludwik Fleck, they are interpreted as germane to the way scientific ideas are communicated and propagated and to the scientific culture of genetics. The article also offers a refinement to Fleck's analysis of textbook construction, which highlights the extent to which textbook examples differ from the original data on which they are based. [ABSTRACT FROM AUTHOR]

Background: Previous observational studies have discovered a connection between depression and mineral status. Confirming this potential connection is challenging due to confounding factors and potential reverse causality which is inherent in observational studies. Materials and Methods: We performed a Mendelian randomization (MR) analysis to estimate the causal association of serum minerals with depression. Leveraging summary-level data on depression, a genome-wide association study (GWAS) was applied. The data on serum minerals were collected from the FinnGen Biobank database. MR assessments representing causality were produced by inverse-variance weighted approaches with multiplicative random and fixed effects. Result: Sensitivity analyses were performed to validate the reliability of the results. A noteworthy correlation emerged between serum zinc levels and reduced risk of depression. An odds ratio (OR) of 0.917 for depression associated with a one standard deviation increase in serum zinc levels (OR = 0.968; 95% CI = 0.953-0.984, p = 1.19 x 10-4, random effects model inverse variance weighted (IVW)); (OR = 0.928; 95% CI = 0.634-1.358, p = 0.766, MR Egger). Sensitivity assessments supported this causation. However, the risk of depression did not exhibit an association with other minerals. Conclusions: In summary, a higher zinc concentration is causally associated with a reduced depression risk. This MR outcome may assist clinicians in the regulation of specific mineral intake, particularly for high-risk patients with serum zinc deficiencies. [ABSTRACT FROM AUTHOR]

Our understanding of plant biology has been revolutionized by modern genetics and biochemistry. However, biochemical genetics can be traced back to the foundation of Mendelian genetics; indeed, one of Mendel's milestone discoveries of seven characteristics of pea plants later came to be ascribed to a mutation in a starch branching enzyme. Here, we review both current and historical strategies for the elucidation of plant metabolic pathways and the genes that encode their component enzymes and regulators. We use this historical review to discuss a range of classical genetic phenomena including epistasis, canalization, and heterosis as viewed through the lens of contemporary high-throughput data obtained via the array of approaches currently adopted in multiomics studies. [ABSTRACT FROM AUTHOR]

Since the rediscovery of Mendelian genetics over a century ago, there has been much debate about the evolutionary importance of mutations with large phenotypic effects. While population genetic models predict that large-effect mutations will typically contribute to adaptation following an abrupt change in environment, the prediction applies to populations of stable size and overlooks the effects of population size change on adaptation (e.g., population decline following habitat loss; growth during range expansion). We evaluate the phenotypic and fitness effects of mutations contributing to adaptation immediately following an abrupt environmental shift that alters both selection and population size dynamics. We show that large-effect mutations are likely to contribute to adaptation in populations declining to a new carrying capacity, somewhat smaller-effect mutations contribute to evolutionary rescue, and small-effect mutations predominate in growing populations. We also show that the relative contributions of positively selected and overdominant mutations to adaptation depend on interactions between the phenotypic effect size distribution for new mutations and the specific form of population size change during adaptation (i.e., growth, decline, or evolutionary rescue). Our results illustrate how population size dynamics can shape the genetic basis of adaptation, which should motivate empirical comparisons of populations adapting in different demographic contexts. [ABSTRACT FROM AUTHOR]

Genomics has revolutionized the field of genetics because we can now study nearly all genes in the genome and carry out genetic studies on (almost) any species. According to gene ontology classification, eight genes were involved in the sugar metabolism in soybean and showed similar functions in I Arabidopsis. i Mutants are often used to study gene function. Mendel postulated transmissible factors, genes, to explain the inheritance of traits. In celebration of the bicentennial of the birth of Gregor Johann Mendel, the genius of genetics, this Special Issue presents seven papers. [Extracted from the article]

The rapid development of genetics at the beginning of the 20th century coincided with the introduction of the fruit fly Drosophila melanogaster into laboratory research. Thomas Hunt Morgan and his students used this humble organism to confirm Mendelian genetics, establish chromosome theory and craft the first ever genetic maps. During this process they created a standardized, ideal genetic model animal that is continued to be used in research to this day. By removing the background genetic variance of the natural populations, this standardization blindsided some researchers, like Hermann Joseph Muller to the importance of genetic diversity. In contrast, others, like Theodosius Dobzhansky, used the genetic variance of a related species, Drosophila pseudoobscura to demonstrate the importance of diversity in natural populations. Muller and Dob zhansky both generalized their observations to human populations and their debate about the merits and vices of positive eugenics and the possible dangers or advantages of genetic diversity still resonate today, in an era of genome editing, preimplantation diagnostics and embryo selection. [ABSTRACT FROM AUTHOR]

