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

Abstract

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 < 0.01 and fold-change > 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.

Differentially Expressed Genes and Molecular Susceptibility to Human Age-Related Diseases

“…With this information in mind, we searched PubMed [ 75 ] and retrieved all available transcriptomes of domestic animals compared to their wild conspecifics ( Table 8 ). As can be seen from the bottom line of Table 8 , RNA-Seq data represent 2866 DEGs in eight tissues of seven domestic animal species compared to their seven wild conspecifics studied in ten original experimental works [ 68 , 74 , 204 , 205 , 206 , 207 , 208 , 209 , 210 , 211 ].…”

“…Downregulation of the human gene FCGR2B , which provides protection against infection, alleviates ARDs [ 117 , 118 ] and matches downregulation of the homologous genes Fcer2 , Fcgr2b , Fcgr3a , Fcgr3b , Fcrl1 , and Fcrl2 in wild rabbits [ 206 ], aggressive rats [ 68 , 204 ], and aggressive foxes [ 208 ] after they and their domestic conspecifics split from their most recent common ancestor ( Table 9 ).…”

“…By contrast, an excess of this immunosuppressor in humans aggravates the cellular-senescence-related immunogenic disease [ 119 , 120 ] and corresponds to the excess of its homologous immunoregulators in cavies [ 205 ], domestic rabbits [ 206 ], tame rats [ 68 , 204 ], and tame foxes [ 208 ] during their microevolution ( Table 9 ).…”

“…Because hypertension contributes to vascular aging [ 66 ] and vice versa, we have previously studied, within this mainstream paradigm, the inbred ISIAH (Inherited Stress-Induced Arterial Hypertension) rat strain [ 67 ] and sequenced transcriptomes in the brain stem [ 47 ], hypothalamus [ 48 ], renal medulla [ 49 ], renal cortex [ 50 ], and adrenal glands [ 51 ], with WAG rats used as controls. Additionally, we have recently obtained and compared transcriptomes of the midbrain tegmentum [ 68 ] in gray rats of a tame and an aggressive outbred strain [ 69 , 70 , 71 , 72 ]; this allowed us to identify, in in silico settings, potential molecular markers for neoteny, which has a power to reverse ARDs [ 73 ]. Furthermore, we have recently profiled transcriptomes in the hippocampus [ 74 ] of tame versus aggressive rat strains, in which deficient β-protocadherins and β-hemoglobin were found to be the statistically significantly most common theranostic molecular markers for ARD-related hypertension.…”

“…Furthermore, we have recently profiled transcriptomes in the hippocampus [ 74 ] of tame versus aggressive rat strains, in which deficient β-protocadherins and β-hemoglobin were found to be the statistically significantly most common theranostic molecular markers for ARD-related hypertension. That is why we sequenced, in the same way, one more transcriptome, that of the periaqueductal gray matter (PAG), in the tame versus aggressive rats, identified the corresponding behavior-related PAG-associated DEGs in them, and compared these DEGs with their homologous PubMed-based [ 75 ] ARD-linked DEGs in animals [ 30 , 32 , 35 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 68 , 74 ] and humans [ 33 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 ] to find out whether there are invariant molecular markers for such diseases among them.…”