ABSTRACT
Modern human ancestors diverged from the ancestors of Neandertals and Denisovans about 600,000 years ago. Until about 40,000 years ago, these three groups existed in parallel, occasionally met, and exchanged genes. A critical question is why modern humans, and not the other two groups, survived, became numerous, and developed complex cultures. Here, we discuss genetic differences among the groups and some of their functional consequences. As more present-day genome sequences become available from diverse groups, we predict that very few, if any, differences will distinguish all modern humans from all Neandertals and Denisovans. We propose that the genetic basis of what constitutes a modern human is best thought of as a combination of genetic features, where perhaps none of them is present in each and every present-day individual.
Subject(s)
Hominidae , Neanderthals , Animals , Humans , Neanderthals/genetics , Research , Hominidae/genetics , Human GeneticsABSTRACT
Searches for the genetic underpinnings of uniquely human traits have focused on human-specific divergence in conserved genomic regions, which reflects adaptive modifications of existing functional elements. However, the study of conserved regions excludes functional elements that descended from previously neutral regions. Here, we demonstrate that the fastest-evolved regions of the human genome, which we term "human ancestor quickly evolved regions" (HAQERs), rapidly diverged in an episodic burst of directional positive selection prior to the human-Neanderthal split, before transitioning to constraint within hominins. HAQERs are enriched for bivalent chromatin states, particularly in gastrointestinal and neurodevelopmental tissues, and genetic variants linked to neurodevelopmental disease. We developed a multiplex, single-cell in vivo enhancer assay to discover that rapid sequence divergence in HAQERs generated hominin-unique enhancers in the developing cerebral cortex. We propose that a lack of pleiotropic constraints and elevated mutation rates poised HAQERs for rapid adaptation and subsequent susceptibility to disease.
Subject(s)
Hominidae , Neanderthals , Animals , Humans , Hominidae/genetics , Regulatory Sequences, Nucleic Acid , Neanderthals/genetics , Genome, Human , GenomicsABSTRACT
The Middle East region is important to understand human evolution and migrations but is underrepresented in genomic studies. Here, we generated 137 high-coverage physically phased genome sequences from eight Middle Eastern populations using linked-read sequencing. We found no genetic traces of early expansions out-of-Africa in present-day populations but found Arabians have elevated Basal Eurasian ancestry that dilutes their Neanderthal ancestry. Population sizes within the region started diverging 15-20 kya, when Levantines expanded while Arabians maintained smaller populations that derived ancestry from local hunter-gatherers. Arabians suffered a population bottleneck around the aridification of Arabia 6 kya, while Levantines had a distinct bottleneck overlapping the 4.2 kya aridification event. We found an association between movement and admixture of populations in the region and the spread of Semitic languages. Finally, we identify variants that show evidence of selection, including polygenic selection. Our results provide detailed insights into the genomic and selective histories of the Middle East.
Subject(s)
Genetics, Population/history , Genome, Human , Animals , Chromosomes, Human, Y/genetics , Databases, Genetic , Gene Pool , Genetic Introgression , Geography , History, Ancient , Human Migration , Humans , Middle East , Models, Genetic , Neanderthals/genetics , Phylogeny , Population Density , Selection, Genetic , Sequence Analysis, DNAABSTRACT
Admixture has played a prominent role in shaping patterns of human genomic variation, including gene flow with now-extinct hominins like Neanderthals and Denisovans. Here, we describe a novel probabilistic method called IBDmix to identify introgressed hominin sequences, which, unlike existing approaches, does not use a modern reference population. We applied IBDmix to 2,504 individuals from geographically diverse populations to identify and analyze Neanderthal sequences segregating in modern humans. Strikingly, we find that African individuals carry a stronger signal of Neanderthal ancestry than previously thought. We show that this can be explained by genuine Neanderthal ancestry due to migrations back to Africa, predominately from ancestral Europeans, and gene flow into Neanderthals from an early dispersing group of humans out of Africa. Our results refine our understanding of Neanderthal ancestry in African and non-African populations and demonstrate that remnants of Neanderthal genomes survive in every modern human population studied to date.