Brugada syndrome (BrS) is a rare hereditary arrhythmia disorder, with a distinctive ECG pattern, correlated with an increased risk of ventricular arrhythmias and sudden cardiac death (SCD) in young adults. BrS is a complex entity in terms of mechanisms, genetics, diagnosis, arrhythmia risk stratification, and management. The main electrophysiological mechanism of BrS requires further research, with prevailing theories centered on aberrant repolarization, depolarization, and current-load match. Computational modelling, pre-clinical, and clinical research show that BrS molecular anomalies result in excitation wavelength (k) modifications, which eventually increase the risk of arrhythmia. Although a mutation in the SCN5A (Sodium Voltage-Gated Channel Alpha Subunit 5) gene was first reported almost two decades ago, BrS is still currently regarded as a Mendelian condition inherited in an autosomal dominant manner with incomplete penetrance, despite the recent developments in the field of genetics and the latest hypothesis of additional inheritance pathways proposing a more complex mode of inheritance. In spite of the extensive use of the next-generation sequencing (NGS) technique with high coverage, genetics remains unexplained in a number of clinically confirmed cases. Except for the SCN5A which encodes the cardiac sodium channel NaV1.5, susceptibility genes remain mostly unidentified. The predominance of cardiac transcription factor loci suggests that transcriptional regulation is essential to the Brugada syndrome's pathogenesis. It appears that BrS is a multifactorial disease, which is influenced by several loci, each of which is affected by the environment. The primary challenge in individuals with a BrS type 1 ECG is to identify those who are at risk for sudden death, researchers propose the use of a multiparametric clinical and instrumental strategy for risk stratification. The aim of this review is to summarize the latest findings addressing the genetic architecture of BrS and to provide novel perspectives into its molecular underpinnings and novel models of risk stratification. [ABSTRACT FROM AUTHOR]

Considerable progress continues to be made with regards to the value and use of disease associated polygenic scores (PGS). PGS aim to capture a person's genetic liability to a condition, disease, or a trait, combining information across many risk variants and incorporating their effect sizes. They are already available for clinicians and consumers to order in Australasia. However, debate is ongoing over the readiness of this information for integration into clinical practice and population health. This position statement provides the viewpoint of the Human Genetics Society of Australasia (HGSA) regarding the clinical application of disease-associated PGS in both individual patients and population health. The statement details how PGS are calculated, highlights their breadth of possible application, and examines their current challenges and limitations. We consider fundamental lessons from Mendelian genetics and their continuing relevance to PGS, while also acknowledging the distinct elements of PGS. Use of PGS in practice should be evidence based, and the evidence for the associated benefit, while rapidly emerging, remains limited. Given that clinicians and consumers can already order PGS, their current limitations and key issues warrant consideration. PGS can be developed for most complex conditions and traits and can be used across multiple clinical settings and for population health. The HGSA's view is that further evaluation, including regulatory, implementation and health system evaluation are required before PGS can be routinely implemented in the Australasian healthcare system. [ABSTRACT FROM AUTHOR]

Understanding genetics, an important topic in the study of biology, is critical for scientific literacy in agriculture, health, and forensic investigations. However, it has been observed that teachers find genetics difficult to teach and pupils do not perform well in it. Teachers can use expository teaching or active learning methods, but the secondary school curriculum in Malawi advocates the latter. The aim of this study was to find out how genetics is taught and how teachers justify their choice of method. This study used a multi-case design involving six teachers and observed their Mendelian genetics lessons and asked them to justify their choice of teaching method. The findings show that teachers mostly use expository methods utilizing lecture and question and answer teaching techniques. Contextual factors such as large classes, limited teaching time, and lack of resources were cited as reasons for their choice of expository techniques. In addition, they said that the topic was abstract and learners could not construct their own understanding. Furthermore, they indicated that they did not know what activities to arrange for the learners. The paper discusses the difficulties experienced in implementing active learning methods in teaching genetics and recommends possible avenues for teacher education and further research in Malawi. [ABSTRACT FROM AUTHOR]

