Differences in human and chimpanzee gene expression patterns define an evolving network of transcription factors in brain

Abstract

Humans differ from other primates by marked differences in cognitive abilities and a significantly larger brain. These differences correlate with metabolic changes, as evidenced by the relative up-regulation of energy-related genes and metabolites in human brain. While the mechanisms underlying these evolutionary changes have not been elucidated, altered activities of key transcription factors (TFs) could play a pivotal role. To assess this possibility, we analyzed microarray data from five tissues from humans and chimpanzees. We identified 90 TF genes with significantly different expression levels in human and chimpanzee brain among which the rapidly evolving KRAB-zinc finger genes are markedly over-represented. The differentially expressed TFs cluster within a robust regulatory network consisting of two distinct but interlinked modules, one strongly associated with energy metabolism functions, and the other with transcription, vesicular transport, and ubiquitination. Our results suggest that concerted changes in a relatively small number of interacting TFs may coordinate major gene expression differences in human and chimpanzee brain.comparative transcriptomics ͉ KRAB-zinc finger genes ͉ primate evolution ͉ gene regulatory network evolution H umans differ from chimpanzees in a number of important anatomical and physiological respects, most strikingly in our enhanced cognitive abilities and a substantial increase in the relative size of the human brain (1). Although the human brain is relatively energy-efficient per cell compared with brains of other species, this increased capacity imposes a significant metabolic and oxidative burden (2, 3). Several studies have noted the up-regulation of genes and metabolites involved in oxidative metabolism and mitochondrial function in human brains compared with chimpanzee brains (2, 4, 5). These data, together with evidence of positive selection acting on the promoters of genes involved in energy metabolism during human evolution, indicate that increased energy production has been essential to the evolution of the human brain (6). The relative up-regulation of human genes in other functional categories, including neuroprotection and synaptic transport, has also been documented (7). However, the molecular mechanisms underlying these welldocumented species differences have not been elucidated.Although some differences in human-chimpanzee gene expression may be due to cis-regulatory element divergence, transcription factors (TFs) represent another potential source of expression variability. Whereas most cis-element mutations would be expected to have limited, localized effects, alterations in TF sequence and/or expression could alter the expression of hundreds of target genes in a coordinated fashion (8, 9). Because of these predicted consequences, it is often assumed that TFs are evolutionarily stable, and indeed, TFs as a class are structurally well conserved (8). However, two recent studies have identified TF genes as enriched among genes with expression patterns that are ...

Widespread establishment and regulatory impact of Alu exons in human genes

“…Moreover, over one-third of transcription factor genes differentially expressed between human and chimpanzee brains encode ZNF transcription factors (20). It has been proposed that these genes function as master regulators of transcriptome evolution and could contribute to the transcriptional and phenotypic differences between humans and nonhuman primates (18,20). Our results reveal Alu exonization as an important mechanism in the lineage-specific regulatory evolution of ZNF genes.…”

“…Approximately 25% of ZNF genes in the human genome are primatespecific, and the majority of ZNF gene groups with primatespecific expansion were subject to strong positive selection according to nonsynonymous/synonymous substitution rate (dN/ dS) analysis (18). Moreover, over one-third of transcription factor genes differentially expressed between human and chimpanzee brains encode ZNF transcription factors (20). It has been proposed that these genes function as master regulators of transcriptome evolution and could contribute to the transcriptional and phenotypic differences between humans and nonhuman primates (18,20).…”

“…Interestingly, ZNF genes underwent rapid expansion and adaptive evolution during primate and human evolution (18,19). Therefore, they have been considered key contributors to lineage-specific transcriptome regulation in primates and humans (18,20).…”

KRAB zinc finger proteins

“…It is thus interesting to note that remarkably elevated levels of TE activity have been recorded in the brain (Erwin et al, 2014), that a higher range of KRAB-ZFPs is expressed in the brain than in most other adult human tissues , and that KRABZFPs disproportionately contribute to differences between the brain gene networks of chimpanzees and humans (Nowick et al, 2009). These observations suggest that the endovirome and its KRAB-ZFP controllers could have played an important role in the expansion of higher brain functions that were key to the emergence of modern humans.…”

Genomic approaches to studying human-specific developmental traits

“…Functional genomics also provides a means to probe human and non-human cells directly for differences in regulatory regions and gene expression (Nowick et al, 2009;Somel et al, 2011), which can then be traced back to genetic determinants. For example, combined analysis of human and chimpanzee gene expression data and sequences suggested that pain perception and nociception may have changed in humans through differential regulation of opioid signaling (Cruz-Gordillo et al, 2010).…”