Variation In Regulatory Genes Research Articles

Association between clinical phenotypes of hypertrophic cardiomyopathy and Ca2+ gene variation gene variation

Objective: To observe the association between clinical phenotypes of hypertrophic cardiomyopathy (HCM) patients and a rare calcium channel and regulatory gene variation (Ca2+ gene variation) and to compare clinical phenotypes of HCM patients with Ca2+ gene variation, a single sarcomere gene variation and without gene variation and to explore the influence of rare Ca2+ gene variation on the clinical phenotypes of HCM. Methods: Eight hundred forty-two non-related adult HCM patients diagnosed for the first time in Xijing Hospital from 2013 to 2019 were enrolled in this study. All patients underwent exon analyses of 96 hereditary cardiac disease-related genes. Patients with diabetes mellitus, coronary artery disease, post alcohol septal ablation or septal myectomy, and patients who carried sarcomere gene variation of uncertain significance or carried>1 sarcomere gene variation or carried>1 Ca2+ gene variation, with HCM pseudophenotype or carrier of ion channel gene variations other than Ca2+ based on the genetic test results were excluded. Patients were divided into gene negative group (no sarcomere or Ca2+ gene variants), sarcomere gene variation group (only 1 sarcomere gene variant) and Ca2+ gene variant group (only 1 Ca2+ gene variant). Baseline data, echocardiography and electrocardiogram data were collected for analysis. Results: A total of 346 patients were enrolled, including 170 patients without gene variation (gene negative group), 154 patients with a single sarcomere gene variation (sarcomere gene variation group) and 22 patients with a single rare Ca2+ gene variation (Ca2+ gene variation group). Compared with gene negative group, patients in Ca2+ gene variation group had higher blood pressure and higher percentage of family history of HCM and sudden cardiac death (P<0.05); echocardiographic results showed that patients in Ca2+ gene variation group had thicker ventricular septum ((23.5±5.8) mm vs. (22.3±5.7) mm, P<0.05); electrocardiographic results showed that patients in Ca2+ gene variation group had prolonged QT interval ((416.6±23.1) ms vs. (400.6±47.2) ms, P<0.05) and higher RV5+SV1 ((4.51±2.26) mv vs. (3.50±1.65) mv, P<0.05). Compared with sarcomere gene variation group, patients in Ca2+ gene variation group had later onset age and higher blood pressure (P<0.05); echocardiographic results showed that there was no significant difference in ventricular septal thickness between two groups; patients in Ca2+ gene variation group had lower percentage of left ventricular outflow tract pressure gradient>30 mmHg (1 mmHg=0.133 kPa, 22.8% vs. 48.1%, P<0.05) and the lower early diastolic peak velocity of the mitral valve inflow/early diastolic peak velocity of the mitral valve annulus (E/e') ratio ((13.0±2.5) vs. (15.9±4.2), P<0.05); patients in Ca2+ gene variation group had prolonged QT interval ((416.6±23.1) ms vs. (399.0±43.0) ms, P<0.05) and lower percentage of ST segment depression (9.1% vs. 40.3%, P<0.05). Conclusion: Compared with gene negative group, the clinical phenotype of HCM is more severe in patients with rare Ca2+ gene variation; compared with patients with sarcomere gene variation, the clinical phenotype of HCM is milder in patients with rare Ca2+ gene variation.

Runx2 rs59983488 polymorphism in class II malocclusion in the Indonesian subpopulation