Cereals like wheat, rice, maize, barley and millets, feed the world. Therefore, global breeding activities, which had been very successful during the last decades, aim at an increase of cereal yields. This, as expected continued success story is the result of the extensive observations and formulation of the fundamental genetic rules that bear his name as Mendel's law of inheritance (T.H. Morgan 1911). Mendel's thinking in "heritable characters" resembling structural "genes", was the basis for a better understanding of the genetic principles of inheritance; The application of these principles in systematic plant breeding has then allowed the continuous development of improved cultivars. Plant characteristics controlled by a few or only one gene were the first candidates for improvement since they allowed the direct application of Mendel's rules. Typical examples are resistances against diseases, e.g. due to fungal pathogens or viruses. Today, most of the wheat and barley cultivars grown in Europe are resistant to many diseases. The discovery of resistance of barley against soil-borne barley yellow mosaic virus disease and the clarification of its genetic control is an impressive example for the direct application of Mendel's law. The respective extensive research was the basis for developing a multitude of resistant barley varieties during recent decades. Numerous further examples for resistance of crop plants against pathogens could be mentioned, here. Such "Mendel genes" can be genetically marked and localized, which subsequently enables marker-assisted selection. They were also among the first to be isolated. Isolated genes are the basis to apply new breeding technologies, e.g. CRISPR/Cas, and to transfer the respective genes to other varieties, species or taxa with the help of biotechnological tools. Due to the obviously increasing effects of climate change, it will be necessary in the future to breed new varieties with higher tolerance to abiotic stress - such as heat and drought. Such traits are usually not controlled by one or a few genes; rather, they are polygenically inherited and therefore show a typical quantitative distribution of respective traits. This also applies to crop yield and relevant quality traits. New approaches have been developed for breeding and improving such complex traits e.g. QTL analyses separating complex traits into several Mendelian loci explaining part of the variance observed and „genomic selection" are widely applied today. In this process, suitable genotypes are examined for genetic variation that indicates a desired trait expression (phenotype). In this way, a continuous optimisation of methodology takes place in today's knowledge-based plant breeding on the basis of Mendel's rules via empirical ("classical") methodology. This will be the cornerstone to improve the yield potential, yield stability and quality of plants in the future. [ABSTRACT FROM AUTHOR]

The rediscovery of Mendel’s work showing that the heredity of phenotypes is controlled by discrete genes was followed by the reconciliation of Mendelian genetics with evolution by natural selection in the middle of the last century with the Modern Synthesis. In the past two decades, dramatic advances in genomic methods have facilitated the identification of the loci, genes, and even individual mutations that underlie phenotypic variants that are the putative targets of natural selection. Moreover, these methods have also changed how we can study adaptation by flipping the problem around, allowing us to first examine what loci show evidence of having been under selection, and then connecting these genetic variants to phenotypic variation. As a result, we now have an expanding list of actual genetic changes that underlie potentially adaptive phenotypic variation. Here, we synthesize how considering the effects of these adaptive loci in the context of cellular environments, genomes, organisms, and populations has provided new insights to the genetic architecture of adaptation. [ABSTRACT FROM AUTHOR]

The "Mendelian Rules" of inheritance are cornerstones of genetics, described in Mendel's seminal publication from 1866. The experimental results and their interpretation have been discussed in numerous ways. This perspective emphasizes the contribution of Mendel's preparations prior to his crossing experiments to the discovery of Mendelian genetics. This thoughtful experimental design, and some fortune, avoided pitfalls that could have resulted in non-Mendelian inheritance. [ABSTRACT FROM AUTHOR]

Background and aims: Observational studies have yielded conflicting results on the association of prescription opioid use (POU) with the risk of cardiovascular diseases (CVD). Residual confounding and potential reverse causality are inevitable in such conventional observational studies. This study used Mendelian randomization (MR) design to estimate the causal effect of POU on the risk of CVD, including coronary heart disease (CHD), myocardial infarction (MI) and ischemic stroke (IS), as well as their common risk factors. Design We estimated the causal effect of genetic liability for POU on CVD in a two‐sample MR framework. Complementary sensitivity analyses were conducted to test the robustness of our results. Setting: Genome‐wide association studies (GWAS) that were based on predominantly European ancestry. Participants: The sample sizes of the GWAS used in this study ranged from 69 033 to 757 601 participants. Measurements Genetic variants predictive of the POU and their corresponding summary‐level information in the outcomes were retrieved and extracted from the respective GWAS. Findings Using univariable MR, we found evidence for a causal effect of genetic liability for POU on an increased risk of CHD [odds ratio (OR) = 1.09; 95% confidence interval (CI) = 1.02–1.16; P = 0.008] and MI (OR = 1.13; 95% CI = 1.04–1.22; P = 0.002). In multivariable MR, the association remained after accounting for comorbid pain conditions, but was attenuated with adjustment for potential mediators, including body mass index (BMI), waist circumference (WC) and type 2 diabetes (T2D). Conclusion: Mendelian randomization estimates provide robust evidence for the causal effects of genetic liability for prescription opioid use on an increased risk of coronary heart disease and myocardial infarction, which might be mediated by obesity‐related traits. [ABSTRACT FROM AUTHOR]

