Pharmacologic analysis of non-synonymous coding 5-HT2A SNPs reveals alterations psychedelic drug potencies and efficacies

Serotonin (5-Hydroxytryptamine; 5-HT) 2A receptor (5-HT2AR) signaling is essential for the actions of classical psychedelic drugs. In this study, we examined whether random sequence variations in the gene (single nucleotide polymorphisms, SNPs) encoding the 5-HT2AR affect the signaling of four commonly used psychedelic drugs. We examined the in vitro pharmacology of seven non-synonymous SNPs, which give rise to S12N, T25N, D48N, I197V, A230T, A447V, and H452Y variant 5-HT2A serotonin receptors. We found that these non-synonymous SNPs exert statistically significant, although modest, effects on the efficacy and potency of four therapeutically relevant hallucinogens. Significantly, the in vitro pharmacological effects of the SNPs drug actions at 5-HT2AR are drug specific.

Transmission distortion and genetic incompatibilities between alleles in a multigenerational mouse advanced intercross line

While direct additive and dominance effects on complex traits have been mapped repeatedly, additional genetic factors contributing to the heterogeneity of complex traits have been scarcely investigated. To assess genetic background effects, we investigated transmission ratio distortions (TRDs) of alleles from parent to offspring using an advanced intercross line (AIL) of an initial cross between the mouse inbred strains C57BL/6NCrl (B6N) and BFMI860-12 (BFMI). 341 males of generation 28 and their respective 61 parents and 66 grandparents were genotyped using Mega Mouse Universal Genotyping Arrays (MegaMUGA). TRDs were investigated using allele transmission asymmetry tests, and pathway overrepresentation analysis was performed. Sequencing data was used to test for overrepresentation of non-synonymous SNPs in TRD regions. Genetic incompatibilities were tested using the Bateson-Dobzhansky-Muller two-locus model. 62 TRD regions were detected, many in close proximity to the telocentric centromere. TRD regions contained 44.5% more non-synonymous SNPs than randomly selected regions (182 vs. 125.9 ± 17.0, P < 1x10−4). Testing for genetic incompatibilities between TRD regions identified 29 genome-wide significant incompatibilities between TRD regions (P(BF) < 0.05). Pathway overrepresentation analysis of genes in TRD regions showed that DNA methylation, epigenetic regulation of RNA, and meiotic/meiosis regulation pathways were affected independent of the parental origin of the TRD. Paternal BFMI TRD regions showed overrepresentation in the small interfering RNA (siRNA) biogenesis and in the metabolism of lipids and lipoproteins. Maternal B6N TRD regions harbored genes involved in meiotic recombination, cell death, and apoptosis pathways. The analysis of genes in TRD regions suggests the potential distortion of protein-protein interactions influencing obesity and diabetic retinopathy as a result of disadvantageous combinations of allelic variants in Aass, Pgx6 and Nme8. Using an AIL significantly improves the resolution at which we can investigate TRD. Our analysis implicates distortion of protein-protein interactions as well as meiotic drive as the underlying mechanisms leading to the observed TRD in our AIL. Furthermore, genes with large amounts of non-synonymous SNPs located in TRD regions are more likely to be involved in pathways that are related to the phenotypic differences between the parental strains. Genes in these TRD regions provide new targets for investigating genetic adaptation, protein-protein interactions, and determinants of complex traits such as obesity.

Identification of Most Lethal Non-synonymous SNPs in Tollip gene- An In-Silico Analysis

The Toll-interacting protein (TOLLIP), first detected by hybrid screening using Interleukin-1 receptor accessory protein in 2000, is ubiquitous and its TLR signaling cascade gets negatively regulated by TOLLIP in particular by impeding the TLR4 and TLR2 pathways. Toll-interacting protein facilitates TLR and TGF-β type 1 receptor intracellular localization and lysosomal degradation and exerts its anti-apoptosis and pro-autophagy effects through interaction with a target of Myb1 membrane trafficking protein 1 (TOM1) in autoimmunity. It also protects intestinal epithelial cells from apoptosis induced by (TNF-α) (IFN-γ) signaling and acts as a cargo adaptor linking (ATG8) autophagy gene 8 and microtubule-associated protein 1 light chain 3. Ubiquitin-modified cell debris along with coated autophagosomes removes harmful protein aggregates and maintains cellular homeostasis. It is therefore structurally and functionally important to detect TOLLIP polymorphisms to indicate the possible malfunctions and therapeutics. We have identified the gap of available data on nsSNPs in the TOLLIP gene in previous studies. Hence, We have used a wide range of bioinformatic techniques in this study to identify the most destructive nsSNPs in the TOLLIP gene. The in-silico tools such as PROVEAN, SIFT, SNP&GO, PhD SNP, and PolyPhen2 have been used followed by I Mutant, MutPred, and ConSurf. The 3-D mapping was carried out with I-TASSER and Phyre2. Though, STRING and GeneMANIA proposed the gene to gene interaction of TOLLIP. Our study identified G19D (rs866744102), G32R (rs1308704061), D71N (rs777772934), and E72G (rs1202660177) as the four most lethal non-synonymous SNPs in TOLLIP genes, which may play an essential part in defects of TOLLIP Protein and probably cause a different type of diseases. This is the first study of its kind, and it could pave the way in the field of medical drugs in the future. The influence of these nsSNPs in the normal functioning of TOLLIP can also be evaluated in animal models to identify the underlying biochemical pathway involved in diseases.

