Evolution is in the details: Regulatory differences in modern human and Neanderthal

Barker, Harlan; Parkkila, Seppo; Tolvanen, Martti

doi:10.1101/2020.09.04.282749

Cited by 5 publications

(5 citation statements)

References 152 publications

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“…This proportion is substantial, considering that all cis-eQTLs are estiamted to be responsible for only ∼6% of expression variation. Consistent with other previous studies that have investigated the regulatory importance of Neandertal DNA and its potential phenotypic consequences for present-day people ( Gittelman et al 2016 ; Dannemann et al 2017 ; McCoy et al 2017 ; Colbran et al 2019 ; Petr et al 2019 ; Silvert et al 2019 ; Gokhman et al 2020 ; Barker et al . 2020 ; Telis et al 2020 ) we show that the inferred genome-wide long-range regulatory implication of archaic DNA that we investigated in our study is associated with various phenotypic effects and some of the underlying archaic variants potential targets of positive selection.…”

Section: Discussionsupporting

confidence: 92%

Long-range regulatory effects of Neandertal DNA in modern humans

et al. 2022

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The admixture between modern humans and Neandertals has resulted in ∼2% of the genomes of present-day non-Africans being composed of Neandertal DNA. Introgressed Neandertal DNA has been demonstrated to significantly affect the transcriptomic landscape in people today and via this molecular mechanism influence phenotype variation as well. However, little is known about how much of that regulatory impact is mediated through long-range regulatory effects that have been shown to explain ∼20% of expression variation. Here we identified 60 transcription factors (TFs) with their top cis-eQTL SNP in GTEx being of Neandertal ancestry and predicted long-range Neandertal DNA-induced regulatory effects by screening for the predicted target genes of those TFs. We show that the TFs form a significantly connected protein-protein interaction network. Among them are JUN and PRDM5, two brain-expressed TFs that have their predicted target genes enriched in regions devoid of Neandertal DNA. Archaic cis-eQTLs for the 60 TFs include multiple candidates for local adaptation, some of which show significant allele frequency increases over the last ∼10,000 years. A large proportion of the cis-eQTL-associated archaic SNPs have additional associations with various immune traits, schizophrenia, blood cell type composition and anthropometric measures. Finally, we demonstrate that our results are consistent with those of Neandertal-DNA-associated empirical trans-eQTLs. Our results suggest that Neandertal DNA significantly influences regulatory networks, that its regulatory reach goes beyond the 40% of genomic sequence that it still covers in present-day non-Africans and that via the investigated mechanism Neandertal DNA influences the phenotypic variation in people today.

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Section: Discussionsupporting

confidence: 92%

Long-range regulatory effects of Neandertal DNA in modern humans

et al. 2022

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“…This proportion is substantial, considering that all cis-eQTLs are estiamted to be responsible for only ∼6% of expression variation. Consistent with other previous studies that have investigated the regulatory importance of Neandertal DNA and its potential phenotypic consequences for present-day people (Barker et al, 2020; Colbran et al, 2019; Dannemann et al, 2017; Gittelman et al, 2016; Gokhman et al, 2020; McCoy et al, 2017; Petr et al, 2019; Silvert et al, 2019; Telis et al, 2020) we show that the inferred genome-wide long-range regulatory implication of archaic DNA that we investigated in our study is associated with various phenotypic effects and some of the underlying archaic variants potential targets of positive selection.…”

Section: Discussionsupporting

confidence: 92%

“…It remains challenging to computationally reconstruct regulatory mechanisms and therefore fully reconstruct the regulatory role of Neandertal DNA through its interaction with TFs. However, the results of our study and other previous work that investigated the impact of Neandertal DNA on the modification of TF binding motif sequences [59,60] have demonstrated the importance of studying the interaction of Neandertal DNA and TF activity in the quest to complete the picture of the impact of Neandertal introgression on the transcriptomic landscape of people today.…”