Mendelian Genetics represents the student’s gateway to Genetics. Although it is essential to understand the basis of inheritance, it does not include two important exceptions occurring in nature that distort Mendelian ratios: (1) gene interactions, or the joint action of several genes contributing to the same phenotype and (2) genetic linkage, or the location of several genes on the same chromosome. On these grounds, we present the Gene Calculator, a web tool that allows us to delve into both aspects. On the one hand, it simulates genetic crossings not only of traditional Mendelian traits but also of traits with all types of existing gene interactions. On the other hand, it allows studying the effect of linkage on Mendelian ratios by estimating genetic distances and generating an output with the graphic representation of the gametes produced by an individual with several linked genes. Finally, we evaluate the educational potential of this tool by proposing a practical activity to be used in the classroom. [ABSTRACT FROM AUTHOR]

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Historiographical analyses of the development of genetics in the first decade of the 20th century have been to a great extent framed in the context of the Mendelian-Biometrician controversy. Much has been discussed on the nature, origin, development, and legacy of the controversy. However, such a framework is becoming less useful and fruitful. This paper challenges the traditional historiography framed by the Mendelian-Biometrician distinction. It argues that the Mendelian-Biometrician distinction fails to reflect the theoretical and methodological diversity in the controversy. It also argues that the Mendelian-Biometrician distinction is not helpful to make a full understanding of the development of genetics in the first decade of the twentieth century. [ABSTRACT FROM AUTHOR]

Mendel, a genius experimentalist, meticulously uncovered the genetic basis of heredity in work that transformed the science of biology. But does the alluring simplicity of Mendel's laws sometimes obscure the true complexity of genetics? Gregor Mendel meticulously uncovered the genetic basis of heredity in work that transformed the science of biology. But does the alluring simplicity of Mendel's laws sometimes obscure the true complexity of genetics? [ABSTRACT FROM AUTHOR]

An enduring legacy from the heyday of Mendelian genetics is talk of 'genes for'. Such talk suggests straightforwardly that genes make characters. But for over a century, thoughtful biologists have insisted such an understanding is mistaken. For them, a gene is a chromosomal difference that, when internal and external environments are otherwise equal, makes a phenotypic difference; 'genes for' talk is but shorthand for this more complex understanding. This paper examines the remarkable durability of the disowned, deterministic character-making understanding, placing particular emphasis on the role of the traditional, start-with-Mendel curriculum in investing that understanding with a heuristic power which later teaching may never fully displace. The paper also reports on recent experimental work exploring the potential of a reordered curriculum for teaching genetics without bolstering genetic determinism. [ABSTRACT FROM AUTHOR]

Background: Dilated cardiomyopathy (DCM) is genetically heterogeneous, with >100 purported disease genes tested in clinical laboratories. However, many genes were originally identified based on candidate-gene studies that did not adequately account for background population variation. Here we define the frequency of rare variation in 2538 patients with DCM across protein-coding regions of 56 commonly tested genes and compare this to both 912 confirmed healthy controls and a reference population of 60 706 individuals to identify clinically interpretable genes robustly associated with dominant monogenic DCM.Methods: We used the TruSight Cardio sequencing panel to evaluate the burden of rare variants in 56 putative DCM genes in 1040 patients with DCM and 912 healthy volunteers processed with identical sequencing and bioinformatics pipelines. We further aggregated data from 1498 patients with DCM sequenced in diagnostic laboratories and the Exome Aggregation Consortium database for replication and meta-analysis.Results: Truncating variants in TTN and DSP were associated with DCM in all comparisons. Variants in MYH7, LMNA, BAG3, TNNT2, TNNC1, PLN, ACTC1, NEXN, TPM1, and VCL were significantly enriched in specific patient subsets, with the last 2 genes potentially contributing primarily to early-onset forms of DCM. Overall, rare variants in these 12 genes potentially explained 17% of cases in the outpatient clinic cohort representing a broad range of adult patients with DCM and 26% of cases in the diagnostic referral cohort enriched in familial and early-onset DCM. Although the absence of a significant excess in other genes cannot preclude a limited role in disease, such genes have limited diagnostic value because novel variants will be uninterpretable and their diagnostic yield is minimal.Conclusions: In the largest sequenced DCM cohort yet described, we observe robust disease association with 12 genes, highlighting their importance in DCM and translating into high interpretability in diagnostic testing. The other genes analyzed here will need to be rigorously evaluated in ongoing curation efforts to determine their validity as Mendelian DCM genes but have limited value in diagnostic testing in DCM at present. This data will contribute to community gene curation efforts and will reduce erroneous and inconclusive findings in diagnostic testing. [ABSTRACT FROM AUTHOR]

