Abstract
Gene regulatory factors (GRFs), such as transcription factors, co-factors and histone-modifying enzymes, play many important roles in modifying gene expression in biological processes. They have also been proposed to underlie speciation and adaptation. To investigate potential contributions of GRFs to primate evolution, we analyzed GRF genes in 27 publicly available primate genomes. Genes coding for zinc finger (ZNF) proteins, especially ZNFs with a Krüppel-associated box (KRAB) domain were the most abundant TFs in all genomes. Gene numbers per TF family differed between all species. To detect signs of positive selection in GRF genes we investigated more than 3,000 human GRFs with their more than 70,000 orthologs in 26 non-human primates. We implemented two independent tests for positive selection, the branch-site-model of the PAML suite and aBSREL of the HyPhy suite, focusing on the human and great ape branch. Our workflow included rigorous procedures to reduce the number of false positives: excluding distantly similar orthologs, manual corrections of alignments, and considering only genes and sites detected by both tests for positive selection. Furthermore, we verified the candidate sites for selection by investigating their variation within human and non-human great ape population data. In order to approximately assign a date to positively selected sites in the human lineage, we analyzed archaic human genomes. Our work revealed with high confidence five GRFs that have been positively selected on the human lineage and one GRF that has been positively selected on the great ape lineage. These GRFs are scattered on different chromosomes and have been previously linked to diverse functions. For some of them a role in speciation and/or adaptation can be proposed based on the expression pattern or association with human diseases, but it seems that they all contributed independently to human evolution. Four of the positively selected GRFs are KRAB-ZNF proteins, that induce changes in target genes co-expression and/or through arms race with transposable elements. Since each positively selected GRF contains several sites with evidence for positive selection, we suggest that these GRFs participated pleiotropically to phenotypic adaptations in humans.
Highlights
Phenotypic differences between individuals and species could be partly explained by the sequence differences in coding parts of genes, and partly by the variation in gene regulatory mechanisms (Lewontin, 1974; Wray, 2007; Wittkopp and Kalay, 2012; Lappalainen et al, 2013; Orgogozo et al, 2015; PerdomoSabogal et al, 2016; Anderson et al, 2020)
We excluded read-through transcripts and gene regulatory factors (GRFs) originating from recent duplication events in the human lineage, i.e., after Homo-Pan divergence, as no thorough orthology relationship could be established for those cases
177 studied GRFs were not dated by GenTree, half of them belonging to the zinc finger family previously seen as harboring many primatespecific genes (Nowick and Stubbs, 2010)
Summary
Phenotypic differences between individuals and species could be partly explained by the sequence differences in coding parts of genes, and partly by the variation in gene regulatory mechanisms (Lewontin, 1974; Wray, 2007; Wittkopp and Kalay, 2012; Lappalainen et al, 2013; Orgogozo et al, 2015; PerdomoSabogal et al, 2016; Anderson et al, 2020) The latter can be caused by changes in the DNA sequence of a regulatory region of a gene that could affect its expression (Siepel and Arbiza, 2014), as well as by changes in the sequence of so-called gene regulatory factors (GRFs) that could affect their target genes (Nowick et al, 2011; Perdomo-Sabogal et al, 2014). Non-deleterious evolutionary changes in GRFs regularly occur both within and outside functionally important regions in homeodomain- and zinc-finger (ZNF) proteins, among other GRF families, exemplifying their role for driving intra- and interspecific morphologic innovations and phenotypic diversity (Wagner and Lynch, 2008; Nowick et al, 2013; Perdomo-Sabogal et al, 2014)
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