Section: Discussionmentioning

confidence: 55%

Long-range regulatory effects of Neandertal DNA in modern humans

Yermakovich

Pankratov

Võsa

et al. 2021

Preprint

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The admixture between modern humans and Neandertals has resulted in ~2% of the genomes of present-day non-Africans still being composed of Neandertal DNA. Association studies have shown that introgressed DNA still significantly influences skin and hair traits, immunity and behavioral phenotypes in people today. Several of the phenotype-associated archaic variants had links to regulatory effects as well. In general, analyses of allele-specific expression, regulatory sequence composition and cis-eQTL have demonstrated a significant contribution of this introgressed DNA to the transcriptomic landscape in people today. However, little is known about the impact of Neandertal DNA on trans-eQTLs - long-range regulatory effects that have been shown to explain ~20% of expression variation. Here, we used blood eQTL results from >30,000 individuals from eQTLGen Consortium. The cohort size allowed for a robust identification of trans-eQTLs and in addition enabled quantifying the role of transcription factors (TF) in mediating long-range regulatory effects. In our study we used this information to (i) annotate trans-eQTLs that are linked to Neandertal variants and (ii) predict long-range regulatory effects that are induced by Neandertal DNA by screening for the predicted target genes of TFs that are cis-eQTLs linked to Neandertal variants. We show that both trans-eQTL-associated Neandertal variants and those predicted to have long-range regulatory effects affect genes in genomic regions devoid of Neandertal DNA. In addition, both types of variants included candidates for local adaptation and show associations with autoimmune disorders, a severe Covid-19 phenotype, blood cell type composition and anthropometric measures. Our results suggest that the regulatory reach of Neandertal DNA goes beyond the 40% of genomic sequence that it still covers in present-day non-Africans and that via this mechanism Neandertal DNA additionally influences the phenotypic variation in people today.

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“…We have previously used patterns of cytosine degradation in ancient samples to reconstruct whole-genome archaic DNA methylation maps ( Gokhman et al, 2020 ; Gokhman et al, 2014 ; Gokhman et al, 2016 ). However, despite various approaches to extract regulatory information from ancient genomes ( Yan and McCoy, 2020 ; Colbran, 2019 ; Gokhman et al, 2016 ; Barker et al, 2020 ; Batyrev et al, 2019 ; Pedersen et al, 2014 ; Silvert et al, 2019 ; Moriano and Boeckx, 2020 ), our understanding of gene regulation in archaic humans remains minimal, with most archaic regulatory information being currently inaccessible ( Yan and McCoy, 2020 ). Additionally, whereas expression quantitative trait locus (eQTL) mapping can be used to identify variants that drive differential expression between individuals, it can only be applied to loci that are variable within the present-day human population.…”

Section: Introductionmentioning

confidence: 99%

The cis-regulatory effects of modern human-specific variants

Weiss

Harshman

Inoue

et al. 2021

eLife

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The Neanderthal and Denisovan genomes enabled the discovery of sequences that differ between modern and archaic humans, the majority of which are noncoding. However, our understanding of the regulatory consequences of these differences remains limited, in part due to the decay of regulatory marks in ancient samples. Here, we used a massively parallel reporter assay in embryonic stem cells, neural progenitor cells, and bone osteoblasts to investigate the regulatory effects of the 14,042 single-nucleotide modern human-specific variants. Overall, 1791 (13%) of sequences containing these variants showed active regulatory activity, and 407 (23%) of these drove differential expression between human groups. Differentially active sequences were associated with divergent transcription factor binding motifs, and with genes enriched for vocal tract and brain anatomy and function. This work provides insight into the regulatory function of variants that emerged along the modern human lineage and the recent evolution of human gene expression.

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Evolution is in the details: Regulatory differences in modern human and Neanderthal

Cited by 5 publications

References 152 publications

Long-range regulatory effects of Neandertal DNA in modern humans

Long-range regulatory effects of Neandertal DNA in modern humans

Long-range regulatory effects of Neandertal DNA in modern humans

The cis-regulatory effects of modern human-specific variants

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