Genetic Explanation Research Articles

Belief that addiction is a discrete category is a stronger correlate with stigma than the belief that addiction is biologically based

BackgroundDrug addiction is stigmatized, and this stigma contributes to poor outcomes for individuals with addiction. Researchers have argued that providing genetic explanations of addiction will reduce stigma, but there has been limited research testing this prediction.MethodsWe presented participants (N = 252) with news articles that either provided genetic or anti-genetic explanations of addiction.ResultsThere was no effect of article condition on stigma. Participants’ biological essentialism correlated with stigma in the context of both opioid and methamphetamine addiction. However, participants’ non-biological essentialism was a significantly stronger correlate with stigma.ConclusionsThis suggests that other essentialist beliefs, like belief that categories are discrete, may be more useful than biological essentialism for understanding addiction stigma.

Exploring the genetic landscape of diphtheria, tetanus and pertussis vaccination-associated seizures or subsequent epilepsies

Diphtheria, Tetanus, and whole-cell Pertussis (DTwP) vaccination-associated seizures form the commonest type of serious adverse event following immunization in India and are an important reason for vaccine hesitancy. Our study explored the genetic explanation of DTwP vaccination-associated seizures or subsequent epilepsies. Between March 2017 and March 2019, we screened 67 children with DTwP vaccination-associated seizures or subsequent epilepsies, and of those, we studied 54 without prior seizures or neurodevelopmental deficits. Our study design was cross-sectional with a 1-year follow-up having both retrospective and prospective cases. We performed clinical exome sequencing focused on 157 epilepsy-associated genes and multiplex ligation-dependent probe amplification of the SCN1A gene at enrolment. We applied the Vineland Social Maturity Scale for neurodevelopmental assessment at follow-up. Of 54 children enrolled and underwent genetic testing (median age 37.5 months, interquartile range 7.7–67.2; diagnosis at enrolment: epilepsy 29, febrile seizure 21, and febrile seizure-plus 4), we found 33 pathogenic variants of 12 genes. Of 33 variants, 13 (39%) were novel. Most pathogenic variants were found in SCN1A gene (n = 21/33; 64%), SCN8A in 2 children, and 10 children had one variant in CDKL5 , DEPDC5 , GNAO1 , KCNA2 , KCNT1 , KCNQ2 , NPRL3 , PCDH19 , RHOBTB2 , and SLC2A1 . Five or more seizures (odds ratio [OR] = 5.3, confidence interval [CI]: 1.6–18.4, p = 0.006), drug-resistant epilepsy (OR = 9.8, 95% CI: 2.6–30.7, p = 0.001) and neurodevelopmental impairment (social quotient < 70) (OR = 5.6, 95% CI: 1.65–17.6, p = 0.006) were significant predictors of genetic diagnosis. Our study provides proof-of-concept for genetic aetiology in children with DTwP vaccination-associated seizures or subsequent epilepsies and has important implications for vaccination policies in developing countries. International Pediatric Association Foundation, Inc. (IPAF): İhsan Doğramaci research award 2016/2017; Indian Council of Medical Research (ICMR), New Delhi, India: No.3/1/3/JRF-2016/HRD/LS/71/10940.

The Roman Mass: From Early Christian Origins to Tridentine Reform by Uwe Michael Lang

