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In recent years, pre-service teacher education programs have recognized the importance of equipping future educators with the necessary skills such as argumentation skills and metacognitive awareness. However, the extent to these skills in ore-service biology teachers remains relatively unexplored. This study aimed to explore the effect of argument-driven inquiry on pre-service biology teachers’ argumentation skills and metacognitive awareness. This study also investigated the correlation between argumentation skills and metacognitive awareness in pre-service biology teachers. This research was conducted as quasi experiment using nonrandomized control group pretest–post-test design with two classes. One class as experiment group (N=44) which participated in series of activities in laboratory work using argument-driven inquiry, and control group (N=44) which participated in the regular laboratory activities. The laboratory work focused on the topic of mendelian genetic. This research was conducted on the second year of pre-service biology teachers in the Department of Biology Education. Data were generated by administrating pre-test and post-test on argumentation skill using open-ended question and metacognitive awareness using Metacognitive Awareness Inventory (MAI). Result showed a significant difference between experimental group and control group in argumentation skills (p value= .016) as well as in metacognitive awareness (p value = .005). However, the correlation between argumentation skills and metacognitive awareness were relatively low (r= -.119). This research findings can be used as suggestions for policy makers and educational institute to integrate argumentation skills and metacognitive awareness in designed for professional development program in teacher training program.

Purpose of Review: Spontaneous coronary artery dissection (SCAD) has been increasingly recognized as a significant cause of acute myocardial infarction (AMI) in young and middle-aged women and arises through mechanisms independent of atherosclerosis. SCAD has a multifactorial etiology that includes environmental, individual, and genetic factors distinct from those typically associated with coronary artery disease. Here, we summarize the current understanding of the genetic factors contributing to the development of SCAD and highlight those factors which differentiate SCAD from atherosclerotic coronary artery disease. Recent Findings: Recent studies have revealed several associated variants with varying effect sizes for SCAD, giving rise to a complex genetic architecture. Associated genes highlight an important role for arterial cells and their extracellular matrix in the pathogenesis of SCAD, as well as notable genetic overlap between SCAD and other systemic arteriopathies such as fibromuscular dysplasia and vascular connective tissue diseases. Further investigation of individual variants (including in the associated gene PHACTR1) along with polygenic score analysis have demonstrated an inverse genetic relationship between SCAD and atherosclerosis as distinct causes of AMI. Summary: SCAD represents an increasingly recognized cause of AMI with opposing clinical and genetic risk factors from that of AMI due to atherosclerosis, and it is often associated with complex underlying genetic conditions. Genetic study of SCAD on a larger scale and with more diverse cohorts will not only further our evolving understanding of a newly defined genetic spectrum for AMI, but it will also inform the clinical utility of integrating genetic testing in AMI prevention and management moving forward. [ABSTRACT FROM AUTHOR]

Mendelian genetics are essential for students seeking to comprehend the complexities of inheritance; although fundamental, these biology concepts are difficult for students to understand. This study examined the effectiveness of task-based learning (TBL) in enhancing the students' conceptual understanding of the Patterns of Mendelian Genetics. A pretest and posttest quasi-experimental research design involved an experimental and a control group. An Intrinsic Motivation Inventory questionnaire was utilized to assess the level of intrinsic motivation for task evaluation for the experimental group. Paired t-test was used to compare the pretest and post-test results. Before the intervention, both groups had a low conceptual understanding of the topic. At the end of the intervention, both groups had significantly increased their performances from pretest to posttest scores. The study revealed that TBL is more effective than Traditional Lecture-Based Instruction (TLI), as seen in their enhanced student performance, implying the effectiveness of the TBL as an innovative instructional approach. Participants from the experimental group expressed enjoyment, competence, and ownership of their task activities, and they did not feel nervous and anxious about doing the tasks. Pearson rcorrelation was used to establish a relationship among the variables. Perceived choice, pressure/tension, and student performance in the experimental group have low positive correlations, and perceived choice, interest/enjoyment, and performance have a negligible correlation. This approach is highly commendable for biology instruction. By illuminating the effectiveness of active learning in improving student's conceptual understanding, this study bridges the gap between theoretical-practical gap in genetics via active learning effectiveness. [ABSTRACT FROM AUTHOR]

