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What causes host-use specificity in herbivorous insects? Population genetic models predict specialization when habitat preference can evolve and there is antagonistic pleiotropy at a performance-affecting locus. But empirically for herbivorous insects, host-use performance is governed by many genetic loci, and antagonistic pleiotropy seems to be rare. Here, we use individual-based quantitative genetic simulation models to investigate the role of pleiotropy in the evolution of sympatric host-use specialization when performance and preference are quantitative traits. We look first at pleiotropies affecting only host-use performance. We find that when the host environment changes slowly the evolution of host-use specialization requires levels of antagonistic pleiotropy much higher than what has been observed in nature. On the other hand, with rapid environmental change or pronounced asymmetries in productivity across host species, the evolution of host-use specialization readily occurs without pleiotropy. When pleiotropies affect preference as well as performance, even with slow environmental change and host species of equal productivity, we observe fluctuations in host-use breadth, with mean specificity increasing with the pervasiveness of antagonistic pleiotropy. So, our simulations show that pleiotropy is not necessary for specialization, although it can be sufficient, provided it is extensive or multifarious.

Common bean (Phaseolus vulgaris) is an annual legume crop that is grown worldwide for its edible dry seeds and tender pods. Marsh spot (MS) of the seeds is a physio-genic stress disease affecting seed quality in beans. Studies have suggested that this disease involves a nutritional disorder caused by manganese deficiency, but the inheritance of resistance to this disease has not been reported. A biparental genetic population composed of 138 recombinant inbred lines (RILs) was developed from a cross between an MS resistant cultivar ‘Cran09’ and an MS susceptible cultivar ‘Messina’. The 138 RILs and their two parents were evaluated for MS resistance during five consecutive years from 2015 to 2019 in sandy and heavy clay soils in Morden, Manitoba, Canada. The MS incidence (MSI) and the MS resistance index (MSRI) representing disease severity were shown to be both highly correlated heritable traits that had high broad-sense heritability values (H2) of 86.5% and 83.2%, respectively. No significant differences for MSI and MSRI were observed between the two soil types in all five- (MSI) or four-year (MSRI) data collection, but significant correlations among years were observed despite MS resistance was moderately affected by year. The MSIs and MSRIs displayed a right-skewed distribution, indicating a mixed genetic model involving a few major genes and polygenes. Using the joint segregation analysis method, the same four major genes with additive-epistasis effects showed the best fit for both traits, explaining 84.4% and 85.3% of the phenotypic variance for MSI and MSRI, respectively. For both traits, the M1, M2, M3 and m4 acted as the favorable (resistant) alleles for the four genes where M and m represent two alleles of each gene. However, due to epistatic effects, only the individuals of the M1M2M3M4 haplotype appeared to be highly resistant, whereas those of the m1m2m3M4 haplotype were the most susceptible. The m4 allele significantly suppressed the additive effects of M1M2M3 on resistance, but decreased susceptibility due to the additive effects of m1m2m3. Further quantitative trait locus (QTL) mapping is warranted to identify and validate individual genes and develop molecular markers for marker-assisted selection of resistant cultivars.

The majority of population genetic theory assumes fully haploid or diploid organisms with obligate sexuality, despite complex life cycles with alternating generations being commonly observed. To reveal how natural selection and genetic drift shape the evolution of haploid-diploid populations, we analyze a stochastic genetic model for populations that consist of a mixture of haploid and diploid individuals, allowing for asexual reproduction and niche separation between haploid and diploid stages. Applying a diffusion approximation, we derive the fixation probability and describe its dependence on the reproductive values of haploid and diploid stages, which depend strongly on the extent of asexual reproduction in each phase and on the ecological differences between them.

In 2020, 2.3 million females identified with breast cancer, and it is the second most frequent cancer among females. As a result, there is severe requirement of an accurate procedure to recognize breast cancer. In accordance with breast cancer organization the breast cancer is divided into two types one is invasive and another one is non-invasive. In Indian cities like Delhi, Kolkata and Mumbai have the highest death rate for female due to breast cancer. Unusual alteration in genes is the prime reason for breast cancer. Our paper contains metabric dataset related to 1905 patients along with 31 clinical characteristics and 331 genes. The novelty of this paper is to find out genes which are highly responsible for death from breast cancer with foremost clinical features and implementation of a hybrid method which is a combination of genetic algorithm and artificial neural network to get the best accuracy with the help of machine learning as this can preserve life of females. For attribute scaling standard scaler is used which range data in between 0 and 1. Attribute selection is performed with the help of ANOVA which is a statistical appliance. With this tool 6 leading clinical attributes are examined. In our research 12 genes gsk3b, kmt2c, map4, tsc2, tnk2, pdgfb, ncoa3, akt1, afdn, sdc4,map2k2 and tubb4b which are extremely responsible for death in our dataset are recognized and our hybrid method implementation gives the perfection of 90.57%.

Attention deficit hyperactivity disorder (ADHD) is a polygenic neurodevelopmental disorder that affects 8-12 % of children and4 % of adults. Environmental factors are believed to interact with genetic predispositions to increase susceptibility to ADHD. No existing rodent model captures all aspects of ADHD, but several show promise. The main genetic models are the spontaneous hypertensive rat, dopamine transporter knock-out (KO) mice, dopamine receptor subtype KO mice, Snap-25 KO mice, guanylyl cyclase-c KO mice, and latrophilin-3 KO mice and rats. Environmental factors thought to contribute to ADHD include ethanol, nicotine, PCBs, lead (Pb), ionizing irradiation, 6-hydroxydopamine, neonatal hypoxia, some pesticides, and organic pollutants. Model validation criteria are outlined, and current genetic models evaluated against these criteria. Future research should explore induced multiple gene KOs given that ADHD is polygenic and epigenetic contributions. Furthermore, genetic models should be combined with environmental agents to test for interactions.

In rodents and humans, the major cellular events at spermatogenesis include self-renewal of spermatogonial stem cells and undifferentiated spermatogonia via mitosis, commitment of spermatogonia to differentiation and transformation to spermatocytes, meiosis, spermiogenesis, and the release of spermatozoa at spermiation. While details of the morphological changes during these cellular events have been delineated, knowledge gap exists between the morphological changes in the seminiferous epithelium and the underlying molecular mechanism(s) that regulate these cellular events. Even though many of the regulatory proteins and biomolecules that modulate spermatogenesis are known based on studies using genetic models, the underlying regulatory mechanism(s), in particular signaling pathways/proteins, remain unexplored since much of the information regarding the signaling regulation is unknown. Studies in the past decade, however, have unequivocally demonstrated that the testis is using several signaling proteins and/or pathways to regulate multiple cellular events to modulate spermatogenesis. These include mTORC1/rpS6/Akt1/2 and p-FAK-Y407. While selective inhibitors and/or agonists and antagonists are available to examine some of these signaling proteins, their use have limitations due to their specificities and also potential systemic cytotoxicity. On the other hand, the use of genetic models has had profound implications for our understanding of the molecular regulation of spermatogenesis, and these knockout (null) models have also revealed the factors that are critical for spermatogenesis. Nonetheless, additional studies using in vitro and in vivo models are necessary to unravel the signaling pathways involved in regulating seminiferous epithelial cycle. Emerging data from studies, such as the use of the adjudin pharmaceutical/toxicant model, have illustrated that this non-hormonal male contraceptive drug is utilizing specific signaling pathways/proteins to induce specific defects in spermatogenesis, yielding mechanistic insights on the regulation of spermatogenesis. We sought to review these recent data in this article, highlighting an interesting approach that can be considered for future studies.

Objectives: The present study was designed to evaluate the association of transporters associated with antigen processing (TAP2) polymorphisms TAP2-379Ile > Val (rs1800454), TAP2-665Thr > Ala (rs241447) and TAP2-565Ala > Thr (rs2228396) as a candidate gene with susceptibility to the Systemic Lupus Erythematosus (SLE). Methods: To analyze these three polymorphic variants, 88 patients with SLE and 100 healthy controls from northeastern Iran were enrolled from May 2018 to July 2019. Genomic DNA polymorphisms were performed by amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) technique. Data were analyzed by SPSS software. Results: In this cross-sectional study, there was a stratification between patients and controls. The distribution of the frequency of Ala73 (41.5%) allele at TAP2/665 and Ile 19 (10.8%) allele at TAP2/379 was higher in patients. Additionally, the Ala/Ala 13(14.8%) and Ala/Thr 49(55.7%) genotypes distributions at 665 positions were higher in SLE patients compared to the controls. Furthermore, frequencies of TAP2*H allele significantly increased in SLE patients 10(5.71%) (P=0.01). Frequency of TAP2*A allele in the control group was 120(60%) (p=0.06) due to the dominant genetic model. This allele has a protective effect against SLE. There was no relationship between TAP2*D, TAP2*E, TAP2*F and TAP2*G alleles with the outbreak of SLE. Conclusions: Our data indicated that genetic variants in TAP2 gene may be associated with SLE disease. A correlation between Ala allele at TAP2/665 and Ile allele at TAP2/379 polymorphisms and pathogenesis of SLE was observed.