Reviewed by: The Roman Mass: From Early Christian Origins to Tridentine Reform by Uwe Michael Lang Stephen Morgan Uwe Michael Lang The Roman Mass: From Early Christian Origins to Tridentine Reform Cambridge: Cambridge University Press, 2022. xi + 445 pages. Hardback. $120. In 1948, when the Austrian scholar-priest Josef Jungmann published his two-volume Missarum Sollemnia it is not inaccurate to say that it marked the full flowering of a century of scholarship which had sought to understand the history of the Roman Rite as part of those various theologico-pastoral efforts the better to engage with the liturgy, and which came to be known as the Liturgical Movement. Jungmann's work, known in its English translation as The Mass of the Roman Rite, appeared within months of Pius XII's encyclical on the liturgy Mediator Dei and shortly before the same pope began to make changes to the Roman Rite that were clearly influenced by the insights of the Liturgical Movement. The subtitle Jungmann had given his book was "A genetic explanation of the Roman Mass." So complete, so thorough, so authoritative was its treatment of the historic development of the Mass in the West that it is possible to talk [End Page 120] of that explanation as being thought to be the culmen et fons of liturgical scholarship in the Roman Rite: the summit of the Liturgical Movement and, as it came to be, the source of so much of the intellectual underpinning of the liturgical teaching of the Second Vatican Council and the post-conciliar reform of the liturgy that came in its wake. It is no overstatement to say that liturgical scholarship of the Roman Rite falls into two periods: before Jungmann and after Jungmann. No respectable liturgical scholar before Jungmann managed so comprehensive a synthesis; no liturgical scholar after him can afford to ignore his work. And yet, The Mass of the Roman Rite was a work of its time. It is seventy-five years old—even its fifth edition, the last published during Jungmann's life, appeared over half a century ago—and it bears all the marks of its age. The number and range of sources that have come to light, the more developed techniques for establishing the age and provenance of texts, the critical examination of those texts, the insights brought to liturgics by anthropology, sociology, psychology, and ritual studies all mean that what could be confidently asserted in 1948 has subsequently been shown to be very much less secure. Where Jungmann's work could be distinguished from the more antiquarian efforts of, for example, Prosper Guéranger or Adrian Fortescue (and that is not to disparage the work of either one iota), by a rather more rigorous attention to detail and to the sources, and rather less reliance upon conjecture, it still bore the marks of early modern and Enlightenment belief in progress. Two presuppositions go largely unexamined in Jungmann: that things develop from the simple to the complex, and that there was once a liturgical epocha aurea, a golden age to which it is possible in part to return if only later corruptions can be stripped away. Neither presupposition is self-evidently true. Indeed, scholarship in many fields has decisively undermined the first as a rule of general development and exposed the anachronistic nature of the second. Consider the insights of linguistics in, for example, the grammar of Old English in comparison to modern English or, in the field of political science the complexity of the constitutional structure of Republican Rome compared with that of the present-day United [End Page 121] States. Contemporary study of ancient literature reveals the prevalence of variant sources appearing to coalesce over time into received texts and anthropologists—insofar as they agree upon anything—seem to agree that what once would have been called "primitive societies" are at the very least as complex and multi-dimensional as modern and post-modern ones. Indeed, it appears at least as true that things progress from the complex to the simple as the other way around. The second rule that Jungmann takes as axiomatic—what we might call the Verfallstheorie—fares no better in the light of...

Scientific explanation as ampliative, specialized embedding: the case of classical genetics

Explanations in genetics have intriguing aspects to both biologists and philosophers, and there is no account that satisfactorily elucidates such explanations. The aim of this article is to analyze the kind of explanations usually given in Classical (Transmission) Genetics (CG) and to present in detail the application of an account of explanation as ampliative, specialized nomological embedding to elucidate the such explanations. First, we present explanations in CG in the classical format of inferences with the explanans as the premises and the explanandum as the conclusion and compare them with explanations in other paradigmatic explanatory fields such as Classical Mechanics. Second, we summarize the main aspects discussed in the literature with regard the peculiarities of genetic explanations. Third, we introduce the account of scientific explanation as ampliative, specialized nomological embedding making use of Sneedian structuralism, in particular the notions of theory-net, fundamental law or guiding principle, specialization, and special laws. Finally, we apply this account to the case of CG and show that this analysis sheds light to the intriguing aspects of genetic explanations and remove most of their alleged oddities.

