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The recent development of high-throughput sequencing platforms provided impressive insights into the field of human genetics and contributed to considering structural variants (SVs) as the hallmark of genome instability, leading to the establishment of several pathologic conditions, including neoplasia and neurodegenerative and cognitive disorders. While SV detection is addressed by next-generation sequencing (NGS) technologies, the introduction of more recent long-read sequencing technologies have already been proven to be invaluable in overcoming the inaccuracy and limitations of NGS technologies when applied to resolve wide and structurally complex SVs due to the short length (100-500 bp) of the sequencing read utilized. Among the long-read sequencing technologies, Oxford Nanopore Technologies developed a sequencing platform based on a protein nanopore that allows the sequencing of "native" long DNA molecules of virtually unlimited length (typical range 1-100 Kb). In this review, we focus on the bioinformatics methods that improve the identification and genotyping of known and novel SVs to investigate human pathological conditions, discussing the possibility of introducing nanopore sequencing technology into routine diagnostics. [ABSTRACT FROM AUTHOR]

Background Congenital anomalies of the kidney and urinary tract (CAKUT) are the leading cause of kidney failure in children with phenotypic and genotypic heterogeneity. Our objective was to describe the genetic spectrum and identify the risk factors for kidney failure in children with CAKUT. Methods Clinical and genetic data were derived from a multicentre network [Chinese Children Genetic Kidney Disease Database (CCGKDD)] and the Chigene database. A total of 925 children with CAKUT who underwent genetic testing from 2014 to 2020 across China were studied. Data for a total of 584 children were obtained from the CCGKDD, including longitudinal data regarding kidney function. The risk factors for kidney failure were determined by the Kaplan–Meier method and Cox proportional hazards models. Results A genetic diagnosis was established in 96 of 925 (10.3%) children, including 72 (8%) with monogenic variants, 20 (2%) with copy number variants (CNVs) and 4 (0.4%) with major chromosomal anomalies. Patients with skeletal abnormalities were more likely to have large CNVs or abnormal karyotypes than monogenic variants. Eighty-two patients from the CCGKDD progressed to kidney failure at a median age of 13.0 years (95% confidence interval 12.4–13.6) and 24 were genetically diagnosed with variants of PAX2, TNXB, EYA1, HNF1B and GATA3 or the 48,XXYY karyotype. The multivariate analysis indicated that solitary kidney, posterior urethral valves, bilateral hypodysplasia, the presence of certain variants and premature birth were independent prognostic factors. Conclusions The genetic spectrum of CAKUT varies among different subphenotypes. The identified factors indicate areas that require special attention. [ABSTRACT FROM AUTHOR]

Large-effect loci--those statistically significant loci discovered by genome-wide association studies or linkage mapping--associated with key traits segregate amidst a background of minor, often undetectable, genetic effects in wild and domesticated plants and animals. Accurately attributing mean differences and variance explained to the correct components in the linear mixed model analysis is vital for selecting superior progeny and parents in plant and animal breeding, gene therapy, and medical genetics in humans. Marker-assisted prediction and its successor, genomic prediction, have many advantages for selecting superior individuals and understanding disease risk. However, these two approaches are less often integrated to study complex traits with different genetic architectures. This simulation study demonstrates that the average semivariance can be applied to models incorporating Mendelian, oligogenic, and polygenic terms simultaneously and yields accurate estimates of the variance explained for all relevant variables. Our previous research focused on largeeffect loci and polygenic variance separately. This work aims to synthesize and expand the average semivariance framework to various genetic architectures and the corresponding mixed models. This framework independently accounts for the effects of large-effect loci and the polygenic genetic background and is universally applicable to genetics studies in humans, plants, animals, and microbes. [ABSTRACT FROM AUTHOR]

In this paper I argue that the extent to which a human trait is genetically caused can causally depend upon whether the trait is categorized within human genetics as genetically caused. This makes the kind genetically caused trait an interactive kind. I demonstrate that this thesis is both conceptually coherent and empirically plausible. I outline the core rationale of this thesis and demonstrate its conceptual coherence by drawing upon Waters' (2007) analysis of genetic causation. I add empirical plausibility to the thesis by describing a hypothetical but empirically plausible mechanism by which the fact that obesity is categorized as genetically caused within human genetics increases the extent to which obesity is in fact genetically caused. [ABSTRACT FROM AUTHOR]

ObjectivesOur aim in this study was to understand how genetics ideas are appropriated and mobilized online toward the political projects of White nationalism and the alt right. Studying three different online venues, we investigated how genetics is used to support racial realism, hereditarianism, and racial hierarchy. We analyzed how these ideas are connected to political and metapolitical projects. In addition, we examined the strategies used to build authority for these interpretations.MethodsWe analyze three online venues in which genetics has been mobilized to advance racial realism and hereditarian explanations of racial differences. These were (a) the use of genetic ancestry tests in online nationalist discussions, (b) blogs and other venues in which the human biodiversity ideas are articulated, (c) activities surrounding the OpenPsych collection of online journals. Ethnographic and interpretive methods were applied to investigate scientific and political meanings of efforts to mobilize genetic ideas.ResultsWe found that White nationalists use genetic ancestry tests to align White identity with ideas of racial purity and diversity, educating each other about genetics, and debating the boundaries of Whiteness. "Human biodiversity" has been mobilized as a movement to catalog and create hereditarian ideas about racial differences and to distribute them as "red pills" to transform online discourse. The OpenPsych journals have allowed amateur hereditarian psychologists to publish papers, coordinate activity, and legitimate their project at the academic margins.ConclusionsThese various appropriations of genetics aim to further racial realism and hereditarian explanations of racial social and behavioral differences. Beyond these substantive aims, on a "metapolitical" level, they serve to reframe concepts and standards for political and scientific discussion of race, challenge structures of academic legitimacy and expertise, and build a cadre of ideological foot soldiers armed with an argumentative toolkit. As professional anthropologists and geneticists aim to accurately communicate their science and its implications for understanding human differences to the public, they must contend with these substantive claims and metapolitical contexts.

