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

Natural Selection Equally Supports the Human Tendencies in Subordination and Domination: A Genome-Wide Study With in silico Confirmation and in vivo Validation in Mice

We proposed the following heuristic decision-making rule: “IF {an excess of a protein relating to the nervous system is an experimentally known physiological marker of low pain sensitivity, fast postinjury recovery, or aggressive, risk/novelty-seeking, anesthetic-like, or similar agonistic-intolerant behavior} AND IF {a single nucleotide polymorphism (SNP) causes overexpression of the gene encoding this protein} THEN {this SNP can be a SNP marker of the tendency in dominance} WHILE {underexpression corresponds to subordination} AND vice versa.” Using this decision-making rule, we analyzed 231 human genes of neuropeptidergic, non-neuropeptidergic, and neurotrophinergic systems that encode neurotrophic and growth factors, interleukins, neurotransmitters, receptors, transporters, and enzymes. These proteins are known as key factors of human social behavior. We analyzed all the 5,052 SNPs within the 70 bp promoter region upstream of the position where the protein-coding transcript starts, which were retrieved from databases Ensembl and dbSNP using our previously created public Web service SNP_TATA_Comparator (http://beehive.bionet.nsc.ru/cgi-bin/mgs/tatascan/start.pl). This definition of the promoter region includes all TATA-binding protein (TBP)-binding sites. A total of 556 and 552 candidate SNP markers contributing to the dominance and the subordination, respectively, were uncovered. On this basis, we determined that 231 human genes under study are subject to natural selection against underexpression (significance p < 0.0005), which equally supports the human tendencies in domination and subordination such as the norm of a reaction (plasticity) of the human social hierarchy. These findings explain vertical transmission of domination and subordination traits previously observed in rodent models. Thus, the results of this study equally support both sides of the century-old unsettled scientific debate on whether both aggressiveness and the social hierarchy among humans are inherited (as suggested by Freud and Lorenz) or are due to non-genetic social education, when the children are influenced by older individuals across generations (as proposed by Berkowitz and Fromm)

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

Transcription Factors as Important Regulators of Changes in Behavior through Domestication of Gray Rats: Quantitative Data from RNA Sequencing

Studies on hereditary fixation of the tame-behavior phenotype during animal domestication remain relevant and important because they are of both basic research and applied significance. In model animals, gray rats Rattus norvegicus bred for either an enhancement or reduction in defensive response to humans, for the first time, we used high-throughput RNA sequencing to investigate differential expression of genes in tissue samples from the tegmental region of the midbrain in 2-month-old rats showing either tame or aggressive behavior. A total of 42 differentially expressed genes (DEGs; adjusted p-value   2) were identified, with 20 upregulated and 22 downregulated genes in the tissue samples from tame rats compared with aggressive rats. Among them, three genes encoding transcription factors (TFs) were detected: Ascl3 was upregulated, whereas Fos and Fosb were downregulated in tissue samples from the brains of tame rats brain. Other DEGs were annotated as associated with extracellular matrix components, transporter proteins, the neurotransmitter system, signaling molecules, and immune system proteins. We believe that these DEGs encode proteins that constitute a multifactorial system determining the behavior for which the rats have been artificially selected. We demonstrated that several structural subtypes of E-box motifs—known as binding sites for many developmental TFs of the bHLH class, including the ASCL subfamily of TFs—are enriched in the set of promoters of the DEGs downregulated in the tissue samples of tame rats’. Because ASCL3 may act as a repressor on target genes of other developmental TFs of the bHLH class, we hypothesize that the expression of TF gene Ascl3 in tame rats indicates longer neurogenesis (as compared to aggressive rats), which is a sign of neoteny and domestication. Thus, our domestication model shows a new function of TF ASCL3: it may play the most important role in behavioral changes in animals

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 p p p > 0.1; binomial distribution), thus enforcing the norm (wild type)

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]

Plant_SNP_TATA_Z-Tester: A Web Service That Unequivocally Estimates the Impact of Proximal Promoter Mutations on Plant Gene Expression

Synthetic targeted optimization of plant promoters is becoming a part of progress in mainstream postgenomic agriculture along with hybridization of cultivated plants with wild congeners, as well as marker-assisted breeding. Therefore, here, for the first time, we compiled all the experimental data—on mutational effects in plant proximal promoters on gene expression—that we could find in PubMed. Some of these datasets cast doubt on both the existence and the uniqueness of the sought solution, which could unequivocally estimate effects of proximal promoter mutation on gene expression when plants are grown under various environmental conditions during their development. This means that the inverse problem under study is ill-posed. Furthermore, we found experimental data on in vitro interchangeability of plant and human TATA-binding proteins allowing the application of Tikhonov’s regularization, making this problem well-posed. Within these frameworks, we created our Web service Plant_SNP_TATA_Z-tester and then determined the limits of its applicability using those data that cast doubt on both the existence and the uniqueness of the sought solution. We confirmed that the effects (of proximal promoter mutations on gene expression) predicted by Plant_SNP_TATA_Z-tester correlate statistically significantly with all the experimental data under study. Lastly, we exemplified an application of Plant_SNP_TATA_Z-tester to agriculturally valuable mutations in plant promoters

Stress Reactivity, Susceptibility to Hypertension, and Differential Expression of Genes in Hypertensive Compared to Normotensive Patients

Although half of hypertensive patients have hypertensive parents, known hypertension-related human loci identified by genome-wide analysis explain only 3% of hypertension heredity. Therefore, mainstream transcriptome profiling of hypertensive subjects addresses differentially expressed genes (DEGs) specific to gender, age, and comorbidities in accordance with predictive preventive personalized participatory medicine treating patients according to their symptoms, individual lifestyle, and genetic background. Within this mainstream paradigm, here, we determined whether, among the known hypertension-related DEGs that we could find, there is any genome-wide hypertension theranostic molecular marker applicable to everyone, everywhere, anytime. Therefore, we sequenced the hippocampal transcriptome of tame and aggressive rats, corresponding to low and high stress reactivity, an increase of which raises hypertensive risk; we identified stress-reactivity-related rat DEGs and compared them with their known homologous hypertension-related animal DEGs. This yielded significant correlations between stress reactivity-related and hypertension-related fold changes (log2 values) of these DEG homologs. We found principal components, PC1 and PC2, corresponding to a half-difference and half-sum of these log2 values. Using the DEGs of hypertensive versus normotensive patients (as the control), we verified the correlations and principal components. This analysis highlighted downregulation of β-protocadherins and hemoglobin as whole-genome hypertension theranostic molecular markers associated with a wide vascular inner diameter and low blood viscosity, respectively

Additional file 1: of 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

Supplementary method. A quantitative sequence-based prediction of binding affinity of TATA-binding protein (TBP) for a human gene promoter. (PDF 161 kb