The outcome of natural selection depends on the demographic processes of birth, death, and development. Here, we derive conditions for protected polymorphism in a population characterized by age- or stage-dependent demography with two sexes. We do so using a novel two-sex matrix population model including basic Mendelian genetics (one locus, two alleles, random mating). Selection may operate on survival, growth, or fertility, any or all of which may differ between the sexes. The model can therefore incorporate genes with arbitrary pleiotropic and sex-specific effects. Conditions for protected polymorphism are expressed in terms of the eigenvalues of the linearization of the model at the homozygote boundary equilibria. We show that in the absence of sexual dimorphism, polymorphism requires heterozygote superiority in the genotypic population growth rate. In the presence of sexual dimorphism, however, heterozygote superiority is not required; an inferior heterozygote may invade, reducing the population growth rate and even leading to extinction (so-called evolutionary suicide). Our model makes no assumptions about separation of time scales between ecological and evolutionary processes, and can thus be used to project sex × stage × genotype dynamics of eco-evolutionary processes. Empirical evidence that sexual dimorphism affects extinction risk is growing, yet sex differences are often ignored in evolutionary demography and in eco-evolutionary models. Our analysis highlights the importance of sexual dimorphism and suggests mechanisms by which an allele can be favored by selection, yet drive a population to extinction, as a result of the structure and interdependence of sex- and stage-specific processes. [ABSTRACT FROM AUTHOR]

In this study, genetic analysis was conducted on the inheritance of qualitative traits, such as leaf color, flower color, seed size, and seed hardness, in the F2 population derived from the cross between var. frutescens and var. crispa. As determined by the separation pattern of each trait in the F2 population, F2 plants with a green color were more common than those with a purple color on the leaf surface, whereas F2 plants with a purple color were more common than those with a green color on the reverse side of the leaf. For flower color, more F2 plants were observed to have a white color. For seed size, more F2 plants were observed to have a seed size of above 2 mm, and for seed hardness, more F2 plants were observed to have characteristics of seed hardness. Our examination of the genetic separation ratios with respect to Mendel’s law of genetics revealed that three traits, leaf color (surface and reverse side) and flower color, did not follow the separation ratio of 1:2:1, and the seed size did not follow the segregation ratio of 3:1, but seed hardness was found to follow the separation ratio of 3:1. The results of this study are expected to provide basic information to help understand the genetic segregation of leaf and seed characteristics in the F2 population derived from the cross between var. frutescens and var. crispa, and also to provide useful information for breeding studies to assist the development of varieties of Perilla crop. [ABSTRACT FROM AUTHOR]

Described as a 'rare genius' by one of his close friends, Hermann Joseph Muller was one of the pioneers of modern genetics in the early decades of the twentieth century. Although his work on mutagenesis and mutations fetched him widespread recognition and glory, thanks to the Nobel Prize he received in 1946, the depth and breadth of his contributions to genetics and allied areas of biology are far more impressive. To many, he brought about a paradigm shift in the way experimental genetics was done. Even the way in which geneticists name genes — the standard genetics symbols and notation is largely as proposed by Muller. From school textbooks to advanced genetics research in genetics labs, from mutation to the mechanism of species formation, the intellectual outputs of Muller are omnipresent in the domain of genetics. His life is an inspiring story of a person waging an immense struggle against personal and political nightmares and yet, almost heroically solving some of the most challenging and fundamental problems in biology at the time. If the early work of William Bateson [1], Thomas Hunt Morgan [2] and others initiated the follow-up to the resurrection of Mendel's laws, it was largely completed by Muller. The purpose of this article is to summarize some of his key contributions to biology. [ABSTRACT FROM AUTHOR]

Mendelian randomization (MR) has been used to estimate the causal effect of body mass index (BMI) on particular traits thought to be affected by BMI. However, BMI may also be a modifiable, causal risk factor for outcomes where there is no prior reason to suggest that a causal effect exists. We performed a MR phenome-wide association study (MR-pheWAS) to search for the causal effects of BMI in UK Biobank (n = 334 968), using the PHESANT open-source phenome scan tool. A subset of identified associations were followed up with a formal two-stage instrumental variable analysis in UK Biobank, to estimate the causal effect of BMI on these phenotypes. Of the 22 922 tests performed, our MR-pheWAS identified 587 associations below a stringent P value threshold corresponding to a 5% estimated false discovery rate. These included many previously identified causal effects, for instance, an adverse effect of higher BMI on risk of diabetes and hypertension. We also identified several novel effects, including protective effects of higher BMI on a set of psychosocial traits, identified initially in our preliminary MR-pheWAS in circa 115,000 UK Biobank participants and replicated in a different subset of circa 223,000 UK Biobank participants. Our comprehensive MR-pheWAS identified potential causal effects of BMI on a large and diverse set of phenotypes. This included both previously identified causal effects, and novel effects such as a protective effect of higher BMI on feelings of nervousness. [ABSTRACT FROM AUTHOR]