A Blueprint for Genetic Determinism

A Blueprint for Genetic Determinism

Germline variants in cancer predisposition genes in patients with uveal melanoma

AbstractPurpose: Patients with uveal melanoma (UM) have an increased risk of other primary tumours; up to 12% of patients belong to families with other cancers.[1] ~2% of unselected patients and 25% of patients with a family history of UM harbour a pathogenic germline variant in the BAP1 gene.[2] Additionally, 12 other genes might contribute to UM susceptibility [3] whereas 75% of patients with familial UM remain without a genetic explanation for UM susceptibility.Methods: We sequenced 312 consecutively enrolled patients with UM for germline variants in 15 genes driving UM tumorigenesis or having a BAP1 association using next‐generation sequencing. Additional 191 cancer‐associated genes were analysed from 108 high‐risk patients who had another cancer, UM at &lt;45 years of age, or either bilateral or familial UM.Results: 6.5% (7/108; 95% CI 2.6–12.9) of the high‐risk patients had a pathogenic or likely pathogenic germline variant in AR, CHEK2, DDX41, RAD50, RET, or SDHB and 8.3% (9/108; 95% CI 3.9–15.2) harboured a cancer‐associated VUS in BMPR1A or CHEK2. Germline variants in UM drivers other than BAP1 did not contribute to UM predisposition.Conclusions: Germline variants in known cancer genes are relatively frequent in selected patients with UM. The family history of cancer should be obtained and the threshold to offer genetic counselling should be low.

DR4/DQ2 haplotype confers susceptibility to T1DM with early clinical disease onset: A retrospective analysis in a tertiary-care hospital in Italy.

T1DM is the most frequent form of diabetes in children. It has a multifactorial pathogenesis in which genetic, environmental and immunological factors are involved. Among genetic explanations a major role is attributed to second class HLA genes, with the greatest risk associated with the simultaneous presence of the haplotypes DR3DQ2 and DR4DQ8. Based on results obtained in other countries, the aim of this research is to verify a possible association between the haplotype DRB1 * 04: 05-DQA1 * 03-DQB1 * 02 and the onset of T1DM among Italian children with possible genotype-phenotype correlations. Greater knowledge of genes which increase or decrease susceptibility is important for genome analysis. 165 patients with type 1 diabetes treated at the Diabetology Unit of the Meyer Children's University Hospital, were clinically analyzed. Data relating to age at diagnosis, pancreatic anti-beta cell autoimmunity, comorbidities with date of diagnosis and family history were retrospectively collected from medical data. A case-control study was conducted to investigate the HLA types of the patients compared to a control group of 819 Tuscan donors enrolled in the National Bone Marrow Donor Register. Typing was carried out using the Eurospital "DIABEGEN" kit, currently in use at the immunology laboratory of the Meyer Children's University Hospital. Mean age at diagnosis was 9.3 years; most children (97%) had anti-pancreatic beta cell autoimmunity; the anti-insulin antibody (IAA) was more frequent among children with early clinical disease onset (0-5 years of age). From the case control comparison performed on HLA typing, it emerged that the greatest risk for the development of type 1 diabetes is conferred by the haplotypes DR3DQ2 and DR4DQ8, but in addition to these haplotypes, already known in other countries, we identified another haplotype, DR4DQ2 (DRB1 * 04: 05-DQA1 * 03-DQB1 * 02) which appears to predispose children to type 1 diabetes (p value 2.80E-08) and it is associated with early clinical disease onset (p-value = 0.002). We report a new haplotype which increases susceptibility to type 1 diabetes among Italian children and which is associated with early clinical disease onset. Given the central role attributed to genetic factors in the pathogenesis of T1DM and to the II class HLA genes, this new haplotype ought to be recognized as a risk factor and included in tests routinely carried out to identify patients with a genetic predisposition to type I diabetes in Italy. These findings could have practical implications in research and prevention programs.

Health Disparities by Sexual Orientation: Implications of Genetic and Environmental Explanations

ABSTRACT Xu and colleagues add to the growing research literature on the role of potential familial (i.e., genetic and shared environment) causes in sexual orientation and in the relation between sexual orientation and poor mental health, in which lesbian, gay, bisexual, and other sexual minority individuals have poorer mental health than heterosexual individuals. I address several implications of the findings by Xu et al. and others. First, the nuance or complexity of genetics is considered, given the implications of genetics for health via a single gene, epistasis, or epigenetics. Second, I highlight the magnitude of the genetic relation between sexual orientation and psychopathology, suggesting some, but not all, sexual minority individuals may differ from heterosexual individuals on psychiatric vulnerability. In turn, this suggests that research should identify for whom or under what circumstances the relation holds. Third, I underscore the need for a within-subjects design, in which attention turns to differences among sexual minority individuals. Fourth, the need to reevaluate Minority Stress Theory, the predominant theory accounting for health disparities by sexual orientation, is addressed because of the implications of genetics for health. Fifth, I acknowledge the concern attached to genetic research for potentially compounding the stigmatization already experienced by sexual minority individuals. Nevertheless, this research is occurring and will likely increase in volume. It will inform understanding of sexual minority individuals.