Subject(s)
Black People/genetics , Evolution, Molecular , Neanderthals/genetics , Animals , Gene Flow , Human Migration , Humans , Models, Genetic , Pedigree , Polymorphism, GeneticABSTRACT
Denisovans are an extinct group of humans whose morphology remains unknown. Here, we present a method for reconstructing skeletal morphology using DNA methylation patterns. Our method is based on linking unidirectional methylation changes to loss-of-function phenotypes. We tested performance by reconstructing Neanderthal and chimpanzee skeletal morphologies and obtained >85% precision in identifying divergent traits. We then applied this method to the Denisovan and offer a putative morphological profile. We suggest that Denisovans likely shared with Neanderthals traits such as an elongated face and a wide pelvis. We also identify Denisovan-derived changes, such as an increased dental arch and lateral cranial expansion. Our predictions match the only morphologically informative Denisovan bone to date, as well as the Xuchang skull, which was suggested by some to be a Denisovan. We conclude that DNA methylation can be used to reconstruct anatomical features, including some that do not survive in the fossil record.
Subject(s)
DNA Methylation/genetics , Neanderthals/anatomy & histology , Neanderthals/genetics , Pan troglodytes/anatomy & histology , Pan troglodytes/genetics , Phenotype , Animals , Base Sequence , Databases, Genetic , Extinction, Biological , Fossils , Genome, Human/genetics , Humans , Polymorphism, Single Nucleotide/genetics , Skeleton , SkullABSTRACT
Genome sequences are known for two archaic hominins-Neanderthals and Denisovans-which interbred with anatomically modern humans as they dispersed out of Africa. We identified high-confidence archaic haplotypes in 161 new genomes spanning 14 island groups in Island Southeast Asia and New Guinea and found large stretches of DNA that are inconsistent with a single introgressing Denisovan origin. Instead, modern Papuans carry hundreds of gene variants from two deeply divergent Denisovan lineages that separated over 350 thousand years ago. Spatial and temporal structure among these lineages suggest that introgression from one of these Denisovan groups predominantly took place east of the Wallace line and continued until near the end of the Pleistocene. A third Denisovan lineage occurs in modern East Asians. This regional mosaic suggests considerable complexity in archaic contact, with modern humans interbreeding with multiple Denisovan groups that were geographically isolated from each other over deep evolutionary time.
Subject(s)
Genetic Introgression/genetics , Haplotypes/genetics , Hominidae/genetics , Animals , Asian People/genetics , Biological Evolution , Gene Flow , Genetic Variation/genetics , Genome, Human/genetics , Humans , Indonesia , Neanderthals/genetics , OceaniaABSTRACT
In this issue, Enard and Petrov present intriguing results on the possibility of genetic traces left behind in our genomes from adaptation to past viral epidemics that may have been initiated by interaction with Neanderthal archaic hominins. The work highlights how powerful infectious agents can act as a selective force to shape our genetic makeup.
Subject(s)
Hominidae/genetics , Neanderthals/genetics , RNA Viruses , Animals , Genome , HumansABSTRACT
Anatomically modern humans interbred with Neanderthals and with a related archaic population known as Denisovans. Genomes of several Neanderthals and one Denisovan have been sequenced, and these reference genomes have been used to detect introgressed genetic material in present-day human genomes. Segments of introgression also can be detected without use of reference genomes, and doing so can be advantageous for finding introgressed segments that are less closely related to the sequenced archaic genomes. We apply a new reference-free method for detecting archaic introgression to 5,639 whole-genome sequences from Eurasia and Oceania. We find Denisovan ancestry in populations from East and South Asia and Papuans. Denisovan ancestry comprises two components with differing similarity to the sequenced Altai Denisovan individual. This indicates that at least two distinct instances of Denisovan admixture into modern humans occurred, involving Denisovan populations that had different levels of relatedness to the sequenced Altai Denisovan. VIDEO ABSTRACT.