The Roman High- (RHA) and Low-(RLA) avoidance rat lines/strains were generated through bidirectional selective breeding for rapid (RHA) vs. extremely poor (RLA) two-way active avoidance acquisition. Compared with RLAs and other rat strains/stocks, RHAs are characterized by increased impulsivity, deficits in social behavior, novelty-induced hyper-locomotion, impaired attentional/cognitive abilities, vulnerability to psychostimulant sensitization and drug addiction. RHA rats also exhibit decreased function of the prefrontal cortex (PFC) and hippocampus, increased functional activity of the mesolimbic dopamine system and a dramatic deficit of central metabotropic glutamate-2 (mGlu2) receptors (due to a stop codon mutation at cysteine 407 in Grm2 -cys407*-), along with increased density of 5-HT2A receptors in the PFC, alterations of several synaptic markers and increased density of pyramidal "thin" (immature) dendrític spines in the PFC. These characteristics suggest an immature brain of RHA rats, and are reminiscent of schizophrenia features like hypofrontality and disruption of the excitation/inhibition cortical balance. RHA rats represent a promising heuristic model of neurodevelopmental schizophrenia-relevant features and comorbidity with drug addiction vulnerability.

Take-all is a devastating soil-borne disease of wheat (Triticum aestivum L.). Cultivating resistant line is an important measure to control this disease. Psathyrostachys huashanica Keng is a valuable germplasm resource with high resistance to take-all. This study reported on a wheat-P. huashanica introgression line H148 with improved take-all resistance compared with its susceptible parent 7182. To elucidate the genetic mechanism of resistance in H148, the F2 genetic segregating population of H148×XN585 was constructed. The mixed genetic model analysis showed that the take-all resistance was controlled by two major genes with additive, dominant and epistasis effects. Bulked segregant analysis combined with wheat axiom 660K genotyping array analysis showed the polymorphic SNPs with take-all resistance from P. huashanica alien introgression were mainly distributed on the chromosome 2A. Genotyping of the F2 population using the KASP marker mapped a major QTL in an interval of 68.8–70.1 Mb on 2AS. Sixty-two genes were found in the target interval of the Chinese Spring reference genome sequence. According to the functional annotation of genes, two protein genes that can improve the systematic resistance of plant roots were predicted as candidate genes. The development of wheat-P. huashanica introgression line H148 and the resistant QTL mapping information are expected to provide some valuable references for the fine mapping of disease-resistance gene and development of take-all resistant varieties through molecular marker-assisted selection.

Changes in the microbiota are associated with alterations in nervous system structure-function and behavior and have been implicated in the etiology of neuropsychiatric and neurodegenerative disorders. Most of these studies have centered on mammalian models due to their phylogenetic proximity to humans. Indeed, the germ-free mouse has been a particularly useful model organism for investigating microbiota-brain interactions. However, microbiota-brain axis research on simpler genetic model organisms with a vast and diverse scientific toolkit (zebrafish, Drosophila melanogaster, and Caenorhabditis elegans) is now also coming of age. In this review, we summarize the current state of microbiota-brain axis research in rodents and humans, and then we elaborate and discuss recent research on the neurobiological and behavioral effects of the microbiota in the model systems of fish, flies, and worms. We propose that a cross-species, holistic and mechanistic approach to unravel the microbiota-brain communication is an essential step toward rational microbiota-based therapeutics to combat brain disorders.

HMG-CoA reductase (Hmgcr) is the rate-limiting enzyme in the mevalonate pathway and is inhibited by statins. In addition to cholesterol, Hmgcr activity is also required for synthesizing nonsterol isoprenoids, such as dolichol, ubiquinone, and farnesylated and geranylgeranylated proteins. Here, we investigated the effects of Hmgcr inhibition on nonsterol isoprenoids in the liver. We have generated new genetic models to acutely delete genes in the mevalonate pathway in the liver using AAV-mediated delivery of Cre-recombinase (AAV-Cre) or CRISPR/Cas9 (AAV-CRISPR). The genetic deletion of Hmgcr by AAV-Cre resulted in extensive hepatocyte apoptosis and compensatory liver regeneration. At the biochemical level, we observed decreased levels of sterols and depletion of the nonsterol isoprenoids, dolichol and ubiquinone. At the cellular level, Hmgcr-null hepatocytes showed ER stress and impaired N-glycosylation. We further hypothesized that the depletion of dolichol, essential for N-glycosylation, could be responsible for ER stress. Using AAV-CRISPR, we somatically disrupted dehydrodolichyl diphosphate synthase subunit (Dhdds), encoding a branch point enzyme required for dolichol biosynthesis. Dhdds-null livers showed ER stress and impaired N-glycosylation, along with apoptosis and regeneration. Finally, the combined deletion of Hmgcr and Dhdds synergistically exacerbated hepatocyte ER stress. Our data show a critical role for mevalonate-derived dolichol in the liver and suggest that dolichol depletion is at least partially responsible for ER stress and apoptosis upon potent Hmgcr inhibition.

In the last years, the field of inheritable ventricular arrhythmia disease modelling has changed significantly with a push towards the use of novel cellular cardiomyocyte based models. However, there is a growing need for new in vivo models to study the disease pathology at the tissue and organ level. Zebrafish provide an excellent opportunity for in vivo modelling of inheritable ventricular arrhythmia syndromes due to the remarkable similarity between their cardiac electrophysiology and that of humans. Additionally, many state-of-the-art methods in gene editing and electrophysiological phenotyping are available for zebrafish research. In this review, we give a comprehensive overview of the published zebrafish genetic models for primary electrical disorders and arrhythmogenic cardiomyopathy. We summarise and discuss the strengths and weaknesses of the different technical approaches for the generation of genetically modified zebrafish disease models, as well as the electrophysiological approaches in zebrafish phenotyping. By providing this detailed overview, we aim to draw attention to the potential of the zebrafish model for studying arrhythmia syndromes at the organ level and as a platform for personalised medicine and drug testing.

Defining the mechanisms by which animals adapt to their ecological niche is an important problem bridging evolution, genetics, and neurobiology. We review the establishment of a powerful genetic model for comparative behavioral analysis and neuroecology, Drosophila sechellia. This island-endemic fly species is closely related to several cosmopolitan generalists, including Drosophila melanogaster, but has evolved extreme specialism, feeding and reproducing exclusively on the noni fruit of the tropical shrub Morinda citrifolia. We first describe the development and use of genetic approaches to facilitate genotype/phenotype associations in these drosophilids. Next, we survey the behavioral, physiological, and morphological adaptations of D. sechellia throughout its life cycle and outline our current understanding of the genetic and cellular basis of these traits. Finally, we discuss the principles this knowledge begins to establish in the context of host specialization, speciation, and the neurobiology of behavioral evolution and consider open questions and challenges in the field.

The aim of the present paper was to summarize the gene polymorphisms of beta-lactoglobulin (BLG) gene and its effects on milk yield in 1840 genotyped Indian dairy cows reported in 17 published studies. The meta-analysis was undertaken using gene frequencies of individual studies under random effects model, whereas for association analysis of genotypes with milk yield, standardized mean differences (SMDs) along with 95% confidence interval (CI) were obtained under four genetic models such as additive (AA vs. BB), dominant (AA+AB vs. BB), completely over dominant (AA+BB vs. AB) and recessive (AA vs. AB+BB). The heterogeneity index (I2) was used to determine heterogeneity between studies. The results of meta-analysis suggested that the pooled allelic frequency of allele A was subsidiary as 0.29 (95% CI 0.24, 0.33, I2 = 88.54%) in targeted population, and also, it was non-significantly (P > 0.05) different between Bos indicus (0.28) and Bos taurus/cross cows (0.30). Egger’s test indicated no risk of publication bias (P > 0.05). The results also revealed that BLG gene variants have non-significant (P > 0.05) association with milk yield under all genetic models. Although positive effects of SMDs under some models were observed, however, they failed to meet statistical significance (P > 0.05) due to high heterogeneity between studies which lead to conclusion of only uncertain influences of SNP genotypes with milk yield. It was concluded that BLG markers may not be beneficial for improving milk yield in Indian dairy cows. However, it is suggested that the revalidation of the present results should be done by using more number of studies.