Abstract Background Malakoplakia is a rare condition characterized by inflammatory masses with specific histological characteristics. These soft tissue masses can mimic tumors and tend to develop in association with chronic or recurrent infections, typically of the urinary tract. A specific defect in innate immunity has been described. In the absence of randomized controlled trials, management is based on an understanding of the biology and on case reports. Case presentation Here we describe a case of presacral malakoplakia in a British Indian woman in her late 30s, presenting with complex unilateral foot drop. Four years earlier, she had suffered a protracted episode of intrapelvic sepsis following a caesarean delivery. Resection of her presacral soft tissue mass was not possible. She received empiric antibiotics, a cholinergic agonist, and ascorbic acid. She responded well to medical management both when first treated and following a recurrence of symptoms after completing an initial 8 months of therapy. Whole exome sequencing of the patient and her parents was undertaken but no clear causal variant was identified. Conclusions Malakoplakia is uncommon but the diagnosis should be considered where soft tissue masses develop at the site of chronic or recurrent infections. Obtaining tissue for histological examination is key to making the diagnosis. This case suggests that surgical resection is not always needed to achieve a good clinical and radiological outcome.

Abstract Introduction The KMT2 family of genes is essential epigenetic regulators promoting gene expression. The gene family contains three subgroups, each with two paralogues: KMT2A and KMT2B; KMT2C and KMT2D; KMT2F and KMT2G. KMT2A‐D are among the most frequent somatically altered genes in several different cancer types. Somatic KMT2A rearrangements are well‐characterized in infant leukemia (IL), and growing evidence supports the role of additional family members (KMT2B, KMT2C, and KMT2D) in leukemogenesis. Enrichment of rare heterozygous frameshift variants in KMT2A and C has been reported in acute myeloid leukemia (AML), IL, and solid tumors. Currently, the non‐synonymous variation, prevalence, and penetrance of these four genes are unknown. Methods This study determined the prevalence of pathogenic/likely pathogenic (P/LP) germline KMT2A‐D variants in a cancer‐free adult population from the Genome Aggregation Database (gnomAD). Two methods of variant interpretation were utilized: a manual genomic variant interpretation and an automated ACMG pipeline. Results The ACMG pipeline identified considerably fewer P/LP variants (n = 89) compared to the manual method (n = 660) in all 4 genes. Consequently, the total P/LP prevalence and allele frequency (AF) were higher in the manual method (1:112, AF = 4.46E‐03) than in ACMG (1:832, AF = 6.01E‐04). Multiple ancestry‐exclusive P/LP variants were identified along with an increased frequency in males compared to females. Many of these variants identified in this population database are also associated with severe juvenile conditions. Conclusion These data demonstrate that putatively functional germline variation in these developmentally important genes is more common than previously appreciated and identification in cancer‐free adults may indicate incomplete penetrance for many of these variants. Future research should examine a genetic predisposing role in IL and other pediatric cancers.

Nature Communications published a correction notice regarding incorrect affiliation details for multiple authors in an article on progressive supranuclear palsy. The correction lists the accurate affiliations for authors from various institutions in the USA, Germany, UK, Belgium, and Spain. The correction ensures the accuracy of author affiliations in the original article. [Extracted from the article]

The article "PERCC1-Related Congenital Enteropathy" published in Clinical Genetics discusses a rare autosomal-recessive type of infantile-onset diarrhea found in Jewish Iraqi families, caused by biallelic deletions affecting the PERCC1 gene. The study highlights the role of PERCC1 in intestinal epithelial development and cell function, with mutations leading to intractable diarrhea and the need for long-term parenteral nutrition. The research aims to increase awareness of PERCC1-related enteropathy, emphasizing the importance of genetic testing and potential missed variants in exome sequencing. [Extracted from the article]

The correction notice addresses errors in the author names and affiliations of the article "ADNP dysregulates methylation and mitochondrial gene expression in the cerebellum of a Helsmoortel–Van Der Aa syndrome autopsy case." The correct author name is Illana Gozes, not lllana Gozes, and Claudia Theys was omitted from the author group. Affiliation 4 was also partly incorrect and has been updated. The corrected version of the article can be accessed online. [Extracted from the article]

Prof. Alberto Piazza, a renowned human population geneticist, passed away at the age of 82. He faced challenges in his early life due to persecution by the Italian fascist regime, but went on to have a successful career in genetics. Piazza made significant contributions to the study of the human histocompatibility system, known as HLA, and collaborated with other prominent scientists in the field. He also held important administrative positions and promoted an ethical approach to genetic research. Piazza's work helped to clarify human genetic variation and the worldwide distribution of certain diseases. He will be remembered as a generous and respected figure in the scientific community. [Extracted from the article]

Dr. Holger Prokisch, a researcher at the Institute of Human Genetics in Germany, has been awarded the GfH Medal of Honour by the German Society of Human Genetics. He is being recognized for his work in identifying the molecular basis of mitochondrial dysfunction and exploring personalized treatment options for mitochondrial disorders. Dr. Prokisch has published over 350 papers in his 30-year career, with a focus on mitochondrial function and disorders. He has also been involved in coordinating national and international research networks and has contributed to the dissemination of his research through conferences and workshops. Despite his scientific successes, Dr. Prokisch has chosen to remain in his current position to focus on his research and prioritize his family. [Extracted from the article]