Introduction: DNA testing for autosomal recessive disease mutations in many dog breeds is now relatively commonplace. There have, however, been few efforts made to determine changes in the frequency of disease causing mutations as a result of probable selection based on the results of DNA testing. This study makes use of genotype data from both DNA test results reported to the UK Kennel Club and where known from a ‘hereditary status’ (where a definitive genotype may be inferred and ascribed based on known parental genotypes) to do so. Results: The results, using all known genotype data, show a general and sizeable decline in disease causing mutation frequency across eight diseases in eight breeds (by between 12–86% in dogs born 2–4 years after publication of the mutation, and by nearly 90% or more in those born 8–10 years after). In contrast, data from test results only, while revealing an almost complete and immediate end to the production of affected individuals, show little general decline in either the derived mutation frequency or the proportion of heterozygote carriers. It appears that the numerical size of the breed is an important determinant on the rate of uptake of a DNA test (as judged by the proportion of a breed born four years after publication of the disease-causing mutation with a known genotype). Conclusion: These results show that dog breeders appear to be incorporating the results of DNA testing into their selection strategies to successfully decrease the frequency of the mutation. It is shown that use of DNA test result data alone does not reveal such trends, possibly as some breeders undertake testing to determine clear stock which can then be used to produce future disease-free generations in the knowledge they are not carrying the disease causing mutation. [ABSTRACT FROM AUTHOR]

Biology teachers consider basic Mendelian genetics to be value-free, objective science, immune to misinterpretation and misuse. It may thus come as a surprise to learn that in the early days of genetics a cornerstone of genetics education, the dihybrid cross, was employed to support claims of the racial superiority of whites over blacks and to provide a "scientific" rationale for laws prohibiting interracial marriages. In 1917 the prominent eugenicist Charles B. Davenport warned of the danger of "disharmonious combinations" of physical and behavioral traits in the second generation of "wide race crosses," equivalent to the F2 generation of a dihybrid cross. He tried and failed to find data to support his arguments in a study of the mixed-race inhabitants of Jamaica. Davenport's analysis was deeply flawed, especially by the racist assumptions underlying this work. Although these events occurred a century ago, biology teachers may still be able to use this regrettable episode as an example of how even the most basic science may be misapplied by those with a social or political agenda. [ABSTRACT FROM AUTHOR]

Summary: In observational studies to estimate treatment effects, unmeasured confounding is often a concern. The instrumental variable (IV) method can control for unmeasured confounding when there is a valid IV. To be a valid IV, a variable needs to be independent of unmeasured confounders and only affect the outcome through affecting the treatment. When applying the IV method, there is often concern that a putative IV is invalid to some degree. We present an approach to sensitivity analysis for the IV method which examines the sensitivity of inferences to violations of IV validity. Specifically, we consider sensitivity when the magnitude of association between the putative IV and the unmeasured confounders and the direct effect of the IV on the outcome are limited in magnitude by a sensitivity parameter. Our approach is based on extending the Anderson–Rubin test and is valid regardless of the strength of the instrument. A power formula for this sensitivity analysis is presented. We illustrate its usage via examples about Mendelian randomization studies and its implications via a comparison of using rare versus common genetic variants as instruments. [ABSTRACT FROM AUTHOR]

Background: Body mass index (BMI) has been suggested to be causally related to cardiovascular health in mid-to-late life, but this has not been explored systematically at younger ages - nor with detailed cardiovascular phenotyping. Recall-by-Genotype (RbG) is an approach that enables the collection of precise phenotypic measures in smaller studies, whilst maintaining statistical power and ability for causal inference.Methods: In this study, we used a combination of conventional multivariable regression analysis, Mendelian randomization (MR) and sub-sample RbG methodologies to estimate the causal effect of BMI on gross-level and detailed cardiovascular health in healthy participants from the Avon Longitudinal Study of Parents and Children at age 17 (N=1420-3108 for different outcomes) and an independent sample from the same cohort (for RbG) study at age 21 (N=386-418).Results: In both MR and RbG analyses, results suggested that higher BMI causes higher blood pressure (BP) and left ventricular mass index (LVMI) in young adults (e.g., difference in LVMI per kg/m2 using MR: 1.07g/m2.7; 95% CI: 0.62, 1.52; P=3.87x10-06 and per 3.58kg/m2 using RbG: 1.65g/m2.7 95% CI: 0.83, 2.47; P=0.0001). Additionally, RbG results suggested a causal role of higher BMI on higher stroke volume (SV: difference per 3.58kg/m2: 1.49ml/m2.04; 95% CI: 0.62, 2.35; P=0.001) and cardiac output (CO: difference per 3.58kg/m2: 0.11l/min/m1.83; 95% CI: 0.03, 0.19; P=0.01) but no strong evidence for a causal role on systemic vascular resistance or total arterial compliance. Neither analysis supported a causal role of higher BMI on heart rate.Conclusions: Complementary MR and RbG causal methodologies, together with a range of sensitivity analyses, suggest that higher BMI is likely to cause worse cardiovascular health, specifically higher BP and LVMI, even in youth. Higher BMI also resulted in increased CO in the RbG study, which appeared to be solely driven by SV, as neither MR nor RbG analyses suggested a causal effect of BMI on heart rate. These consistent results support efforts to reduce BMI from a young age to prevent later adverse cardiovascular health and illustrate the potential for phenotypic resolution with maintained analytical power using RbG. [ABSTRACT FROM AUTHOR]

The article discusses the approaches in the advent of next-generation sequencing (NGS) techniques. It highlights the significance of whole exome sequencing (WES) for the treatment of rare Mendelian diseases. Also emphasized is the effect of inborn errors of immunity, the combined immunodeficiency disorders (CIDs) in dysfunctional lymphocyte.