Reductionist methodology and the ambiguity of the categories of race and ethnicity in biomedical research: an exploratory study of recent evidence

In this article, we analyse how researchers use the categories of race and ethnicity with reference to genetics and genomics. We show that there is still considerable conceptual “messiness” (despite the wide-ranging and popular debate on the subject) when it comes to the use of ethnoracial categories in genetics and genomics that among other things makes it difficult to properly compare and interpret research using ethnoracial categories, as well as draw conclusions from them. Finally, we briefly reconstruct some of the biases of reductionism to which geneticists (as well as other researchers referring to genetic methods and explanations) are particularly exposed to, and we analyse the problem in the context of the biologization of ethnoracial categories. Our work constitutes a novel, in-depth contribution to the debate about reporting race and ethnicity in biomedical and health research. First, we reconstruct the theoretical background assumptions about racial ontology which researchers implicitly presume in their studies with the aid of a sample of recent papers published in medical journals about COVID-19. Secondly, we use the typology of the biases of reductionism to the problem of biologization of ethnoracial categories with reference to genetics and genomics.

Immune and Genomic Analysis of Boxer Dog Breed and Its Relationship with Leishmania infantum Infection.

Leishmaniosis, one of the most important zoonoses in Europe, is caused by Leishmania infantum, an intracellular protozoan parasite. This disease is endemic in the Mediterranean area, where the main reservoir is the dog. Several studies indicate a possible susceptibility to L. infantum infection with clinical signs in some canine breeds. One of them is the boxer breed, which shows a high prevalence of disease. In this study, immunological and genomic characterization of serum samples from boxer dogs living in the Mediterranean area were evaluated to analyze the immune response and the possible genetic explanation for this susceptibility. Serum levels of cytokines IFN-γ, IL-2, IL-6, IL-8, and IL-18 were determined by ELISA commercial tests, while the genotyping study was performed using the CanineHD DNA Analysis BeadChip. The results show relevant differences in the serum levels of cytokines compared to published data on other canine breeds, as well as sequence changes that could explain the high susceptibility of the boxer breed to the disease. Concretely, polymorphic variants in the CIITA, HSF2BP, LTBP1, MITF, NOXA1, PKIB, RAB38, RASEF, TLE1, and TLR4 genes were found, which could explain the susceptibility of this breed to L. infantum infection.

Homozygous Missense Variant in the N-Terminal Region of ANK3 Gene Is Associated with Developmental Delay, Seizures, Speech Abnormality, and Aggressive Behavior

Introduction: Intellectual disability (ID) is a lifelong disability that affects an individual’s learning capacity and adaptive behavior. Such individuals depend on their families for day-to-day survival and pose a significant challenge to the healthcare system, especially in developing countries. ID is a heterogeneous condition, and genetic studies are essential to unravel the underlying cellular pathway for brain development and functioning. Methods: Here we studied a female index patient, born to a consanguineous Pakistani couple, showing clinical symptoms of ID, ataxia, hypotonia, developmental delay, seizures, speech abnormality, and aggressive behavior. Whole exome sequencing (WES) coupled with Sanger sequencing was performed for molecular diagnosis. Further, 3D protein modeling was performed to see the effect of variant on protein structure. Results: WES identified a novel homozygous missense variant (c.178T>C; p.Tyr60His) in the ANK3 gene. In silico analysis and 3-dimensional (3D) protein modeling supports the deleterious impact of this variant on the encoding protein, which compromises the protein’s overall structure and function. Conclusion: Our finding supports the clinical and genetic diversity of the ANK3 gene as a plausible candidate gene for ID syndrome. Intelligence is a complex polygenic human trait, and understanding molecular and biological pathways involved in learning and memory can solve the complex puzzle of how cognition develops. Intellectual disability (ID) is defined as a deficit in an individual’s learning and adaptive behavior at an early age of onset [American Psychiatric Association, 2013]. It is one of the major medical, and cognitive disorders with a prevalence of 1–3% in the population worldwide [Leonard and Wen, 2002]. ID often exists with other disabling mental conditions such as autism, attention deficit hyperactivity disorder, epilepsy, schizophrenia, bipolar disorder, or depression. Almost half of the cases appear to have a genetic explanation that ranges from cytogenetically visible abnormalities to monogenic defects [Flint, 2001; Ropers, 2010; Tucker-Drob et al., 2013]. Intellectual disability is a genetically heterogeneous condition, and more than 700 genes have been identified to cause ID alone or as a part of the syndrome. Research in X-linked ID has identified more than 100 disease-causing genes on the X chromosome that play a role in cognition; however, research into autosomal causes of ID is still ongoing [Vissers et al., 2016].