Mendelian genetics are essential for students seeking to comprehend the complexities of inheritance; although fundamental, these biology concepts are difficult for students to understand. This study examined the effectiveness of task-based learning (TBL) in enhancing the students' conceptual understanding of the Patterns of Mendelian Genetics. A pretest and posttest quasi-experimental research design involved an experimental and a control group. An Intrinsic Motivation Inventory questionnaire was utilized to assess the level of intrinsic motivation for task evaluation for the experimental group. Paired t-test was used to compare the pretest and post-test results. Before the intervention, both groups had a low conceptual understanding of the topic. At the end of the intervention, both groups had significantly increased their performances from pretest to posttest scores. The study revealed that TBL is more effective than Traditional Lecture-Based Instruction (TLI), as seen in their enhanced student performance, implying the effectiveness of the TBL as an innovative instructional approach. Participants from the experimental group expressed enjoyment, competence, and ownership of their task activities, and they did not feel nervous and anxious about doing the tasks. Pearson r-correlation was used to establish a relationship among the variables. Perceived choice, pressure/tension, and student performance in the experimental group have low positive correlations, and perceived choice, interest/enjoyment, and performance have a negligible correlation. This approach is highly commendable for biology instruction. By illuminating the effectiveness of active learning in improving student’s conceptual understanding, this study bridges the gap between theoretical-practical gap in genetics via active learning effectiveness.

Purpose of Review: Spontaneous coronary artery dissection (SCAD) is a significant cause of acute myocardial infarction that is increasingly recognized in young and middle-aged women. The etiology of SCAD is likely multifactorial and may include the interaction of environmental and individual factors. Here, we summarize the current understanding of the genetic factors contributing to the development of SCAD. Recent Findings: The molecular findings underlying SCAD have been demonstrated to include a combination of rare DNA sequence variants with large effects, common variants contributing to a complex genetic architecture, and variants with intermediate impact. The genes associated with SCAD highlight the role of arterial cells and their extracellular matrix in the pathogenesis of the disease and shed light on the relationship between SCAD and other disorders, including fibromuscular dysplasia and connective tissue diseases. Summary: While up to 10% of affected individuals may harbor a rare variant with large effect, SCAD most often presents as a complex genetic condition. Analyses of larger and more diverse cohorts will continue to improve our understanding of risk susceptibility loci and will also enable consideration of the clinical utility of genetic testing strategies in the management of SCAD. [ABSTRACT FROM AUTHOR]

NUSAP1 encodes a cell cycle‐dependent protein with key roles in mitotic progression, spindle formation, and microtubule stability. Both over‐ and under‐expression of NUSAP1 lead to dysregulation of mitosis and impaired cell proliferation. Through exome sequencing and Matchmaker Exchange, we identified two unrelated individuals with the same recurrent, de novo heterozygous variant (NM_016359.5 c.1209C > A; p.(Tyr403Ter)) in NUSAP1. Both individuals had microcephaly, severe developmental delay, brain abnormalities, and seizures. The gene is predicted to be tolerant of heterozygous loss‐of‐function mutations, and we show that the mutant transcript escapes nonsense mediated decay, suggesting that the mechanism is likely dominant‐negative or toxic gain of function. Single‐cell RNA‐sequencing of an affected individual's post‐mortem brain tissue indicated that the NUSAP1 mutant brain contains all main cell lineages, and that the microcephaly could not be attributed to loss of a specific cell type. We hypothesize that pathogenic variants in NUSAP1 lead to microcephaly possibly by an underlying defect in neural progenitor cells. [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 utilising 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.

Coccidioidomycosis is a human fungal disease cause by inhalation of aerosol spores produced by Coccidioides posadasii or Coccidioides immitis. This disease is a common cause of community-acquired pneumonia in the endemic areas of the Southwestern United States. It also can present as a life-threatening disease as the fungal cells disseminate to skin, bone, and central nervous system. The outcome of coccidioidomycosis is largely determined by the nature of host immune response to the infection. Escalation of symptomatic infections and increased cost of long-term antifungal treatment warrant a concerted effort to better understand the innate and adaptive immune responses and the genetics associated with coccidioidomycosis susceptibility. This knowledge can be harnessed for development of a human vaccine against Coccidioides and advance clinic management of this disease. This review discusses recently reported studies on innate and adaptive immunity to Coccidioides infection, Mendelian susceptibility to disseminated disease and progress toward a human vaccine against this formidable disease.

