Benjamin Vernot’s research while affiliated with Max Planck Institute for Evolutionary Anthropology and other places

Pluripotent stem cells from diverse humans offer the potential to study human functional variation in controlled culture environments. A portion of this variation originates from ancient admixture between modern humans and Neandertals, which introduced alleles that left a phenotypic legacy on individual humans today. Here we show that a large repository of human induced pluripotent stem cells (iPSCs) harbors extensive Neandertal DNA, including most known functionally relevant Neandertal alleles present in modern humans. This resource contains Neandertal DNA that contributes to human phenotypes and diseases, encodes hundreds of amino acid changes, and alters gene expression in specific tissues. Human iPSCs thus provide an opportunity to experimentally explore the Neandertal contribution to present-day phenotypes, and potentially study Neandertal traits.

By examining the genomes of present-day people from Asia, researchers show that modern humans met and interbred with Denisovans, distant relatives to Neanderthals, on at least two occasions. As a result, people today carry DNA from two different Denisovan populations. By examining the genomes of present-day people from Asia, researchers show that modern humans met and interbred with Denisovans, distant relatives to Neanderthals, on at least two occasions. As a result, people today carry DNA from two different Denisovan populations.

Revelations from a Vindija Neandertal genome Neandertals clearly interbred with the ancestors of non-African modern humans, but many questions remain about our closest ancient relatives. Prüfer et al. present a 30-fold-coverage genome sequence from 50,000- to 65,000-year-old samples from a Neandertal woman found in Vindija, Croatia, and compared this sequence with genomes obtained from the Altai Neandertal, the Denisovans, and ancient and modern humans (see the Perspective by Bergström and Tyler-Smith). Neandertals likely lived in small groups and had lower genetic diversity than modern humans. The findings increase the number of Neandertal variants identified within populations of modern humans, and they suggest that a larger number of phenotypic and diseaserelated variants with Neandertal ancestry remain in the modern Eurasian gene pool than previously thought. Science , this issue p. 655 ; see also p. 586

Results of differential gene expression analyses.Excel file (*.xlsx) with multiple sheets containing results of all differential expression analyses presented in the manuscript as well as GO enrichment analysis for the differentially expressed (DE) genes: Sheet 1: Genes specific to APs, not DE between chimpanzee and human; Sheet 2: GO enrichment analysis for genes of sheet 1; Sheet 3: Genes specific to Neurons, not DE between chimpanzee and human; Sheet 4: GO enrichment analysis for genes of sheet 3; Sheet 5: Genes specific to APs and upregulated to human compared to chimpanzee; Sheet 6: GO enrichment analysis for genes of sheet 6; Sheet 7: Genes specific to Neurons and upregulated to human compared to chimpanzee; Sheet 8: GO enrichment analysis for genes of sheet 7; Sheet 9: Genes specific to APs and upregulated to chimpanzee compared to human; Sheet 10: GO enrichment analysis for genes of sheet 6; Sheet 11: Genes specific to Neurons and upregulated to chimpanzee compared to human; Sheet 12: GO enrichment analysis for genes of sheet 11; Sheet 13: GO enrichment data used to generate Figure 3F.DOI: http://dx.doi.org/10.7554/eLife.18683.012

Processed single-cell RNA-seq data for chimpanzee cells.*.txt file containing processed chimpanzee single-cell RNA-seq data (344 single cells) in log2(FPKM) with genes in columns and cells in rows. The first 7 columns contain metadata for each cell: cortex: assignment of cell to cortex (1) or to other regions within organoid(0); tSNE_1: tSNE1 loading for each cell; tSNE_2: tSNE2 loading for each cell; PC1: PC1 loading for each cell; PC2: PC2 loading for each cell; species: species of origin for each cell; cell_id: unique ID for each cell, with information about the experiment and the age of the organoid of origin for each cell.DOI: http://dx.doi.org/10.7554/eLife.18683.004

Processed single-cell RNA-seq data for human cells.*.txt file containing processed human single-cell RNA-seq data (207 single cells) in log2(FPKM) with metadata in first 4 columns for each cell: cell_id: unique ID for each cell; experiment: the experiment during which each cell was isolated; species: species of origin for each cell; cortex: assignment of cell to cortex (1) or to other regions within organoid (0).DOI: http://dx.doi.org/10.7554/eLife.18683.011

Human neocortex expansion likely contributed to the remarkable cognitive abilities of humans. This expansion is thought to primarily reflect differences in proliferation versus differentiation of neural progenitors during cortical development. Here, we have searched for such differences by analysing cerebral organoids from human and chimpanzees using immunohistofluorescence, live imaging, and single-cell transcriptomics. We find that the cytoarchitecture, cell type composition, and neurogenic gene expression programs of humans and chimpanzees are remarkably similar. Notably, however, live imaging of apical progenitor mitosis uncovered a lengthening of prometaphase-metaphase in humans compared to chimpanzees that is specific to proliferating progenitors and not observed in non-neural cells. Consistent with this, the small set of genes more highly expressed in human apical progenitors points to increased proliferative capacity, and the proportion of neurogenic basal progenitors is lower in humans. These subtle differences in cortical progenitors between humans and chimpanzees may have consequences for human neocortex evolution.

Durations of all mitotic phases.Numerical values in minutes for the duration of all mitotic phases ± SEM used in the graphs in Figures 5, 6 and 7, in Figure 5—figure supplement 1, 2 and 3, and in Figure 6—figure supplement 1.DOI: http://dx.doi.org/10.7554/eLife.18683.016

Genes describing cell populations in the chimpanzee organoids.List of genes identified by PCA on all chimpanzee organoid single-cell transcriptomes as being most informative for defining cell populations.DOI: http://dx.doi.org/10.7554/eLife.18683.005

Denisovan DNA retained in Melanesians Modern humans carry remnants of DNA from interbreeding events with archaic lineages, such as Neandertals. However, people from Oceania also retain genes from a second ancient lineage, the Denisovans. Vernot et al. surveyed archaic genomic sequences in a worldwide sample of modern humans, including 35 individuals from the Melanesian Islands. All non-African genomes surveyed contained Neandertal DNA, but a significant Denisovan component was found only in the Melanesians. Reconstruction of this genetic history suggests that Neandertals bred with modern humans multiple times, but Denosivans only once, in ancestors of modern-day Melanesians. Science , this issue p. 235