Subject(s)
Genome, Human , Animals , Asian People/genetics , Humans , Neanderthals/genetics , Selection, Genetic , Exome SequencingABSTRACT
Neanderthals and modern humans interbred at least twice in the past 100,000 years. While there is evidence that most introgressed DNA segments from Neanderthals to modern humans were removed by purifying selection, less is known about the adaptive nature of introgressed sequences that were retained. We hypothesized that interbreeding between Neanderthals and modern humans led to (1) the exposure of each species to novel viruses and (2) the exchange of adaptive alleles that provided resistance against these viruses. Here, we find that long, frequent-and more likely adaptive-segments of Neanderthal ancestry in modern humans are enriched for proteins that interact with viruses (VIPs). We found that VIPs that interact specifically with RNA viruses were more likely to belong to introgressed segments in modern Europeans. Our results show that retained segments of Neanderthal ancestry can be used to detect ancient epidemics.
Subject(s)
Hybridization, Genetic/genetics , Neanderthals/genetics , RNA Viruses/genetics , Alleles , Animals , Biological Evolution , Genome, Human/genetics , Haplotypes , Hominidae/genetics , Humans , Phylogeny , RNA Viruses/pathogenicity , Selection, Genetic/geneticsABSTRACT
Regulatory variation influencing gene expression is a key contributor to phenotypic diversity, both within and between species. Unfortunately, RNA degrades too rapidly to be recovered from fossil remains, limiting functional genomic insights about our extinct hominin relatives. Many Neanderthal sequences survive in modern humans due to ancient hybridization, providing an opportunity to assess their contributions to transcriptional variation and to test hypotheses about regulatory evolution. We developed a flexible Bayesian statistical approach to quantify allele-specific expression (ASE) in complex RNA-seq datasets. We identified widespread expression differences between Neanderthal and modern human alleles, indicating pervasive cis-regulatory impacts of introgression. Brain regions and testes exhibited significant downregulation of Neanderthal alleles relative to other tissues, consistent with natural selection influencing the tissue-specific regulatory landscape. Our study demonstrates that Neanderthal-inherited sequences are not silent remnants of ancient interbreeding but have measurable impacts on gene expression that contribute to variation in modern human phenotypes.
Subject(s)
Evolution, Molecular , Gene Expression , Neanderthals/genetics , Animals , Brain/metabolism , Gene Expression Regulation , Humans , Male , Organ Specificity , Polymorphism, Single Nucleotide , Quantitative Trait Loci , Testis/metabolismABSTRACT
Humans differ in the outcome that follows exposure to life-threatening pathogens, yet the extent of population differences in immune responses and their genetic and evolutionary determinants remain undefined. Here, we characterized, using RNA sequencing, the transcriptional response of primary monocytes from Africans and Europeans to bacterial and viral stimuli-ligands activating Toll-like receptor pathways (TLR1/2, TLR4, and TLR7/8) and influenza virus-and mapped expression quantitative trait loci (eQTLs). We identify numerous cis-eQTLs that contribute to the marked differences in immune responses detected within and between populations and a strong trans-eQTL hotspot at TLR1 that decreases expression of pro-inflammatory genes in Europeans only. We find that immune-responsive regulatory variants are enriched in population-specific signals of natural selection and show that admixture with Neandertals introduced regulatory variants into European genomes, affecting preferentially responses to viral challenges. Together, our study uncovers evolutionarily important determinants of differences in host immune responsiveness between human populations.