Identification of Most Lethal Non-synonymous SNPs in Tollip gene- An In-Silico Analysis

The Toll-interacting protein (TOLLIP), first detected by hybrid screening using Interleukin-1 receptor accessory protein in 2000, is ubiquitous and its TLR signaling cascade gets negatively regulated by TOLLIP in particular by impeding the TLR4 and TLR2 pathways. Toll-interacting protein facilitates TLR and TGF-β type 1 receptor intracellular localization and lysosomal degradation and exerts its anti-apoptosis and pro-autophagy effects through interaction with a target of Myb1 membrane trafficking protein 1 (TOM1) in autoimmunity. It also protects intestinal epithelial cells from apoptosis induced by (TNF-α) (IFN-γ) signaling and acts as a cargo adaptor linking (ATG8) autophagy gene 8 and microtubule-associated protein 1 light chain 3. Ubiquitin-modified cell debris along with coated autophagosomes removes harmful protein aggregates and maintains cellular homeostasis. It is therefore structurally and functionally important to detect TOLLIP polymorphisms to indicate the possible malfunctions and therapeutics. We have identified the gap of available data on nsSNPs in the TOLLIP gene in previous studies. Hence, We have used a wide range of bioinformatic techniques in this study to identify the most destructive nsSNPs in the TOLLIP gene. The in-silico tools such as PROVEAN, SIFT, SNP&GO, PhD SNP, and PolyPhen2 have been used followed by I Mutant, MutPred, and ConSurf. The 3-D mapping was carried out with I-TASSER and Phyre2. Though, STRING and GeneMANIA proposed the gene to gene interaction of TOLLIP. Our study identified G19D (rs866744102), G32R (rs1308704061), D71N (rs777772934), and E72G (rs1202660177) as the four most lethal non-synonymous SNPs in TOLLIP genes, which may play an essential part in defects of TOLLIP Protein and probably cause a different type of diseases. This is the first study of its kind, and it could pave the way in the field of medical drugs in the future. The influence of these nsSNPs in the normal functioning of TOLLIP can also be evaluated in animal models to identify the underlying biochemical pathway involved in diseases.

Single nucleotide polymorphisms within the cps loci: another potential source of clinically important genetic variation for Streptococcus pneumoniae ?

The Streptococcus pneumoniae capsule is essential for disease pathogenesis, suggesting that even minor genetic changes within the cps locus could potentially have important consequences. Arends et al. have identified 79 different non-synonymous SNPs in the cps locus of 338 19A serotype strains, and shown significant variations between strains in nucleotide sugars content and capsule shedding. Further work is required to characterise whether any of these changes have important functional consequences on capsule/host interactions.

Transmission distortion and genetic incompatibilities between alleles in a multigenerational mouse advanced intercross line

Background/Objectives: While direct additive and dominance effects on complex traits have been mapped repeatedly, additional genetic factors contributing to the heterogeneity of complex traits have been scarcely investigated. To assess genetic background effects, we investigated transmission ratio distortions (TRDs) of alleles from parent to offspring using an advanced intercross line (AIL) of an initial cross between the mouse inbred strains C57BL/6NCrl (B6N) and BFMI860-12 (BFMI). Subjects/Methods: 341 males of generation 28 and their respective 61 parents and 66 grandparents were genotyped using Mega Mouse Universal Genotyping Arrays (MegaMUGA). TRDs were investigated using allele transmission asymmetry tests, and pathway overrepresentation analysis was performed. Sequencing data was used to test for overrepresentation of non-synonymous SNPs in TRD regions. Genetic incompatibilities were tested using the Bateson-Dobzhansky-Muller two-locus model. Results: 62 TRD regions were detected, many in close proximity to the telocentric centromere. TRD regions contained 44.5% more non-synonymous SNPs than randomly selected regions (182 vs. 125.9 17.0, P < 1x10-4). Testing for genetic incompatibilities between TRD regions identified 29 genome-wide significant incompatibilities between TRD regions (P(BF) < 0.05). Pathway overrepresentation analysis of genes in TRD regions showed that DNA methylation, epigenetic regulation of RNA, and meiotic/meiosis regulation pathways were affected independent of the parental origin of the TRD. Paternal BFMI TRD regions showed overrepresentation in the small interfering RNA (siRNA) biogenesis and in the metabolism of lipids and lipoproteins. Maternal B6N TRD regions harbored genes involved in meiotic recombination, cell death, and apoptosis pathways. The analysis of genes in TRD regions suggests the potential distortion of protein-protein interactions accounting for obesity and diabetic retinopathy as a result of disadvantageous combinations of allelic variants in Aass, Pgx6 and Nme8. Conclusions: Since genes in TRD regions showed a significant increase in the number of non-synonymous SNPs, these loci likely co-evolved to ensure protein-protein interaction compatibility, survival and optimal adaptation to the genetic background environment. Genes in these regions provide new targets for investigating genetic adaptation, protein-protein interactions, and determinants of complex traits such as obesity.