Plateau essential hypertension is a common chronic harmful disease of permanent residents in plateau areas. Studies have shown some single nucleotide polymorphisms (SNPs) associations with hypertension, but few have been verified in plateau area-lived people. In this paper, we examined some hypertension-related gene loci to analyze the relationship between risk SNPs and plateau essential hypertension in residents in Qinghai-Tibet plateau area. We screened hypertension-related SNPs from the literature, Clinvar database, GHR database, GTR database, and GWAS database, and then selected 101 susceptible SNPs for detection. Illumina MiSeq NGS platform was used to perform DNA sequencing on the blood samples from 185 Tibetan dwellings of Qinghai, and bioinformatic tools were used to make genotyping. Genetic models adjusted by gender and age were used to calculate the risk effects of genotypes. Four known SNPs as well as a new locus were found associated with PHE, which were rs2493134 (AGT), rs9349379 (PHACTR1), rs1371182 (CYP2C56P-PRPS1P1), rs567481079 (CYP2C56P-PRPS1P1), and chr14:61734822 (HIF1A). Among them, genotypes of rs2493134, rs9349379, and rs567481079 were risk factors, genotypes of rs1371182 and chr14:61734822 were protective factors. The rs2493134 in AGT was found associated with an increased risk of the plateau essential hypertension by 3.24-, 3.24-, and 2.06-fold in co-dominant, dominant, and Log-additive models, respectively. The rs9349379 in PHACTR1 is associated with a 2.61-fold increased risk of plateau essential hypertension according to the dominant model. This study reveals that the alleles of AGT, HIF1A, and PHACTR1 are closely related to plateau essential hypertension risk in the plateau Tibetan population.

David Corredor-Orlandelli,1,* Santiago Sambracos-Parrado,1,* Santiago Mantilla-García,1 Josué Tovar-Tirado,1 Valentina Vega-Ramírez,1 Santiago David Mendoza-Ayús,1 Laura Catalina Peña,1 María Fernanda Leal,1 Juliana Rodríguez-Carrillo,1 Juanita León-Torres,1 Juan Mauricio Pardo-Oviedo,2 Katherine Parra Abaunza,3 Nora Contreras Contreras Bravo,1 Oscar Ortega-Recalde,1 Dora Janeth Fonseca Mendoza1 1Center for Research in Genetics and Genomics – CIGGUR, GENIUROS Research Group, School of Medicine and Health Sciences, Universidad Del Rosario, Bogotá, Colombia; 2School of Medicine and Health Sciences, Universidad del Rosario, Bogotá, Colombia; 3Hospital Universitario Mayor – Méderi, Universidad del Rosario, Bogotá, Colombia*These authors contributed equally to this workCorrespondence: Dora Janeth Fonseca MendozaCenter for Research in Genetics and Genomics (CIGGUR), GENIUROS Research Group, School of Medicine and Health Sciences, Universidad del Rosario, Cra 24 # 63C69, Bogotá, 112111, ColombiaTel/Fax +57 12920200Email dora.fonseca@urosario.edu.coBackground: Paraoxonase-1 (PON1), a glycoprotein associated with serum high-density lipoprotein (HDL), has a central role in metabolizing lipid peroxides, exhibiting antiatherogenic properties. The polymorphism p.Q192R has been previously associated with coronary artery disease (CAD) susceptibility and clopidogrel response.Purpose: We aimed at investigating the association of PON1 p.Q192R with CAD and clopidogrel response in Colombian population.Patients and Methods: The study was conducted among 163 patients diagnosed with CAD and treated with clopidogrel. The allele frequencies for the PON1 192Q and 192R alleles were determined in cases and Latin-American controls obtained from the public database gnomAD (n = 17,711). Response to clopidogrel was determined by assessing the platelet function using the INNOVANCE PFA-200 System. We determined the association between PON1 p.Q192R polymorphism, increased susceptibility to CAD and high on-treatment platelet reactivity (HPR) by using odds ratio (OR) and 95% confidence interval (CI) on four genetic models.Results: The allele frequencies for the PON1 192Q and 192R alleles were 0.60 and 0.40, respectively. The allele distribution was found to be statistically different from the control group and other ethnic groups. The allele 192R was positively associated with decreased susceptibility to CAD under a dominant model (OR, 0.58; 95% CI, 0.42– 0.8; P < 0.01). We found no association between the polymorphism and HPR.Conclusion: We propose that PON1 p.Q192R is a potentially useful marker for CAD susceptibility in the Colombian population and lacks association with HPR under clopidogrel treatment.Keywords: PON1, genetic risk, cardiovascular disease susceptibility, platelet reactivity, clopidogrel

Genes related to human longevity have not been studied so far, and need to be investigated thoroughly. This study aims to explore the relationship among ABO gene variants, lipid levels, and longevity phenotype in individuals (≥90yrs old) without adverse outcomes. A genotype-phenotype study was performed based on 5803 longevity subjects and 7026 younger controls from the Chinese Longitudinal Healthy Longevity Survey (CLHLS). Four ABO gene variants associated with healthy longevity (rs8176719 C, rs687621 G, rs643434 A, and rs505922 C) were identified and replicated in the CLHLS GWAS data analysis and found significantly higher in longevity individuals than controls. The Bonferroni adjusted p-value and OR range were 0.013-0.020 and 1.126-1.151, respectively. According to the results of linkage disequilibrium (LD) analysis, the above four variants formed a block on the ABO gene (D'=1, r2range = 0.585-0.995). The carriers with genotypes rs687621 GG, rs643434 AX, or rs505922 CX (prange = 2.728 x 10-107-5.940 x 10-14; ORrange = 1.004-4.354) and haplotype CGAC/XGXX (p = 2.557 x 10-27; OR = 2.255) had a substantial connection with longevity, according to the results of genetic model analysis. Following the genotype and metabolic phenotype analysis, it has been shown that the longevity individuals with rs687621 GG, rs643434 AX, and rs505922 CX had a positive association with HDL-c, LDL-c, TC, TG (prange = 2.200 x 10-5-0.036, ORrange = 1.546-1.709), and BMI normal level (prange = 2.690 x 10-4-0.026, ORrange = 1.530-1.997). Finally, two pathways involving vWF/ADAMTS13 and the inflammatory markers (sE-selectin/ICAM1) that co-regulated lipid levels by glycosylation and effects on each other were speculated. In conclusion, the association between the identified longevity-associated ABO variants and better health lipid profile was elucidated, thus the findings can help in maintaining normal lipid metabolic phenotypes in the longevity population.

Information on the genetic control of resistance to Fusarium oxysporum f.sp.cubense (FOC) race (1) and fruit quality traits in Sukali Ndizi cultivar of banana is key to its genetic improvement. The mode of resistance to Fusarium wilt in Sukali Ndizi was analyzed in 536 hybrids and 5 parental lines and quality attributes in 137 hybrids and two parental lines, grown in same environment. Fruit quality was assessed by physical measurements and fruit composition whereas resistance to Fusarium wilt was assessed by corm discoloration symptoms. All the assessed traits were quantitatively inherited. Flavor attributes, and pulp texture showed a predominance of additive inheritance with complementary gene action whereas total soluble solutes showed non-additive gene with dominant gene action. Fruit acidity had incomplete dominancy with the genetic model explained by both single gene and certain multiple genes. Resistance to Fusarium wilt showed dominant gene action and polygenic effects. Involvement of a few genes governing wilt resistance suggested the ease of breeding for this trait. Pedigree breeding method could be recommended for incorporating various traits in (cv. Sukali Ndizi) of banana. Key words: Sukali Ndizi, quantitative inheritance, fruit quality, Fusarium wilt resistance.

