Prenatal diagnosis of recurrent hypoplastic left heart syndrome associated with MYH6 variants: a case report.

BACKGROUND: Hypoplastic left heart syndrome (HLHS) is a rare but genetically complex and clinically and anatomically severe form of congenital heart disease (CHD). CASE PRESENTATION: Here, we report on the use of rapid prenatal whole-exome sequencing for the prenatal diagnosis of a severe case of neonatal recurrent HLHS caused by heterozygous compound variants in the MYH6 gene inherited from the (healthy) parents. MYH6 is known to be highly polymorphic; a large number of rare and common variants have variable effects on protein levels. We postulated that two hypomorphic variants led to severe CHD when associated in trans; this was consistent with the autosomal recessive pattern of inheritance. In the literature, dominant transmission of MYH6-related CHD is more frequent and is probably linked to synergistic heterozygosity or the specific combination of a single, pathogenic variant with common MYH6 variants. CONCLUSIONS: The present report illustrates the major contribution of whole-exome sequencing (WES) in the characterization of an unusually recurrent fetal disorder and considered the role of WES in the prenatal diagnosis of disorders that do not usually have a genetic etiology.

The era of the Dawn of Mendelian research in the field of psychiatry: Rüdin's 1922 review paper "regarding the heredity of mental disturbances".

On September 27, 1922, Ernst Rüdin gave an address to the Annual Conference of the German Society of Genetics entitled "Regarding the Heredity of Mental Disturbances." Published in a 37-page article, Rüdin reviewed the progress in the field of Mendelian psychiatric genetics, then hardly more than a decade old. Topics included (a) the status of Mendelian analyses of dementia praecox and manic-depressive insanity which had expanded to include two and three locus and early polygenic models and sometimes included, respectively, schizoid and cyclothymic personalities; (b) a critique of theories for the explanation of co-occurrence of different psychiatric disorders within families; and (c) a sharp methodologic critique of Davenport and Rosanoff's contemporary work which emphasized Rüdin's commitment to careful, expert phenotyping, a primary focus on well-validated psychiatric disorders and not broad spectra of putatively inter-related conditions, and an emphasis on rigorous statistical modeling as seen in his continued collaboration with Wilhelm Weinberg.

Transgenerational Epigenetic Inheritance of Traumatic Experience in Mammals.

In recent years, we have seen an increasing amount of evidence pointing to the existence of a non-genetic heredity of the effects of events such as separation from parents, threat to life, or other traumatising experiences such as famine. This heredity is often mediated by epigenetic regulations of gene expression and may be transferred even across several generations. In this review, we focus on studies which involve transgenerational epigenetic inheritance (TEI), with a short detour to intergenerational studies focused on the inheritance of trauma or stressful experiences. The reviewed studies show a plethora of universal changes which stress exposure initiates on multiple levels of organisation ranging from hormonal production and the hypothalamic-pituitary-adrenal (HPA) axis modulation all the way to cognition, behaviour, or propensity to certain psychiatric or metabolic disorders. This review will also provide an overview of relevant methodology and difficulties linked to implementation of epigenetic studies. A better understanding of these processes may help us elucidate the evolutionary pathways which are at work in the course of emergence of the diseases and disorders associated with exposure to trauma, either direct or in a previous generation.

Karl Grassmann's 1896 paper "critical overview of contemporary theories of the heredity of the psychoses".

Four years before the rediscovery of Mendel's work in 1900, Karl Grassmann published a detailed, scholarly review of the heredity of psychosis which we here review. A full translation is in the appendix. We emphasize seven major conclusions from this review. First, while recognizing the key importance of heredity in the etiology of psychosis. Grassmann was critical of many of the highly speculative extant theories. Second, he reviewed most of the major methodologic concerns in the literature from what kinds of heredity to investigate to the problems with the global use of insanity as a diagnostic category. Third, he discussed in detail genetic theories associated with Degeneration theory, maintaining considerable skepticism. Fourth, he recognized nongenetic contribution to familial transmission. Fifth, he reviewed evidence for both homogeneous and heterogeneous transmission of forms of mental illness in families, suggesting that both were important. Sixth, while he noted that mania, melancholia, and cyclothymia commonly replaced each other in families, Verrücktheit (delusional psychoses) rarely co-segregated in families with these mood disorders. Seventh, Grassmann, like other 19th century writers, saw relatives to be of value only in assessing the level of hereditary predisposition in patients and had limited appreciation of the need for controlled studies.

