Disruptive Selection of Human Immunostimulatory and Immunosuppressive Genes Both Provokes and Prevents Rheumatoid Arthritis, Respectively, as a Self-Domestication Syndrome.

Using our previously published Web service SNP_TATA_Comparator, we conducted a genome-wide study of single-nucleotide polymorphisms (SNPs) within core promoters of 68 human rheumatoid arthritis (RA)-related genes. Using 603 SNPs within 25 genes clinically associated with RA-comorbid disorders, we predicted 84 and 70 candidate SNP markers for overexpression and underexpression of these genes, respectively, among which 58 and 96 candidate SNP markers, respectively, can relieve and worsen RA as if there is a neutral drift toward susceptibility to RA. Similarly, we predicted natural selection toward susceptibility to RA for 8 immunostimulatory genes (e.g., IL9R) and 10 genes most often associated with RA (e.g., NPY). On the contrary, using 25 immunosuppressive genes, we predicted 70 and 109 candidate SNP markers aggravating and relieving RA, respectively (e.g., IL1R2 and TGFB2), suggesting that natural selection can simultaneously additionally yield resistance to RA. We concluded that disruptive natural selection of human immunostimulatory and immunosuppressive genes is concurrently elevating and reducing the risk of RA, respectively. So, we hypothesize that RA in human could be a self-domestication syndrome referring to evolution patterns in domestic animals. We tested this hypothesis by means of public RNA-Seq data on 1740 differentially expressed genes (DEGs) of pets vs. wild animals (e.g., dogs vs. wolves). The number of DEGs in the domestic animals corresponding to worsened RA condition in humans was significantly larger than that in the related wild animals (10 vs. 3). Moreover, much less DEGs in the domestic animals were accordant to relieved RA condition in humans than those in the wild animals (1 vs. 8 genes). This indicates that the anthropogenic environment, in contrast to a natural one, affects gene expression across the whole genome (e.g., immunostimulatory and immunosuppressive genes) in a manner that likely contributes to RA. The difference in gene numbers is statistically significant as confirmed by binomial distribution (p < 0.01), Pearson's χ2 (p < 0.01), and Fisher's exact test (p < 0.05). This allows us to propose RA as a candidate symptom within a self-domestication syndrome. Such syndrome might be considered as a human's payment with health for the benefits received during evolution.

A Bioinformatics Model of Human Diseases on the Basis of Differentially Expressed Genes (of Domestic Versus Wild Animals) That Are Orthologs of Human Genes Associated with Reproductive-Potential Changes.

Earlier, after our bioinformatic analysis of single-nucleotide polymorphisms of TATA-binding protein-binding sites within gene promoters on the human Y chromosome, we suggested that human reproductive potential diminishes during self-domestication. Here, we implemented bioinformatics models of human diseases using animal in vivo genome-wide RNA-Seq data to compare the effect of co-directed changes in the expression of orthologous genes on human reproductive potential and during the divergence of domestic and wild animals from their nearest common ancestor (NCA). For example, serotonin receptor 3A (HTR3A) deficiency contributes to sudden death in pregnancy, consistently with Htr3a underexpression in guinea pigs (Cavia porcellus) during their divergence from their NCA with cavy (C. aperea). Overall, 25 and three differentially expressed genes (hereinafter, DEGs) in domestic animals versus 11 and 17 DEGs in wild animals show the direction consistent with human orthologous gene-markers of reduced and increased reproductive potential. This indicates a reliable association between DEGs in domestic animals and human orthologous genes reducing reproductive potential (Pearson's χ2 test p < 0.001, Fisher's exact test p < 0.05, binomial distribution p < 0.0001), whereas DEGs in wild animals uniformly match human orthologous genes decreasing and increasing human reproductive potential (p > 0.1; binomial distribution), thus enforcing the norm (wild type).

Disruptive natural selection by male reproductive potential prevents underexpression of protein-coding genes on the human Y chromosome as a self-domestication syndrome.