Peptide:N-glycanase is an evolutionarily conserved deglycosylating enzyme that catalyses the removal of N-linked glycans from cytosolic glycoproteins. Recessive mutations that inactivate this enzyme cause NGLY1 deficiency, a multisystemic disorder with symptoms including developmental delay and defects in cognition and motor control. Developing treatments for NGLY1 deficiency will require an understanding of how failure to deglycosylate NGLY1 substrates perturbs cellular and organismal function. In this review, I highlight insights into peptide:N-glycanase biology gained by studies in the highly tractable genetic model animal Caenorhabditis elegans. I focus on the recent discovery of SKN-1A/Nrf1, an N-glycosylated transcription factor, as a peptide:N-glycanase substrate critical for regulation of the proteasome. I describe the elaborate post-translational mechanism that culminates in activation of SKN-1A/Nrf1 via NGLY1-dependent ‘sequence editing’ and discuss the implications of these findings for our understanding of NGLY1 deficiency.

Gender-specific features of associations of functionally significant polymorphic loci of matrix metalloproteinase genes with the development of peptic ulcer disease (PUD) in the population of the European part of Russia were studied. The study included 305 men (patients with PUD—188, control group—117) and 441 women (patients with PUD—211, control group—230). Ten functionally significant polymorphic loci of matrix metalloproteinase genes were genotyped: rs1799750 MMP1, rs243865 MMP2, rs679620 MMP3, rs1940475 MMP8, rs3918242, rs3918249, rs17576, rs3787268, rs2250889, rs17577 of the MMP9 gene. Associations of polymorphic loci of MMP genes with PUD were studied by logistic regression (dominant, recessive, and additive genetic models of allele interaction were evaluated). It was found that alleles C rs3918249 (OR = 1.61, pperm = 0.048) and G rs17576 (OR = 1.48–2.08, pperm ≤ 0.042) of the MMP9 gene were risk factors for the occurrence of PUD in men. In women, the 2G rs1799750 allele of the MMP1 gene had a protective value for the development of the disease (OR = 0.74, pperm = 0.047). Polymorphic loci associated with PUD in men and women exhibit pronounced epigenetic effects (they affect the affinity of DNA motifs for various transcription factors, are located in the region of promoters and enhancers in the stomach and duodenum, and are associated with gene expression in various parts of the digestive system). Gender-specific features of associations of polymorphism of MMP genes with the development of PUD were revealed: rs3918249 and rs17576 of the MMP9 gene determine the susceptibility to the development of PUD in men, and rs1799750 of the MMP1 gene determines the susceptibility in women.

For over a century, researchers have used mice as models and adapted many new methods to create novel mutations in them. In the past 100+ years, we have gone from breeding strains for selected traits to inducing random mutations throughout the genome to creating designer alleles with multiple functions. Each method offers opportunities and challenges for researchers as they try to address specific research questions with mouse models.

Background. Ischemic stroke (IS) is the most common form of cerebrovascular accident which its precise etiology remains mysterious. Renalase is a catecholamine-degrading enzyme playing a major role in blood pressure control. Recent studies show the effect of renalase activity on various diseases like IS. In the current study, we examined the possible effects of renalase gene (RNLS) rs2576178 and rs10887800 variants at the 5 ′ -flanking and intron 6 regions on IS, respectively. Methods. One hundred and fifty-four IS patients younger than 50 years and 165 age- and sex-matched controls were recruited in the study. For genotyping of rs2576178 and rs10887800 variants, the PCR-RFLP method was used. Results. The RNLS rs10887800 AG genotype was more repeated in IS patients, but the difference was marginally nonsignificant ( P = 0.054 ). This variant was associated with IS in the overdominant model, and the AG genotype is associated with a1.6-fold increased risk of IS compared to AA+ GG genotypes ( OR = 1.6 , 95% CI: 1-2.5, P = 0.033 ). No relationship was observed between RNLS rs2576178 polymorphism and IS in all genetic models. The findings of the haplotype and combination effects of rs10887800 and rs2576178 variants on IS showed no significant association. The in silico analysis showed no effect of rs2576178 and rs10887800 polymorphisms in the RNA structure, but the alteration of RNA sequence in rs2576178 results in the lack of a MBNL1 protein binding site. Conclusions. RNLS rs10887800 but not rs2576178 polymorphism was associated with IS susceptibility in the overdominant model (AG vs AA+ GG genotypes).

Migraine is a neurological disorder which impairs the patient’s quality of life. Several association studies investigating the association between MTHFR gene C677T and A1298C polymorphisms and susceptibility to migraine were published. But the results were conflicting, so authors performed a meta-analysis of published case control studies to find out the exact association between MTHFR polymorphism and migraine susceptibility. Four databases were searched for suitable studies up to December, 2018. Odds ratios (OR) with 95% confidence intervals (CI) was calculated adopting additive, homozygote, co-dominant, dominant, and recessive genetic models. Results of MTHFR C677T polymorphism studies meta-analysis showed significant association with migraine risk using allele contrast, homozygote, dominant and recessive genetic models (T vs. C: OR = 1.18, 95% CI = 1.00–1.26, p = 0.05; TT vs. CC: OR = 1.24, 95% CI = 1.0–1.5, p = 0.04; CT vs. CC: OR = 1.08, 95% CI = 0.97–1.07, p = 0.25; TT + CT vs. CC: OR = 1.15, 95% CI = 1.0–1.29, p = 0.04; TT vs. CT + CC: OR = 1.97, 95% CI = 1.28–3.42, p = 0.002). However, results of MTHFR A1298 polymorphism studies meta-analysis did not show any association with migraine. Subgroup analysis based on ethnicity and migraine types i.e. migraine with aura (MA) and without aura (MO) were also performed. Results of present meta-analysis indicate overall association between MTHFR C677T polymorphism with migraine in total 24 studies, in Asian population and in MA cases but did not show any association with Caucasian population and MO cases.

Understanding dynamic changes in the genetic architecture of quantitative traits is crucial in developmental genetics. Functional mapping is an appropriate method that passes a mathematical equation to describe a biological developmental process with the genetic mapping framework. Appropriate genetic model and applicable mapping population are indispensable condition for functional mapping of important agronomic traits in plants. Based on the Wang-Lan-Ding model, we ever applied a DH population to carry out functional mapping QTLs underlying growth trajectory on tiller number. However, inconsistent genetic background among the DH lines might disturb the mapping results. With the advent of innovative research materials, single segment substitution lines, allows us to do more precise genetic analyses. Thus functional mapping was again conducted on tiller number using the Wang-Lan-Ding model and a single segment substitution line population with the genetic background of Huajingxian 74 so as to explore QTL dynamic mechanism to regulate developmental traits. We detected that all five single segment substitution lines harbored tillering QTLs with additives and/or dominances to influence the four functional parameters, the optimum tillering time (t0), the maximum tiller number (K), the tillering increased rate (r) and the tillering decreased rate (c), which were estimated from the Wang-Lan-Ding model and with some biological meaning. They mainly brought the inflexion point (t0) delay, the peak increase (K) and the degradation (c) acceleration, while the growth (r) slow down. Moreover, epistatic interactions among these QTLs were confirmed to be prevalent. A total of 39 significant epistatic effects were detected to associate with the four parameters, occupying 34.8% of 112 pairs of epistatic interactions investigated. Contrary to the QTL effects, these epistatic effects largely decreased t0, K and c, while increased r. Our results indicated that the five QTL effects and their epistatic effects significantly changed the shape and trajectory of tiller number via influence of the four functional parameters. Rational use of these QTLs is expected to improve tillering number of rice by molecular design breeding.

Alzheimer’s disease(AD) is an age-associated neurodegenerative disease that results in deterioration of memory and cognitive function. As a currently untreatable disorder, AD has emerged as one of the defining biomedical challenges of our time. Thus, new approaches that can examine the cellular and molecular mechanisms underlying age-related AD pathology are sorely needed. One of the hallmarks of Alzheimer’s disease is the hyperphosphorylation of the tau protein. Caenorhabditis elegans have been previously used to study the genetic pathways impacted by tau proteotoxic stress; however, currently, available C. elegans tau models express the human protein solely in neurons, which are unresponsive to global RNA interference (RNAi). This limits powerful RNAi screening methods from being utilized effectively in these disease models. Our goal was to develop a C. elegans tau model that has pronounced tau-induced disease phenotypes in cells that can be modified by feeding RNAi methods. Towards this end, we generated a novel C. elegans transgenic line with codon-optimized human 0N4R V337M tau expressed in the body wall muscle under the myo-3 promoter. Immunoblotting experiments revealed that the expressed tau is phosphorylated on epitopes canonically associated with human AD pathology. The tau line has significantly reduced health metrics, including egg laying, growth rate, paralysis, thrashing frequency, crawling speed, and lifespan. These defects are suppressed by RNAi directed against the tau mRNA. Taken together, our results suggest that this alternative tau genetic model could be a useful tool for uncovering the mechanisms that influence the hyperphosphorylation and toxicity of human tau via RNAi screening and other approaches. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11357-021-00436-9.