Recruitment of CTCF to an Fto enhancer is responsible for transgenerational inheritance of BPA-induced obesity.

The mechanisms by which environmentally-induced epiphenotypes are transmitted transgenerationally in mammals are poorly understood. Here we show that exposure of pregnant mouse females to bisphenol A (BPA) results in obesity in the F2 progeny due to increased food intake. This epiphenotype can be transmitted up to the F6 generation. Analysis of chromatin accessibility in sperm of the F1-F6 generations reveals alterations at sites containing binding motifs for CCCTC-binding factor (CTCF) at two cis-regulatory elements (CREs) of the Fto gene that correlate with transmission of obesity. These CREs show increased interactions in sperm of obese mice with the Irx3 and Irx5 genes, which are involved in the differentiation of appetite-controlling neurons. Deletion of the CTCF site in Fto results in mice that have normal food intake and fail to become obese when ancestrally exposed to BPA. The results suggest that epigenetic alterations of Fto can lead to the same phenotypes as genetic variants.

First experimental evidence for active farming in ambrosia beetles and strong heredity of garden microbiomes.

Fungal cultivation is a defining feature for advanced agriculture in fungus-farming ants and termites. In a third supposedly fungus-farming group, wood-colonizing ambrosia beetles, an experimental proof for the effectiveness of beetle activity for selective promotion of their food fungi over others is lacking and farming has only been assumed based on observations of social and hygienic behaviours. Here, we experimentally removed mothers and their offspring from young nests of the fruit-tree pinhole borer, Xyleborinus saxesenii. By amplicon sequencing of bacterial and fungal communities of nests with and without beetles we could show that beetles are indeed able to actively shift symbiont communities. Although being consumed, the Raffaelea food fungi were more abundant when beetles were present while a weed fungus (Chaetomium sp.) as well as overall bacterial diversity were reduced in comparison to nests without beetles. Core symbiont communities were generally of low diversity and there were strong signs for vertical transmission not only for the cultivars, but also for secondary symbionts. Our findings verify the existence of active farming, even though the exact mechanisms underlying the selective promotion and/or suppression of symbionts need further investigation.

The limits of metabolic heredity in protocells.

The universal core of metabolism could have emerged from thermodynamically favoured prebiotic pathways at the origin of life. Starting with H₂ and CO₂, the synthesis of amino acids and mixed fatty acids, which self-assemble into protocells, is favoured under warm anoxic conditions. Here, we address whether it is possible for protocells to evolve greater metabolic complexity, through positive feedbacks involving nucleotide catalysis. Using mathematical simulations to model metabolic heredity in protocells, based on branch points in protometabolic flux, we show that nucleotide catalysis can indeed promote protocell growth. This outcome only occurs when nucleotides directly catalyse CO₂ fixation. Strong nucleotide catalysis of other pathways (e.g. fatty acids and amino acids) generally unbalances metabolism and slows down protocell growth, and when there is competition between catalytic functions cell growth collapses. Autocatalysis of nucleotide synthesis can promote growth but only if nucleotides also catalyse CO₂ fixation; autocatalysis alone leads to the accumulation of nucleotides at the expense of CO₂ fixation and protocell growth rate. Our findings offer a new framework for the emergence of greater metabolic complexity, in which nucleotides catalyse broad-spectrum processes such as CO₂ fixation, hydrogenation and phosphorylation important to the emergence of genetic heredity at the origin of life.

Impossibility results about inheritance and order of death.

If several relatives died with no will, the order of their deaths could affect the inheritance result. When the order of death is unknown, there are three approaches to determine the inheritance result in this simultaneous death situation: apply an inheritance method that is not affected by the order of death; artificially assign the order of death; stipulate that persons with unknown orders do not inherit each other. The last approach is adopted by the current French Civil Code (denoted as the French Approach). We prove that under some basic requirements, the French Approach is the only valid solution to the order of death problem. Therefore, the inheritance law of a country that does not adopt the French Approach either has unsolvable inheritance problems or violates basic requirements. In the appendix, we study the existence and uniqueness of inheritance methods that are invariant for different orders of death and only violate one requirement, such as gender equality.