Introduction: Phototype has been associated with an increased risk of prostate cancer, and it is yet unknown if it is related to other hormone-dependent cancers, such as breast cancer or whether this association could be considered causal. Methods: We examined the association between the phototype and breast and prostate cancers using a Mendelian randomization analysis. We studied 1,738 incident cases of breast cancer and another 817 cases of prostate cancer. To perform a Mendelian randomization analysis on the phototype—cancer relationship, a genetic pigmentation score was required that met the following criteria: (1) the genetic pigmentation score was associated with phototype in controls; (2) the genetic pigmentation score was not associated with confounders in the relationship between phototype and cancer, and (3) the genetic pigmentation score was associated with cancer only through its association with phototype. Once this genetic score is available, the association between genetic pigmentation score and cancer can be identified as the association between phototype and cancer. Results: The association between the genetic pigmentation score and phototype in controls showed that a higher genetic pigmentation score was associated with fair skin, blond hair, blue eyes and the presence of freckles. Applying the Mendelian randomization analysis, we verified that there was no association between the genetic pigmentation score and cancers of the breast and prostate. Conclusions: Phototype is not associated with breast or prostate cancer. [ABSTRACT FROM AUTHOR]

Background: Observational studies on pubertal timing and asthma, mainly performed in females, have provided conflicting results about a possible association of early puberty with higher risk of adult asthma, possibly due to residual confounding. To overcome issues of confounding, we used Mendelian randomisation (MR), i.e., genetic variants were used as instrumental variables to estimate causal effects of early puberty on post-pubertal asthma in both females and males.Methods and Findings: MR analyses were performed in UK Biobank on 243,316 women using 254 genetic variants for age at menarche, and on 192,067 men using 46 variants for age at voice breaking. Age at menarche, recorded in years, was categorised as early (<12), normal (12-14), or late (>14); age at voice breaking was recorded and analysed as early (younger than average), normal (about average age), or late (older than average). In females, we found evidence for a causal effect of pubertal timing on asthma, with an 8% increase in asthma risk for early menarche (odds ratio [OR] 1.08; 95% CI 1.04 to 1.12; p = 8.7 × 10(-5)) and an 8% decrease for late menarche (OR 0.92; 95% CI 0.89 to 0.97; p = 3.4 × 10(-4)), suggesting a continuous protective effect of increasing age at puberty. In males, we found very similar estimates of causal effects, although with wider confidence intervals (early voice breaking: OR 1.07; 95% CI 1.00 to 1.16; p = 0.06; late voice breaking: OR 0.93; 95% CI 0.87 to 0.99; p = 0.03). We detected only modest pleiotropy, and our findings showed robustness when different methods to account for pleiotropy were applied. BMI may either introduce pleiotropy or lie on the causal pathway; secondary analyses excluding variants associated with BMI yielded similar results to those of the main analyses. Our study relies on self-reported exposures and outcomes, which may have particularly affected the power of the analyses on age at voice breaking.Conclusions: This large MR study provides evidence for a causal detrimental effect of early puberty on asthma, and does not support previous observational findings of a U-shaped relationship between pubertal timing and asthma. Common biological or psychological mechanisms associated with early puberty might explain the similarity of our results in females and males, but further research is needed to investigate this. Taken together with evidence for other detrimental effects of early puberty on health, our study emphasises the need to further investigate and address the causes of the secular shift towards earlier puberty observed worldwide. [ABSTRACT FROM AUTHOR]