Single nucleotide polymorphisms within genes encoding microRNAs may alter the expression of microRNAs and their target genes, contributing to the etiology of psychiatric disorders. We aimed to investigate the link between rs4705342T/C and rs4705343T/C polymorphisms in the promoter region of miR-143 and the risk of schizophrenia (SCZ) in a sample of an Iranian population. In this experimental study, a total of 398 subjects were recruited. Genotyping carried out using allele‐specific PCR (AS‐PCR) method. Different bioinformatics databases and Cytoscape V3.4.0 software were used for the analysis of the gene-miRNA interaction network. The genotypic analysis of rs4705342C/T showed that CC genotype in the co-dominant model significantly decreased the risk of SCZ (p

The pathogenesis of Parkinson's disease (PD) remains elusive, but mitochondrial dysfunction is believed to be one crucial step in its pathogenesis. The mitochondrial unfolded protein response (UPRmt) is an important mitochondrial quality control strategy that maintains mitochondrial function in response to disturbances of mitochondrial protein homeostasis. Activation of the UPRmt and the beneficial effect of rescuing mitochondrial proteostasis have been reported in several genetic models of PD. However, the pathogenic relevance of the UPRmt in idiopathic PD is unknown. The present study examined the link between the UPRmt and mitochondrial dysfunction in 1-methyl-4-phenylpyridinium (MPP+)-treated SH-SY5Y cells. Treatment with MPP + induced activation of the UPRmt, reflected by an increase in the expression of UPRmt-related chaperones, proteases, and transcription mediators. UPRmt activation that was induced by overexpressing mutant ornithine transcarbamylase significantly reduced the production of mitochondrial reactive oxygen species (ROS) and improved cell survival in SH-SY5Y cells following MPP+ treatment. Moreover, the overexpression of activating transcription factor 5 (mammalian UPRmt transcription factor) conferred protection against MPP+-induced ROS production and against cell death in SH-SY5Y cells. Overall, our results demonstrate the beneficial effect of UPRmt activation in MPP + -treated cells, shedding new light on the mechanism of mitochondrial dysfunction in the pathogenesis of PD.

A critical cell type participating in cardiac outflow tract development is a subpopulation of the neural crest cells, the cardiac neural crest cells (NCCs), whose defect causes a spectrum of cardiovascular abnormalities. Accumulating evidence indicates that mTOR, which belongs to the PI3K-related kinase family and impacts multiple signaling pathways in a variety of contexts, plays a pivotal role for NCC development. Here, we investigated functional roles of mTOR for cardiac neural crest development using several lines of mouse genetic models. We found that disruption of mTOR caused NCC defects and failure of cardiac outflow tract separation, which resulted in a spectrum of cardiac defects including persistent truncus arteriosus, ventricular septal defect and ventricular wall defect. Specifically, mutant neural crest cells showed reduced migration into the cardiac OFT and prematurely exited the cell cycle. A number of critical factors and fundamental signaling pathways, which are important for neural crest and cardiomyocyte development, were impaired. Moreover, actin dynamics was disrupted by mTOR deletion. Finally, by phenotyping the neural crest Rptor and Rictor knockout mice respectively, we demonstrate that mTOR acts principally through the mTORC1 pathway for cardiac neural crest cells. Altogether, these data established essential roles of mTOR for cardiac NCC development and imply that dysregulation of mTOR in NCCs may underline a spectrum of cardiac defects.

Although parasite-mediated selection is thought to be a major driver of host evolution, its influence on genetic variation for parasite resistance is not yet well understood. We monitored a large population of the planktonic crustacean Daphnia magna over eight years, as it underwent yearly epidemics of the bacterial pathogen Pasteuria ramosa. We observed a cyclical pattern of resistance evolution: resistant phenotypes increased in frequency throughout the epidemics, but susceptibility was restored each spring when hosts hatched from sexual resting stages, a phenomenon described as genetic slippage in response to sex. Collecting and hatching D. magna resting stages across multiple seasons showed that largely resistant host populations can produce susceptible offspring through recombination. Resting stages produced throughout the planktonic season accurately represent the hatching population cohort of the following spring. A genetic model of resistance developed for this host–parasite system, based on multiple loci and strong epistasis, is in partial agreement with these findings. Our results reveal that, despite strong selection for resistance in a natural host population, genetic slippage after sexual reproduction has the potential to maintain genetic diversity of host resistance.

The International Maize and Wheat Improvement Center develops and annually distributes elite wheat lines to public and private breeders worldwide. Trials have been created in multiple sites over many years to assess the lines' performance for use in breeding and release as varieties, and to provide iterative feedback on refining breeding strategies1. The collaborator test sites are experiencing climate change, with new implications for how wheat genotypes are bred and selected2. Using a standard quantitative genetic model to analyse four International Maize and Wheat Improvement Center global spring wheat trial datasets, we examine how genotype-environment interactions have changed over recent decades. Notably, crossover interactions-a critical indicator of changes in the ranking of cultivar performance in different environments-have increased over time. Climatic factors explained over 70% of the year-to-year variability in crossover interactions for yield. Yield responses of all lines in trial environments from 1980 to 2018 revealed that climate change has increased the ranking change in breeding targeted to favourable environments by ~15%, while it has maintained or reduced the ranking change in breeding targeted to heat and drought stress by up to 13%. Genetic improvement has generally increased crossover interactions, particularly for wheat targeted to high-yielding environments. However, the latest wheat germplasm developed under heat stress was better adapted and more stable, partly offsetting the increase in ranking changes under the warmer climate.

Glioma is a common and fatal primary malignant tumor of the central nervous system, and its prognosis is poor. To determine the susceptibility markers of gliomas in Chinese population we conducted a genome-wide association study (GWAS) of glioma in the Han Chinese population, with a total of 485 glioma cases and 485 controls. Genotyping was conducted using the Applied Biosystems Axiom Precision Medicine Diversity Array. Besides, we carried out imputation using IMPUTE 2.0 software, and the 1000 Genomes Phase 3 was used as the reference panel. The logistic regression model was used to analyze the association of each SNP with glioma risk, assuming an additive genetic model, which was implemented in PLINK version 1.9. Odds ratio (OR) and 95% confidence interval (CI) were estimated from logistic regression analysis with adjustment for age and gender. The results revealed that the SNP (rs688755) in the exon region of CYP4F12 at 19p13.12 reached genome-wide significance associated with gliomas (P = 2.35 × 10-8 , OR = 3.55, 95% CI = 2.20-5.74). Our findings provide deeper insight into the genetic contribution to glioma in different populations.

Background The essential nutrient choline provides one-carbon units for metabolite synthesis and epigenetic regulation in tissues including brain. Dietary choline intake is often inadequate, and higher intakes are associated with improved cognitive function. Objective Choline supplements confer cognitive improvement for those diagnosed with fetal alcohol spectrum disorder (FASD), a common set of neurodevelopmental impairments; however, the effect sizes have been modest. In this retrospective analysis, we report that genetic polymorphisms affecting choline utilization are associated with cognitive improvement following choline intervention. Methods Fifty-two children from the upper midwestern United States and diagnosed with FASD, ages 2-5 y, were randomly assigned to receive choline (500 mg/d; n = 26) or placebo (n = 26) for 9 mo, and were genotyped for 384 choline-related single nucleotide polymorphisms (SNPs). Memory and cognition were assessed at enrollment, study terminus, and at 4-y follow-up for a subset. Results When stratified by intervention (choline vs. placebo), 14-16 SNPs within the cellular choline transporter gene solute carrier family 44 member 1 (SLC44A1) were significantly associated with performance in an elicited imitation sequential memory task, wherein the effect alleles were associated with the greatest pre-/postintervention improvement. Of these, rs3199966 is a structural variant (S644A) and rs2771040 is a single-nucleotide variant within the 3' untranslated region of the plasma membrane isoform. An additive genetic model best explained the genotype associations. Lesser associations were observed for cognitive outcome and polymorphisms in flavin monooxygenase-3 (FMO3), methylenetetrahydrofolate dehydrogenase-1 (MTHFD1), fatty acid desaturase-2 (FADS2), and adiponectin receptor 1 (ADIPOR1). Conclusions These SLC44A1 variants were previously associated with greater vulnerability to choline deficiency. Our data potentially support the use of choline supplements to improve cognitive function in individuals diagnosed with FASD who carry these effect alleles. Although these findings require replication in both retrospective and prospective confirmatory trials, they emphasize the need to incorporate similar genetic analyses of choline-related polymorphisms in other FASD-choline trials, and to test for similar associations within the general FASD population. This trial was registered at www.clinicaltrials.gov as NCT01149538.