The human genome contains vast genetic diversity as naturally occurring coding variants, yet the impact of these variants on protein function and physiology is poorly understood. RGS14 is a multifunctional signaling protein that suppresses synaptic plasticity in dendritic spines of hippocampal neurons. RGS14 also is a nucleocytoplasmic shuttling protein, suggesting that balanced nuclear import/export and dendritic spine localization are essential for RGS14 functions. We identified genetic variants L505R (LR) and R507Q (RQ) located within the nuclear export sequence (NES) of human RGS14. Here we report that RGS14 encoding LR or RQ profoundly impacts protein functions in hippocampal neurons. RGS14 membrane localization is regulated by binding Gαi-GDP, whereas RGS14 nuclear export is regulated by Exportin 1 (XPO1). Remarkably, LR and RQ variants disrupt RGS14 binding to Gαi1-GDP and XPO1, nucleocytoplasmic equilibrium, and capacity to inhibit long-term potentiation (LTP). Variant LR accumulates irreversibly in the nucleus, preventing RGS14 binding to Gαi1, localization to dendritic spines, and inhibitory actions on LTP induction, while variant RQ exhibits a mixed phenotype. When introduced into mice by CRISPR/Cas9, RGS14-LR protein expression was detected predominantly in the nuclei of neurons within hippocampus, central amygdala, piriform cortex, and striatum, brain regions associated with learning and synaptic plasticity. Whereas mice completely lacking RGS14 exhibit enhanced spatial learning, mice carrying variant LR exhibit normal spatial learning, suggesting that RGS14 may have distinct functions in the nucleus independent from those in dendrites and spines. These findings show that naturally occurring genetic variants can profoundly alter normal protein function, impacting physiology in unexpected ways.

The article offers information on the sociopolitical aspects of human genetics research and the need for genetics educators to engage with these factors. Topics include the historical and ongoing use of race as a proxy for describing human genetic variation; the influence of power and privilege dynamics on genetics research; and the call for a shift in scientific practice to address these issues.

Summary: Vascular calcification is a hallmark of atherosclerotic disease and serves as a strong predictor and risk factor for cardiovascular events. Growing evidence suggests that autophagy may play a protective role in early atherosclerosis. The precise effects of autophagy on VSMC-mediated calcification remain unknown. In this study, we utilized multi-omic profiling to investigate impaired autophagy at the transcriptional level as a key driver of VSMC calcification. Our findings revealed that impaired autophagy is an essential determinant of VSMC calcification. We observed that an osteogenic environment affects the open chromatin status of VSMCs, compromising the transcriptional activation of autophagy initiation genes. In vivo experiments involve pharmacological and genetic activation of autophagy using mouse models of spontaneous large (Mgp−/−) and small (Abcc6−/−) artery calcification. Taken together, these data advance our mechanistic understanding of vascular calcification and provide important insights for a broad range of cardiovascular diseases involving VSMC phenotype switch.

Summary: Repetitive sequences represent about 45% of the human genome. Some are transposable elements (TEs) with the ability to change their position in the genome, creating genetic variability both as insertions or deletions, with potential pathogenic consequences. We used long-read nanopore sequencing to identify TE variants in the genomes of 24 patients with antithrombin deficiency. We identified 7 344 TE insertions and 3 056 TE deletions, 2 926 were not previously described in publicly available databases. The insertions affected 3 955 genes, with 6 insertions located in exons, 3 929 in introns, and 147 in promoters. Potential functional impact was evaluated with gene annotation and enrichment analysis, which suggested a strong relationship with neuron-related functions and autism. We conclude that this study encourages the generation of a complete map of TEs in the human genome, which will be useful for identifying new TEs involved in genetic disorders.

Summary: In South Tyrol (Eastern Italian Alps), during Late Antiquity-Early Middle Ages, archeological records indicate cultural hybridization among alpine groups and peoples of various origin. Using paleogenomics, we reconstructed the ancestry of 20 individuals (4th–7th cent. AD) from a cemetery to analyze whether they had heterogeneous or homogeneous ancestry and to study their social organization. The results revealed a primary genetic ancestry from southern Europe and additional ancestries from south-western, western, and northern Europe, suggesting that cultural hybridization was accompanied by complex genetic admixture. Kinship analyses found no genetic relatedness between the only two individuals buried with grave goods. Instead, a father-son pair was discovered in one multiple grave, together with unrelated individuals and one possible non-local female. These genetic findings indicate the presence of a high social status familia, which is supported by the cultural materials and the proximity of the grave to the most sacred area of the church.

Summary: Recent studies suggest that pleiotropic effects may explain the genetic architecture of cardiovascular diseases (CVDs). We conducted a comprehensive gene-centric pleiotropic association analysis for ten CVDs using genome-wide association study (GWAS) summary statistics to identify pleiotropic genes and pathways that may underlie multiple CVDs. We found shared genetic mechanisms underlying the pathophysiology of CVDs, with over two-thirds of the diseases exhibiting common genes and single-nucleotide polymorphisms (SNPs). Significant positive genetic correlations were observed in more than half of paired CVDs. Additionally, we investigated the pleiotropic genes shared between different CVDs, as well as their functional pathways and distribution in different tissues. Moreover, six hub genes, including ALDH2, XPO1, HSPA1L, ESR2, WDR12, and RAB1A, as well as 26 targeted potential drugs, were identified. Our study provides further evidence for the pleiotropic effects of genetic variants on CVDs and highlights the importance of considering pleiotropy in genetic association studies.

