Modern humans appeared in Europe by at least 45,000 years ago
, but the extent of their interactions with Neanderthals, who disappeared by about 40,000 years ago
, and their relationship to the ...broader expansion of modern humans outside Africa are poorly understood. Here we present genome-wide data from three individuals dated to between 45,930 and 42,580 years ago from Bacho Kiro Cave, Bulgaria
. They are the earliest Late Pleistocene modern humans known to have been recovered in Europe so far, and were found in association with an Initial Upper Palaeolithic artefact assemblage. Unlike two previously studied individuals of similar ages from Romania
and Siberia
who did not contribute detectably to later populations, these individuals are more closely related to present-day and ancient populations in East Asia and the Americas than to later west Eurasian populations. This indicates that they belonged to a modern human migration into Europe that was not previously known from the genetic record, and provides evidence that there was at least some continuity between the earliest modern humans in Europe and later people in Eurasia. Moreover, we find that all three individuals had Neanderthal ancestors a few generations back in their family history, confirming that the first European modern humans mixed with Neanderthals and suggesting that such mixing could have been common.
DNase I hypersensitive sites (DHSs) are markers of regulatory DNA and have underpinned the discovery of all classes of cis-regulatory elements including enhancers, promoters, insulators, silencers ...and locus control regions. Here we present the first extensive map of human DHSs identified through genome-wide profiling in 125 diverse cell and tissue types. We identify ∼2.9 million DHSs that encompass virtually all known experimentally validated cis-regulatory sequences and expose a vast trove of novel elements, most with highly cell-selective regulation. Annotating these elements using ENCODE data reveals novel relationships between chromatin accessibility, transcription, DNA methylation and regulatory factor occupancy patterns. We connect ∼580,000 distal DHSs with their target promoters, revealing systematic pairing of different classes of distal DHSs and specific promoter types. Patterning of chromatin accessibility at many regulatory regions is organized with dozens to hundreds of co-activated elements, and the transcellular DNase I sensitivity pattern at a given region can predict cell-type-specific functional behaviours. The DHS landscape shows signatures of recent functional evolutionary constraint. However, the DHS compartment in pluripotent and immortalized cells exhibits higher mutation rates than that in highly differentiated cells, exposing an unexpected link between chromatin accessibility, proliferative potential and patterns of human variation.
Reconciliation extracts information from the topological incongruence between gene and species trees to infer duplications and losses in the history of a gene family. The inferred duplication-loss ...histories provide valuable information for a broad range of biological applications, including ortholog identification, estimating gene duplication times, and rooting and correcting gene trees. While reconciliation for binary trees is a tractable and well studied problem, there are no algorithms for reconciliation with non-binary species trees. Yet a striking proportion of species trees are non-binary. For example, 64% of branch points in the NCBI taxonomy have three or more children. When applied to non-binary species trees, current algorithms overestimate the number of duplications because they cannot distinguish between duplication and incomplete lineage sorting. We present the first algorithms for reconciling binary gene trees with non-binary species trees under a duplication-loss parsimony model. Our algorithms utilize an efficient mapping from gene to species trees to infer the minimum number of duplications in O(|V(G) | x (k(S) + h(S))) time, where |V(G)| is the number of nodes in the gene tree, h(S) is the height of the species tree and k(S) is the size of its largest polytomy. We present a dynamic programming algorithm which also minimizes the total number of losses. Although this algorithm is exponential in the size of the largest polytomy, it performs well in practice for polytomies with outdegree of 12 or less. We also present a heuristic which estimates the minimal number of losses in polynomial time. In empirical tests, this algorithm finds an optimal loss history 99% of the time. Our algorithms have been implemented in NOTUNG, a robust, production quality, tree-fitting program, which provides a graphical user interface for exploratory analysis and also supports automated, high-throughput analysis of large data sets.
One of the features that distinguishes modern humans from our extinct relatives and ancestors is a globular shape of the braincase 1–4. As the endocranium closely mirrors the outer shape of the ...brain, these differences might reflect altered neural architecture 4, 5. However, in the absence of fossil brain tissue, the underlying neuroanatomical changes as well as their genetic bases remain elusive. To better understand the biological foundations of modern human endocranial shape, we turn to our closest extinct relatives: the Neandertals. Interbreeding between modern humans and Neandertals has resulted in introgressed fragments of Neandertal DNA in the genomes of present-day non-Africans 6, 7. Based on shape analyses of fossil skull endocasts, we derive a measure of endocranial globularity from structural MRI scans of thousands of modern humans and study the effects of introgressed fragments of Neandertal DNA on this phenotype. We find that Neandertal alleles on chromosomes 1 and 18 are associated with reduced endocranial globularity. These alleles influence expression of two nearby genes, UBR4 and PHLPP1, which are involved in neurogenesis and myelination, respectively. Our findings show how integration of fossil skull data with archaic genomics and neuroimaging can suggest developmental mechanisms that may contribute to the unique modern human endocranial shape.
