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

Abstract

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.

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

“…In this work, we verified our whole-genome sequence-based a priori hypothesis (derived in silico [ 41 ]) that human reproductive potential can diminish during self-domestication [ 42 ], as depicted in Figure 1 and described in the Section 3 .…”

“…As the bioinformatics model development, first of all, we compiled the set of all the 275 human genes whose effects on human reproductive potential have been a priori estimated by means of SNPs within their 70 bp proximal promoters in our previous articles on this matter [ 37 , 38 , 39 , 40 , 41 ] and, next, updated literary sources in line with the current state of PubMed [ 43 ], as shown in Figure 1 (Step-1) and presented in Table S1 (hereinafter, see Supplementary Materials ). Then, by means of PubMed [ 43 ], we compiled independent publicly available experimental in vivo RNA-Seq data sets on domestic versus wild animals [ 26 , 28 , 29 ], as depicted in Figure 1 (Step-2) and presented in Table 1 .…”

“…Within this model framework, we successfully confirmed ( Table 2 and Table 4 ) our a priori hypothesis (derived in silico) that human reproductive potential can diminish during self-domestication [ 42 ]. This hypothesis was formulated on the basis of our genome-wide sequence-based analysis of SNPs within 70 bp proximal promoters of human Y-linked genes [ 41 ]. As we presented in Table 2 , Table 3 , Table 4 , Table 5 and Table 6 , DEGs of domestic versus wild animals of the same species indicate genetic differences among all intergroup differences that are statistically significant in comparison with the variability within the species in question.…”

“…Here, we studied 275 human genes, which are described in Table S1 (see Supplementary Materials ) according to the results of our in silico analysis of the effect of the SNPs (located in proximal promoters) on human reproductive health [ 37 , 38 , 39 , 40 , 41 ]; the literature supporting these data was updated according to the current state of the PubMed database [ 43 ], as depicted in Figure 1 (Step-1).…”

“…In our previous works, we performed genome-wide analyses of single-nucleotide polymorphisms (SNPs) of TATA-binding protein (TBP)-binding sites in the promoters of genes associated with human reproductive health [ 37 , 38 , 39 , 40 , 41 ]. As a result of these bioinformatic estimates, we proposed that human reproductive potential diminishes during self-domestication [ 42 ].…”