BACKGROUND: In population ecology, the concept of reproductive potential denotes the most vital indicator of chances to produce and sustain a healthy descendant until his/her reproductive maturity under the best conditions. This concept links quality of life and longevity of an individual with disease susceptibilities encoded by his/her genome. Female reproductive potential has been investigated deeply, widely, and comprehensively in the past, but the male one has not received an equal amount of attention. Therefore, here we focused on the human Y chromosome and found candidate single-nucleotide polymorphism (SNP) markers of male reproductive potential. RESULTS: Examining in silico (i.e., using our earlier created Web-service SNP_TATA_Z-tester) all 1206 unannotated SNPs within 70 bp proximal promoters of all 63 Y-linked genes, we found 261 possible male-reproductive-potential SNP markers that can significantly alter the binding affinity of TATA-binding protein (TBP) for these promoters. Among them, there are candidate SNP markers of spermatogenesis disorders (e.g., rs1402972626), pediatric cancer (e.g., rs1483581212) as well as male anxiety damaging family relationships and mother's and children's health (e.g., rs187456378). First of all, we selectively verified in vitro both absolute and relative values of the analyzed TBP-promoter affinity, whose Pearson's coefficients of correlation between predicted and measured values were r = 0.84 (significance p <  0.025) and r = 0.98 (p <  0.025), respectively. Next, we found that there are twofold fewer candidate SNP markers decreasing TBP-promoter affinity relative to those increasing it, whereas in the genome-wide norm, SNP-induced damage to TBP-promoter complexes is fourfold more frequent than SNP-induced improvement (p <  0.05, binomial distribution). This means natural selection against underexpression of these genes. Meanwhile, the numbers of candidate SNP markers of an increase and decrease in male reproductive potential were indistinguishably equal to each other (p <  0.05) as if male self-domestication could have happened, with its experimentally known disruptive natural selection. Because there is still not enough scientific evidence that this could have happened, we discuss the human diseases associated with candidate SNP markers of male reproductive potential that may correspond to domestication-related disorders in pets. CONCLUSIONS: Overall, our findings seem to support a self-domestication syndrome with disruptive natural selection by male reproductive potential preventing Y-linked underexpression of a protein.

Unannotated single nucleotide polymorphisms in the TATA box of erythropoiesis genes show in vitro positive involvements in cognitive and mental disorders.

BACKGROUND: Hemoglobin is a tetramer consisting of two α-chains and two ß-chains of globin. Hereditary aberrations in the synthesis of one of the globin chains are at the root of thalassemia, one of the most prevalent monogenic diseases worldwide. In humans, in addition to α- and ß-globins, embryonic zeta-globin and fetal γ-globin are expressed. Immediately after birth, the expression of fetal Aγ- and Gγ-globin ceases, and then adult ß-globin is mostly expressed. It has been shown that in addition to erythroid cells, hemoglobin is widely expressed in nonerythroid cells including neurons of the cortex, hippocampus, and cerebellum in rodents; embryonic and adult brain neurons in mice; and mesencephalic dopaminergic brain cells in humans, mice, and rats. Lately, there is growing evidence that different forms of anemia (changes in the number and quality of blood cells) may be involved in (or may accompany) the pathogenesis of various cognitive and mental disorders, such as Alzheimer's and Parkinson's diseases, depression of various severity levels, bipolar disorders, and schizophrenia. Higher hemoglobin concentrations in the blood may lead to hyperviscosity, hypovolemia, and lung diseases, which may cause brain hypoxia and anomalies of brain function, which may also result in cognitive deficits. METHODS: In this study, a search for unannotated single-nucleotide polymorphisms (SNPs) of erythroid genes was initially performed using our previously created and published SNP-TATA_Z-tester, which is a Web service for computational analysis of a given SNP for in silico estimation of its influence on the affinity of TATA-binding protein (TBP) for TATA and TATA-like sequences. The obtained predictions were finally verified in vitro by an electrophoretic mobility shift assay (EMSA). RESULTS: On the basis of these experimental in vitro results and literature data, we studied TATA box SNPs influencing both human erythropoiesis and cognitive abilities. For instance, TBP-TATA affinity in the HbZ promoter decreases 6.6-fold as a result of a substitution in the TATA box (rs113180943), thereby possibly disrupting stage-dependent events of "switching" of hemoglobin genes and thus causing erythroblastosis. Therefore, rs113180943 may be a candidate marker of severe hemoglobinopathies with comorbid cognitive and mental disorders associated with cerebral blood flow disturbances. CONCLUSIONS: The literature data and experimental and computations results suggest that the uncovered candidate SNP markers of erythropoiesis anomalies may also be studied in cohorts of patients with cognitive and/or mental disorders with comorbid erythropoiesis diseases in comparison to conventionally healthy volunteers. Research into the regulatory mechanisms by which the identified SNP markers contribute to the development of hemoglobinopathies and of the associated cognitive deficits will allow physicians not only to take timely and adequate measures against hemoglobinopathies but also to implement strategies preventing cognitive and mental disorders.