Summary: Chronic kidney disease (CKD) is a common disease that seriously endangers human health. However, the potential relationship between xanthine oxidoreductase (XOR) activity and CKD remains unclear. In this study, we used clinical data, CKD datasets from the Gene Expression Omnibus database, and untargeted metabolomics to explain the relationship between XOR activity and CKD. First, XOR activity showed high correlation with the biomarkers of CKD, such as serum creatinine, blood urea nitrogen, uric acid, and estimated glomerular filtration rate. Then, we used least absolute shrinkage and selection operator logical regression algorithm and random forest algorithm to screen CKD molecular markers from differentially expressed genes, and the results of qRT-PCR of XDH, KOX-1, and ROMO1 were in accordance with the results of bioinformatics analyses. In addition, untargeted metabolomics analysis revealed that the purine metabolism pathway was significantly enriched in CKD patients in the simulated models of kidney fibrosis.

Summary: Cardiac fibrosis is a major type of adverse remodeling, predisposing the disease progression to ultimate heart failure. However, the complexity of pathogenesis has hampered the development of therapies. One of the key mechanisms of cardiac diseases has recently been identified as long non-coding RNA (lncRNA) dysregulation. Through in vitro and in vivo studies, we identified an lncRNA NONMMUT067673.2, which is named as a cardiac fibrosis related lncRNA (CFRL). CFRL was significantly increased in both mouse model and cell model of cardiac fibrosis. In vitro, CFRL was proved to promote the proliferation and migration of cardiac fibroblasts by competitively binding miR-3113-5p and miR-3473d and indirectly up-regulating both CTGF and FN1. In vivo, silencing CFRL significantly mitigated cardiac fibrosis and improved left ventricular function. In short, CFRL may exert an essential role in cardiac fibrosis and interfering with CFRL might be considered as a multitarget strategy for cardiac fibrosis and heart failure.

Summary: Crohn's disease (CD) and ulcerative colitis (UC) are two etiologically related yet distinctive subtypes of the inflammatory bowel diseases (IBD). Differentiating CD from UC can be challenging using conventional clinical approaches in a subset of patients. We designed and evaluated a novel molecular-based prediction model aggregating genetics, serum biomarkers, and tobacco smoking information to assist the diagnosis of CD and UC in over 30,000 samples. A joint model combining genetics, serum biomarkers and smoking explains 46% (42–50%, 95% CI) of phenotypic variation. Despite modest overlaps with serum biomarkers, genetics makes unique contributions to distinguishing IBD subtypes. Smoking status only explains 1% (0–6%, 95% CI) of the phenotypic variance suggesting it may not be an effective biomarker. This study reveals that molecular-based models combining genetics, serum biomarkers, and smoking information could complement current diagnostic strategies and help classify patients based on biologic state rather than imperfect clinical parameters.

Summary: The Báthory family was one of the most powerful noble families in the medieval Hungarian Kingdom. Their influence peaked during the Ottoman occupation of Hungary, when the only partially autonomous region of the country was Transylvania, under Turkish protectorate. Several members of the family became Princes of Transylvania, and one of them, István Báthory, was also the elected King of Poland. We hereby present the first genetic data about this extinct family. Archaeological excavations in Pericei, a settlement now part of Romania, revealed the former family chapel of the Báthory family. Through this work, two Báthory family members were successfully identified among the 13 skeletons found at the site. The presence of Y chromosome haplogroup R-S498 fits the historical account describing the family’s German (Swabian) origins. Their genomic composition also indicates a family of Germanic origin that intermixed with medieval Hungarians.

Summary: While lipid traits are known essential mediators of cardiovascular disease, few approaches have taken advantage of their shared genetic effects. We apply a Bayesian multivariate size estimator, mash, to GWAS of four lipid traits in the Million Veterans Program (MVP) and provide posterior mean and local false sign rates for all effects. These estimates borrow information across traits to improve effect size accuracy. We show that controlling local false sign rates accurately and powerfully identifies replicable genetic associations and that multivariate control furthers the ability to explain complex diseases. Our application yields high concordance between independent datasets, more accurately prioritizes causal genes, and significantly improves polygenic prediction beyond state-of-the-art methods by up to 59% for lipid traits. The use of Bayesian multivariate genetic shrinkage has yet to be applied to human quantitative trait GWAS results, and we present a staged approach to prediction on a polygenic scale.

Summary: Transcriptome prediction models built with data from European-descent individuals are less accurate when applied to different populations because of differences in linkage disequilibrium patterns and allele frequencies. We hypothesized that methods that leverage shared regulatory effects across different conditions, in this case, across different populations, may improve cross-population transcriptome prediction. To test this hypothesis, we made transcriptome prediction models for use in transcriptome-wide association studies (TWASs) using different methods (elastic net, joint-tissue imputation [JTI], matrix expression quantitative trait loci [Matrix eQTL], multivariate adaptive shrinkage in R [MASHR], and transcriptome-integrated genetic association resource [TIGAR]) and tested their out-of-sample transcriptome prediction accuracy in population-matched and cross-population scenarios. Additionally, to evaluate model applicability in TWASs, we integrated publicly available multiethnic genome-wide association study (GWAS) summary statistics from the Population Architecture using Genomics and Epidemiology (PAGE) study and Pan-ancestry genetic analysis of the UK Biobank (PanUKBB) with our developed transcriptome prediction models. In regard to transcriptome prediction accuracy, MASHR models performed better or the same as other methods in both population-matched and cross-population transcriptome predictions. Furthermore, in multiethnic TWASs, MASHR models yielded more discoveries that replicate in both PAGE and PanUKBB across all methods analyzed, including loci previously mapped in GWASs and loci previously not found in GWASs. Overall, our study demonstrates the importance of using methods that benefit from different populations’ effect size estimates in order to improve TWASs for multiethnic or underrepresented populations.