Resistance to Fluoroquinolones in Pseudomonas aeruginosa from Human, Animal, Food and Environmental Origin: The Role of CrpP and Mobilizable ICEs.

Fluoroquinolone resistance and the associated genetic mechanisms were assessed by antimicrobial susceptibility and whole genome sequencing in 56 Pseudomonas aeruginosa strains from human, animal, food and environmental origins. P. aeruginosa PAO1, PA7 and PA14 reference strains were also included in the study. Twenty-two strains (37%) were resistant to, at least, one fluoroquinolone agent. Correlation between the number of changes in GyrA and ParC proteins and the level of fluoroquinolone resistance was observed. Mutations or absence of genes, such as mexZ, mvaT and nalD encoding efflux pumps regulators, were also found in resistant strains. The crpP gene was detected in 43 strains (72.9%; 17 of them non-clinical strains), and coded seven different CrpP variants, including a novel one (CrpP-7). The crpP gene was located in 23 different chromosomal mobile integrative and conjugative elements (ICEs), inserted in two tRNAs integration sites. A great variety of structures was detected in the crpP-ICEs elements, e.g., the fimbriae related cup clusters, the mercury resistance mer operon, the pyocin S5 or S8 bacteriocin encoding genes, and mobilization genes. The location of crpP-like genes in mobilizable ICEs and linked to heavy metal resistance and virulence factors is of significant concern in P. aeruginosa. This work provides a genetic explanation of the fluoroquinolone resistance and crpP-associated pathogenesis of P. aeruginosa from a One-Health approach.

Narratives of Genetic Selfhood.

This essay considers the mid‐twentieth century adoption of genetic explanations for three biological phenomena: nutritional adaptation, antibiotic resistance, and antibody production. This occurred at the same time as the hardening of the neo‐Darwinian Synthesis in evolutionary theory. I argue that these concurrent changes reflect an ascendant narrative of genetic selfhood, which prioritized random hereditary variation and selection through competition, and marginalized physiological or environmental adaptation. This narrative was further reinforced by the Central Dogma of molecular biology and fit well with liberal political thought, with its focus on the autonomous individual. However, bringing biological findings into line with this narrative required modifying the notion of the gene to account for various kinds of non‐Mendelian inheritance. Hans‐Jörg Rheinberger's reflections on narrative and experiment are valuable in thinking about the friction between the postwar ideal of genetic selfhood and actual observations of how organisms adapt in response to the environment.

Novel homozygous stop-gain pathogenic variant of PPP1R13L gene leads to arrhythmogenic cardiomyopathy

BackgroundArrhythmogenic cardiomyopathy (ACM) is a heritable cardiac disease with two main features: electric instability and myocardial fibro-fatty replacement. There is no defined treatment except for preventing arrhythmias and sudden death. Detecting causative mutations helps identify the disease pathogenesis and family members at risk. We used whole-exome sequencing to determine a genetic explanation for an ACM-positive patient from a consanguineous family.MethodsAfter clinical analysis, cardiac magnetic resonance, and pathology, WES was performed on a two-year-old ACM proband. Variant confirmation and segregation of available pedigree members were performed by PCR and Sanger sequencing. The PPP1R13L gene was also analyzed for possible causative variants and their hitherto reported conditions.ResultsWe found a novel homozygous stop-gain pathogenic variant, c.580C > T: p.Gln194Ter, in the PPP1R13L gene, which was confirmed and segregated by PCR and Sanger sequencing. This variant was not reported in any databases.ConclusionsWES is valuable for the identification of novel candidate genes. To our knowledge, this research is the first report of the PPP1R13L c.580C > T variant. The PPP1R13L variant was associated with ACM as confirmed by cardiac magnetic resonance and pathology. Our findings indicate that PPP1R13L should be included in ACM genetic testing to improve the identification of at-risk family members and the diagnostic yield.