Background: Class II malocclusion is one of the main orthodontic issues for patients in seeking treatment. The prevalence of class II malocclusion varies in different populations. Variation in skeletal profile is mainly controlled internally by a regulatory gene. Runt-related transcription factor-2 (Runx2) plays a role in osteoblast differentiation and is highly expressed during development. Purpose: This study aimed to evaluate the relation of regulatory gene variation in the Runx2 promoter with class II malocclusion. Methods: DNA samples were acquired from 95 orthodontic patients in Jakarta, Indonesia, who were divided into two groups: class I skeletal malocclusion (control group) and class II malocclusion. A single nucleotide polymorphism was investigated using the polymerase chain reaction and restriction fragment length polymorphism techniques. The distribution of alleles was assessed using the Hardy-Weinberg test. The relationship between polymorphism and skeletal variation was assessed with the Chi-Square test and logistic regression. Results: The frequency distributions of genotypes and alleles were tested for Hardy-Weinberg equilibrium and found to be slightly deviated. There was an equal distribution of G and T alleles throughout class II and class I skeletal malocclusions and the Chi-Square test showed that this relationship was not significant (p=0.5). Conclusion: Runx2 rs59983488 polymorphism was found in the Indonesian subpopulation; however, an association between Runx2 rs59983488 polymorphism and class II skeletal malocclusion was not found.

Differential HDAC6 Activity Modulates Ciliogenesis and Subsequent Mechanosensing of Endothelial Cells Derived from Pluripotent Stem Cells

The role of primary cilia in mechanosensation is essential in endothelial cell (EC) shear responsiveness. Here, we find that venous, capillary, and progenitor ECs respond to shear stress invitro in a cilia-dependent manner. We then demonstrate thatprimary cilia assembly in human induced pluripotent stem cell (hiPSC)-derived ECs varies between different cell lines with marginal influence of differentiation protocol. hiPSC-derived ECs lacking cilia do not align to shear stress, lack stress fiber assembly, have uncoordinated migration during wound closure invitro, and have aberrant calcium influx upon shear exposure. Transcriptional analysis reveals variation in regulatory genes involved in ciliogenesis among different hiPSC-derived ECs. Moreover, inhibition of histone deacetylase 6 (HDAC6) activity in hiPSC-ECs lacking cilia rescues cilia formation and restores mechanical sensing. Taken together, these results show the importance of primary cilia in hiPSC-ECmechano-responsiveness and its modulation through HDAC6 activity varies among hiPSC-ECs.

Genome-Wide Association Study Identifies Novel Candidate Genes for Aggressiveness, Deoxynivalenol Production, and Azole Sensitivity in Natural Field Populations of Fusarium graminearum.

Genome-wide association studies can identify novel genomic regions and genes that affect quantitative traits. Fusarium head blight is a destructive disease caused by Fusarium graminearum that exhibits several quantitative traits, including aggressiveness, mycotoxin production, and fungicide resistance. Restriction site-associated DNA sequencing was performed for 220 isolates of F. graminearum. A total of 119 isolates were phenotyped for aggressiveness and deoxynivalenol (DON) production under natural field conditions across four environments. The effective concentration of propiconazole that inhibits isolate growth in vitro by 50% was calculated for 220 strains. Approximately 29,000 single nucleotide polymorphism markers were associated to each trait, resulting in 50, 29, and 74 quantitative trait nucleotides (QTNs) that were significantly associated to aggressiveness, DON production, and propiconazole sensitivity, respectively. Approximately 41% of these QTNs caused nonsynonymous substitutions in predicted exons, while the remainder were synonymous substitutions or located in intergenic regions. Three QTNs associated with propiconazole sensitivity were significant after Bonferroni correction. These QTNs were located in genes not previously associated with azole sensitivity. The majority of the detected QTNs were located in genes with predicted regulatory functions, suggesting that nucleotide variation in regulatory genes plays a major role in the corresponding quantitative trait variation.

Effects of genetic variation in H3K79 methylation regulatory genes on clinical blood pressure and blood pressure response to hydrochlorothiazide.