Summary: Colorectal cancer (CRC) shows high incidence and mortality, partly due to the tumor microenvironment (TME), which is viewed as an active promoter of disease progression. Macrophages are among the most abundant cells in the TME. These immune cells are generally categorized as M1, with inflammatory and anti-cancer properties, or M2, which promote tumor proliferation and survival. Although the M1/M2 subclassification scheme is strongly influenced by metabolism, the metabolic divergence between the subtypes remains poorly understood. Therefore, we generated a suite of computational models that characterize the M1- and M2-specific metabolic states. Our models show key differences between the M1 and M2 metabolic networks and capabilities. We leverage the models to identify metabolic perturbations that cause the metabolic state of M2 macrophages to more closely resemble M1 cells. Overall, this work increases understanding of macrophage metabolism in CRC and elucidates strategies to promote the metabolic state of anti-tumor macrophages.

Summary: To identify ancestry-linked genetic risk variants associated with COVID-19 hospitalization, we performed an integrative analysis of two genome-wide association studies and resolved four single nucleotide polymorphisms more frequent in COVID-19-hospitalized patients with non-European ancestry. Among them, the COVID-19 risk SNP rs16831827 shows the largest difference in minor allele frequency (MAF) between populations with African and European ancestry and also shows higher MAF in hospitalized COVID-19 patients among cohorts of mixed ancestry (odds ratio [OR] = 1.20, 95% CI: 1.10–1.30) and entirely African ancestry (OR = 1.30, 95% CI: 1.02–1.67). rs16831827 is an expression quantitative trait locus of MAP3K19. MAP3K19 expression is induced during ciliogenesis and most abundant in ciliated tissues including lungs. Single-cell RNA sequencing analyses revealed that MAP3K19 is highly expressed in multiple ciliated cell types. As rs16831827∗T is associated with reduced MAP3K19 expression, it may increase the risk of severe COVID-19 by reducing MAP3K19 expression.

The borders between cell and developmental biology, which have always been permeable, have largely dissolved. One manifestation is the blossoming of cilia biology, with cell and developmental approaches (increasingly complemented by human genetics, structural insights, and computational analysis) fruitfully advancing understanding of this fascinating, multifunctional organelle. The last eukaryotic common ancestor probably possessed a motile cilium, providing evolution with ample opportunity to adapt cilia to many jobs. Over the last decades, we have learned how non-motile, primary cilia play important roles in intercellular communication. Reflecting their diverse motility and signaling functions, compromised cilia cause a diverse range of diseases collectively called "ciliopathies." In this review, we highlight how cilia signal, focusing on how second messengers generated in cilia convey distinct information; how cilia are a potential source of signals to other cells; how evolution may have shaped ciliary function; and how cilia research may address thorny outstanding questions. Evolution has shaped cilia into sophisticated motility and signaling organelles, and disruption in ciliary function affects development and physiology and, in humans, causes ciliopathies. In this review, Derderian et al. discuss recent advances in ciliary biology, highlighting how genetic, biochemical, and structural approaches contribute to cell and developmental understanding. [ABSTRACT FROM AUTHOR]

I was attracted to hematology because by combining clinical findings with the use of a microscope and simple laboratory tests, one could often make a diagnosis. I was attracted to genetics when I learned about inherited blood disorders, at a time when we had only hints that somatic mutations were also important. It seemed clear that if we understood not only what genetic changes caused what diseases but also the mechanisms through which those genetic changes contribute to cause disease, we could improve management. Thus, I investigated many aspects of the glucose-6-phosphate dehydrogenase system, including cloning of the gene, and in the study of paroxysmal nocturnal hemoglobinuria (PNH), I found that it is a clonal disorder; subsequently, we were able to explain how a nonmalignant clone can expand, and I was involved in the first trial of PNH treatment by complement inhibition. I was fortunate to do clinical and research hematology in five countries; in all of them, I learned from mentors, from colleagues, and from patients. [ABSTRACT FROM AUTHOR]

Domestic dogs display a wide array of heritable behaviors that have intermediate genetic complexity thanks to a long history of human-influenced selection. Comparative genetics in dogs could address the scarcity of non-human neurogenetic systems relevant to human neuropsychiatric disorders, which are characterized by mental, emotional, and behavioral symptoms and involve vastly complex genetic and non-genetic risk factors. Our review describes the diverse behavioral "phenome" of domestic dogs, past and ongoing sources of behavioral selection, and the state of canine behavioral genetics. We highlight two naturally disordered behavioral domains that illustrate how dogs may prove useful as a comparative, forward neurogenetic system: canine age-related cognitive dysfunction, which can be examined more rapidly given the attenuated lifespan of dogs, and compulsive disorders, which may have genetic roots in purpose-bred behaviors. Growing community science initiatives aimed at the companion dog population will be well suited to investigating such complex behavioral phenotypes and offer a comparative resource that parallels human genomic initiatives in scale and dimensionality. [ABSTRACT FROM AUTHOR]

The article focuses on a project that aims to map the Levitic-Cohanic Tribal Tree and its historical significance. Topics include the mapping of Kohenite lines and haplogroups, the identification of surnames associated with Cohanic ancestry, and the exploration of different branches and sub-branches within the Austrasia Line.