Utilizing an inquiry-learning space (ILS) via the Go-Lab platform, we investigated students' technology acceptance, knowledge integration [KI] process, and learning outcomes of both the high-achiever KI student and low-achiever KI student. This study aimed to understand how students engage in knowledge integration tasks using an inquiry-learning space to learn Mendelian genetics and realize the relationship between student KI and domain knowledge. Using a quasi-experimental design, we examined 41 seventh-grade students in Taiwan completing Mendelian genetics KI tasks in ILS, pre/post-testing of domain knowledge tests, and a technology acceptance questionnaire. The analysis of students' interaction in the ILS and domain knowledge tests was conducted through descriptive statistics, t-tests, Pearson's correlation, and content analysis to indicate the direction and relationship between students' KI processes and learning outcomes. A technology acceptance questionnaire was analyzed through descriptive statistics and Pearson's correlation to reveal whether students accepted learning on the Go-Lab platform. The study showed that (i) students responded positively to the perceived usefulness of the Go-Lab platform, (ii) the high-achiever KI students could gradually construct links from simple to complex and diverse among genetic ideas, and the low-achiever almost built simple links, but (iii) the high-achiever and low-achiever KI students had similar learning outcomes. These findings have implications that the instruction design of knowledge integration tasks promotes students' Mendelian genetics conceptual understanding and KI progress. [ABSTRACT FROM AUTHOR]

This essay documents the century-long efforts of Peter Darby, Ernest S. Salmon, and Ray Neve, all of whom were directors of England’s Hop Research Program. While these scientists engaged in myriad projects, the central story surrounds the development and release of hybrid hop varieties for use in beer. In contrast with the brewing industry that turned toward mechanization and industrial advancements in the twentieth century, the English hop breeding program steadily relied on hand-pollinating characteristic of Mendelian genetics. Crossbreeding, or hybridization, of hops (and scores of other dioicous plants—that is, those with two distinct sexes) traditionally occurred with scientists selecting specimens that exhibited desirable traits that could be traced to their hereditary makeup. The process was painstakingly slow, requiring countless dustings of pollen from male plants onto female flowers. Darby, Salmon, and Neve engaged in this process thousands of times before deciding on which offspring to select from the greenhouses to transplant into fields. Their promising and successful specimens today populate England’s experimental hop garden for their potential in brewing or breeding future crosses; the most outstanding progeny can be found in beers near and far. [ABSTRACT FROM AUTHOR]

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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]

This paper contributes to the ongoing reassessment of the controversy between William Bateson and Karl Pearson by characterising what we call "Batesonian Mendelism" and "Pearsonian biometry" as coherent and competing scientific outlooks. Contrary to the thesis that such a controversy stemmed from diverging theoretical commitments on the nature of heredity and evolution, we argue that Pearson's and Bateson's alternative views on those processes ultimately relied on different appraisals of the methodological value of the statistical apparatus developed by Francis Galton. Accordingly, we contend that Bateson's belief in the primacy of cross-breeding experiments over statistical analysis constituted a minimal methodological unifying condition ensuring the internal coherence of Batesonian Mendelism. Moreover, this same belief implied a view of the study of heredity and evolution as an experimental endeavour and a conception of heredity and evolution as fundamentally discontinuous processes. Similarly, we identify a minimal methodological unifying condition for Pearsonian biometry, which we characterise as the view that experimental methods had to be subordinate to statistical analysis, according to methodological standards set by biometrical research. This other methodological commitment entailed conceiving the study of heredity and evolution as subsumable under biometry and primed Pearson to regard discontinuous hereditary and evolutionary processes as exceptions to a statistical norm. Finally, we conclude that Batesonian Mendelism and Pearsonian biometry represented two potential versions of a single genetics-based evolutionary synthesis since the methodological principles and the phenomena that played a central role in the former were also acknowledged by the latter—albeit as fringe cases—and conversely. [ABSTRACT FROM AUTHOR]

The Genotype-Phenotype (G-P) distinction was proposed in the context of Mendelian genetics, in the wake of late nineteenth century studies about heredity. In this paper, we provide a conceptual analysis that highlights that the G-P distinction was grounded on three pillars: observability, transmissibility, and causality. Originally, the genotype is the non-observable and transmissible cause of its observable and non-transmissible effect, the phenotype. We argue that the current developments of biology have called the validity of such pillars into question. First, molecular biology has unveiled the putative material substrate of the genotype (qua DNA), making it an observable object. Second, numerous findings on non-genetic heredity suggest that some phenotypic traits can be directly transmitted. Third, recent organicist approaches to biological phenomena have emphasized the reciprocal causality between parts of a biological system, which notably applies to the relation between genotypes and phenotypes. As a consequence, we submit that the G-P distinction has lost its general validity, although it can still apply to specific situations. This calls for forging new frameworks and concepts to better describe heredity and development. [ABSTRACT FROM AUTHOR]