Identification of Most Lethal Non-synonymous SNPs in Tollip gene- An In-Silico Analysis

The Toll-interacting protein (TOLLIP), first detected by hybrid screening using Interleukin-1 receptor accessory protein in 2000, is ubiquitous and its TLR signaling cascade gets negatively regulated by TOLLIP in particular by impeding the TLR4 and TLR2 pathways. Toll-interacting protein facilitates TLR and TGF-β type 1 receptor intracellular localization and lysosomal degradation and exerts its anti-apoptosis and pro-autophagy effects through interaction with a target of Myb1 membrane trafficking protein 1 (TOM1) in autoimmunity. It also protects intestinal epithelial cells from apoptosis induced by (TNF-α) (IFN-γ) signaling and acts as a cargo adaptor linking (ATG8) autophagy gene 8 and microtubule-associated protein 1 light chain 3. Ubiquitin-modified cell debris along with coated autophagosomes removes harmful protein aggregates and maintains cellular homeostasis. It is therefore structurally and functionally important to detect TOLLIP polymorphisms to indicate the possible malfunctions and therapeutics. We have identified the gap of available data on nsSNPs in the TOLLIP gene in previous studies. Hence, We have used a wide range of bioinformatic techniques in this study to identify the most destructive nsSNPs in the TOLLIP gene. The in-silico tools such as PROVEAN, SIFT, SNP&GO, PhD SNP, and PolyPhen2 have been used followed by I Mutant, MutPred, and ConSurf. The 3-D mapping was carried out with I-TASSER and Phyre2. Though, STRING and GeneMANIA proposed the gene to gene interaction of TOLLIP. Our study identified G19D (rs866744102), G32R (rs1308704061), D71N (rs777772934), and E72G (rs1202660177) as the four most lethal non-synonymous SNPs in TOLLIP genes, which may play an essential part in defects of TOLLIP Protein and probably cause a different type of diseases. This is the first study of its kind, and it could pave the way in the field of medical drugs in the future. The influence of these nsSNPs in the normal functioning of TOLLIP can also be evaluated in animal models to identify the underlying biochemical pathway involved in diseases.

Identification of Most Lethal Non-synonymous SNPs in Tollip gene- An In-Silico Analysis

The Toll-interacting protein (TOLLIP), first detected by hybrid screening using Interleukin-1 receptor accessory protein in 2000, is ubiquitous and its TLR signaling cascade gets negatively regulated by TOLLIP in particular by impeding the TLR4 and TLR2 pathways. Toll-interacting protein facilitates TLR and TGF-β type 1 receptor intracellular localization and lysosomal degradation and exerts its anti-apoptosis and pro-autophagy effects through interaction with a target of Myb1 membrane trafficking protein 1 (TOM1) in autoimmunity. It also protects intestinal epithelial cells from apoptosis induced by (TNF-α) (IFN-γ) signaling and acts as a cargo adaptor linking (ATG8) autophagy gene 8 and microtubule-associated protein 1 light chain 3. Ubiquitin-modified cell debris along with coated autophagosomes removes harmful protein aggregates and maintains cellular homeostasis. It is therefore structurally and functionally important to detect TOLLIP polymorphisms to indicate the possible malfunctions and therapeutics. We have identified the gap of available data on nsSNPs in the TOLLIP gene in previous studies. Hence, We have used a wide range of bioinformatic techniques in this study to identify the most destructive nsSNPs in the TOLLIP gene. The in-silico tools such as PROVEAN, SIFT, SNP&GO, PhD SNP, and PolyPhen2 have been used followed by I Mutant, MutPred, and ConSurf. The 3-D mapping was carried out with I-TASSER and Phyre2. Though, STRING and GeneMANIA proposed the gene to gene interaction of TOLLIP. Our study identified G19D (rs866744102), G32R (rs1308704061), D71N (rs777772934), and E72G (rs1202660177) as the four most lethal non-synonymous SNPs in TOLLIP genes, which may play an essential part in defects of TOLLIP Protein and probably cause a different type of diseases. This is the first study of its kind, and it could pave the way in the field of medical drugs in the future. The influence of these nsSNPs in the normal functioning of TOLLIP can also be evaluated in animal models to identify the underlying biochemical pathway involved in diseases.