The advancements, challenges, and future implications of the CRISPR/Cas9 system in swine research.

Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (CRISPR/Cas9) genome editing technology has dramatically influenced swine research by enabling the production of high-quality disease-resistant pig breeds, thus improving yields. In addition, CRISPR/Cas9 has been used extensively in pigs as one of the tools in biomedical research. In this review, we present the advancements of the CRISPR/Cas9 system in swine research, such as animal breeding, vaccine development, xenotransplantation, and disease modeling. We also highlight the current challenges and some potential applications of the CRISPR/Cas9 technologies.

Origins of human genetics. A personal perspective.

Genetics evolved as a field of science after 1900 with new theories being derived from experiments obtained in fruit flies, bacteria, and viruses. This personal account suggests that the origins of human genetics can best be traced to the years 1949 to 1959. Several genetic scientific advances in genetics in 1949 yielded results directly relating to humans for the first time, except for a few earlier observations. In 1949 the first textbook of human genetics was published, the American Journal of Human Genetics was founded, and in the previous year the American Society of Human Genetics. In 1940 in Britain a textbook entitled Introduction to Medical Genetics served as a foundation for introducing genetic aspects into medicine. The introduction of new methods for analyzing chromosomes and new biochemical assays using cultured cells in 1959 and subsequent years revealed that many human diseases, including cancer, have genetic causes. It became possible to arrive at a precise cause-related genetic diagnosis. As a result the risk of occurrence or re-occurrence of a disease within a family could be assessed correctly. Genetic counseling as a new concept became a basis for improved patient care. Taken together the advances in medically orientated genetic research and patient care since 1949 have resulted in human genetics being both, a basic medical and a basic biological science. Prior to 1949 genetics was not generally viewed in a medical context. Although monogenic human diseases were recognized in 1902, their occurrence and distribution were considered mainly at the population level.

High genes: Genetic underpinnings of cannabis use phenotypes.

Cannabis is one of the most widely used substances across the globe and its use has a substantial heritable component. However, the heritability of cannabis use varies according to substance use phenotype, suggesting that a unique profile of gene variants may contribute to the different stages of use, such as age of use onset, lifetime use, cannabis use disorder, and withdrawal and craving during abstinence. Herein, we review a subset of genes identified by candidate gene, family-based linkage, and genome-wide association studies related to these cannabis use phenotypes. We also describe their relationships with other substances, and their functions at the neurobiological, cognitive, and behavioral levels to hypothesize the role of these genes in cannabis use risk. Delineating genetic risk factors in the various stages of cannabis use will provide insight into the biological mechanisms related to cannabis use and highlight points of intervention prior to and following the development of dependence, as well as identify targets to aid drug development for treating problematic cannabis use.

Systemic neuro-dysregulation in depression: Evidence from genome-wide association.

Depression is the world's leading cause of disability. Greater understanding of the neurobiological basis of depression is necessary for developing novel treatments with improved efficacy and acceptance. Recently, major advances have been made in the search for genetic variants associated with depression which may help to elucidate etiological mechanisms. The present review has two major objectives. First, we offer a brief review of two major biological systems with strong evidence for involvement in depression pathology: neurotransmitter systems and the stress response. Secondly, we provide a synthesis of the functions of the 269 genes implicated by the most recent genome-wide meta-analysis, supporting the importance of these systems in depression and providing insights into other possible mechanisms involving neurodevelopment, neurogenesis, and neurodegeneration. Our goal is to undertake a broad, preliminary stock-taking of the most recent hypothesis-free findings and examine the weight of the evidence supporting these existing theories and highlighting novel directions. This qualitative review and accompanying gene function table provides a valuable resource and guide for basic and translational researchers, with suggestions for future mechanistic research, leveraging genetics to prioritize studies on the neurobiological processes involved in depression etiology and treatment.

[Panorama on congenital disorders of glycosylation (CDG): from 1980 to 2020]. / Anomalies congénitales de la glycosylation (CDG) - 1980-2020, 40 ans pour comprendre.

Glycosylation is an essential and complex cellular process where monosaccharides are added one by one onto an acceptor molecule, most of the time a protein or a lipid, so called glycoprotein or glycolipid. This cellular process is found in every living organism and is tightly conserved during evolution. In human, if one of the glycosylation reactions is genetically impaired, Congenital Disorders of Glycosylation (CDG) appear. CDG are a growing family of more than a hundred genetic diseases. This review offers a panorama of CDGs from 1980 to the present, their discoveries, diagnoses and treatments.