Aims Catecholaminergic polymorphic ventricular tachycardia (CPVT) and short QT syndrome (SQTS) are inherited arrhythmogenic disorders that can cause sudden death. Numerous genes have been reported to cause these conditions, but evidence supporting these gene–disease relationships varies considerably. To ensure appropriate utilization of genetic information for CPVT and SQTS patients, we applied an evidence-based reappraisal of previously reported genes. Methods and results Three teams independently curated all published evidence for 11 CPVT and 9 SQTS implicated genes using the ClinGen gene curation framework. The results were reviewed by a Channelopathy Expert Panel who provided the final classifications. Seven genes had definitive to moderate evidence for disease causation in CPVT, with either autosomal dominant (RYR2, CALM1, CALM2, CALM3) or autosomal recessive (CASQ2, TRDN, TECRL) inheritance. Three of the four disputed genes for CPVT (KCNJ2, PKP2, SCN5A) were deemed by the Expert Panel to be reported for phenotypes that were not representative of CPVT, while reported variants in a fourth gene (ANK2) were too common in the population to be disease-causing. For SQTS, only one gene (KCNH2) was classified as definitive, with three others (KCNQ1, KCNJ2, SLC4A3) having strong to moderate evidence. The majority of genetic evidence for SQTS genes was derived from very few variants (five in KCNJ2 , two in KCNH2 , one in KCNQ1 / SLC4A3). Conclusions Seven CPVT and four SQTS genes have valid evidence for disease causation and should be included in genetic testing panels. Additional genes associated with conditions that may mimic clinical features of CPVT/SQTS have potential utility for differential diagnosis. [ABSTRACT FROM AUTHOR]

Victor Almon McKusick (VAM) is widely recognized as the father of the field of medical genetics. He established one of the first medical genetics clinics in the United States at Johns Hopkins in 1957 and developed a robust training program with the tripartite mission of education, research, and clinical care. Thousands of clinicians and scientists were educated over the years through the Short Course in Medical and Molecular Genetics, which VAM founded with Dr. Thomas Roderick in 1960. His Online Mendelian Inheritance in Man (OMIM), a catalog of human genes and genetic disorders, serves as the authoritative reference for geneticists around the globe. Throughout his career he was an advocate for mapping the human genome. He collaborated with Dr. Frank Ruddle in founding the International Human Gene Mapping Workshops in the early 70's and was an avid proponent of the Human Genome Project. He was the founding President of the Human Genome Organization and a founding editor of the journal Genomics. His prodigious contributions to the field of medical genetics were recognized by multiple honors, culminating with the Japan Prize in 2008. [ABSTRACT FROM AUTHOR]

A critical challenge in genetic diagnostics is the computational assessment of candidate splice variants, specifically the interpretation of nucleotide changes located outside of the highly conserved dinucleotide sequences at the 5′ and 3′ ends of introns. To address this gap, we developed the Super Quick Information-content Random-forest Learning of Splice variants (SQUIRLS) algorithm. SQUIRLS generates a small set of interpretable features for machine learning by calculating the information-content of wild-type and variant sequences of canonical and cryptic splice sites, assessing changes in candidate splicing regulatory sequences, and incorporating characteristics of the sequence such as exon length, disruptions of the AG exclusion zone, and conservation. We curated a comprehensive collection of disease-associated splice-altering variants at positions outside of the highly conserved AG/GT dinucleotides at the termini of introns. SQUIRLS trains two random-forest classifiers for the donor and for the acceptor and combines their outputs by logistic regression to yield a final score. We show that SQUIRLS transcends previous state-of-the-art accuracy in classifying splice variants as assessed by rank analysis in simulated exomes, and is significantly faster than competing methods. SQUIRLS provides tabular output files for incorporation into diagnostic pipelines for exome and genome analysis, as well as visualizations that contextualize predicted effects of variants on splicing to make it easier to interpret splice variants in diagnostic settings. [ABSTRACT FROM AUTHOR]

