A Rat Model of Human Behavior Provides Evidence of Natural Selection Against Underexpression of Aggressiveness-Related Genes in Humans

Abstract

Aggressiveness is a hereditary behavioral pattern that forms a social hierarchy and affects the individual social rank and accordingly quality and duration of life. Thus, genome-wide studies of human aggressiveness are important. Nonetheless, the aggressiveness-related genome-wide studies have been conducted on animals rather than humans. Recently, in our genome-wide study, we uncovered natural selection against underexpression of human aggressiveness-related genes and proved it using F1 hybrid mice. Simultaneously, this natural selection equally supports two opposing traits in humans (dominance and subordination) as if self-domestication could have happened with its disruptive natural selection. Because there is still not enough scientific evidence that this could happen, here, we verified this natural selection pattern using quantitative PCR and two outbred rat lines (70 generations of artificial selection for aggressiveness or tameness, hereinafter: domestication). We chose seven genes-Cacna2d3, Gad2, Gria2, Mapk1, Nos1, Pomc, and Syn1-over-or underexpression of which corresponds to aggressive or domesticated behavior (in humans or mice) that has the same direction as natural selection. Comparing aggressive male rats with domesticated ones, we found that these genes are overexpressed statistically significantly in the hypothalamus (as a universal behavior regulator), not in the periaqueductal gray, where there was no aggressiveness-related expression of the genes in males. Database STRING showed statistically significant associations of the human genes homologous to these rat genes with long-term depression, circadian entrainment, Alzheimer's disease, and the central nervous system disorders during chronic IL-6 overexpression. This finding more likely supports positive perspectives of further studies on self-domestication syndromes.

Neuromorphological changes following selection for tameness and aggression in the Russian fox-farm experiment

“…We found that selection on social behavior has altered the anatomy of distributed gray matter networks which included, among other regions, prefrontal cortex, hippocampus, amygdala, caudate, nucleus accumbens, cerebellum, and hypothalamus. This agrees generally with past findings in these foxes 19–23 and on the neural correlates of wolf-to-dog domestication 8–10,19–21,30–33 . Although some of our prefrontal results are located on the dorsolateral surface of the brain (i.e., the prorean gyrus), this region is likely not homologous to the granular dorsolateral prefrontal cortex of humans and macaque monkeys, as that region is thought to be unique to primates 34,35 .…”

“…These latter measurements revealed links with individual variation in behavior, including in brain regions that did not show volumetric differences, notably, the hypothalamus. Additionally, Network 3 consisted primarily of the hypothalamus and prefrontal cortex, two regions strongly implicated in both fox and dog domestication [8][9][10][19][20][21][30][31][32][33] . In this network, factor loadings did not differentiate the tame from aggressive strains; rather, the selectively-bred strains together were differentiated from the conventional strain ( Figure 3C).…”

Domestication Explains Two-Thirds of Differential-Gene-Expression Variance between Domestic and Wild Animals; The Remaining One-Third Reflects Intraspecific and Interspecific Variation

“…Behavioral "Glove" Test [20] respectively. Filled circles depict the statistically significant DEGs in the hypothalamus of tame vs. aggressive rats according to the independent qPCR-based identification published elsewhere [34]. These qPCR [34] and RNA-Seq [this work] data are given in Table S1, where their Pearson's linear correlation is statistically significant, r = 0.71 at p < 0.05 (hereinafter, see Supplementary Materials).…”

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

“…We developed our Web service SNP_TATA_Comparator 1 (Ponomarenko et al, 2015), whose input consists of two promoter DNA sequences representing ancestral and minor alleles of the SNP being examined; the software generates TBP-binding affinity estimates for these promoter alleles (± standard error) and significance α of their difference with Fisher's Z-test (Waardenberg et al, 2015). We applied it from SNP to SNP to predict their contribution to diseases [e.g., chronopathologies (Ponomarenko et al, 2016)] and selectively verified the obtained results using F1-hybrid mice , real-time polymerase chain reaction (Oshchepkov et al, 2019), RNA-Seq data (Vasiliev et al, 2021), gel retardation assay, stopped-flow spectrometry, biosensors, or bioluminescence, as reviewed (Ponomarenko et al, 2017). SNP_TATA_Comparator (Ponomarenko et al, 2015) is already used in independent clinical studies [e.g., in a pulmonary tuberculosis case-control study (Varzari et al, 2018)].…”