Palatogenesis is a complex and intricate process involving the formation of the palate through various morphogenetic events highly dependent on the surrounding context. These events comprise outgrowth of palatal shelves from embryonic maxillary prominences, their elevation from a vertical to a horizontal position above the tongue, and their subsequent adhesion and fusion at the midline to separate oral and nasal cavities. Disruptions in any of these processes can result in cleft palate, a common congenital abnormality that significantly affects patient's quality of life, despite surgical intervention. Although many genes involved in palatogenesis have been identified through studies on genetically modified mice and human genetics, the precise roles of these genes and their products in signaling networks that regulate palatogenesis remain elusive. Recent investigations have revealed that palatal shelf growth, patterning, adhesion, and fusion are intricately regulated by numerous transcription factors and signaling pathways, including Sonic hedgehog (Shh), bone morphogenetic protein (Bmp), fibroblast growth factor (Fgf), transforming growth factor beta (Tgf-β), Wnt signaling, and others. These studies have also identified a significant number of genes that are essential for palate development. Integrated information from these studies offers novel insights into gene regulatory networks and dynamic cellular processes underlying palatal shelf elevation, contact, and fusion, deepening our understanding of palatogenesis, and facilitating the development of more efficacious treatments for cleft palate. [ABSTRACT FROM AUTHOR]

Lymphoid cells play a critical role in the immune system, which includes three subgroups of T, B, and NK cells. Recognition of the complexity of the human genetics transcriptome in lymphopoiesis has revolutionized our understanding of the regulatory potential of RNA in normal lymphopoiesis and lymphoid malignancies. Long non-coding RNAs (lncRNAs) are a class of RNA molecules greater than 200 nucleotides in length. LncRNAs have recently attracted much attention due to their critical roles in various biological processes, including gene regulation, chromatin organization, and cell cycle control. LncRNAs can also be used for cell differentiation and cell fate, as their expression patterns are often specific to particular cell types or developmental stages. Additionally, lncRNAs have been implicated in lymphoid differentiation, such as regulating T-cell and B-cell development, and their expression has been linked to immune-associated diseases such as leukemia and lymphoma. In addition, lncRNAs have been investigated as potential biomarkers for diagnosis, prognosis, and therapeutic response to disease management. In this review, we provide an overview of the current knowledge about the regulatory role of lncRNAs in physiopathology processes during normal lymphopoiesis and lymphoid leukemia. [ABSTRACT FROM AUTHOR]

MECOM deficiency is a recently identified inborn error of immunity and inherited bone marrow failure syndrome caused by haploinsufficiency of the hematopoietic transcription factor MECOM. It is unique among inherited bone marrow failure syndromes, many of which present during later childhood or adolescence, because of the early age of onset and severity of the pancytopenia, emphasizing the importance and gene dose dependency of MECOM during hematopoiesis. B-cell lymphopenia and hypogammaglobulinemia have been described in a subset of patients with MECOM deficiency. While the mechanisms underlying the B-cell deficiency are currently unknown, recent work has provided mechanistic insights into the function of MECOM in hematopoietic stem cell (HSC) maintenance. MECOM binds to regulatory enhancers that control the expression of a network of genes essential for HSC maintenance and self-renewal. Heterozygous mutations, as seen in MECOM-deficient bone marrow failure, lead to dysregulated MECOM network expression. Extra-hematopoietic manifestations of MECOM deficiency, including renal and cardiac anomalies, radioulnar synostosis, clinodactyly, and hearing loss, have been reported. Individuals with specific genotypes have some of the systemic manifestations with isolated mild thrombocytopenia or without hematologic abnormalities, highlighting the tissue specificity of mutations in some MECOM domains. Those infants with MECOM-associated bone marrow failure require HSC transplantation for survival. Here, we review the expanding cohort of patient phenotypes and accompanying genotypes resulting in MECOM deficiency, and the proposed mechanisms underlying MECOM regulation of human HSC maintenance and B-cell development. [ABSTRACT FROM AUTHOR]

Malaria has exhibited the strongest known selective pressure on the human genome in recent history and is the evolutionary driving force behind genetic conditions, such as sickle-cell disease, glucose-6-phosphatase deficiency, and some other erythrocyte defects. Genomic studies (e.g., The 1000 Genomes project) have provided an invaluable baseline for human genetics, but with an estimated two thousand ethno-linguistic groups thought to exist across the African continent, our understanding of the genetic differences between indigenous populations and their implications on disease is still limited. Low-cost sequencing-based approaches make it possible to target specific molecular markers and genes of interest, leading to potential insights into genetic diversity. Here we demonstrate the versatility of custom dual-indexing technology and Illumina next generation sequencing to generate a genetic profile of human polymorphisms associated with malaria pathology. For 100 individuals diagnosed with severe malaria in Northeast Tanzania, variants were successfully characterised on the haemoglobin subunit beta (HBB), glucose-6-phosphate dehydrogenase (G6PD), atypical chemokine receptor 1 (ACKR1) genes, and the intergenic Dantu genetic blood variant, then validated using pre-existing genotyping data. High sequencing coverage was observed across all amplicon targets in HBB, G6PD, ACKR1, and the Dantu blood group, with variants identified at frequencies previously observed within this region of Tanzania. Sequencing data exhibited high concordance rates to pre-existing genotyping data (> 99.5%). Our work demonstrates the potential utility of amplicon sequencing for applications in human genetics, including to personalise medicine and understand the genetic diversity of loci linked to important host phenotypes, such as malaria susceptibility. [ABSTRACT FROM AUTHOR]

In this research, a biped robot is programmed to learn to walk using genetic algorithms. The biped robot has the ability to rise after a fall. The system is made according to human genetics, where a child tries to learn to walk, takes a few steps, falls, and then stands up somehow after a fall. After this process, the system restarts and tries to walk again. The biped robot evolves after each generation, and after each generation it will have a more natural walking posture. The system is unpredictable, because the biped robot sometimes evolves faster and sometimes evolves slower, like in human genetics where some children are faster and other children are slower to walk. The biped robot is considered to have evolved enough after having a walking posture similar to that of a human and does not fall. [ABSTRACT FROM AUTHOR]