Candidate SNP Markers of Atherogenesis Significantly Shifting the Affinity of TATA-Binding Protein for Human Gene Promoters show stabilizing Natural Selection as a Sum of Neutral Drift Accelerating Atherogenesis and Directional Natural Selection Slowing It.

(1) Background: The World Health Organization (WHO) regards atherosclerosis-related myocardial infarction and stroke as the main causes of death in humans. Susceptibility to atherogenesis-associated diseases is caused by single-nucleotide polymorphisms (SNPs). (2) Methods: Using our previously developed public web-service SNP_TATA_Comparator, we estimated statistical significance of the SNP-caused alterations in TATA-binding protein (TBP) binding affinity for 70 bp proximal promoter regions of the human genes clinically associated with diseases syntonic or dystonic with atherogenesis. Additionally, we did the same for several genes related to the maintenance of mitochondrial genome integrity, according to present-day active research aimed at retarding atherogenesis. (3) Results: In dbSNP, we found 1186 SNPs altering such affinity to the same extent as clinical SNP markers do (as estimated). Particularly, clinical SNP marker rs2276109 can prevent autoimmune diseases via reduced TBP affinity for the human MMP12 gene promoter and therefore macrophage elastase deficiency, which is a well-known physiological marker of accelerated atherogenesis that could be retarded nutritionally using dairy fermented by lactobacilli. (4) Conclusions: Our results uncovered SNPs near clinical SNP markers as the basis of neutral drift accelerating atherogenesis and SNPs of genes encoding proteins related to mitochondrial genome integrity and microRNA genes associated with instability of the atherosclerotic plaque as a basis of directional natural selection slowing atherogenesis. Their sum may be stabilizing the natural selection that sets the normal level of atherogenesis.

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

BACKGROUND: The 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. RESULTS: A 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. CONCLUSIONS: According 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.

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 Alzheimer's 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].

Obesity-related known and candidate SNP markers can significantly change affinity of TATA-binding protein for human gene promoters.

BACKGROUND: Obesity affects quality of life and life expectancy and is associated with cardiovascular disorders, cancer, diabetes, reproductive disorders in women, prostate diseases in men, and congenital anomalies in children. The use of single nucleotide polymorphism (SNP) markers of diseases and drug responses (i.e., significant differences of personal genomes of patients from the reference human genome) can help physicians to improve treatment. Clinical research can validate SNP markers via genotyping of patients and demonstration that SNP alleles are significantly more frequent in patients than in healthy people. The search for biomedical SNP markers of interest can be accelerated by computer-based analysis of hundreds of millions of SNPs in the 1000 Genomes project because of selection of the most meaningful candidate SNP markers and elimination of neutral SNPs. RESULTS: We cross-validated the output of two computer-based methods: DNA sequence analysis using Web service SNP_TATA_Comparator and keyword search for articles on comorbidities of obesity. Near the sites binding to TATA-binding protein (TBP) in human gene promoters, we found 22 obesity-related candidate SNP markers, including rs10895068 (male breast cancer in obesity); rs35036378 (reduced risk of obesity after ovariectomy); rs201739205 (reduced risk of obesity-related cancers due to weight loss by diet/exercise in obese postmenopausal women); rs183433761 (obesity resistance during a high-fat diet); rs367732974 and rs549591993 (both: cardiovascular complications in obese patients with type 2 diabetes mellitus); rs200487063 and rs34104384 (both: obesity-caused hypertension); rs35518301, rs72661131, and rs562962093 (all: obesity); and rs397509430, rs33980857, rs34598529, rs33931746, rs33981098, rs34500389, rs63750953, rs281864525, rs35518301, and rs34166473 (all: chronic inflammation in comorbidities of obesity). Using an electrophoretic mobility shift assay under nonequilibrium conditions, we empirically validated the statistical significance (α < 0.00025) of the differences in TBP affinity values between the minor and ancestral alleles of 4 out of the 22 SNPs: rs200487063, rs201381696, rs34104384, and rs183433761. We also measured half-life (t1/2), Gibbs free energy change (ΔG), and the association and dissociation rate constants, ka and kd, of the TBP-DNA complex for these SNPs. CONCLUSIONS: Validation of the 22 candidate SNP markers by proper clinical protocols appears to have a strong rationale and may advance postgenomic predictive preventive personalized medicine.