Abstract Background International guidelines for variant interpretation in Mendelian disease set stringent criteria to report a variant as (likely) pathogenic, prioritising control of false-positive rate over test sensitivity and diagnostic yield. Genetic testing is also more likely informative in individuals with well-characterised variants from extensively studied European-ancestry populations. Inherited cardiomyopathies are relatively common Mendelian diseases that allow empirical calibration and assessment of this framework. Methods We compared rare variants in large hypertrophic cardiomyopathy (HCM) cohorts (up to 6179 cases) to reference populations to identify variant classes with high prior likelihoods of pathogenicity, as defined by etiological fraction (EF). We analysed the distribution of variants using a bespoke unsupervised clustering algorithm to identify gene regions in which variants are significantly clustered in cases. Results Analysis of variant distribution identified regions in which variants are significantly enriched in cases and variant location was a better discriminator of pathogenicity than generic computational functional prediction algorithms. Non-truncating variant classes with an EF ≥ 0.95 were identified in five established HCM genes. Applying this approach leads to an estimated 14–20% increase in cases with actionable HCM variants, i.e. variants classified as pathogenic/likely pathogenic that might be used for predictive testing in probands’ relatives. Conclusions When found in a patient confirmed to have disease, novel variants in some genes and regions are empirically shown to have a sufficiently high probability of pathogenicity to support a “likely pathogenic” classification, even without additional segregation or functional data. This could increase the yield of high confidence actionable variants, consistent with the framework and recommendations of current guidelines. The techniques outlined offer a consistent and unbiased approach to variant interpretation for Mendelian disease genetic testing. We propose adaptations to ACMG/AMP guidelines to incorporate such evidence in a quantitative and transparent manner.

Hereditary motor neuropathies are clinically and genetically diverse disorders characterized by length-dependent axonal degeneration of lower motor neurons. Although currently as many as 26 causal genes are known, there is considerable missing heritability compared to other inherited neuropathies such as Charcot-Marie-Tooth disease. Intriguingly, this genetic landscape spans a discrete number of key biological processes within the peripheral nerve. Also, in terms of underlying pathophysiology, hereditary motor neuropathies show striking overlap with several other neuromuscular and neurological disorders. In this review, we provide a current overview of the genetic spectrum of hereditary motor neuropathies highlighting recent reports of novel genes and mutations or recent discoveries in the underlying disease mechanisms. In addition, we link hereditary motor neuropathies with various related disorders by addressing the main affected pathways of disease divided into five major processes: axonal transport, tRNA aminoacylation, RNA metabolism and DNA integrity, ion channels and transporters and endoplasmic reticulum. [ABSTRACT FROM AUTHOR]

This introduction offers a synoptic overview of some of Evelyn Fox Keller's influential works on the role and nature of metaphor in science, followed by a short précis of each of the contributed papers. [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]

Genetic sexing strains (GSS) used in sterile insect technique (SIT) programs are textbook examples of how classical Mendelian genetics can be directly implemented in the management of agricultural insect pests. Although the foundation of traditionally developed GSS are single locus, autosomal recessive traits, their genetic basis are largely unknown. With the advent of modern genomic techniques, the genetic basis of sexing traits in GSS can now be further investigated. This study is the first of its kind to integrate traditional genetic techniques with emerging genomics to characterize a GSS using the tephritid fruit fly pest Bactrocera cucurbitae as a model. These techniques include whole-genome sequencing, the development of a mapping population and linkage map, and quantitative trait analysis. The experiment designed to map the genetic sexing trait in B. cucurbitae, white pupae (wp), also enabled the generation of a chromosome-scale genome assembly by integrating the linkage map with the assembly. Quantitative trait loci analysis revealed SNP loci near position 42 MB on chromosome 3 to be tightly linked to wp. Gene annotation and synteny analysis show a near perfect relationship between chromosomes in B. cucurbitae and Muller elements A–E in Drosophila melanogaster. This chromosome-scale genome assembly is complete, has high contiguity, was generated using a minimal input DNA, and will be used to further characterize the genetic mechanisms underlying wp. Knowledge of the genetic basis of genetic sexing traits can be used to improve SIT in this species and expand it to other economically important Diptera.

