I. V. Chadaeva

Candidate SNP Markers of Chronopathologies Are Predicted by a Significant Change in the Affinity of TATA-Binding Protein for Human Gene Promoters

Variations in human genome (e.g., single nucleotide polymorphisms, SNPs) may be associated with hereditary diseases, their complications, comorbidities, and drug responses. Using Web service SNP_TATA_Comparator presented in our previous paper, here we analyzed immediate surroundings of known SNP markers of diseases and identified several candidate SNP markers that can significantly change the affinity of TATA-binding protein for human gene promoters, with circadian consequences. For example, rs572527200 may be related to asthma, where symptoms are circadian (worse at night), and rs367732974 may be associated with heart attacks that are characterized by a circadian preference (early morning). By the same method, we analyzed the 90 bp proximal promoter region of each protein-coding transcript of each human gene of the circadian clock core. This analysis yielded 53 candidate SNP markers, such as rs181985043 (susceptibility to acute Q fever in male patients), rs192518038 (higher risk of a heart attack in patients with diabetes), and rs374778785 (emphysema and lung cancer in smokers). If they are properly validated according to clinical standards, these candidate SNP markers may turn out to be useful for physicians (to select optimal treatment for each patient) and for the general population (to choose a lifestyle preventing possible circadian complications of diseases).

Candidate SNP markers of aggressiveness-related complications and comorbidities of genetic diseases are predicted by a significant change in the affinity of TATA-binding protein for human gene promoters

BackgroundAggressiveness in humans is a hereditary behavioral trait that mobilizes all systems of the body—first of all, the nervous and endocrine systems, and then the respiratory, vascular, muscular, and others—e.g., for the defense of oneself, children, family, shelter, territory, and other possessions as well as personal interests. The level of aggressiveness of a person determines many other characteristics of quality of life and lifespan, acting as a stress factor. Aggressive behavior depends on many parameters such as age, gender, diseases and treatment, diet, and environmental conditions. Among them, genetic factors are believed to be the main parameters that are well-studied at the factual level, but in actuality, genome-wide studies of aggressive behavior appeared relatively recently. One of the biggest projects of the modern science—1000 Genomes—involves identification of single nucleotide polymorphisms (SNPs), i.e., differences of individual genomes from the reference genome. SNPs can be associated with hereditary diseases, their complications, comorbidities, and responses to stress or a drug. Clinical comparisons between cohorts of patients and healthy volunteers (as a control) allow for identifying SNPs whose allele frequencies significantly separate them from one another as markers of the above conditions. Computer-based preliminary analysis of millions of SNPs detected by the 1000 Genomes project can accelerate clinical search for SNP markers due to preliminary whole-genome search for the most meaningful candidate SNP markers and discarding of neutral and poorly substantiated SNPs.ResultsHere, we combine two computer-based search methods for SNPs (that alter gene expression) {i} Web service SNP_TATA_Comparator (DNA sequence analysis) and {ii} PubMed-based manual search for articles on aggressiveness using heuristic keywords. Near the known binding sites for TATA-binding protein (TBP) in human gene promoters, we found aggressiveness-related candidate SNP markers, including rs1143627 (associated with higher aggressiveness in patients undergoing cytokine immunotherapy), rs544850971 (higher aggressiveness in old women taking lipid-lowering medication), and rs10895068 (childhood aggressiveness-related obesity in adolescence with cardiovascular complications in adulthood).ConclusionsAfter validation of these candidate markers by clinical protocols, these SNPs may become useful for physicians (may help to improve treatment of patients) and for the general population (a lifestyle choice preventing aggressiveness-related complications).

Candidate SNP Markers of Familial and Sporadic Alzheimer's Diseases Are Predicted by a Significant Change in the Affinity of TATA-Binding Protein for Human Gene Promoters

While year after year, conditions, quality, and duration of human lives have been improving due to the progress in science, technology, education, and medicine, only eight diseases have been increasing in prevalence and shortening human lives because of premature deaths according to the retrospective official review on the state of US health, 1990-2010. These diseases are kidney cancer, chronic kidney diseases, liver cancer, diabetes, drug addiction, poisoning cases, consequences of falls, and Alzheimers disease (AD) as one of the leading pathologies. There are familial AD of hereditary nature (~4% of cases) and sporadic AD of unclear etiology (remaining ~96% of cases; i.e., non-familial AD). Therefore, sporadic AD is no longer a purely medical problem, but rather a social challenge when someone asks oneself: “What can I do in my own adulthood to reduce the risk of sporadic AD at my old age to save the years of my lifespan from the destruction caused by it?” Here, we combine two computational approaches for regulatory SNPs: Web service SNP_TATA_Comparator for sequence analysis and a PubMed-based keyword search for articles on the biochemical markers of diseases. Our purpose was to try to find answers to the question: “What can be done in adulthood to reduce the risk of sporadic AD in old age to prevent the lifespan reduction caused by it?” As a result, we found 89 candidate SNP markers of familial and sporadic AD (e.g., rs562962093 is associated with sporadic AD in the elderly as a complication of stroke in adulthood, where natural marine diets can reduce risks of both diseases in case of the minor allele of this SNP). In addition, rs768454929, and rs761695685 correlate with sporadic AD as a comorbidity of short stature, where maximizing stature in childhood and adolescence as an integral indicator of health can minimize (or even eliminate) the risk of sporadic AD in the elderly. After validation by clinical protocols, these candidate SNP markers may become interesting to the general population [may help to choose a lifestyle (in childhood, adolescence, and adulthood) that can reduce the risks of sporadic AD, its comorbidities, and complications in the elderly].