•We use fossil skull data to derive an index of endocranial shape in human MRI scans•In 4,468 Europeans, we screen introgressed Neandertal SNPs for association with the index•Lead SNPs consistently associate with reduced globularity in five separate subsamples•These SNPs affect neural expression of two genes linked to neurogenesis and myelination
Gunz, Tilot et al. combine paleoanthropology, archaic genomics, neuroimaging, and gene expression to study biological foundations of the characteristic modern human endocranial shape. They find introgressed Neandertal alleles that associate with reduced endocranial globularity and affect expression of genes linked to neurogenesis and myelination.
The use of hybridization capture has enabled a massive upscaling in sample sizes for ancient DNA studies, allowing the analysis of hundreds of skeletal remains or sediments in single studies. ...Nevertheless, demands in throughput continue to grow, and hybridization capture has become a limiting step in sample preparation due to the large consumption of reagents, consumables and time. Here, we explored the possibility of improving the economics of sample preparation via multiplex capture, that is, the hybridization capture of pools of double‐indexed ancient DNA libraries. We demonstrate that this strategy is feasible, at least for small genomic targets such as mitochondrial DNA, if the annealing temperature is increased and PCR cycles are limited in post‐capture amplification to avoid index swapping by jumping PCR, which manifests as cross‐contamination in resulting sequence data. We also show that the reamplification of double‐indexed libraries to PCR plateau before or after hybridization capture can sporadically lead to small, but detectable cross‐contamination even if libraries are amplified in separate reactions. We provide protocols for both manual capture and automated capture in 384‐well format that are compatible with single‐ and multiplex capture and effectively suppress cross‐contamination and artefact formation. Last, we provide a simple computational method for quantifying cross‐contamination due to index swapping in double‐indexed libraries, which we recommend using for routine quality checks in studies that are sensitive to cross‐contamination.
Cellular-state information between generations of developing cells may be propagated via regulatory regions. We report consistent patterns of gain and loss of DNase I-hypersensitive sites (DHSs) as ...cells progress from embryonic stem cells (ESCs) to terminal fates. DHS patterns alone convey rich information about cell fate and lineage relationships distinct from information conveyed by gene expression. Developing cells share a proportion of their DHS landscapes with ESCs; that proportion decreases continuously in each cell type as differentiation progresses, providing a quantitative benchmark of developmental maturity. Developmentally stable DHSs densely encode binding sites for transcription factors involved in autoregulatory feedback circuits. In contrast to normal cells, cancer cells extensively reactivate silenced ESC DHSs and those from developmental programs external to the cell lineage from which the malignancy derives. Our results point to changes in regulatory DNA landscapes as quantitative indicators of cell-fate transitions, lineage relationships, and dysfunction.
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•Cell fate and lineage relationships can be derived from DHS patterns•The proportion of a cell’s DHSs shared with ESCs is a benchmark of maturity•Developmentally stable DHSs encode binding sites for self-regulating TFs•Cancer cells reactivate both ESC DHSs and those from noncognate lineages
Gains and losses of DNase I-hypersensitive sites (DHSs) during cellular differentiation provide a measure of developmental maturity and lineage relationships between cell types. Whereas developing cells exhibit a steady pruning of DHSs shared with ESCs, cancer cells show a disordered acquisition of multiple unrelated DHSs.