Objective: The Phenotype Risk Score (PheRS) is a method to detect Mendelian disease patterns using phenotypes from the electronic health record (EHR). We compared the performance of different approaches mapping EHR phenotypes to Mendelian disease features.Materials and Methods: PheRS utilizes Mendelian diseases descriptions annotated with Human Phenotype Ontology (HPO) terms. In previous work, we presented a map linking phecodes (based on International Classification of Diseases [ICD]-Ninth Revision) to HPO terms. For this study, we integrated ICD-Tenth Revision codes and lab data. We also created a new map between HPO terms using customized groupings of ICD codes. We compared the performance with cases and controls for 16 Mendelian diseases using 2.5 million de-identified medical records.Results: PheRS effectively distinguished cases from controls for all 15 positive controls and all approaches tested (P < 4 × 1016). Adding lab data led to a statistically significant improvement for 4 of 14 diseases. The custom ICD groupings improved specificity, leading to an average 8% increase for precision at 100 (-2% to 22%). Eight of 10 adults with cystic fibrosis tested had PheRS in the 95th percentile prio to diagnosis.Discussion: Both phecodes and custom ICD groupings were able to detect differences between affected cases and controls at the population level. The ICD map showed better precision for the highest scoring individuals. Adding lab data improved performance at detecting population-level differences.Conclusions: PheRS is a scalable method to study Mendelian disease at the population level using electronic health record data and can potentially be used to find patients with undiagnosed Mendelian disease. [ABSTRACT FROM AUTHOR]

Plants and animals have always been the sources of food for the human race. The daily practice of hunting, fishing and the gathering of various plant parts underwent constant changes as the nomadic life was gradually replaced by a settled existence. This change was of decisive importance, as it paved the way for the domestication of plants and animals. During the process of domestication favourable traits are selected, such as yield, nutritional value and adaptability, all with an aim to ensure the nutrition requirements of mankind. In early times the selection for desirable traits was mostly instinctive, but over the course of millennia plant breeding gradually became a highly conscious process. As the available techniques developed, the level of knowledge required for selection also increased. This paper aims to summarise the milestones achieved over the last two centuries; it is also a tribute to the 80-year-old Professor van Staden, the botanist and plant physiologist who has deservedly won international renown for his outstanding work on the preservation of biological diversity. • From Gregor Mendel's laws of heredity to the discovery of chromosomes. • Classical plant breeding by mutagenesis and hybridization. • Molecular plant breeding. • The age of genetic engineering. • The dawn of genome editing. [ABSTRACT FROM AUTHOR]

• The Museum of Comparative Zoology's domesticated animals exhibit revealed links between genetics, animal fancying, and experimental breeding. • Fancy poultry from Charles B. Davenport and guinea pigs illustrating Mendelian inheritance from William E. Castle proved surprisingly popular. • This exhibition modernized the natural history museum, which was still aligned with its founder Louis Agassiz's views against evolution. In 1905 the Museum of Comparative Zoology at Harvard University began planning for a new domesticated animals exhibition in honor of the 100th anniversary of the birth of its founder Louis Agassiz. The resulting displays of variation and heredity in poultry, pigeons, rabbits, mice, and guinea pigs proved surprisingly popular to museumgoers. Some of these specimens still exist in the museum's storage facilities, namely a series of poultry donated by the biologist Charles B. Davenport and an elaborate set of guinea pigs from the experimental evolutionist William E. Castle. Situating these domesticated animal displays within academic and popular cultures of poultry fancying, animal breeding, and evolutionary science reveals how a nineteenth-century museum known for its ties to anti-evolutionary principles attempted to modernize its public exhibits. [ABSTRACT FROM AUTHOR]

In this paper, I explore how seamless embedding of four mathematical concepts: counting, ratio, distribution, and statistical significance, into a unit on inheritance enables students to gain a deeper insight into biological phenomena than a qualitative only approach achieves. The topic of Mendelian inheritance is used to illustrate this proposal. An introductory activity is presented that separates the specialized genetics vocabulary from the inheritance process, allowing the initial mathematical relationship to be developed and subsequently followed by the language requirements. [ABSTRACT FROM AUTHOR]

Coccidioidomycosis is a human fungal disease cause by inhalation of aerosol spores produced by Coccidioides posadasii or Coccidioides immitis. This disease is a common cause of community-acquired pneumonia in the endemic areas of the Southwestern United States. It also can present as a life-threatening disease as the fungal cells disseminate to skin, bone, and central nervous system. The outcome of coccidioidomycosis is largely determined by the nature of host immune response to the infection. Escalation of symptomatic infections and increased cost of long-term antifungal treatment warrant a concerted effort to better understand the innate and adaptive immune responses and the genetics associated with coccidioidomycosis susceptibility. This knowledge can be harnessed for development of a human vaccine against Coccidioides and advance clinic management of this disease. This review discusses recently reported studies on innate and adaptive immunity to Coccidioides infection, Mendelian susceptibility to disseminated disease and progress toward a human vaccine against this formidable disease. [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]

