What drove the evolution of humans and hominids: the case study of core promoters evolution
Whole-genome comparisons of protein-coding sequences between humans and chimpanzees or gorilla suggest that they differ by 1‑2% only, which is in sharp contrast with the significant morphological and ecological differences. There are sets of functionally-related genes, which are most strongly driven by adaptive evolution. In all three species, the primary evolving entities were spermatogenesis, receptors, the immune system, genes for signal transduction (for example, G-proteins) and embryogenesis regulation [1-5]. It was anticipated that the elevated rate of the evolution of certain brain genes observed in the human lineage would be species-specific. However, to date a very few genes have been found showing prominent brain-specific expression along with a signature of an adaptive evolution of protein-coding sequences in humans, but not in other anthropoids [1-5]. Missense- or loss-of-function mutations in genes showing accelerated evolution in human lineage may lead to severe pathologies and can be deleterious in human and animal populations . It is conceivable that the selection acting on compensatory genetic variants interfering with deleterious mutations may also contribute to the process of adaptive evolution. Modern humans possess at least one feature that makes them be strongly different from anthropoids (chimpanzee and gorilla): the broad tolerances to the environment or, as Th. Dobzhansky spoke – “man is genetically specialized to be unspecialized” . As a result, humans can live in a broad spectrum of habitats and landscapes, spreading across the continents [7-9]. This broad tolerance to the environment is associated with a widening norm-of-reaction  of the genotype . Consequently, the sought-for hominoid-specific vector of selection may have been directed at widening the norm-of-reaction, that is, being associated not so much with the reduced or increased level of expression of the specific genes as with the enhanced regulatory plasticity of the genes or ability to vary the gene expression level within a broad range. To our knowledge no search for evidence of such selection using whole-genome data has been performed as yet.
In this study, we focused on the structural and functional evolution of the core promoters of human genes, especially of those expressed in the brain prefrontal cortex. In 2011, a map with TATA-box locations for 17181 human genes was reported . At that time, the map was exclusively based on Cap-analysis gene expression (CAGE) data counting capped 5′ ends of transcript sequences. At present, the location of a gene promoter is considered to be clearly determined if more than one independent experimental approaches identifies the same position [13, 14]. In this study, the positions of promoters were inferred from two independent sources of experimental information: 1) CAGE data obtained from a large number of tissue-specific experiments, and 2) СhIP-seq data revealing the presence of transcriptionally active promoters in certain genomic regions marked by trimethylated histones H3K4 (H3K4me3), a chromatin protein associated with transcriptional start sites (TSS). According to modern views, transcription does not proceed continuously, but by jerks called “transcriptional bursts”, the magnitude of which “is a promoter-specific property that is relatively robust to sequence mutations but is strongly dependent on the interaction between the TATA box and promoter nucleosomes” , which, in turn, is dependent on the abundance of CG dinucleotides in the promoter . Moreover, there are a plenty of papers arguing whether increasing CpG sites (DNA regions enriched with CG dinucleotides) in a promoter can increase the range of transcriptional levels [17, 18]. Considering this view, we have performed an analysis of the evolution of three features of the upstream region of core promoter [‑600; -1]: (1) appearance or disappearance of CG dinucleotides, (2) predicted nucleosomal packing levels (nucleosome/DNA affinity), and (3) predicted affinity for TATA-binding protein (TBP/DNA affinity).
As a result, we demonstrated that the trend to increased spectrum regulatory capacities for the core promoters of genes accumulated during the evolution of two ancestral lineages preceding the divergences the ancestor of all hominids (humans, chimpanzee and gorilla) and the divergence of chimpanzee and humans was continued in the evolution of human lineage. In the anthropoid lineages (chimpanzee, gorilla and orangutan), the reverse is true: changes in promoters that narrow this spectrum prevail. This implies that, first, the origin of Homo sapiens is associated with a selection for widening the norm-of-reaction of gene expression regulation. Second, by contrast, the origins of the three ape species (especially gorilla and chimpanzee) are associated with a species-specific selection for narrowing the norm-of-reaction of gene expression regulation. Third, the selective trend towards widening the norm-of-reaction of gene regulation in the hominids is quite ancient – at least more ancient than the chimpanzee/humans split event occurring 5-6 million years ago.
17. Frith MC, FANTOM consortium. Explaining the correlations among properties of mammalian promoters. Nucleic Acids Res 2014;42:4823-4832.
18. Tatarinova T et al. Cross-species analysis of genic GC3 content and DNA methylation patterns. Genome Biol Evol. 2013;5:1443-1456.