Subject(s)
Adaptation, Physiological/genetics , Adaptation, Physiological/immunology , Adaptive Immunity , Neanderthals/genetics , Neanderthals/immunology , Adaptive Immunity/genetics , Alleles , Animals , Bacterial Infections/genetics , Bacterial Infections/immunology , Base Sequence , Biological Evolution , Black People/genetics , Gene Expression Regulation , Genetic Variation , Humans , Immune System , Quantitative Trait Loci , RNA/genetics , Selection, Genetic , Sequence Analysis, RNA , Toll-Like Receptors/genetics , Transcription, Genetic , Virus Diseases/genetics , Virus Diseases/immunology , White People/geneticsABSTRACT
Denisovans, a group of now extinct humans who lived in Eastern Eurasia in the Middle and Late Pleistocene, were first identified from DNA sequences just over a decade ago. Only ten fragmentary remains from two sites have been attributed to Denisovans based entirely on molecular information. Nevertheless, there has been great interest in using genetic data to understand Denisovans and their place in human history. From the reconstruction of a single high-quality genome, it has been possible to infer their population history, including events of admixture with other human groups. Additionally, the identification of Denisovan DNA in the genomes of present-day individuals has provided insights into the timing and routes of dispersal of ancient modern humans into Asia and Oceania, as well as the contributions of archaic DNA to the physiology of present-day people. In this Review, we synthesize more than a decade of research on Denisovans, reconcile controversies and summarize insights into their population history and phenotype. We also highlight how our growing knowledge about Denisovans has provided insights into our own evolutionary history.
Subject(s)
Hominidae , Neanderthals , Animals , Humans , Neanderthals/genetics , Biological Evolution , DNA , Genetic Research , Genome, HumanABSTRACT
Modern humans overlapped in time and space with other hominins, such as Neanderthals and Denisovans, and limited amounts of hybridization occurred. Here, we review recent work that has identified archaic hominin sequence that survives in modern human genomes and what these genomic excavations reveal about human evolutionary history.
Subject(s)
Biological Evolution , Neanderthals/genetics , Animals , Genetics, Medical , Genome, Human , Hominidae/genetics , Humans , Neanderthals/classification , Selection, GeneticABSTRACT
The Middle to Upper Palaeolithic transition in Europe is associated with the regional disappearance of Neanderthals and the spread of Homo sapiens. Late Neanderthals persisted in western Europe several millennia after the occurrence of H. sapiens in eastern Europe1. Local hybridization between the two groups occurred2, but not on all occasions3. Archaeological evidence also indicates the presence of several technocomplexes during this transition, complicating our understanding and the association of behavioural adaptations with specific hominin groups4. One such technocomplex for which the makers are unknown is the Lincombian-Ranisian-Jerzmanowician (LRJ), which has been described in northwestern and central Europe5-8. Here we present the morphological and proteomic taxonomic identification, mitochondrial DNA analysis and direct radiocarbon dating of human remains directly associated with an LRJ assemblage at the site Ilsenhöhle in Ranis (Germany). These human remains are among the earliest directly dated Upper Palaeolithic H. sapiens remains in Eurasia. We show that early H. sapiens associated with the LRJ were present in central and northwestern Europe long before the extinction of late Neanderthals in southwestern Europe. Our results strengthen the notion of a patchwork of distinct human populations and technocomplexes present in Europe during this transitional period.
Subject(s)
Human Migration , Animals , Humans , Body Remains/metabolism , DNA, Ancient/analysis , DNA, Mitochondrial/analysis , DNA, Mitochondrial/genetics , Europe , Extinction, Biological , Fossils , Germany , History, Ancient , Neanderthals/classification , Neanderthals/genetics , Neanderthals/metabolism , Proteomics , Radiometric Dating , Human Migration/history , Time FactorsABSTRACT
Humans display substantial interindividual clinical variability after SARS-CoV-2 infection1-3, the genetic and immunological basis of which has begun to be deciphered4. However, the extent and drivers of population differences in immune responses to SARS-CoV-2 remain unclear. Here we report single-cell RNA-sequencing data for peripheral blood mononuclear cells-from 222 healthy donors of diverse ancestries-that were stimulated with SARS-CoV-2 or influenza A virus. We show that SARS-CoV-2 induces weaker, but more heterogeneous, interferon-stimulated gene activity compared with influenza A virus, and a unique pro-inflammatory signature in myeloid cells. Transcriptional responses to viruses display marked population differences, primarily driven by changes in cell abundance including increased lymphoid differentiation associated with latent cytomegalovirus infection. Expression quantitative trait loci and mediation analyses reveal a broad effect of cell composition on population disparities in immune responses, with genetic variants exerting a strong effect on specific loci. Furthermore, we show that natural selection has increased population differences in immune responses, particularly for variants associated with SARS-CoV-2 response in East Asians, and document the cellular and molecular mechanisms by which Neanderthal introgression has altered immune functions, such as the response of myeloid cells to viruses. Finally, colocalization and transcriptome-wide association analyses reveal an overlap between the genetic basis of immune responses to SARS-CoV-2 and COVID-19 severity, providing insights into the factors contributing to current disparities in COVID-19 risk.