BackgroundNearly one-third of the United States adult population suffers from hypertension. Hydrochlorothiazide (HCTZ), one of the most commonly used medications to treat hypertension, has variable efficacy. The renal epithelial sodium channel (ENaC) provides a mechanism for fine-tuning sodium excretion, and is a major regulator of blood pressure homeostasis. DOT1L, MLLT3, SIRT1, and SGK1 encode genes in a pathway that controls methylation of the histone H3 globular domain at lysine 79 (H3K79), thereby modulating expression of the ENaCα subunit. This study aimed to determine the role of variation in these regulatory genes on blood pressure response to HCTZ, and secondarily, untreated blood pressure.MethodsWe investigated associations between genetic variations in this candidate pathway and HCTZ blood pressure response in two separate hypertensive cohorts (clinicaltrials.gov NCT00246519 and NCT00005520). In a secondary, exploratory analysis, we measured associations between these same genetic variations and untreated blood pressure. Associations were measured by linear regression, with only associations with P ≤ 0.01 in one cohort and replication by P ≤ 0.05 in the other cohort considered significant.ResultsIn one cohort, a polymorphism in DOT1L (rs2269879) was strongly associated with greater systolic (P = 0.0002) and diastolic (P = 0.0016) blood pressure response to hydrochlorothiazide in Caucasians. However, this association was not replicated in the other cohort. When untreated blood pressure levels were analyzed, we found directionally similar associations between a polymorphism in MLLT3 (rs12350051) and greater untreated systolic (P < 0.01 in both cohorts) and diastolic (P < 0.05 in both cohorts) blood pressure levels in both cohorts. However, when further replication was attempted in a third hypertensive cohort and in smaller, normotensive samples, significant associations were not observed.ConclusionsOur data suggest polymorphisms in DOT1L, MLLT3, SIRT1, and SGK1 are not likely associated with blood pressure response to HCTZ. However, a possibility exists that rs2269879 in DOT1L could be associated with HCTZ response in Caucasians. Additionally, exploratory analyses suggest rs12350051 in MLLT3 may be associated with untreated blood pressure in African-Americans. Replication efforts are needed to verify roles for these polymorphisms in human blood pressure regulation.

Strain-resolved community genomic analysis of gut microbial colonization in a premature infant

The intestinal microbiome is a critical determinant of human health. Alterations in its composition have been correlated with chronic disorders, such as obesity and inflammatory bowel disease in adults, and may be associated with neonatal necrotizing enterocolitis in premature infants. Increasing evidence suggests that strain-level genomic variation may underpin distinct ecological trajectories within mixed populations, yet there have been few strain-resolved analyses of genotype-phenotype connections in the context of the human ecosystem. Here, we document strain-level genomic divergence during the first 3 wk of life within the fecal microbiota of an infant born at 28-wk gestation. We observed three compositional phases during colonization, and reconstructed and intensively curated population genomic datasets from the third phase. The relative abundance of two Citrobacter strains sharing ~99% nucleotide identity changed significantly over time within a community dominated by a nearly clonal Serratia population and harboring a lower abundance Enterococcus population and multiple plasmids and bacteriophage. Modeling of Citrobacter strain abundance suggests differences in growth rates and host colonization patterns. We identified genotypic variation potentially responsible for divergent strain ecologies, including hotspots of sequence variation in regulatory genes and intergenic regions, and in genes involved in transport, flagellar biosynthesis, substrate metabolism, and host colonization, as well as differences in the complements of these genes. Our results demonstrate that a community genomic approach can elucidate gut microbial colonization at the resolution required to discern medically relevant strain and species population dynamics, and hence improve our ability to diagnose and treat microbial community-mediated disorders.

Promoting Regulatory Gene Variation in Sodium Reabsorption

Many genes in an individual genome exist as allelic variants with 1 dimorphic form inherited from each parent. Although these alleles share a common regulatory environment within the same nucleus, they do not necessarily respond to it in the same way. Variation in the promoter sequences of genes, most of which are single base substitutions, may alter the binding of transcription factors that regulate expression of the gene. The result is allelic expression, a condition in which the number of transcripts present that have been produced from 1 parental allele consistently differs from that produced from the other allele. Allelic expression is garnering a great deal of interest in several fields. In evolutionary genetics there is a strong case to be made that the divergence of species relies more heavily on the evolution of regulatory rather than structural variation in genes.1 However, in genomics we are beginning to understand that homeostasis is the output of gene networks and that variation in many genes can shift the state of a gene network and alter its capacity to achieve homeostasis in its regulated outputs.2 Amplifying interest in allelic expression is the fact that functional implications of genetic variation creating allelic expression extend beyond the statistical relationship between the variant and phenotype that is the usual output of population genetic studies. This contrasts with some well-established associations between gene variants and complex disease susceptibility, such as that between Alzheimer disease and the epsilon 4 allele of apolipoprotein E, for which no sufficient functional relationship has yet been uncovered to explain the link between the gene variation and disease risk. The …

Functional protein divergence in the evolution of Homo sapiens.