TITLE: Anomalies congénitales de la glycosylation (CDG) - 1980-2020, 40 ans pour comprendre. ABSTRACT: La glycosylation est un processus cellulaire complexe conduisant à des transferts successifs de monosaccharides sur une molécule acceptrice, le plus souvent une protéine ou un lipide. Ce processus est universel chez tous les organismes vivants et est très conservé au cours de l'évolution. Chez l'homme, des perturbations survenant au cours d'une ou plusieurs réactions de glycosylation sont à l'origine de glycopathologies génétiques rares, appelées anomalies congénitales de la glycosylation ou congenital disorders of glycosylation (CDG). Cette revue propose de revisiter ces CDG, de 1980 à aujourd'hui, en présentant leurs découvertes, leurs diagnostics, leurs causes biochimiques et les traitements actuellement disponibles.

Going wild for functional genomics: RNA interference as a tool to study gene-behavior associations in diverse species and ecological contexts.

Identifying the genetic basis of behavior has remained a challenge for biologists. A major obstacle to this goal is the difficulty of examining gene function in an ecologically relevant context. New tools such as CRISPR/Cas9, which alter the germline of an organism, have taken center stage in functional genomics in non-model organisms. However, germline modifications of this nature cannot be ethically implemented in the wild as a part of field experiments. This impediment is more than technical. Gene function is intimately tied to the environment in which the gene is expressed, especially for behavior. Most lab-based studies fail to recapitulate an organism's ecological niche, thus most published functional genomics studies of gene-behavior relationships may provide an incomplete or even inaccurate assessment of gene function. In this review, we highlight RNA interference as an especially effective experimental method to deepen our understanding of the interplay between genes, behavior, and the environment. We highlight the utility of RNAi for researchers investigating behavioral genetics, noting unique attributes of RNAi including transience of effect and the feasibility of releasing treated animals into the wild, that make it especially useful for studying the function of behavior-related genes. Furthermore, we provide guidelines for planning and executing an RNAi experiment to study behavior, including challenges to consider. We urge behavioral ecologists and functional genomicists to adopt a more fully integrated approach which we call "ethological genomics". We advocate this approach, utilizing tools such as RNAi, to study gene-behavior relationships in their natural context, arguing that such studies can provide a deeper understanding of how genes can influence behavior, as well as ecological aspects beyond the organism that houses them.

Cushing syndrome: Old and new genes.

Cushing syndrome (CS) describes the signs and symptoms caused by exogenous or endogenous hypercortisolemia. Endogenous CS is caused by either ACTH-dependent sources (pituitary or ectopic) or ACTH-independent (adrenal) hypercortisolemia. Several genes are currently known to contribute to the pathogenesis of CS. Germline gene defects, such as MEN1, AIP, PRKAR1A and others, often present in patients with pituitary or adrenal involvement as part of a genetic syndrome. Somatic defects in genes, such as USP8, TP53, and others, are also involved in the development of pituitary or adrenal tumors in a large percentage of patients with CS, and give insight in pathways involved in pituitary or adrenal tumorigenesis.

Advances in Knowledge of Candidate Genes Acting at the Beta-Cell Level in the Pathogenesis of T1DM.

T1DM (type 1 diabetes mellitus), which results from the irreversible elimination of beta-cells mediated by autoreactive T cells, is defined as an autoimmune disease. It is widely accepted that T1DM is caused by a combination of genetic and environmental factors, but the precise underlying molecular mechanisms are still unknown. To date, more than 50 genetic risk regions contributing to the pathogenesis of T1DM have been identified by GWAS (genome-wide association studies). Notably, more than 60% of the identified candidate genes are expressed in islets and beta-cells, which makes it plausible that these genes act at the beta-cell level and play a key role in the pathogenesis of T1DM. In this review, we focus on the current status of candidate genes that act at the beta-cell level by regulating the innate immune response and antiviral activity, affecting susceptibility to proapoptotic stimuli and influencing the pancreatic beta-cell phenotype.

An overview of 20 years of genetic studies in pheochromocytoma and paraganglioma.

Paragangliomas and pheochromocytomas (PPGL) are rare neuroendocrine tumours characterized by a strong genetic determinism. Over the past 20 years, evolution of PPGL genetics has revealed that around 40% of PPGL are genetically determined, secondary to a germline mutation in one of more than twenty susceptibility genes reported so far. More than half of the mutations occur in one of the SDHx genes (SDHA, SDHB, SDHC, SDHD, SDHAF2), which encode the different subunits and assembly protein of a mitochondrial enzyme, succinate dehydrogenase. These susceptibility genes predispose to early forms (VHL, RET, SDHD, EPAS1, DLST), syndromic (RET, VHL, EPAS1, NF1, FH), multiple (SDHD, TMEM127, MAX, DLST, MDH2, GOT2) or malignant (SDHB, FH, SLC25A11) PPGL. The discovery of a germline mutation in one of these genes changes the patient's follow-up and allows genetic screening of affected families and the presymptomatic follow-up of relatives carrying a mutation.