A key question in teaching a General Genetics course is whether to present the major concepts of Mendelian genetics first, or to start with the essential ideas of molecular genetics. A comparison of two sequential courses at Creighton University with similar groups of students indicated that there were no statistically significant differences in exam scores or final grades with the two approaches. It thus may be better to focus on the questions of how best to present the material in each area to contemporary students and how better to prepare them to take exams that involve different types of questions requiring analytical, numerical, and writing skills. These issues are discussed in the context of the modern biology curriculum. [ABSTRACT FROM AUTHOR]

While genetic determinants strongly influence HDL cholesterol (HDLc) levels, most genetic causes underlying variation in HDLc remain unknown. We aimed to identify novel rare mutations with large effects in candidate genes contributing to extreme HDLc in humans, utilizing family-based Mendelian genetics. We performed next-generation sequencing of 456 candidate HDLc-regulating genes in 200 unrelated probands with extremely low (≤10th percentile) or high (≥90th percentile) HDLc. Probands were excluded if known mutations existed in the established HDLc-regulating genes ABCA1, APOA1, LCAT, cholesteryl ester transfer protein (CETP), endothelial lipase (LIPG), and UDP-N-acetyl-α-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 2 (GALNT2). We identified 93 novel coding or splice-site variants in 72 candidate genes. Each variant was genotyped in the proband's family. Family-based association analyses were performed for variants with sufficient power to detect significance at P < 0.05 with a total of 627 family members being assessed. Mutations in the genes glucokinase regulatory protein (GCKR), RNase L (RNASEL), leukocyte immunoglobulin-like receptor 3 (LILRA3), and dynein axonemal heavy chain 10 (DNAH10) segregated with elevated HDLc levels in families, while no mutations associated with low HDLc. Taken together, we have identified mutations in four novel genes that may play a role in regulating HDLc levels in humans.

Aim Hypertrophic cardiomyopathy (HCM) exhibits genetic heterogeneity that is dominated by variation in eight sarcomeric genes. Genetic variation in a large number of non-sarcomeric genes has also been implicated in HCM but not formally assessed. Here we used very large case and control cohorts to determine the extent to which variation in non-sarcomeric genes contributes to HCM. Methods and results We sequenced known and putative HCM genes in a new large prospective HCM cohort (n = 804) and analysed data alongside the largest published series of clinically genotyped HCM patients (n = 6179), previously published HCM cohorts and reference population samples from the exome aggregation consortium (ExAC, n = 60 706) to assess variation in 31 genes implicated in HCM. We found no significant excess of rare (minor allele frequency < 1:10 000 in ExAC) protein-altering variants over controls for most genes tested and conclude that novel variants in these genes are rarely interpretable, even for genes with previous evidence of co-segregation (e.g. ACTN2). To provide an aid for variant interpretation, we integrated HCM gene sequence data with aggregated pedigree and functional data and suggest a means of assessing gene pathogenicity in HCM using this evidence. Conclusion We show that genetic variation in the majority of non-sarcomeric genes implicated in HCM is not associated with the condition, reinforce the fact that the sarcomeric gene variation is the primary cause of HCM known to date and underscore that the aetiology of HCM is unknown in the majority of patients. [ABSTRACT FROM AUTHOR]

Genetic sexing strains (GSS) used in sterile insect technique (SIT) programs are textbook examples of how classical Mendelian genetics can be directly implemented in the management of agricultural insect pests. Although the foundation of traditionally developed GSS are single locus, autosomal recessive traits, their genetic basis are largely unknown. With the advent of modern genomic techniques, the genetic basis of sexing traits in GSS can now be further investigated. This study is the first of its kind to integrate traditional genetic techniques with emerging genomics to characterize a GSS using the tephritid fruit fly pest Bactrocera cucurbitae as a model. These techniques include whole-genome sequencing, the development of a mapping population and linkage map and quantitative trait analysis. The experiment designed to map the genetic sexing trait in B. cucurbitae, white pupae (wp), also enabled the generation of a chromosome-scale genome assembly by integrating the linkage map with the assembly. Quantitative trait loci analysis revealed SNP loci near position 42 MB on chromosome 3 to be tightly linked to wp. Gene annotation and synteny analysis show a near perfect relationship between chromosomes in B. cucurbitae and Muller elements A-E in Drosophila melanogaster. This chromosome-scale genome assembly is complete, has high contiguity, was generated using a minimal input DNA and will be used to further characterize the genetic mechanisms underlying wp. Knowledge of the genetic basis of genetic sexing traits can be used to improve SIT in this species and expand it to other economically important Diptera. [ABSTRACT FROM AUTHOR]