Introduction Behçet disease (BD) is a systemic vasculitis involving vessels from any size with various clinical features. Most BD cases are multifactorial and associated with the HLA B51 antigen. In rare and severe early onset cases, dominant Mendelian transmission has been linked to mutations in the TNFAIP3 gene encoding A20. Herein, we propose a systematic review of the literature about the haploinsufficiency A20 (HA20) published cases. Systematic review Our review of the 45 cases of HA20 from literature highlights the similarities and the differences between this genetic auto-inflammatory disease and classical BD. HA20 looks like BD if we consider recurrent oral (87%) and genital (67%) ulcers, arthralgia or arthritis (42%), skin involvement (53%) such as erythema nodosum or abdominal symptoms (60%) such as abdominal pain, digestive ulcers or diarrhea. However, HA20 differs from classical BD because its geographical distribution is ubiquitous, sex ratio is inversed (one man for two women), first symptoms occur in early childhood (median age = 5.5 years; interquartile range: 1–10) instead of adulthood, recurrent fever is common (62%) unlike classical BD, HLA B51 antigen is uncommon and abdominal symptoms are over-represented compared to classical BD. In addition, response to colchicine in HA20 is inconstant (24%) unlike classical BD. Discussion/conclusion High fever flares and digestive involvement starting in early childhood seem to be hallmarks of HA20 clinical features. Response to colchicine is unpredictable and biotherapies like anti-TNFα and anti IL1 appear to be treatments of choice, like for other auto-inflammatory diseases. Prospective description of larger cohort of HA20 cases is needed to understand better when this disease must be looked for and how to treat these patients. [ABSTRACT FROM AUTHOR]

Parkinson disease (PD) is known as a common progressive neurodegenerative disease which is clinically diagnosed by the manifestation of numerous motor and nonmotor symptoms. PD is a genetically heterogeneous disorder with both familial and sporadic forms. To date, researches in the field of Parkinsonism have identified 23 genes or loci linked to rare monogenic familial forms of PD with Mendelian inheritance. Biochemical studies revealed that the products of these genes usually play key roles in the proper protein and mitochondrial quality control processes, as well as synaptic transmission and vesicular recycling pathways within neurons. Despite this, large number of patients affected with PD typically tends to show sporadic forms of disease with lack of a clear family history. Recent genome-wide association studies (GWAS) meta-analyses on the large sporadic PD case-control samples from European populations have identified over 12 genetic risk factors. However, the genetic etiology that underlies pathogenesis of PD is also discussed, since it remains unidentified in 40% of all PD-affected cases. Nowadays, with the emergence of new genetic techniques, international PD genomics consortiums and public online resources such as PDGene, there are many hopes that future large-scale genetics projects provide further insights into the genetic etiology of PD and improve diagnostic accuracy and therapeutic clinical trial designs. [ABSTRACT FROM AUTHOR]

Background: Instrumental variable (IV) methods are often used to identify 'local' causal effects in a subgroup of the population of interest. Such 'local' effects may not be ideal for informing clinical or policy decision making. When the instrument is non-causal, additional difficulties arise for interpreting 'local' effects. Little attention has been paid to these difficulties, even though commonly proposed instruments in epidemiology are non-causal (e.g. proxies for physician's preference; genetic variants in some Mendelian randomization studies).Methods: For IV estimates obtained from both causal and non-causal instruments under monotonicity, we present results to help investigators pose four questions about the local effect estimates obtained in their studies. (1) To what subgroup of the population does the effect pertain? Can we (2) estimate the size of or (3) describe the characteristics of this subgroup relative to the study population? (4) Can the sensitivity of the effect estimate to deviations from monotonicity be quantified?Results: We show that the common interpretations and approaches for answering these four questions are generally only appropriate in the case of causal instruments.Conclusions: Appropriate interpretation of an IV estimate under monotonicity as a 'local' effect critically depends on whether the proposed instrument is causal or non-causal. The results and formal proofs presented here can help in the transparent reporting of IV results and in enhancing the use of IV estimates in informing decision-making efforts. [ABSTRACT FROM AUTHOR]

Inbreeding increases the risk of certain Mendelian disorders in humans but may also reduce fitness through its effects on complex traits and diseases. Such inbreeding depression is thought to occur due to increased homozygosity at causal variants that are recessive with respect to fitness. Until recently it has been difficult to amass large enough sample sizes to investigate the effects of inbreeding depression on complex traits using genome-wide single nucleotide polymorphism (SNP) data in population-based samples. Further, it is difficult to infer causation in analyses that relate degree of inbreeding to complex traits because confounding variables (e.g., education) may influence both the likelihood for parents to outbreed and offspring trait values. The present study used runs of homozygosity in genome-wide SNP data in up to 400,000 individuals in the UK Biobank to estimate the proportion of the autosome that exists in autozygous tracts—stretches of the genome which are identical due to a shared common ancestor. After multiple testing corrections and controlling for possible sociodemographic confounders, we found significant relationships in the predicted direction between estimated autozygosity and three of the 26 traits we investigated: age at first sexual intercourse, fluid intelligence, and forced expiratory volume in 1 second. Our findings corroborate those of several published studies. These results may imply that these traits have been associated with Darwinian fitness over evolutionary time. However, some of the autozygosity-trait relationships were attenuated after controlling for background sociodemographic characteristics, suggesting that alternative explanations for these associations have not been eliminated. Care needs to be taken in the design and interpretation of ROH studies in order to glean reliable information about the genetic architecture and evolutionary history of complex traits. [ABSTRACT FROM AUTHOR]