Neanderthal Adaptively Introgressed Genetic Variants Regulate Human Immune Genes In Vitro.
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA715632 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14004308.fastq.gz | Fastqsanger.gz | |||
| SRR14004309.fastq.gz | Fastqsanger.gz | |||
| SRR14004310.fastq.gz | Fastqsanger.gz | |||
| SRR14004311.fastq.gz | Fastqsanger.gz | |||
| SRR14004312.fastq.gz | Fastqsanger.gz |
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Project description:Some Neanderthal introgressed variation underwent selective sweeps, but little is known about their functional significance. We used a Massively Parallel Reporter Assay (MPRA) to test 5,353 high-frequency introgressed variants for evidence of being in active cis-regulatory elements (CREs) and modulating gene expression in immune cell lines. We identified 2,546 variants in CREs and 292 expression-modulating variants (emVars). These emVars are predicted to regulate genes that are enriched for function in innate immune pathways including interferon signaling, toll like receptor pathways, and anti-viral response; one such emVar is significantly associated with protection against severe COVID-19 response. Using CRISPR-Cas9, we deleted two CREs containing expression-modulation variants linked to immune function, rs11624425 and rs80317430, identifying their primary genic targets as ELMSAN1, and PAN2 and STAT2 respectively, three genes differentially expressed during influenza infection. Overall, we present the first database of directly identified expression-modulating Neanderthal-introgressed alleles contributing to potential immune response in modern humans.
2022-01-19 | GSE169200 | GEO
Project description:Humans co-existed and interbred with other hominins which later became extinct. These archaic hominins are known to us only through fossil records and for two cases, genome sequences. Here we engineer Neanderthal and Denisovan sequences into thousands of artificial genes to reconstruct the pre-mRNA processing patterns of these extinct populations. Of the 5,224 alleles tested in this massively parallel splicing reporter assay (MaPSy), we report 969 exonic splicing mutations (ESMs) that correspond to differences in exon recognition between extant and extinct hominins. Using MaPSy splicing variants, predicted splicing variants, and splicing quantitative trait loci, we show that splice-disrupting variants experienced greater purifying selection in anatomically modern humans than in Neanderthals. Adaptively introgressed variants were enriched for moderate effect splicing variants, consistent with positive selection for alternative spliced alleles following introgression. As particularly compelling examples, we characterized a novel tissue-specific alternative splicing variant at the adaptively introgressed innate immunity gene TLR1, as well as a novel Neanderthal introgressed alternative splicing variant in the gene HSPG2 that encodes perlecan. We further identified potentially pathogenic splicing variants found only in Neanderthals and Denisovans in genes related to sperm maturation and immunity. Finally, we found splicing variants that may contribute to variation among modern humans in total bilirubin, balding, hemoglobin levels, and lung capacity. Our findings provide novel insights into natural selection acting on splicing in human evolution and demonstrate how functional assays can be used to identify candidate causal variants underlying differences in gene regulation and phenotype.
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Project description:Facial appearance is one of the most variable morphological traits in humans, influenced by both rare and common genetic variants that can impact facial form between individuals and in disease. Deletion of an enhancer cluster 1.45 megabases upstream of the SOX9 gene (EC1.45) results in Pierre Robin sequence, a human craniofacial disorder characterised by underdevelopment of the lower jaw and frequently associated with cleft palate. We reasoned that single nucleotide variants in EC1.45 may cause more subtle alterations to facial morphology. Here, we took advantage of recent human evolution, and the distinct morphology of the Neanderthal lower jaw, to investigate the impact of three Neanderthal-derived single nucleotide variants on EC1.45 function and jaw development. Utilising a dual enhancer-reporter system in zebrafish, we observed enhanced Neanderthal regulatory activity relative to the human orthologue during a specific developmental window. At this same stage, we show that EC1.45 appears to be selectively active in neural crest- derived progenitor cells which lie in close apposition with and are transcriptionally related to precartilaginous condensations that contribute to craniofacial skeletal development. To examine the potential consequences of increased SOX9 expression in this specific cellular population during jaw development, we overexpressed human SOX9 specifically in EC1.45-active cells and observed an increase in the volume of developing cartilaginous precursors. Taken together, our work implicates Neanderthal-derived variants in increased regulatory activity for a disease- associated enhancer with the potential to impact craniofacial skeletal development and jaw morphology across recent hominin evolution.
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Project description:While Neanderthals are extinct, fragments of their genome still persist in the genomes of contemporary humans. Here, we show that such Neanderthal-like sequences are not distributed randomly in contemporary human genomes. Specifically, while genome-wide frequency of Neanderthal-like sites is close to 6% in all out-of-Africa populations, genes involved in lipid catabolism contain large excess Neanderthal-like sequences in Europeans (24.3%), but not in Asians (12.4%). While lipid catabolism cannot be assayed in Neanderthals, we took advantage of genetic divergence between human populations, chimpanzees and Neanderthals to predict metabolic divergence expected from the observed excess of Neanderthal gene flow into Europeans. We confirmed predicted changes in lipid catabolism using hydrophobic metabolome measurements in the brain tissue and further linked these metabolic changes to gene expression divergence. 14 human and 6 chimpanzee samples were sequenced.
2014-03-31 | E-GEOD-45263 | biostudies-arrayexpress
Project description:While Neanderthals are extinct, fragments of their genome still persist in the genomes of contemporary humans. Here, we show that such Neanderthal-like sequences are not distributed randomly in contemporary human genomes. Specifically, while genome-wide frequency of Neanderthal-like sites is close to 6% in all out-of-Africa populations, genes involved in lipid catabolism contain large excess Neanderthal-like sequences in Europeans (24.3%), but not in Asians (12.4%). While lipid catabolism cannot be assayed in Neanderthals, we took advantage of genetic divergence between human populations, chimpanzees and Neanderthals to predict metabolic divergence expected from the observed excess of Neanderthal gene flow into Europeans. We confirmed predicted changes in lipid catabolism using hydrophobic metabolome measurements in the brain tissue and further linked these metabolic changes to gene expression divergence.
2014-03-31 | GSE45263 | GEO
Project description:Neanderthal-derived variants increase SOX9 enhancer activity in craniofacial progenitors that shape jaw development
| PRJNA1268529 | ENA
Project description:Although some variation introgressed from Neanderthals has undergone selective sweeps, little is known about its functional significance. We used a Massively Parallel Reporter Assay (MPRA) to assay 5,353 high-frequency introgressed variants for their ability to modulate the gene expression within 170 bp of endogenous sequence. We identified 2,548 variants in active putative cis-regulatory elements (CREs) and 292 expression-modulating variants (emVars). These emVars are predicted to alter the binding motifs of important immune transcription factors, are enriched for associations with neutrophil and white blood cell count, and are associated with the expression of genes that function in innate immune pathways including inflammatory response and antiviral defense. We combined the MPRA data with other data sets to identify strong candidates to be driver variants of positive selection including an emVar that may contribute to protection against severe COVID-19 response. We endogenously deleted two CREs containing expression-modulation variants linked to immune function, rs11624425 and rs80317430, identifying their primary genic targets as ELMSAN1, and PAN2 and STAT2, respectively, three genes differentially expressed during influenza infection. Overall, we present the first database of experimentally identified expression-modulating Neanderthal-introgressed alleles contributing to potential immune response in modern humans.
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Project description: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, 1,791 (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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