The mechanism by which TATA-box polymorphisms associated with human hereditary diseases influence interactions with the TATA-binding protein.

SNPs in ТАТА boxes are the cause of monogenic diseases, contribute to a large number of complex diseases, and have implications for human sensitivity to external and internal environmental signals. The aim of this work was to explore the kinetic characteristics of the formation of human ТВР complexes with ТАТА boxes, in which the SNPs are associated with ß-thalassemias of diverse severity, immunosuppression, neurological disorders, and so on. It has for the first time been demonstrated, using an electrophoretic mobility shift assay, that TBP interacts with SNP-containing ТАТА boxes with a significant (8-36-fold) decrease in TBP/ТАТА association rate constant (ka ) as compared with that in healthy people, a smaller decrease in dissociation rate constant (kd ) and changes in the half-lives of TBP/ТАТА complexes. Carriers of the -24G allele (rs 1800202T>G) in the TATA box of the triosephosphate isomerase gene promoter, associated with neurological and muscular disorders, were observed to have a 36-fold decrease in TBP/TATA association rate constant that are consistent with TPI deficiency shown for patients who carry this defective allele. The kinetic characteristics of TBP/ТАТА complexes obtained suggest that, at a molecular level, hereditary diseases are largely caused by changes in TBP/ТАТА association rates and these changes have a bearing on disease severity.

An experimental verification of the predicted effects of promoter TATA-box polymorphisms associated with human diseases on interactions between the TATA boxes and TATA-binding protein.

Human genome sequencing has resulted in a great body of data, including a stunningly large number of single nucleotide polymorphisms (SNPs) with unknown phenotypic manifestations. Identification and comprehensive analysis of regulatory SNPs in human gene promoters will help quantify the effects of these SNPs on human health. Based on our experimental and computer-aided study of SNPs in TATA boxes and the use of literature data, we have derived an equation for TBP/TATA equilibrium binding in three successive steps: TATA-binding protein (TBP) sliding along DNA due to their nonspecific affinity for each other ↔ recognition of the TATA box ↔ stabilization of the TBP/TATA complex. Using this equation, we have analyzed TATA boxes containing SNPs associated with human diseases and made in silico predictions of changes in TBP/TATA affinity. An electrophoretic mobility shift assay (EMSA)-based experimental study performed under the most standardized conditions demonstrates that the experimentally measured values are highly correlated with the predicted values: the coefficient of linear correlation, r, was 0.822 at a significance level of α<10⁻7 for equilibrium K(D) values, (-ln K(D)), and 0.785 at a significance level of α<10⁻³ for changes in equilibrium K(D) (δ) due to SNPs in the TATA boxes (δ= -ln[K(D,TATAMut)]-(-ln[K(D,TATAMut)])). It has been demonstrated that the SNPs associated with increased risk of human diseases such as α-, ß- and δ-thalassemia, myocardial infarction and thrombophlebitis, changes in immune response, amyotrophic lateral sclerosis, lung cancer and hemophilia B Leyden cause 2-4-fold changes in TBP/TATA affinity in most cases. The results obtained strongly suggest that the TBP/TATA equilibrium binding equation derived can be used for analysis of TATA-box sequences and identification of SNPs with a potential of being functionally important.