Lipoprotein lipase (LPL) is an enzyme involved in lipid metabolism and distribution of fatty acids hence its role in the initiation and development of dyslipidemia and adiposity. Single nucleotide polymorphisms (SNPs) across the LPL gene have been associated with dyslipidemia, however, the association with obesity has been limited towards specific populations. This study examined the association between LPL gene polymorphisms with plasma lipid levels and body mass index (BMI) in the Kuwaiti population. We examined a total of 486 adults (303 and 183 females and males respectively) with plasma lipid levels and BMI. DNA samples were genotyped for two LPL gene polymorphisms (rs1534649 and rs28645722) using TaqMan allelic discrimination. The relationship between the genotypes with both plasma lipid levels and BMI were assessed using linear regression using “SNPassoc” package from R statistical software. Using an additive genetic model, linear regression analysis showed the T-allele of rs1534649 to be associated with increased BMI in a dose-dependent trend β = 2.13 (95% CI 1.33–2.94); p = 1.7 × 10−7. In addition, a borderline significance was observed between the T-allele and low levels of high density lipoprotein-cholesterol β = −0.04 (95% CI −0.08, −0.006); p = 0.02. There were no associations between rs28645722 and plasma lipid levels (p > 0.05). However, a trend was observed between the A-allele and increased BMI β = 1.75 (95% CI 0.14–3.35); p = 0.03. Our study shows intron one polymorphism rs1534649 to increase the risk of obesity and dyslipidemia. Our findings warrant further investigation of the mechanism of LPL on the development of obesity along with the role of intron one and its impact on LPL gene activity.

Female fertility in mammals requires iterative remodeling of the entire adult female reproductive tract across the menstrual/estrous cycle. However, while transcriptome dynamics across the estrous cycle have been reported in human and bovine models, no global analysis of gene expression across the estrous cycle has yet been reported for the mouse. Here, we examined the cellular composition and global transcriptional dynamics of the mouse oviduct along the anteroposterior axis and across the estrous cycle. We observed robust patterns of differential gene expression along the anteroposterior axis, but we found surprisingly few changes in gene expression across the estrous cycle. Notable gene expression differences along the anteroposterior axis included a surprising enrichment for genes related to embryonic development, such as Hox and Wnt genes. The relatively stable transcriptional dynamics across the estrous cycle differ markedly from other mammals, leading us to speculate that this is an evolutionarily derived state that may reflect the extremely rapid five-day mouse estrous cycle. This dataset fills a critical gap by providing an important genomic resource for a highly tractable genetic model of mammalian female reproduction.

Background Recent studies identifying methylenetetrahydrofolate reductase (MTHFR) polymorphisms associated with breast cancer (BC), ovarian cancer (OC), cervical cancer, and endometrial cancer (EC) have reported conflicting results and been underpowered. To clarify the correlation between MTHFR mutations and these common female malignancies, we conducted a comprehensive meta-analysis incorporating all eligible publications. Methods Relevant reports published before January 20, 2020, were retrieved from PubMed, Embase, the Cochrane Library, and the China National Knowledge Infrastructure databases. The odds ratio and 95% confidence interval summaries for the MTHFR 677C/T and 1298A/C polymorphisms in BC, OC, cervical cancer, and EC were estimated. Results A total of 171 studies comprising 56,675 cancer cases and 67,559 controls were included. The results showed a markedly elevated risk of cancer susceptibility related to MTHFR 677C/T based on all genetic models. Similarly, we identified a significant correlation between 1298A/C mutation and cancer risk based on overall comparisons among all models, except the heterozygous model. Moreover, subgroup analysis by cancer type revealed a significantly increased risk of BC associated with 677C/T in the five models and of cervical cancer associated with 1298A/C in some models. Based on ethnicity, significant associations were observed between Asian, African, and mixed populations for 677C/T and the Asian population for 1298A/C. With regard to the sample type used for analysis, we detected a positive association between using blood as the DNA source and cancer risk for 677C/T in all genetic models and for 1298A/C in some genetic models. Further stratification of the results revealed that a notably increased risk was associated with the use of polymerase chain reaction-restriction fragment-length polymorphism or TaqMan as the genotyping method, as well as with the use of population-or hospital-based groups as the controls for 677C/T and 1298A/C, respectively. Conclusion This meta-analysis suggests that MTHFR 677C/T and 1298A/C polymorphisms correlate with the risk of common gynecological cancers, with these findings potentially applicable for overall comparisons of related data.

CRISPR-Cas9 technologies have dramatically increased the ease of targeting DNA sequences in the genomes of living systems. The fusion of chromatin-modifying domains to nuclease-deactivated Cas9 (dCas9) has enabled targeted epigenome editing in both cultured cells and animal models. However, delivering large dCas9 fusion proteins to target cells and tissues is an obstacle to the widespread adoption of these tools for in vivo studies. Here, we describe the generation and characterization of two conditional transgenic mouse lines for epigenome editing, Rosa26:LSL-dCas9-p300 for gene activation and Rosa26:LSL-dCas9-KRAB for gene repression. By targeting the guide RNAs to transcriptional start sites or distal enhancer elements, we demonstrate regulation of target genes and corresponding changes to epigenetic states and downstream phenotypes in the brain and liver in vivo, and in T cells and fibroblasts ex vivo. These mouse lines are convenient and valuable tools for facile, temporally controlled, and tissue-restricted epigenome editing and manipulation of gene expression in vivo. Two conditional transgenic mouse lines based on CRISPRa and CRISPRi enable epigenome editing in vivo.

Coronary heart disease (CHD) is a disease that seriously harms human health. Genetic factors seriously affect the CHD susceptibility. The CYP20A1, CYP4F2 and CYP2D6 are important drug metabolism enzymes in the human body. We aimed to explore the association between CYP20A1, CYP4F2, CYP2D6 single nucleotide polymorphisms (SNPs) and CHD risk in the Chinese Southern Han population. Based on the ‘case–control’ experimental design (505 cases and 508 controls), we conducted an association study between 5 candidate SNPs selected from CYP20A1 (rs2043449), CYP4F2 (rs2108622, rs3093106, rs309310), CYP2D6 (rs1065852) and CHD risk. Logistic regression was used to analyze the CHD susceptibility under different genetic models. Multi-factor dimensionality reduction (MDR) was used to analyze the interaction of ‘SNP-SNP’ in CHD risk. Our results showed that under multiple genetic models, CYP2D6 rs1065852 significantly increased the CHD risk in these participants who are ≤ 60 years old (OR 1.40, CI 1.07–1.82, p = 0.013), smokers (OR 1.40, CI 1.02–1.93, p = 0.039), or have family history (OR 1.24, CI 1.02–1.51, p = 0.035). CYP4F2 SNPs rs2108622 (OR 0.63, CI 0.43–0.93, p = 0.020), rs3093106 (OR 0.52, CI 0.29–0.92, p = 0.023), and rs309310 (OR 0.55, CI 0.31–0.96, p = 0.033) were potentially associated with the course of CHD patients. Our study found that CY2D6 rs1065852 has an outstanding and significant association with increased CHD risk. Our study provided data supplements for CHD genetic susceptibility loci, and also provided a new and valuable reference for CHD drug treatment.

Identification of host genetic factors influencing the risk of developing hepatocellular carcinoma (HCC) in patients with chronic hepatitis C virus (HCV) infection may help to refine patients’ selection to benefit from specific preventative measures and/or adapted screening policies. Thus, this study aimed to investigate the association of MTHFR c.677C > T and c.1298A > C in addition to TYMS 3′-UTR 6-bp ins/del polymorphisms with the susceptibility to HCV-related HCC in an Egyptian population. Polymerase chain reaction–restriction fragment length polymorphism was performed to genotype the polymorphisms in 194 HCV-infected patients subdivided into liver cirrhotic (LC, n = 104) and HCC (n = 90) patients as well as 100 healthy subjects. In healthy controls, the MTHFR c.677C > T polymorphism under the homozygous and recessive models (p = 0.005) and the c.1298A > C polymorphism under all the tested genetic models (p-values range from T polymorphism under the homozygous, dominant, and recessive models (p-values range from 0.001 to 0.007), as well as MTHFR c.1298A > C under the homozygous model only (p = 0.014), increased the susceptibility to HCC. The C/C and T/C haplotypes of MTHFR c.677C > T and MTHFR c.1298A > C polymorphisms were contributed to an increased risk of healthy subjects to develop HCC (p-values range from T and c.1298A > C in addition to their haplotypes may contribute to the development of HCV-related HCC in an Egyptian population. These findings may aid in the early diagnosis and management of HCC.