[SMA: from gene discovery to gene therapy]. / Amyotrophie spinale infantile - De la découverte du gène à la thérapie génique.

Spinal muscular atrophy (SMA) is the most common genetic disease leading to infant mortality. This neuro-muscular disorder is caused by the loss or mutation of the telomeric copy of the 'survival of motor neuron' (Smn) gene, termed SMN1. Loss of SMN1 leads to reduced SMN protein levels, inducing degeneration of motor neurons (MN) and progressive muscle weakness and atrophy. Gene therapy, consisting of reintroducing SMN1 in the MNs, is an attractive approach for SMA. We showed the most efficient rescue of SMA mice to date after a single intravenous injection of an AAV9 expressing SMN1, highlighting the considerable potential of this method for the treatment of human SMA. Recently, a startup led by the Dr Kaspar decided to test this experimental approach in children with SMA type 1. Dr Mendell, in charge of this clinical project, showed a very significant increase of the lifespan and motor function of the patients (until 4 years) after a single injection of AAV9-SMN1 (named ZolgenSMA®) into an arm or leg vein. This gene therapy treatment obtained a marketing authorization by the FDA in May 24 and is now the first efficient therapy for neuromuscular disease.

TITLE: Amyotrophie spinale infantile - De la découverte du gène à la thérapie génique. ABSTRACT: L'amyotrophie spinale ou SMA est la maladie génétique la plus fréquente menant à la mortalité infantile. Cette maladie neuromusculaire est due à l'altération du gène SMN1. Cette anomalie génétique provoque la réduction des taux de protéine Smn, induisant la dégénérescence des neurones moteurs, la faiblesse et l'atrophie musculaire. La thérapie génique, consistant à réintroduire le gène SMN1 normal dans les motoneurones constitue une thérapie de choix pour la SMA. Nous avons montré l'efficacité sans précédent de cette approche chez la souris modèle de SMA après une simple injection intraveineuse d'un AAV9 exprimant SMN1. Une jeune société de biotechnologie, dirigée par le Dr Kaspar, a testé cette approche expérimentale chez de jeunes patients atteints de SMA type 1. Le Dr Mendell, en charge de ce projet clinique, a montré une augmentation significative de la survie et des fonctions motrices des patients (jusqu'à 4 ans) après une seule injection de l'AAV9-SMN (appelé ZolgenSMA) dans la veine du bras ou de la jambe. Cette thérapie, qui a obtenu l'AMM par la FDA le 24 mai 2019, est actuellement la première thérapie génique efficace dans les maladies neuromusculaires.

Genetic causes of PD: A pathway to disease modification.

The underline neuropathology of Parkinson disease is pleiomorphic and its genetic background diverse. Possibly because of this heterogeneity, no effective disease modifying therapy is available. In this paper we give an overview of the genetics of Parkinson disease and explain how this is relevant for the development of new therapies. This article is part of the special issue entitled 'The Quest for Disease-Modifying Therapies for Neurodegenerative Disorders'.

Old and new genes in primary aldosteronism.

Primary aldosteronism (PA) is the most common form of secondary hypertension affecting 5%-10% of patients with arterial hypertension. In PA, high blood pressure is associated with high aldosterone and low renin levels, and often hypokalemia. In a majority of cases, autonomous aldosterone production by the adrenal gland is caused by an aldosterone producing adenoma (APA) or bilateral adrenal hyperplasia (BAH). During the last ten years, a better knowledge of the pathophysiology of PA came from the discovery of somatic and germline mutations in different genes in both sporadic and familial forms of the disease. Those genes code for ion channels and pumps, as well as proteins involved in adrenal cortex development and function. Targeted next generation sequencing following immunohistochemistry guided detection of aldosterone synthase expression allows detection of somatic mutations in up to 90% of APA, while whole exome sequencing has discovered the genetic causes of four different familial forms of PA. The identification, in BAH, of somatic mutations in aldosterone producing cell clusters open new perspectives in our understanding of the bilateral form of the disease and the development of new therapeutic approaches.

Integrating genome-wide association study and methylation functional annotation data identified candidate genes and pathways for schizophrenia.