Single‐cell nucleic acid sequencing reinforces to reveal signal‐ dependent pathways contributing to cellular heterogeneity

Single‐cell nucleic acid sequencing reinforces to reveal signal‐ dependent pathways contributing to cellular heterogeneity

Impact of molecular features on outcome in African American or Black women with type 1 endometrial cancer.

5597 Background: Among women with endometrial cancer (EC), African American or Black (AAoB) population share a disproportionate burden of cancer deaths. Previous research exploring genetic and molecular explanations revealed White (W) women with EC are more likely to have mutations in PTEN, while AAoB women have higher rates of mutations in p53. However, these studies did not stratify EC by subtype, which occur at different rates among racial groups. Here, we aim to focus on molecular differences between racial groups, specifically in Type 1 EC (T1EC). Methods: Molecular data from TCGA Uterine Corpus Endometrial Carcinoma datasets on cBioPortal was used. Cancer type was filtered to Uterine Endometrioid Carcinoma Type 1 and separated by race. A total of 711 cases were analyzed for gene alterations, expression versus copy number variations, survival curves, and OncoPrints; significant findings and differences between racial groups were noted. The Surveillance, Epidemiology, and End Results (SEER) database was used to access the frequency, rate, and survival of AAoB and W with EC. Results: The genes analyzed on cBioPortal (575 W, 136 AAoB) depicted a similar alteration rate between the two groups, except for the most altered gene, PTEN (66% altered in W, 38% in AAoB). W women with a PTEN and PIK3CA alterations had significantly increased 5-year survival periods (P-value = 1.573e-3), while these alterations had no effect survival in AAoB. Six of the ten most altered genes between the two subgroups, and 6 of the 17 most actionable genes, were statistically significant for W but not for AAoB. SEER analyses depicted a frequency of 51,677 W and 3,915 AAoB, with a rate of 5.7% and 3.9%, respectively. The observed survival was 96.1% after 1 year and 85.6% after 5 years for W, compared to 92.8% after 1 year and 76.9% after 5 years for AAoB. Conclusions: Based on 5 years of data, overall survival (OS) rates among W women with T1EC are better than AAoB. PTEN mutation confers a survival advantage in W but not in AAoB, indicating that in AAoB, PTEN may play a different role or other factors may override the PTEN advantage. Additional analyses revealed non-remarkable findings, suggesting that molecular factors play a minor role in T1EC disparities or that a larger AAoB sample size is necessary. A better understanding of the downstream signaling pathways of common mutations in T1EC is necessary to further elucidate factors that contribute to racial disparities in T1EC. [Table: see text]

The Emerging Roles of Long Non-Coding RNAs in Intellectual Disability and Related Neurodevelopmental Disorders.

In the human brain, long non-coding RNAs (lncRNAs) are widely expressed in an exquisitely temporally and spatially regulated manner, thus suggesting their contribution to normal brain development and their probable involvement in the molecular pathology of neurodevelopmental disorders (NDD). Bypassing the classic protein-centric conception of disease mechanisms, some studies have been conducted to identify and characterize the putative roles of non-coding sequences in the genetic pathogenesis and diagnosis of complex diseases. However, their involvement in NDD, and more specifically in intellectual disability (ID), is still poorly documented and only a few genomic alterations affecting the lncRNAs function and/or expression have been causally linked to the disease endophenotype. Considering that a significant fraction of patients still lacks a genetic or molecular explanation, we expect that a deeper investigation of the non-coding genome will unravel novel pathogenic mechanisms, opening new translational opportunities. Here, we present evidence of the possible involvement of many lncRNAs in the etiology of different forms of ID and NDD, grouping the candidate disease-genes in the most frequently affected cellular processes in which ID-risk genes were previously collected. We also illustrate new approaches for the identification and prioritization of NDD-risk lncRNAs, together with the current strategies to exploit them in diagnosis.