Quantification of the divergence of proteins by functional category shows that morphological changes in metazoa have been driven by variation in regulatory genes.

Evolutionary relationships between gene-structure and gene-regulation variation inDrosophila melanogaster

The evolutionary relationship between gene-structure and gene-regulation variation was examined by using data on allozyme and activity variation for a group of enzyme loci inDrosophila melanogaster. No significant correlation between the two kinds of variation was found, although the present data set is small and probably not sensitive for tests of association. Various hypotheses of association between the two types of variation are discussed and it is shown that any association between gene-structure and gene-regulation variation (positive or negative) would be sensitive to distortion by repeated bottlenecks and genetic drift. Furthermore, random forces would affect gene-structure (allozyme) variation, which is often controlled by one gene, more severely than enzyme activity variation, which is usually controlled by many genes. Measurements of activity variation would appear to provide an evolutionarily more stable and reliable estimate of. loci-specific ‘molecular flexibility’ than measurements of structural variation. It is suggested that locus-specific gene regulation studies employing a set of major alleles would provide a better test of association between gene-structure and gene-regulation variation. The relationship between gene regulation and quantitative variation is discussed and a number of population-genetic questions related to regulatory gene variation are formulated.

Studies of esterase 6 inDrosophila melanogaster: XI. Modification of esterase 6 activity by unlinked genes

SUMMARYThe often remarkable similarity in structural gene products among related species has led to the hypothesis that species differences may reside largely in changes at regulatory gene loci. This hypothesis assumes that groups capable of speciating have allelic variation at regulatory loci in their natural populations. We have undertaken an analysis of the mode of regulation of theesterase 6(Est 6) locus inDrosophila melanogasterto determine the nature and extent of regulatory gene variation in natural populations. Analyses of esterase 6 (EST 6) activity among strains carrying the same thermostability variants reveal that significant, specific-activity differences are present. Reciprocal crosses between lines having high and low EST 6 activity show that loci other than theEst 6structural gene influence EST 6 activity. Analyses of male hybrids from crosses betweenD. melanogasterandsimulansindicate that theXchromosome of these flies affects the expression of theEst 6locus, resulting in unequal levels of enzyme activity from the two alleles. The effect is sex and tissue specific. Female hybrids carrying theXchromosomes of both species exhibit equal expression of the twoEst 6alleles. We have determined whether natural populations are polymorphic forXchromosomes which affect EST 6 activity by extracting singleXchromosomes from wild-collected males and placing these chromosomes in identical genetic backgrounds. Stocks which are otherwise genetically identical but carry independently derivedXchromosomes show significant differences in the activity of EST 6. These data suggest that regulatory loci may be commonly polymorphic in natural populations.

Gene regulation in adaptive evolution.

It has been suggested that gene regulation may play a critical role in adaptive evolution. However, gene regulation has proved to be most refractory to experimental investigation in multicellular organisms. Using specially constructed stocks of Drosophila melanogaster, we have demonstrated the following. (1) The existence in natural populations of ample variation in regulatory genes that modify the activity of alcohol dehydrogenase (ADH), an enzyme coded by a structural gene locus, Adh, located on the second chromosome; the regulatory genes are located on the third chromosome, and thus are not adjacent to the structural locus. (2) The regulatory genes act not by means of post-transcriptional or post-translational modification of the gene product, but rather by controlling the number of ADH molecules; this is consistent with the hypothesis of gene regulation by means of macromolecules specifically binding at control sites adjacent to the structural gene locus. (3) The variation in regulatory genes is adaptively significant; adaptation to higher levels of environmental alcohol takes place not by changes in the Adh structural locus, but by changes in regulatory genes that control the number of ADH molecules in the organisms. Our results provide direct evidence of the importance of gene regulation in eucaryotic evolution.