BackgroundThe TNF, LTA, and TNFRSF1B genes have been implicated in various traits related to menarche and menopause.AimTo analyse the TNF, LTA, and TNFRSF1B genes for their association with ages at menarche (AM) and natural menopause (ANM).Subjects and methodsThe study sample consisted of 314 unrelated females of European ancestry. Twenty SNPs located in and near the genes were analysed using various statistical methods. In addition, the functional significance of the loci associated with AM and ANM was analysed in silico.ResultsLocus rs2229094 of the LTA gene was associated with AM according to the additive (β = -0.295, Pperm = 0.016) and recessive (β = -0.940, Pperm = 0.016) genetic models. Haplotype GG rs1148459-rs590368 of the TNFRSF1B gene was associated with AM (β = 0.307, Pperm = 0.023). Haplotype GCA rs2844484-rs2229094-rs1799964 was associated with ANM after adjustment for covariates (β = -1.020, Pperm = 0.035). All studied loci were associated with ANM after adjustment for breastfeeding (raw P < 0.05). In addition, eight most significant models of interlocus interactions were associated with AM and five with ANM.ConclusionThe results of the present study suggest that the TNF, LTA, and TNFRSF1B genes are associated with AM and ANM.

Intact Disc1-L100P mice carrying a point mutation DISC1Rgsc1390 in the second exon of the DISC1 gene (genetic model of schizophrenia) differ from the parental C57BL/6NCrl strain by higher content of CD3+ T cells and reduced number of CD19+B cells in the peripheral blood and spleen. Analysis of T cell subpopulations revealed an increase in the number of CD3+CD4+ T helpers in the blood of mutant mice and a decrease in the level of CD3+CD8+ suppressor/cytotoxic T cells and CD3+CD4+CD25+ T-regulatory cells. The distribution pattern of inflammatory (IL-1β, IL-2, IL-6, IL-17, IFNγ, and TNFα) and anti-inflammatory (IL-4, IL-10) cytokines specific for Disc1-L100P mice was revealed in the brain structures involved in the pathogenesis of schizophrenia. A possible implication of immune mechanisms in the development of schizophrenia-like endophenotype of Disc1-L100P mice is discussed.

The estrogen-related receptor (ERR) family of orphan nuclear receptors are transcriptional activators for genes involved in mitochondrial bioenergetics and metabolism. The goal of this study was to explore the role of ERRα in lipid metabolism and the potential effect of inhibiting ERRα on the development of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). In the current study, three experimental mouse models: high-fat diet, high-carbohydrate diet, and a genetic model of hepatic insulin resistance where the liver hyperinsulinemia signal is mimicked via hepatic deletion of Pten (phosphatase and tensin homolog deleted on chromosome 10), the negative regulator of the insulin/phosphatidylinositol 3-kinase signaling pathway, were used. A recently developed small-molecule inhibitor for ERRα was used to demonstrate that inhibiting ERRα blocked NAFLD development induced by either high-carbohydrate diet or high-fat diet feeding. ERRα inhibition also diminished lipid accumulation and attenuated NASH development in the Pten null mice. Glycerolipid synthesis was discovered as an additional mechanism for ERRα-regulated NAFLD/NASH development and glycerophosphate acyltransferase 4 was identified as a novel transcriptional target of ERRα. In summary, these results establish ERRα as a major transcriptional regulator of lipid biosynthesis in addition to its characterized primary function as a regulator for mitochondrial function. This study recognizes ERRα as a potential target for NAFLD/NASH treatment and elucidates novel signaling pathways regulated by ERRα.

OBJECTIVE: Letrozole is a non-steroidal aromatase inhibitor (AI) used to treat hormone receptor positive (HR+) breast cancer. Variability in letrozole efficacy and toxicity may be partially attributable to variable systemic drug exposure, which may be influenced by germline variants in the enzymes responsible for letrozole metabolism including Cytochrome P450 2A6 (CYP2A6). The objective of this genome-wide association study (GWAS) was to identify polymorphisms associated with steady state letrozole concentrations. METHODS: The Exemestane and Letrozole Pharmacogenetics (ELPh) Study randomized post-menopausal patients with HR+ non-metastatic breast cancer to letrozole or exemestane treatment. Germline DNA was collected pre-treatment and blood samples were collected after 1 or 3 months of treatment to measure steady-state letrozole (and exemestane) plasma concentrations via HPLC/MS. Genome-wide genotyping was conducted on the Infinium Global Screening Array (>650,000 variants) followed by imputation. The association of each germline variant with age- and body mass index-adjusted letrozole concentrations was tested in self-reported white patients via linear regression assuming an additive genetic model. RESULTS: There were 228 patients who met the study specific inclusion criteria and had both DNA and letrozole concentration data for this GWAS. The association for one genotyped polymorphism (rs7937) with letrozole concentration surpassed genome-wide significance (p=5.26x10(−10)), explaining 13% of the variability in untransformed steady-state letrozole concentrations. Imputation around rs7937 and in silico analyses identified rs56113850, a variant in the CYP2A6 intron that may affect CYP2A6 expression and activity. rs7937 was associated with age- and body mass index-adjusted letrozole levels even after adjusting for genotype-predicted CYP2A6 metabolic phenotype (p=3.86x10(−10)). CONCLUSIONS: Our GWAS findings confirm that steady-state letrozole plasma concentrations are partially determined by germline polymorphisms that affect CYP2A6 activity, including variants near rs7937 such as the intronic rs56113850 variant. Further research is needed to confirm whether rs56113850 directly affects CYP2A6 activity and to integrate non-exonic variants into CYP2A6 phenotypic activity prediction systems.

Cells metabolize nutrients for biosynthetic and bioenergetic needs to fuel growth and proliferation. The uptake of nutrients from the environment and their intracellular metabolism is a highly controlled process that involves cross talk between growth signaling and metabolic pathways. Despite constant fluctuations in nutrient availability and environmental signals, normal cells restore metabolic homeostasis to maintain cellular functions and prevent disease. A central signaling molecule that integrates growth with metabolism is the mechanistic target of rapamycin (mTOR). mTOR is a protein kinase that responds to levels of nutrients and growth signals. mTOR forms two protein complexes, mTORC1, which is sensitive to rapamycin, and mTORC2, which is not directly inhibited by this drug. Rapamycin has facilitated the discovery of the various functions of mTORC1 in metabolism. Genetic models that disrupt either mTORC1 or mTORC2 have expanded our knowledge of their cellular, tissue, as well as systemic functions in metabolism. Nevertheless, our knowledge of the regulation and functions of mTORC2, particularly in metabolism, has lagged behind. Since mTOR is an important target for cancer, aging, and other metabolism-related pathologies, understanding the distinct and overlapping regulation and functions of the two mTOR complexes is vital for the development of more effective therapeutic strategies. This review discusses the key discoveries and recent findings on the regulation and metabolic functions of the mTOR complexes. We highlight findings from cancer models but also discuss other examples of the mTOR-mediated metabolic reprogramming occurring in stem and immune cells, type 2 diabetes/obesity, neurodegenerative disorders, and aging.

Cerebral cavernous malformations are acquired vascular anomalies that constitute a common cause of central nervous system hemorrhage and stroke. The past 2 decades have seen a remarkable increase in our understanding of the pathogenesis of this vascular disease. This new knowledge spans genetic causes of sporadic and familial forms of the disease, molecular signaling changes in vascular endothelial cells that underlie the disease, unexpectedly strong environmental effects on disease pathogenesis, and drivers of disease end points such as hemorrhage. These novel insights are the integrated product of human clinical studies, human genetic studies, studies in mouse and zebrafish genetic models, and basic molecular and cellular studies. This review addresses the genetic and molecular underpinnings of cerebral cavernous malformation disease, the mechanisms that lead to lesion hemorrhage, and emerging biomarkers and therapies for clinical treatment of cerebral cavernous malformation disease. It may also serve as an example for how focused basic and clinical investigation and emerging technologies can rapidly unravel a complex disease mechanism.