The synergism hypothesis (revisited): a theory whose time has come?

A major theoretical issue in evolutionary biology over the past two decades has concerned the rise of complexity over time in the natural world, and a search has been underway for "a Grand Unified Theory" - as biologist Daniel McShea characterized it - that is consistent with Darwin's great vision. As it happens, such a theory already exists. It was first proposed many years ago in The Synergism Hypothesis: A Theory of Progressive Evolution, and it involves an economic (or perhaps bioeconomic) theory of complexity. Simply stated, cooperative interactions of various kinds, however they may occur, can produce novel combined effects - synergies - with functional advantages that may, in turn, become direct causes of natural selection. In other words, the Synergism Hypothesis is a theory about the unique combined effects produced by the relationships between things. I refer to it as Holistic Darwinism; it is entirely con - sistent with natural selection theory, properly understood. Because the Synergism Hypothesis was first proposed during a time when the genecentric, neo-Darwinist paradigm was domi nant in evolutionary biology, it was largely overlooked. But times have changed. Biologist Richard Michod has concluded that "cooperation is now seen as the primary creative force behind ever greater levels of complexity and organization in all of biology." And Martin Nowak has called cooperation "the master architect of evolution." Here I will revisit this theory in the light of the many theoretical developments and research findings in recent years that are supportive of it, including the role of symbiogenesis in evolution, the phenomenon of hybridization, lateral gene transfer in prokaryotes, "developmental plasticity" (evo-devo), epigenetic inheritance, the role of behaviour (and teleonomy) in evolution, and gene-culture coevolution. The Synergism Hypothesis is especially relevant to the evolution of humankind.

[Extended heredity in biomedicine: Breaking the silence]. / L'hérédité étendue en biomédecine - Briser le silence.

The extension of biological inheritance beyond gene-centrism is at the center of many debates in evolutionary biology, but it has been relatively ignored in the field of biomedicine. The purpose of this prospective paper is to highlight the potential impact of a new vision of inheritance on medical theory, notably on the concept of hereditary disease. It is also to underline some related practical and social issues.

Title: L'hérédité étendue en biomédecine - Briser le silence. Abstract: L'extension du concept d'hérédité au-delà du tout génétique a fait l'objet de nombreux débats en biologie de l'évolution, mais elle a été relativement ignorée dans le champ de la biomédecine. L'objectif de cet article prospectif est de souligner les conséquences potentielles d'une vision renouvelée de l'hérédité sur la théorie médicale, notamment sur le concept de maladie héréditaire, ainsi que de mettre en évidence certains enjeux pratiques et sociaux connexes.

"Batesonian Mendelism" and "Pearsonian biometry": shedding new light on the controversy between William Bateson and Karl Pearson.

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.

Is nationalizing universalizing and/or vice-versa? : A review essay on ELISE K. BURTON, Genetic Crossroads: The Middle East and the science of human heredity, Stanford University Press, 2021. IAN MCGONIGLE, Genomic Citizenship: the molecularization of identity in the contemporary Middle East. The MIT Press 2021.

This is a review essay of two books published in 2021 on the history of human heredity-genetics/genomics investigations-in the Middle East. Both books are structured comparatively. Both books grapple with the many uses of biology in nationalizing projects in the Middle East and the unavoidable tension between these particularizing projects and the scientific claim of biology to universality. Furthermore, both grapple with issues of classifications of humans and their uses in biology: the presumably biological human classifications of race, ethnos, and ancestry, and the properly sociocultural ones, such as historical-traditional, by language, by religion. Combined, the two books offer a keen gaze on the complex entwinement of genetics and nationalism in the Middle East from WWI to the present.