Ancient DNA recovered from Pleistocene sediments represents a rich resource for the study of past hominin and environmental diversity. However, little is known about how DNA is preserved in sediments ...and the extent to which it may be translocated between archaeological strata. Here, we investigate DNA preservation in 47 blocks of resin-impregnated archaeological sediment collected over the last four decades for micromorphological analyses at 13 prehistoric sites in Europe, Asia, Africa, and North America and show that such blocks can preserve DNA of hominins and other mammals. Extensive microsampling of sediment blocks from Denisova Cave in the Altai Mountains reveals that the taxonomic composition of mammalian DNA differs drastically at the millimeter-scale and that DNA is concentrated in small particles, especially in fragments of bone and feces (coprolites), suggesting that these are substantial sources of DNA in sediments. Three microsamples taken in close proximity in one of the blocks yielded Neanderthal DNA from at least two male individuals closely related to
, a Neanderthal toe bone previously recovered from the same layer. Our work indicates that DNA can remain stably localized in sediments over time and provides a means of linking genetic information to the archaeological and ecological records on a microstratigraphic scale.
Artefacts made from stones, bones and teeth are fundamental to our understanding of human subsistence strategies, behaviour and culture in the Pleistocene. Although these resources are plentiful, it ...is impossible to associate artefacts to specific human individuals
who can be morphologically or genetically characterized, unless they are found within burials, which are rare in this time period. Thus, our ability to discern the societal roles of Pleistocene individuals based on their biological sex or genetic ancestry is limited
. Here we report the development of a non-destructive method for the gradual release of DNA trapped in ancient bone and tooth artefacts. Application of the method to an Upper Palaeolithic deer tooth pendant from Denisova Cave, Russia, resulted in the recovery of ancient human and deer mitochondrial genomes, which allowed us to estimate the age of the pendant at approximately 19,000-25,000 years. Nuclear DNA analysis identifies the presumed maker or wearer of the pendant as a female individual with strong genetic affinities to a group of Ancient North Eurasian individuals who lived around the same time but were previously found only further east in Siberia. Our work redefines how cultural and genetic records can be linked in prehistoric archaeology.
Gene family evolution is determined by microevolutionary processes (e.g., point mutations) and macroevolutionary processes (e.g., gene duplication and loss), yet macroevolutionary considerations are ...rarely incorporated into gene phylogeny reconstruction methods. We present a dynamic program to find the most parsimonious gene family tree with respect to a macroevolutionary optimization criterion, the weighted sum of the number of gene duplications and losses. The existence of a polynomial delay algorithm for duplication/loss phylogeny reconstruction stands in contrast to most formulations of phylogeny reconstruction, which are NP-complete. We next extend this result to obtain a two-phase method for gene tree reconstruction that takes both micro- and macroevolution into account. In the first phase, a gene tree is constructed from sequence data, using any of the previously known algorithms for gene phylogeny construction. In the second phase, the tree is refined by rearranging regions of the tree that do not have strong support in the sequence data to minimize the duplication/lost cost. Components of the tree with strong support are left intact. This hybrid approach incorporates both micro- and macroevolutionary considerations, yet its computational requirements are modest in practice because the two-phase approach constrains the search space. Our hybrid algorithm can also be used to resolve nonbinary nodes in a multifurcating gene tree. We have implemented these algorithms in a software tool, NOTUNG 2.0, that can be used as a unified framework for gene tree reconstruction or as an exploratory analysis tool that can be applied post hoc to any rooted tree with bootstrap values. The NOTUNG 2.0 graphical user interface can be used to visualize alternate duplication/loss histories, root trees according to duplication and loss parsimony, manipulate and annotate gene trees, and estimate gene duplication times. It also offers a command line option that enables high-throughput analysis of a large number of trees.
The characteristics and evolutionary forces acting on regulatory variation in humans remains elusive because of the difficulty in defining functionally important noncoding DNA. Here, we combine ...genome-scale maps of regulatory DNA marked by DNase I hypersensitive sites (DHSs) from 138 cell and tissue types with whole-genome sequences of 53 geographically diverse individuals in order to better delimit the patterns of regulatory variation in humans. We estimate that individuals likely harbor many more functionally important variants in regulatory DNA compared with protein-coding regions, although they are likely to have, on average, smaller effect sizes. Moreover, we demonstrate that there is significant heterogeneity in the level of functional constraint in regulatory DNA among different cell types. We also find marked variability in functional constraint among transcription factor motifs in regulatory DNA, with sequence motifs for major developmental regulators, such as HOX proteins, exhibiting levels of constraint comparable to protein-coding regions. Finally, we perform a genome-wide scan of recent positive selection and identify hundreds of novel substrates of adaptive regulatory evolution that are enriched for biologically interesting pathways such as melanogenesis and adipocytokine signaling. These data and results provide new insights into patterns of regulatory variation in individuals and populations and demonstrate that a large proportion of functionally important variation lies beyond the exome.
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