Abstract
Social behavior and neuronal connectivity in rodents have been shown to be shaped by the prototypical T lymphocyte-derived pro-inflammatory cytokine Interferon-gamma (IFNγ). It has also been demonstrated that STAT1 (Signal Transducer And Activator Of Transcription 1), a transcription factor (TF) crucially involved in the IFNγ pathway, binds consensus sequences that, in humans, are located with a high frequency in the LTRs (Long Terminal Repeats) of the MER41 family of primate-specific HERVs (Human Endogenous Retroviruses). However, the putative role of an IFNγ/STAT1/MER41 pathway in human cognition and/or behavior is still poorly documented. Here, we present evidence that the promoter regions of intellectual disability-associated genes are uniquely enriched in LTR sequences of the MER41 HERVs. This observation is specific to MER41 among more than 130 HERVs examined. Moreover, we have not found such a significant enrichment in the promoter regions of genes that associate with autism spectrum disorder (ASD) or schizophrenia. Interestingly, ID-associated genes exhibit promoter-localized MER41 LTRs that harbor TF binding sites (TFBSs) for not only STAT1 but also other immune TFs such as, in particular, NFKB1 (Nuclear Factor Kappa B Subunit 1) and STAT3 (Signal Transducer And Activator Of Transcription 3). Moreover, IL-6 (Interleukin 6) rather than IFNγ, is identified as the main candidate cytokine regulating such an immune/MER41/cognition pathway. Of note, differences between humans and chimpanzees are observed regarding the insertion sites of MER41 LTRs in the promoter regions of ID-associated genes. Finally, a survey of the human proteome has allowed us to map a protein-protein network which links the identified immune/MER41/cognition pathway to FOXP2 (Forkhead Box P2), a key TF involved in the emergence of human speech. Our work suggests that together with the evolution of immune genes, the stepped self-domestication of MER41 in the genomes of primates could have contributed to cognitive evolution. We further propose that non-inherited forms of ID might result from the untimely or quantitatively inappropriate expression of immune signals, notably IL-6, that putatively regulate cognition-associated genes via promoter-localized MER41 LTRs.
Highlights
Interferon gamma (IFNγ), the prototypical T Helper 1 (TH1) cytokine, is a T-cell derived pro-inflammatory molecule exerting several effects on innate immune cells and others on nonimmune cells including neurons (Litteljohn et al, 2014)
We found that the promoter regions of genes causatively linked to genetically determined intellectual disability (ID) are highly significantly enriched in Long Terminal Repeats (LTRs) sequences of the MER41 family
In the human genome, the promoter regions of ID-associated genes are uniquely enriched in MER41 LTRs
Summary
Interferon gamma (IFNγ), the prototypical T Helper 1 (TH1) cytokine, is a T-cell derived pro-inflammatory molecule exerting several effects on innate immune cells and others on nonimmune cells including neurons (Litteljohn et al, 2014). It was recently hypothesized that the horizontal transfer of genetic material by viral and non-viral vectors might have prompted the emergence of language in the human species (Benítez-Burraco and Uriagereka, 2016) To address these issues, we followed a bioinformatics workflow relying on the use of two recently generated web tools allowing a survey of HERV sequences and their associated transcription factor binding sites (TFBSs) in the entire human genome. We followed a bioinformatics workflow relying on the use of two recently generated web tools allowing a survey of HERV sequences and their associated transcription factor binding sites (TFBSs) in the entire human genome Using this approach, we found that the promoter regions of genes causatively linked to genetically determined intellectual disability (ID) are highly significantly enriched in LTR sequences of the MER41 family. This way, we were able to unravel a HERV-driven evolutionary-determined connection between cognition and immunity with a potential impact on language evolution and the pathophysiology of ID
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