Three legs of the missing heritability problem

The so-called ‘missing heritability problem’ is often characterized by behavior geneticists as a numerical discrepancy between alternative kinds of heritability. For example, while ‘traditional heritability’ derived from twin and family studies indicates that approximately ∼50% of variation in intelligence is attributable to genetics, ‘SNP heritability’ derived from genome-wide association studies indicates that only ∼10% of variation in intelligence is attributable to genetics. This 40% gap in variance accounted for by alternative kinds of heritability is frequently referred to as what's “missing.” Philosophers have picked up on this reading, suggesting that “dissolving” the missing heritability problem is merely a matter of closing the numerical gap between traditional and molecular kinds of heritability. We argue that this framing of the problem undervalues the severity of the many challenges to scientific understanding of the “heritability” of human behavior. On our view, resolving the numerical discrepancies between alternative kinds of heritability will do little to advance scientific explanation and understanding of behavior genetics. Thus, we propose a new conceptual framework of the missing heritability problem that comprises three independent methodological and explanatory challenges: the numerical gap, the prediction gap, and the mechanism gap.

Whole Exome Sequencing Identifies a Rare Mutation in NACAD as a Possible Cause of COVID orchitis in Brothers

IntroductionLittle is known of SARS-CoV2 (COVID-19) pathogenicity, but organ inflammation syndromes have been well observed and documented in the lungs, heart, liver, kidneys, and testes. While the blood-testis barrier is known to protect testes from antigens, current evidence suggests COVID-19 can affect the testis. Reports of bilateral orchitis are growing. Current hypotheses consider causes of (1) cellular induced cytokine storm or (2) IgG deposits in the vascular endothelium to be at blame but causal genes or underlying genetic susceptibility have not yet been identified.ObjectiveThis project sought to uncover genetic explanations as to why certain men face increased susceptibility to developing COVID orchitis.MethodsWe identified and examined six COVID-19 patients who all were confirmed with polymerase chain reaction (PCR), including three COVID-19 (+) men without orchitis (controls) and three COVID (+) men with orchitis (bilateral testicular pain for at least 5 days around the time of testing PCR positive). Of note, among the three men with COVID-19 who had orchitis, two of them were siblings. DNA extraction and whole exome sequencing were performed on blood using the QIAmp blood maxi kit on five of the six patients. Variants were prioritized by being shared between the three patients affected with orchitis, absent in controls, and introducing nonsense, frameshift, splicing or non‐synonymous amino acid changes and less than 10% in population prevalence. Based on WES findings, DuoSet® Human ACE2 reagent kit 2 (catalog number: DY933-05) was purchased from R&D Systems, USA, and used to measure the level of soluble ACE2 in the plasma samples.ResultsThe average age of the men in the study was 25 years old. The average duration of COVID symptoms (fever, sore throat, cough, body aches) were 7 days. Among the men who developed bilateral testis pain, the symptoms lasted for an average of 22 days. A list of 16 variants was generated that found to be shared between the two siblings with COVID orchitis along with the unrelated subject with COVID orchitis, and not present in the two controls. Among the 16 variants, a nonsynonymous non-frameshit deletion in NACAD variant on chromosome 7 with a frequency of 3.9% prevalence in ExAC was prioritized based on known involvement in the ACE2 pathway, read depth, and genotype quality. Phenotypically, we found that circulating levels of soluble ACE2 was 3.72 ng/ml among men who had COVID orchitis and was lower than men who developed COVID without orchitis.ConclusionsWe observed a stop mutation in NACAD in 2 brothers and 1 unrelated man who developed COVID orchitis. Interestingly, we found lower circulating ACE2 serum levels in both brothers with orchitis and the one nonrelated orchitis subject but normal serum levels in all controls. NACAD when involved with cellular ability to shuttle out ACE2 becomes critical for COVID symptomatology. With decreased transcellular and extracellular transport of ACE2 being possible in subjects with the gene mutation, it can be postulated more ACE2 will be found intracellularly leading to increased cellular entry of SARS CoV-2 and possibility of orchitis sequelae.DisclosureNo

Overcoming barriers to sustainable, healthy diets

Overcoming barriers to sustainable, healthy diets