BACKGROUND: Schizophrenia (SCZ) is a severe mental disorder. Both environmental and genetic factors contribute to the development of SCZ. The estimated heritability of SCZ is about 80%. Previous genetic studies of SCZ mainly focused on the genetic variations associated the risk of SCZ. Limited efforts are paid to explore the roles and biological mechanism of nuclear acid methylation implicated in the pathogenesis of SCZ. METHODS: A two-stage integrative analysis of SCZ GWAS and nuclear acid methylation functional annotation data (including meQTLs and m6A) was performed in this study. First, the discovery GWAS of SCZ was aligned with genomic meQTLs and m6A annotation data to identify the candidate genes associated with SCZ. Second, another independent replication GWAS dataset of SCZ was applied to validate the discovery results. Furthermore, the functional relevance of identified candidate genes with SCZ were validated by the mRNA expression profiling of SCZ brain tissues. Gene ontology (GO) and pathway enrichment analysis of identified candidate genes was performed by the DAVID tool. RESULTS: The two-stage integrative analysis detected 106 meQTLs related candidate genes for SCZ. After comparing with the differentially expressed genes in SCZ brain tissues, 49 overlapped genes were identified for meQTLs, such as ZSCAN12, BTN3A2 and HLA-DQA1. Besides, for meQTLs, 29 SCZ associated pathways and 56 SCZ associated GO terms were detected, such as cell adhesion molecules and asthma. For m6A, 25 candidate genes were detected by the two-stage integrative analysis for SCZ, such as ZSCAN12, HLA-DQA1 and SNX19. Furthermore, 17 of the 25 genes were detected in the mRNA expression profiling of SCZ brain tissues. CONCLUSION: This study identified multiple SCZ associated genes and pathways, supporting the implication of nuclear acid methylation in the pathogenesis of SCZ.

Trends in Systems Biology for the Analysis and Engineering of Clostridium acetobutylicum Metabolism.

Clostridium acetobutylicum has received renewed interest worldwide as a promising producer of biofuels and bulk chemicals such as n-butanol, 1,3-propanediol, 1,3-butanediol, isopropanol, and butyrate. To develop commercial processes for the production of bulk chemicals via a metabolic engineering approach it is necessary to better characterize both the primary metabolism and metabolic regulation of C. acetobutylicum. Here, we review the history of the development of omics studies of C. acetobutylicum, summarize the recent application of quantitative/integrated omics approaches to the physiological analysis and metabolic engineering of this bacterium, and provide directions for future studies to address current challenges.

DSP variants may be associated with longitudinal change in quantitative emphysema.

BACKGROUND: Emphysema, characterized by lung destruction, is a key component of Chronic Obstructive Pulmonary Disease (COPD) and is associated with increased morbidity and mortality. Genome-wide association studies (GWAS) have identified multiple genetic factors associated with cross-sectional measures of quantitative emphysema, but the genetic determinants of longitudinal change in quantitative measures of emphysema remain largely unknown. Our study aims to identify genetic variants associated with longitudinal change in quantitative emphysema measured by computed tomography (CT) imaging. METHODS: We included current and ex-smokers from two longitudinal cohorts: COPDGene, a study of Non-Hispanic Whites (NHW) and African Americans (AA), and the Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE). We calculated annual change in two quantitative measures of emphysema based on chest CT imaging: percent low attenuation area (≤ - 950HU) (%LAA-950) and adjusted lung density (ALD). We conducted GWAS, separately in 3030 NHW and 1158 AA from COPDGene and 1397 Whites from ECLIPSE. We further explored effects of 360 previously reported variants and a lung function based polygenic risk score on annual change in quantitative emphysema. RESULTS: In the genome-wide association analysis, no variants achieved genome-wide significance (P < 5e-08). However, in the candidate region analysis, rs2076295 in the DSP gene, previously associated with COPD, lung function and idiopathic pulmonary fibrosis, was associated with change in %LAA-950 (ß (SE) = 0.09 (0.02), P = 3.79e-05) and in ALD (ß (SE) = - 0.06 (0.02), P = 2.88e-03). A lung function based polygenic risk score was associated with annual change in %LAA-950 (P = 4.03e-02) and with baseline measures of quantitative emphysema (P < 1e-03) and showed a trend toward association with annual change in ALD (P = 7.31e-02). CONCLUSIONS: DSP variants may be associated with longitudinal change in quantitative emphysema. Additional investigation of the DSP gene are likely to provide further insights into the disease progression in emphysema and COPD. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT00608764 , NCT00292552 .

Global Genetic Networks and the Genotype-to-Phenotype Relationship.