Prevalence of thrombophilia-associated genetic risk factors in blood donors of a regional hospital in southern Brazil

ABSTRACT Introduction: Thromboembolic events occur due to an imbalance in the hemostasis and some factors associated with this condition can be inherited. In order to evaluate the frequency of genotypes considered to be common hereditary risk factors for thrombophilia associated with venous thrombosis (g.1691G>A and g.20210G>A) and hyperhomocysteinemia (g.677C>T and g.1298A>C), samples from voluntary healthy blood donors at the Hospital de Clínicas de Porto Alegre were tested. Methods: We examined 325 blood samples from blood donors collected from October 2017 to July 2018. Blood was collected on filter paper and the DNA was extracted for single nucleotide polymorphisms (SNPs) analysis using the qualitative real time polymerase chain reaction. Results: The calculated frequencies of each genetic variant in heterozygosity were 4% for the FV gene (g.1691G> A), 4% for the F2 gene (g.20210G> A) and 42% and 39% for methylenetetrahydrofolate reductase (MTHFR), g.677C>T and g.1298A>C, respectively. Only the genetic variants of MTHFR were found in homozygosity, with frequencies of 14% and 6% (g.677C>T and g.1298A>C), respectively. Discussion: Altogether, these results describe the frequencies of genetic variants associated with venous thrombosis and hyperhomocysteinemia in the analyzed group and are important to enhance our current knowledge about the genetic profiles of Brazilian blood donors.

Cambridge geneticists and the chromosome theory of inheritance: William Bateson, Leonard Doncaster and Reginald Punnett 1879-1940.

Early in the 20th century Bateson, Doncaster and Punnett formed a cooperative collective to share research findings on the chromosome theory of heredity (CTH). They cross-bred plants and animals to correlate behaviour of chromosomes and heredity of individual traits. Doncaster was the most enthusiastic proponent of the new theory and worked for years to convince Bateson and Punnett on its relevance to their own research. The two younger biologists collaborated with Bateson, the preeminent geneticist in England. As their own reputations developed, their research findings allied with the consensus on the importance of the CTH by the broader scientific community. After Doncaster's tragic death in 1920, major objections to the theory had been resolved; Bateson and Punnett then utilized the CTH to construct chromosome maps detailing locations of specific genes on particular chromosomes in several different species. The marriage of heredity and cytology enhanced confidence that the theory was an accurate mechanism to explain inheritance in both plants and animals.

Development and Heredity in the Interwar Period: Hans Spemann and Fritz Baltzer on Organizers and Merogones.

This article explores the collaborative research of the Nobel laureate Hans Spemann (1869-1941) and the Swiss zoologist Fritz Baltzer (1884-1974) on problems at the intersection of development and heredity and raises more general questions concerning science and politics in Germany in the interwar period. It argues that Spemann and Baltzer's collaborative work made a significant contribution to the then ongoing debates about the relation between developmental physiology and hereditary studies, although Spemann distanced himself from Drosophila genetics because of his anti-reductionist position. The article analyzes how Spemann framed the issues of heredity in terms of an epigenetic principle in the context of his work on the "organizer," and it explores the experimental dynamics of research on newt merogones carried out by Baltzer in a methodological development of Spemann's constriction experiments. Finally, these research attempts are discussed as part of a broader "prehistory" of the mid-twentieth century cell nuclear transplantation experiments, which provided the basis for later animal cloning.

Unpaid balance of the transgenerational legacy: the separation-individuation process involved in the early genesis of eating disorders / Saldo não liquidado do legado transgeracional: o processo de separação-individuação na gênese precoce dos transtornos alimentares

RESUMO: Este estudo investigou a experiência de maternagem em mulheres cujas filhas foram diagnosticadas com anorexia nervosa ou bulimia nervosa, buscando identificar aspectos do vínculo precoce mãe-filha que guardam relação com os sintomas psicopatológicos. Partimos da suposição de que sintomas graves na esfera alimentar expressam elementos específicos da dinâmica relacional precoce com a figura materna. Na perspectiva da teoria da transmissão psíquica transgeracional, conjecturamos que a constituição do sintoma tem como elemento articulador um vínculo fusional e involucra uma tentativa malograda de colocar um traço de separação e proteção da filha contra intrusões e excessos maternos. São estabelecidas relações com conteúdos transgeracionais.

Abstract: This study investigated the experience of mothering in women whose daughters were diagnosed with anorexia nervosa or bulimia nervosa, seeking to identify aspects of the early mother-daughter bond that are related to psychopathological symptoms. We started from the assumption that severe symptoms in the eating sphere express specific elements of the early relational dynamics with the mother figure. Considering the theory of transgenerational psychic transmission, we conjecture that the constitution of the symptom has as an articulating element a fusional bond and involves an unsuccessful attempt to place a trace of separation and protection of the daughter against maternal intrusions and excesses. Relationships with transgenerational contents are established.