Genetic variants in regions that include the mitochondrial genes thioredoxin reductase 2 (TXNRD2) and malic enzyme 3 (ME3) are associated with primary open-angle glaucoma (POAG) in genome-wide association studies (GWASs). To assess their clinical impact, we investigated whether TXNRD2 and ME3 genetic risk scores (GRSs) are associated with specific glaucoma phenotypes. Cross-sectional study. A total of 2617 patients with POAG and 2634 control participants from the National Eye Institute Glaucoma Human Genetics Collaboration Hereditable Overall Operational Database (NEIGHBORHOOD) consortium. All POAG-associated single nucleotide polymorphisms (SNPs) in the TXNRD2 and ME3 loci were identified using GWAS data (P < 0.05). Of these, 20 TXNRD2 and 24 ME3 SNPs were selected after adjusting for linkage disequilibrium. The correlation between SNP effect size and gene expression levels was investigated using the Gene-Tissue Expression database. Genetic risk scores were constructed for each individual using the unweighted sum of TXNRD2 , ME3 , and TXNRD2 + ME3 combined risk alleles. Age- and sex-adjusted odds ratios (ORs) for POAG diagnosis were calculated per decile for each GRS. Additionally, the clinical features of patients with POAG in the top 1%, 5%, and 10% of each GRS were compared with those in the bottom 1%, 5%, and 10%, respectively. Primary open-angle glaucoma OR per GRS decile, maximum treated intraocular pressure (IOP), and prevalence of paracentral visual field loss among patients with POAG with high versus low GRSs. A larger SNP effect size strongly correlated with higher TXNRD2 and lower ME3 expression levels (r = 0.95 and r = –0.97, respectively; P < 0.05 for both). Individuals in decile 10 of the TXNRD2 + ME3 GRS had the highest odds of POAG diagnosis (OR, 1.79 compared with decile 1; 95% confidence interval, 1.39–2.30; P < 0.001). Patients with POAG in the top 1% of the TXNRD2 GRS showed higher mean maximum treated IOP compared with the bottom 1% (19.9 mmHg vs. 15.6 mmHg; adjusted P = 0.03). Patients with POAG in the top 1% of the ME3 and TXNRD2 + ME3 GRS showed a higher prevalence of paracentral field loss than the bottom 1% (72.7% vs. 14.3% for ME3 GRS and 88.9% vs. 33.3% for TXNRD2 + ME3 GRS; adjusted P = 0.03 for both). Patients with POAG with higher TXNRD2 and ME3 GRSs showed higher treated IOP and a greater prevalence of paracentral field loss. Functional studies exploring how these variants impact mitochondrial function in patients with glaucoma are warranted. Proprietary or commercial disclosure may be found after the references. [ABSTRACT FROM AUTHOR]

Female gynephilia (i.e., sexual attraction to adult females) is considered an evolutionary paradox because it reduces direct reproduction, yet it is influenced by genetic factors and has persisted over time and across different cultures. The Kin Selection Hypothesis proposes that same-sex attracted individuals offset their lowered direct reproduction by engaging in kin-directed altruism that increases the reproduction of close genetic relatives, thereby enhancing inclusive fitness. Previous research on male same-sex attraction found evidence to support this hypothesis in some cultures. The present study employed a Thai sample to compare altruistic tendencies towards kin and non-kin children in heterosexual women (n = 285), lesbian women (n = 59), toms (i.e., masculine gynephilic females who take on a nonbinary gender identity; n = 181), and dees (i.e., feminine gynephilic females who are attracted to toms; n = 154). The Kin Selection Hypothesis of same-sex attraction predicts that gynephilic groups would show increased kin-directed altruism compared with heterosexual women, but we did not find evidence supporting this prediction. Instead, the tendency to invest more towards kin than non-kin children was more exaggerated in heterosexual women than lesbian women. Also, heterosexual women showed greater dissociation between kin and non-kin altruistic tendencies compared with toms and dees, which may suggest the former's cognition is better attuned for kin-directed altruism. Thus, the present findings were contrary to the Kin Selection Hypothesis for female gynephilia. Alternative explanations regarding the maintenance of genetic factors predisposing individuals to female gynephilia are discussed and require further investigation. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the main cause of dementia worldwide, and the genetic mechanism of which is not yet fully understood. Much evidence has accumulated over the past decade to suggest that after the first large-scale genome-wide association studies (GWAS) were conducted, the problem of "missing heritability" in AD is still a great challenge. Epistasis has been considered as one of the main causes of "missing heritability" in AD, which has been largely ignored in human genetics. The focus of current genome-wide epistasis studies is usually on single nucleotide polymorphisms (SNPs) that have significant individual effects, and the amount of heritability explained by which was very low. Moreover, AD is characterized by progressive cognitive decline and neuronal damage, and some studies have suggested that hyperphosphorylated tau (P-tau) mediates neuronal death by inducing necroptosis and inflammation in AD. Therefore, this study focused on identifying epistasis between two-marker interactions at marginal main effects across the whole genome using cerebrospinal fluid (CSF) P-tau as quantitative trait (QT). We sought to detect interactions between SNPs in a multi-GPU based linear regression method by using age, gender, and clinical diagnostic status (cds) as covariates. We then used the STRING online tool to perform the PPI network and identify two-marker epistasis at the level of gene–gene interaction. A total of 758 SNP pairs were found to be statistically significant. Particularly, between the marginal main effect SNP pairs, highly significant SNP–SNP interactions were identified, which explained a relatively high variance at the P-tau level. In addition, 331 AD-related genes were identified, 10 gene–gene interaction pairs were replicated in the PPI network. The identified gene-gene interactions and genes showed associations with AD in terms of neuroinflammation and neurodegeneration, neuronal cells activation and brain development, thereby leading to cognitive decline in AD, which is indirectly associated with the P-tau pathological feature of AD and in turn supports the results of this study. Thus, the results of our study might be beneficial for explaining part of the "missing heritability" of AD. [ABSTRACT FROM AUTHOR]