Genetic interactions identify combinations of genetic variants that impinge on phenotype. With whole-genome sequence information available for thousands of individuals within a species, a major outstanding issue concerns the interpretation of allelic combinations of genes underlying inherited traits. In this Review, we discuss how large-scale analyses in model systems have illuminated the general principles and phenotypic impact of genetic interactions. We focus on studies in budding yeast, including the mapping of a global genetic network. We emphasize how information gained from work in yeast translates to other systems, and how a global genetic network not only annotates gene function but also provides new insights into the genotype-to-phenotype relationship.

Current trends of genetics in apical periodontitis research.

Genetics is an emerging topic in endodontic research focusing on the host response regarding the pathogenesis of apical periodontitis (AP). A number of genetic epidemiological studies carried out by many investigators worldwide have shown evidence of an association between certain candidate genes and AP. Some studies have been conducted on knockout mice with a deficiency in certain proteins, leading to more or less severe AP, and thus suggesting a pivotal role of these genes in AP pathogenesis. Other research has evaluated the association between genetic polymorphisms in humans with different AP aspects; these studies pointed out that genetic polymorphisms in some candidate genes are involved in inter-individual variations in their response to AP. Therefore, the objective of this report was to provide an updated overview of the genes involved in AP pathogenesis, with a focus on the most relevant candidate genes.

Towards frailty biomarkers: Candidates from genes and pathways regulated in aging and age-related diseases.

OBJECTIVE: Use of the frailty index to measure an accumulation of deficits has been proven a valuable method for identifying elderly people at risk for increased vulnerability, disease, injury, and mortality. However, complementary molecular frailty biomarkers or ideally biomarker panels have not yet been identified. We conducted a systematic search to identify biomarker candidates for a frailty biomarker panel. METHODS: Gene expression databases were searched (http://genomics.senescence.info/genes including GenAge, AnAge, LongevityMap, CellAge, DrugAge, Digital Aging Atlas) to identify genes regulated in aging, longevity, and age-related diseases with a focus on secreted factors or molecules detectable in body fluids as potential frailty biomarkers. Factors broadly expressed, related to several "hallmark of aging" pathways as well as used or predicted as biomarkers in other disease settings, particularly age-related pathologies, were identified. This set of biomarkers was further expanded according to the expertise and experience of the authors. In the next step, biomarkers were assigned to six "hallmark of aging" pathways, namely (1) inflammation, (2) mitochondria and apoptosis, (3) calcium homeostasis, (4) fibrosis, (5) NMJ (neuromuscular junction) and neurons, (6) cytoskeleton and hormones, or (7) other principles and an extensive literature search was performed for each candidate to explore their potential and priority as frailty biomarkers. RESULTS: A total of 44 markers were evaluated in the seven categories listed above, and 19 were awarded a high priority score, 22 identified as medium priority and three were low priority. In each category high and medium priority markers were identified. CONCLUSION: Biomarker panels for frailty would be of high value and better than single markers. Based on our search we would propose a core panel of frailty biomarkers consisting of (1) CXCL10 (C-X-C motif chemokine ligand 10), IL-6 (interleukin 6), CX3CL1 (C-X3-C motif chemokine ligand 1), (2) GDF15 (growth differentiation factor 15), FNDC5 (fibronectin type III domain containing 5), vimentin (VIM), (3) regucalcin (RGN/SMP30), calreticulin, (4) PLAU (plasminogen activator, urokinase), AGT (angiotensinogen), (5) BDNF (brain derived neurotrophic factor), progranulin (PGRN), (6) α-klotho (KL), FGF23 (fibroblast growth factor 23), FGF21, leptin (LEP), (7) miRNA (micro Ribonucleic acid) panel (to be further defined), AHCY (adenosylhomocysteinase) and KRT18 (keratin 18). An expanded panel would also include (1) pentraxin (PTX3), sVCAM/ICAM (soluble vascular cell adhesion molecule 1/Intercellular adhesion molecule 1), defensin α, (2) APP (amyloid beta precursor protein), LDH (lactate dehydrogenase), (3) S100B (S100 calcium binding protein B), (4) TGFß (transforming growth factor beta), PAI-1 (plasminogen activator inhibitor 1), TGM2 (transglutaminase 2), (5) sRAGE (soluble receptor for advanced glycosylation end products), HMGB1 (high mobility group box 1), C3/C1Q (complement factor 3/1Q), ST2 (Interleukin 1 receptor like 1), agrin (AGRN), (6) IGF-1 (insulin-like growth factor 1), resistin (RETN), adiponectin (ADIPOQ), ghrelin (GHRL), growth hormone (GH), (7) microparticle panel (to be further defined), GpnmB (glycoprotein nonmetastatic melanoma protein B) and lactoferrin (LTF). We believe that these predicted panels need to be experimentally explored in animal models and frail cohorts in order to ascertain their diagnostic, prognostic and therapeutic potential.