Spontaneous mutations can alter tissue dynamics and lead to cancer initiation. While large-scale sequencing projects have illustrated processes that influence somatic mutation and subsequent tumour evolution, the mutational dynamics operating in the very early stages of cancer development are currently not well understood. In order to explore mutational dynamics in the early stages of cancer evolution we exploited neoplasia arising spontaneously in the Drosophila intestine. We analysed whole-genome sequencing data through the development of a dedicated bioinformatic pipeline to detect structural variants, single nucleotide variants, and indels. We found neoplasia formation to be driven largely through the inactivation of Notch by structural variants, many of which involve highly complex genomic rearrangements. Strikingly, the genome-wide mutational burden of neoplasia - at six weeks of age - was found to be similar to that of several human cancers. Finally, we identified genomic features associated with spontaneous mutation and defined the evolutionary dynamics and mutational landscape operating within intestinal neoplasia over the short lifespan of the adult fly. Our findings provide unique insight into mutational dynamics operating over a short time scale in the genetic model system, Drosophila melanogaster.

Enteroendocrine cells (EECs) in both invertebrates and vertebrates derive from intestinal stem cells (ISCs) and are scattered along the digestive tract, where they function in sensing various environmental stimuli and subsequently secrete neurotransmitters or neuropeptides to regulate diverse biological and physiological processes. To fulfill these functions, EECs are specified into multiple subtypes that occupy specific gut regions. With advances in single-cell technology, organoid culture experimental systems, and CRISPR/Cas9 mediated genomic editing, rapid progress has been made towards characterization of EEC subtypes in mammals. Additionally, studies of genetic model organisms-especially Drosophila melanogaster-have also provided insights about the molecular processes underlying EEC specification from ISCs and about the establishment of diverse EEC subtypes. In this review we compare the regulation of EEC specification and function in mammals and Drosophila, with a focus on EEC subtype characterization, on how internal and external regulators mediate EEC subtype specification, and on how EEC-mediated intra- and inter-organ communications affect gastrointestinal physiology and pathology.

Background and aims Animal models of human disease are a key component of translational hepatology research, yet there is no consensus on which model is optimal for NAFLD. Approach and results We generated a database of 3,920 rodent models of NAFLD. Study designs were highly heterogeneous, and therefore, few models had been cited more than once. Analysis of genetic models supported the current evidence for the role of adipose dysfunction and suggested a role for innate immunity in the progression of NAFLD. We identified that high-fat, high-fructose diets most closely recapitulate the human phenotype of NAFLD. There was substantial variability in the nomenclature of animal models: a consensus on terminology of specialist diets is needed. More broadly, this analysis demonstrates the variability in preclinical study design, which has wider implications for the reproducibility of in vivo experiments both in the field of hepatology and beyond. Conclusions This systematic analysis provides a framework for phenotypic assessment of NAFLD models and highlights the need for increased standardization and replication.

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory lung disease affecting primarily distal respiratory pathways and lung parenchyma. This study aimed to determine possible genetic association of chemokine and chemokine receptor genes polymorphisms with COPD in a Tatar population from Russia. SNPs of CCL20, CCR6, CXCL8, CXCR1, CXCR2, CCL8, CCL23, CCR2, and CX3CL1 genes and their gene–gene interactions were analyzed for association with COPD in cohort of 601 patients and 617 controls. As a result statistically significant associations with COPD in the study group under the biologically plausible assumption of additive genetic model were identified in CCL20 (rs6749704) (P = 0.00001, OR 1.55), CCR6 (rs3093024) (P = 0.0003, OR 0.74), CCL8 (rs3138035) (P = 0.0001, OR 0.67), CX3CL1 (rs170364) (P = 0.023, OR 1.21), CXCL8 (rs4073) (P = 0.007, OR 1.23), CXCR2 (rs2230054) (P = 0.0002, OR 1.32). Following SNPs CCL20 (rs6749704), CX3CL1 (rs170364), CCL8 (rs3138035), CXCL8 (rs4073), CXCR2 (rs2230054) showed statistically significant association with COPD only in smokers. The association of CCR6 (rs3093024) with COPD was confirmed both in smokers and in non-smokers. A relationship between smoking index and CCL20 (rs6749704) (P = 0.04), CCR6 (rs3093024) (P = 0.007), CCL8 (rs3138035) (P = 0.0043), and CX3CL1 (rs170364) (P = 0.04) was revealed. A significant genotype-dependent variation of Forced Vital Capacity was observed for CCL23 (rs854655) (P = 0.04). Forced Expiratory Volume in 1 s / Forced Vital Capacity ratio was affected by CCL23 (rs854655) (P = 0.05) and CXCR2 (rs1126579) (P = 0.02). Using the APSampler algorithm, we obtained nine gene–gene combinations that remained significantly associated with COPD; loci CCR2 (rs1799864) and CCL8 (rs3138035) were involved in the largest number of the combinations. Our results indicate that CCL20 (rs6749704), CCR6 (rs3093024), CCR2 (rs1799864), CCL8 (rs3138035), CXCL8 (rs4073), CXCR1 (rs2234671), CXCR2 (rs2230054), and CX3CL1 (rs170364) polymorphisms are strongly associated with COPD in Tatar population from Russia, alone and in combinations. For the first time combination of the corresponding SNPs were considered and as a result 8 SNP patterns were associated with increased risk of COPD

ATG16L1 is a ubiquitous autophagy gene responsible, in part, for formation of the double-membrane bound autophagosome that delivers unwanted cellular debris and intracellular pathogens to the lysosome for degradation. A single, nonsynonymous adenine to guanine polymorphism resulting in a threonine to alanine amino acid substitution (T300A) directly preceded by a caspase cleavage site (DxxD) causes an increased susceptibility to Crohn’s disease (CD) in humans. The mechanism behind this increased susceptibility is still being elucidated, however, the amino acid change caused by this point mutation results in increased ATG16L1 protein sensitivity to caspase 3-mediated cleavage. To generate novel rat strains carrying genetic alterations in the rat Atg16l1 gene, we first characterized the wild-type rat gene. We identified four alternative splice variants with tissue-specific expression. Using CRISPR-Cas9 genome editing technology, we developed a knock-in rat model for the human ATG16L1 T300A CD risk polymorphism, as well as a knock-out rat model to evaluate the role of Atg16l1 in autophagy as well as its potential effect on CD susceptibility. These are the first reported rat strains with alterations of the Atg16l1 gene. Consistent with studies of the effects of human ATG16L1 polymorphisms, models exhibit morphological abnormalities in both Paneth and goblet cells, but do not develop spontaneous intestinal permeability or inflammatory bowel disease. Analysis of the gut microbiota does not show inherent differences in bacterial composition between wild-type and genetically modified animals. These Atg16l1 strains are valuable new animal models for the study of both autophagy and CD susceptibility.

Background Substantial evidence indicates that a microdeletion on human chromosome 16p11.2 is linked to neurodevelopmental disorders, including autism spectrum disorder (ASD). Carriers of this deletion show divergent symptoms besides the core features of autism spectrum disorder, such as anxiety and emotional symptoms. The neural mechanisms underlying these symptoms are poorly understood. Methods We used mice heterozygous for a deletion allele of the genomic region corresponding to the human 16p11.2 microdeletion locus (i.e., 16p11.2 del/+ mice) and their sex-matched wild-type littermates for the study and examined their anxiety-related behaviors, auditory perception, and central amygdala circuit function using behavioral, circuit tracing, and electrophysiological techniques. Results Mice heterozygous for a deletion allele of the genomic region corresponding to the human 16p11.2 microdeletion locus (i.e., 16p11.2 del/+ mice) had sex-specific anxiety-related behavioral and neural circuit changes. Specifically, we found that female, but not male, 16p11.2 del/+ mice showed enhanced fear generalization—a hallmark of anxiety disorders—after auditory fear conditioning and displayed increased anxiety-like behaviors after physical restraint stress. Notably, such sex-specific behavioral changes were paralleled by an increase in activity in central amygdala neurons projecting to the globus pallidus in female, but not male, 16p11.2 del/+ mice. Conclusions Together, these results reveal female-specific anxiety phenotypes related to 16p11.2 microdeletion syndrome and a potential underlying neural circuit mechanism. Our study therefore identifies previously underappreciated sex-specific behavioral and neural changes in a genetic model of 16p11.2 microdeletion syndrome and highlights the importance of investigating female-specific aspects of this syndrome for targeted treatment strategies.