Candidate SNP markers of social dominance, which may affect the affinity of the TATA-binding protein for human gene promoters

The following heuristic hypothesis has been proposed: if an excess of a protein in several animal organs was experimentally identified as a physiological marker of increased aggressiveness, and if a single nucleotide polymorphism (SNP) can cause the overexpression of a human gene homologous to the animal gene encoding this protein, then this polymorphism can be a candidate SNP marker of social dominance. In turn, a deficient expression would correspond to subordinate behavior. Within this hypothesis, we analyzed 21 human genes, ADORA2A, BDNF, CC2D1A, CC2D1B, ESR2, FEV, FOS, GH1, GLTSCR2, GRIN1, HTR1B, HTR1A, HTR2A, HTR2C, LGI4, LEP, MAOA, SLC17A7, SLC6A3, SNCA, and TH, which determine the functions of the proteins known as the physiological markers of aggressive behavior in animals. These genes encode for hormones and their receptors, biosynthetic enzymes, receptors of neurotransmitters, and transcription and neurotrophic factors. These proteins have been postulated to play important roles in determining the hierarchical relationships in social animals. Using our previously developed Web-service SNP_TATA_Comparator (http://beehive.bionet.nsc.ru/cgi-bin/mgs/tatascan/start.pl), we analyzed 381 SNPs within the [–70;–20] region preceding the start of the protein-coding transcripts, obtained from the database dbSNP, v.147. This is the region for all the known TATA-binding protein (TBP) binding sites. As a result, we found 45 and 47 candidate SNP markers of dominance and subordination, respectively (e.g., rs373600960 and rs747572588). Within the proposed heuristic hypotheses and dbSNP database v.147, we found statistically significant (α < 10–5) evidence of the effects of natural selection against the deficient expression of genes, which can affect the predisposition to dominate. We also obtained evidence favoring the hypothesis that both subordinate and dominant behavior can be the norm of reaction of aggressiveness (difference not significant: α > 0.35). The proposed hypothesis, the candidate SNP markers obtained on its basis, and the observed regularities of the effects of their natural selection on the human genome are discussed in comparison with the published data with respect to whether these markers can have an effect on the expression of social dominance in human society. We conclude that our candidate SNPs, identified with a computational model, require further experimental verification.

Candidate SNP markers of reproductive potential are predicted by a significant change in the affinity of TATA-binding protein for human gene promoters

BackgroundThe progress of medicine, science, technology, education, and culture improves, year by year, quality of life and life expectancy of the populace. The modern human has a chance to further improve the quality and duration of his/her life and the lives of his/her loved ones by bringing their lifestyle in line with their sequenced individual genomes. With this in mind, one of genome-based developments at the junction of personalized medicine and bioinformatics will be considered in this work, where we used two Web services: (i) SNP_TATA_Comparator to search for alleles with a single nucleotide polymorphism (SNP) that alters the affinity of TATA-binding protein (TBP) for the TATA boxes of human gene promoters and (ii) PubMed to look for retrospective clinical reviews on changes in physiological indicators of reproductive potential in carriers of these alleles.ResultsA total of 126 SNP markers of female reproductive potential, capable of altering the affinity of TBP for gene promoters, were found using the two above-mentioned Web services. For example, 10 candidate SNP markers of thrombosis (e.g., rs563763767) can cause overproduction of coagulation inducers. In pregnant women, Hughes syndrome provokes thrombosis with a fatal outcome although this syndrome can be diagnosed and eliminated even at the earliest stages of its development. Thus, in women carrying any of the above SNPs, preventive treatment of this syndrome before a planned pregnancy can reduce the risk of death. Similarly, seven SNP markers predicted here (e.g., rs774688955) can elevate the risk of myocardial infarction. In line with Bowles’ lifespan theory, women carrying any of these SNPs may modify their lifestyle to improve their longevity if they can take under advisement that risks of myocardial infarction increase with age of the mother, total number of pregnancies, in multiple pregnancies, pregnancies under the age of 20, hypertension, preeclampsia, menstrual cycle irregularity, and in women smokers.ConclusionsAccording to Bowles’ lifespan theory—which links reproductive potential, quality of life, and life expectancy—the above information was compiled for those who would like to reduce risks of diseases corresponding to alleles in own sequenced genomes. Candidate SNP markers can focus the clinical analysis of unannotated SNPs, after which they may become useful for people who would like to bring their lifestyle in line with their sequenced individual genomes.