The Caenorhabditis elegans (C. elegans) is an ideal model organism for studying human diseases and genetics due to its transparency and suitability for optical imaging. However, manually sorting a large population of C. elegans for experiments is tedious and inefficient. The microfluidic-assisted C. elegans sorting chip is considered a promising platform to address this issue due to its automation and ease of operation. Nevertheless, automated C. elegans sorting with multiple parameters requires efficient identification technology due to the different research demands for worm phenotypes. To improve the efficiency and accuracy of multi-parameter sorting, we developed a deep learning model using You Only Look Once (YOLO)v7 to detect and recognize C. elegans automatically. We used a dataset of 3931 annotated worms in microfluidic chips from various studies. Our model showed higher precision in automated C. elegans identification than YOLOv5 and Faster R-CNN, achieving a mean average precision (mAP) at a 0.5 intersection over a union (mAP@0.5) threshold of 99.56%. Additionally, our model demonstrated good generalization ability, achieving an mAP@0.5 of 94.21% on an external validation set. Our model can efficiently and accurately identify and calculate multiple phenotypes of worms, including size, movement speed, and fluorescence. The multi-parameter identification model can improve sorting efficiency and potentially promote the development of automated and integrated microfluidic platforms. [ABSTRACT FROM AUTHOR]

Human genetics has validated de-repression of fetal gamma globin (HBG) in adult erythroblasts as a powerful therapeutic paradigm in diseases involving defective adult beta globin (HBB)1. To identify factors involved in the switch from HBG to HBB expression, we performed Assay for Transposase Accessible Chromatin with high-throughput sequencing (ATAC-seq)2 on sorted erythroid lineage cells derived from bone marrow (BM) or cord blood (CB), representing adult and fetal states, respectively. BM to CB cell ATAC-seq profile comparisons revealed genome-wide enrichment of NFI DNA binding motifs and increased NFIX promoter chromatin accessibility, suggesting that NFIX may repress HBG. NFIX knockdown in BM cells increased HBG mRNA and fetal hemoglobin (HbF) protein levels, coincident with increased chromatin accessibility and decreased DNA methylation at the HBG promoter. Conversely, overexpression of NFIX in CB cells reduced HbF levels. Identification and validation of NFIX as a new target for HbF activation has implications in the development of therapeutics for hemoglobinopathies. ATAC-seq on fetal and adult erythroid lineage cell populations facilitates the identification and validation of NFIX as a fetal hemoglobin repressor. [ABSTRACT FROM AUTHOR]

The benefits of large-scale genetic studies for healthcare of the populations studied are well documented, but these genetic studies have traditionally ignored people from some parts of the world, such as South Asia. Here we describe whole genome sequence (WGS) data from 4806 individuals recruited from the healthcare delivery systems of Pakistan, India and Bangladesh, combined with WGS from 927 individuals from isolated South Asian populations. We characterize population structure in South Asia and describe a genotyping array (SARGAM) and imputation reference panel that are optimized for South Asian genomes. We find evidence for high rates of reproductive isolation, endogamy and consanguinity that vary across the subcontinent and that lead to levels of rare homozygotes that reach 100 times that seen in outbred populations. Founder effects increase the power to associate functional variants with disease processes and make South Asia a uniquely powerful place for population-scale genetic studies. South Asia is home to almost 2 billion people but is extremely underrepresented in human genetics. This study uses genomes from ~5,000 South Asians to characterize genetic variation and help facilitate future South Asian genetic studies. [ABSTRACT FROM AUTHOR]

Twins' memoirs and autobiographies both enlighten and entertain. These works, often overlooked by researchers, may suggest new avenues for investigation, such as nonshared environmental events that propel twins in different directions. Of course, MZ twins' generally parallel experiences and DZ twins generally criss-crossing paths are the bases of fascinating life stories. The following sections examined recent research on fetal reduction in twin pregnancy, twins' personality and military service, growth restriction in twins, and advances in conjoined twin separation. This article closes with reports of a scientist who performed gene editing on twins, a twin conception from 33-year-old embryos, twins' physical outcomes from dietary differences, fraternal twins with the world's largest height difference and the Twin Home Experts who conquer rat infestation in New York. [ABSTRACT FROM AUTHOR]

Regarding human identification in armed conflicts, various complications can be observed. Usually, such difficulties can be social-related, which can include the lack of access to the relative's genetic material, or the unwillingness of administrative and judicial authorities to participate in the process of identification. In the case of genetics, the analysis allows identifying the individual from a blood sample, a part of an organ, or from skeletal remains, which is why it is considered a much more extensive and effective method when compared with fingerprint techniques or odontology. However, several factors can prevent this identification, such as considerably degraded genetic material. For successful identification, it is mandatory to have access to antemortem biological samples unequivocally attributed to the individual in question, using recombinant nuclear markers, as well as using biological samples from close relatives, whether parents or sons. Nevertheless, the problems associated with armed conflicts make this type of study very difficult. In this article, we focus on the main difficulties encountered when identifying an individual victim of an armed conflict, as well as on the possibilities that exist and on viable measures that could be required to improve the identification of these victims. [ABSTRACT FROM AUTHOR]

In the early twentieth century, psychiatric research in heredity took up statistical approaches from human genetics. On this basis, the psychiatrist and eugenicist Ernst Rüdin developed a programme for calculating probabilities of disease in different populations. Rüdin and his colleagues collected data for this research at the Basel Heil- und Pflegeanstalt Friedmatt from 1925 to 1928. This article shows on a micro level how psychiatric research in the clinic generated data for statistical analysis of heredity. The patients view here is central to an understanding of scientific research. Furthermore, the contribution offers new perspectives to the historical-anthropological study of illness and family. [ABSTRACT FROM AUTHOR]