Purpose: Developmentally regulated Guanosine-5'-triphosphate-binding protein 1 (DRG1) is a highly conserved member of a class of GTPases implicated in translation. Although the expression of mammalian DRG1 is elevated in the central nervous system during development, and its function has been implicated in fundamental cellular processes, no pathogenic germline variants have yet been identified. Here, we characterize the clinical and biochemical consequences of DRG1 variants., Methods: We collate clinical information of 4 individuals with germline DRG1 variants and use in silico, in vitro, and cell-based studies to study the pathogenicity of these alleles., Results: We identified private germline DRG1 variants, including 3 stop-gained p.Gly54 ∗ , p.Arg140 ∗ , p.Lys263 ∗ , and a p.Asn248Phe missense variant. These alleles are recessively inherited in 4 affected individuals from 3 distinct families and cause a neurodevelopmental disorder with global developmental delay, primary microcephaly, short stature, and craniofacial anomalies. We show that these loss-of-function variants (1) severely disrupt DRG1 messenger RNA/protein stability in patient-derived fibroblasts, (2) impair its GTPase activity, and (3) compromise its binding to partner protein ZC3H15. Consistent with the importance of DRG1 in humans, targeted inactivation of mouse Drg1 resulted in preweaning lethality., Conclusion: Our work defines a new Mendelian disorder of DRG1 deficiency. This study highlights DRG1's importance for normal mammalian development and underscores the significance of translation factor GTPases in human physiology and homeostasis., Competing Interests: Conflict of Interest Maryam Najafi and Salem Alawbathani are employees of Centogene. All other authors declare no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Systemic sclerosis (SSc) is a rheumatologic disease with a multifactorial etiology. Genome-wide association studies imply a polygenic, complex mode of inheritance with contributions from variation at the human leukocyte antigen locus and non-coding variation at a locus on chromosome 6p21, among other modestly impactful loci. Here we describe an 8-year-old female proband presenting with diffuse cutaneous SSc/scleroderma and a family history of SSc in a grandfather and maternal aunt. Methods: We employed whole exome sequencing (WES) of three members of this family. We examined rare missense, nonsense, splice-altering, and coding indels matching an autosomal dominant inheritance model. We selected one missense variant for Sanger sequencing confirmation based on its predicted impact on gene function and location in a known SSc genetic locus. Results: Bioinformatic analysis found eight candidate variants meeting our criteria. We identified a very rare missense variant in the regulatory NODP domain of NOTCH4 located at the 6p21 locus, c.4245G > A:p.Met1415Ile, segregating with the phenotype. This allele has a frequency of 1.83 × 10-5 by the data of the Exome Aggregation Consortium. Conclusion: This family suggests a novel mechanism of SSc pathogenesis in which a rare and penetrant coding variation can substantially elevate disease risk in contrast to the more modest non-coding variation typically found at this locus. These results suggest that modulation of the NOTCH4 gene might be responsible for the association signal at chromosome 6p21 in SSc. [ABSTRACT FROM AUTHOR]

The origins of genetics are to be found in Gregor Mendel's memoir on plant hybridization (1865). However, the word ‘genetics’ was only coined in 1906, to designate the new science of heredity. Founded upon the Mendelian method for analyzing the products of crosses, this science is distinguished by its explicit purpose of being a general ‘science of heredity’, and by the introduction of totally new biological concepts (in particular those of gene, genotype, and phenotype). In the 1910s, Mendelian genetics fused with the chromosomal theory of inheritance, giving rise to what is still called ‘classical genetics’. Within this framework, the gene is simultaneously a unit of function and transmission, a unit of recombination, and of mutation. Until the early 1950s, these concepts of the gene coincided. But when DNA was found to be the material basis of inheritance, this congruence dissolved. Then began the venture of molecular biology, which has never stopped revealing the complexity of the way in which hereditary material functions. [ABSTRACT FROM AUTHOR]