Computer analysis of colocalization of the TFs’ binding sites in the genome according to the ChIP-seq data

A computer program for calculating clusters of binding sites of various transcription factors (TFs) according to the genomic coordinates of the ChIP-seq (Chromatin ImmunoPrecipitation-sequencing) profile peaks is developed. The statistical features of the distribution of the transcription factors’ binding sites (TFBSs) in the mouse genome, obtained with the help of ChIP-seq experiments in embryonic stem cells, are considered. Clusters of sites containing at least four binding sites of various TFs in the mouse genome are determined and their localization relative to the regulatory regions of the genes is described. Two types of colocalization of the sites are confirmed: clusters containing binding sites of factors Oct4, Nanog, and Sox2 located in the distal regions and clusters with n-Myc and c-Myc binding sites located mainly in the promoter regions of mouse genes. Analysis of the new ChIP-seq data on the binding of TFs Nr5a2, Tbx3, Cep, SRF, and USF1 in the same cell type confirmed the differentiation of clusters of the TFBSs into two types: those containing pluripotency regulator binding sites (Oct4, Nanog, and Sox2) and those not containing them. A computer program for the statistical processing of the data on the location of the sites in the genes is developed; it uses the experimental data on site localization obtained by ChIP-seq methods in mouse and human genomes. With the help of this program, the localization patterns of the binding sites of various TFs are detected. The distances between the closest binding sites of the TF groups Oct4, Nanog, and Sox2 and the binding sites of other factors in site clusters that serve as a basis for the analysis of the joint binding of protein complexes to DNA are calculated. The fraction of the presence of the known nucleotide motifs of TFBSs in the genomic regions of ChIP-seq is calculated. The weight matrices for such nucleotide motifs are recalculated. The correlation between the presence of motifs and the ChIP-seq binding intensity is shown. The programs implementing the computerized methods for assessing the clustering of binding sites of various TFs for new ChIP-seq data are available upon request from the authors.

Differential alternative splicing in brain regions of rats selected for aggressive behavior

Profiles of alternative mRNA isoforms have been determined in three brain regions of rats from an aggressive and a tame line selected for 74 generations. Among 2319 genes with alternatively spliced exons, approximately 84% were confirmed by analyzing public databases. Based on Gene Ontology-guided clustering of alternatively spliced genes, it has been found that the sample was enriched in synapse-specific genes (FDR < 10–17). Patterns of gene expression in the brains of animals with genetically determined high or low aggression were more frequently found to differ in the use of alternatively spliced exons than in animals environmentally conditioned for increased or lowered propensity to aggression. For the Adcyap1r1 gene, five alternatively spliced mRNA isoforms have been represented differentially in aggressive animals. A detailed analysis of the gene that encodes glutamate ionotropic receptor NMDA type subunit 1 (Grin1) has confirmed significant differences in the levels of its alternatively spliced isoforms in certain brain regions of tame and aggressive rats. These differences may affect the behavior in rats genetically selected for aggression levels.

Flanking monomer repeats determine decreased context complexity of single nucleotide polymorphism sites in the human genome

The study of the dependence of the mutation frequency in human genome was conducted by the example of a set of documented single nucleotide polymorphisms (SNPs) from the 1000 genomes project. The tasks of the development of new computer methods for the statistical analysis of genetic texts based on estimations of sequences complexity were considered. The application of the complexity profiles in a sliding window to the analysis of sites containing single nucleotide polymorphisms in the human genome was demonstrated. A local decrease in the text complexity near SNPs was established. Based on the analysis of the complexity profiles in the regions containing SNPs, it was demonstrated that the flanking monomer repeats determine the decreased context complexity of single nucleotide polymorphism sites in human genome. The effect of local decrease in the text complexity level for sequences flanking SNP sites was confirmed for the data on polymorphisms in the rat and mouse genomes. Differences in the context organization for coding and regulatory sequences (that are reflected in the text complexity of nucleotide sequences containing SNPs) were determined. Changes in the point mutation frequencies were previously demonstrated for the sequences containing microsatellites. Using more general mathematical apparatus and more complete data, a saturation of local genomic surroundings containing SNPs with polytracts and simple repeated sequences was demonstrated in this work. Oligonucleotides with increased frequency in the genomic SNP surroundings in human were determined; their association with polytracts was demonstrated. The presence of polytracts can indicate a greater probability of a break in the double DNA strand at this point (resulting in an increased frequency of nucleotide substitutions). The obtained estimations were determined by a previously developed complex of computer programs, which allows us to efficiently determine the frequency spectrum of oligonucleotides with a fixed length, to compare nucleotide frequencies in a larger sample (in addition to estimating the complexity of the phased sequences).