Subject(s)
COVID-19 , Genetics, Population , SARS-CoV-2 , Single-Cell Gene Expression Analysis , Animals , Humans , Cell Differentiation , COVID-19/genetics , COVID-19/immunology , COVID-19/virology , Cytomegalovirus/physiology , East Asian People/genetics , Genetic Introgression , Influenza A virus/pathogenicity , Influenza A virus/physiology , Interferons/immunology , Leukocytes, Mononuclear/immunology , Leukocytes, Mononuclear/metabolism , Myeloid Cells/immunology , Neanderthals/genetics , Neanderthals/immunology , SARS-CoV-2/genetics , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity , SARS-CoV-2/physiology , Selection, Genetic , Virus LatencyABSTRACT
Genomic analyses of Neanderthals have previously provided insights into their population history and relationship to modern humans1-8, but the social organization of Neanderthal communities remains poorly understood. Here we present genetic data for 13 Neanderthals from two Middle Palaeolithic sites in the Altai Mountains of southern Siberia: 11 from Chagyrskaya Cave9,10 and 2 from Okladnikov Cave11-making this one of the largest genetic studies of a Neanderthal population to date. We used hybridization capture to obtain genome-wide nuclear data, as well as mitochondrial and Y-chromosome sequences. Some Chagyrskaya individuals were closely related, including a father-daughter pair and a pair of second-degree relatives, indicating that at least some of the individuals lived at the same time. Up to one-third of these individuals' genomes had long segments of homozygosity, suggesting that the Chagyrskaya Neanderthals were part of a small community. In addition, the Y-chromosome diversity is an order of magnitude lower than the mitochondrial diversity, a pattern that we found is best explained by female migration between communities. Thus, the genetic data presented here provide a detailed documentation of the social organization of an isolated Neanderthal community at the easternmost extent of their known range.
Subject(s)
Neanderthals , Animals , Female , Humans , Caves , Genome/genetics , Hybridization, Genetic , Neanderthals/genetics , Siberia , DNA, Mitochondrial/genetics , Y Chromosome/genetics , Male , Family , HomozygoteABSTRACT
It has long been believed that climate shifts during the last 2 million years had a pivotal role in the evolution of our genus Homo1-3. However, given the limited number of representative palaeo-climate datasets from regions of anthropological interest, it has remained challenging to quantify this linkage. Here, we use an unprecedented transient Pleistocene coupled general circulation model simulation in combination with an extensive compilation of fossil and archaeological records to study the spatiotemporal habitat suitability for five hominin species over the past 2 million years. We show that astronomically forced changes in temperature, rainfall and terrestrial net primary production had a major impact on the observed distributions of these species. During the Early Pleistocene, hominins settled primarily in environments with weak orbital-scale climate variability. This behaviour changed substantially after the mid-Pleistocene transition, when archaic humans became global wanderers who adapted to a wide range of spatial climatic gradients. Analysis of the simulated hominin habitat overlap from approximately 300-400 thousand years ago further suggests that antiphased climate disruptions in southern Africa and Eurasia contributed to the evolutionary transformation of Homo heidelbergensis populations into Homo sapiens and Neanderthals, respectively. Our robust numerical simulations of climate-induced habitat changes provide a framework to test hypotheses on our human origin.
Subject(s)
Hominidae , Neanderthals , Animals , Archaeology , Biological Evolution , Ecosystem , Fossils , HumansABSTRACT
Homo sapiens was present in northern Asia by around 40,000 years ago, having replaced archaic populations across Eurasia after episodes of earlier population expansions and interbreeding1-4. Cultural adaptations of the last Neanderthals, the Denisovans and the incoming populations of H. sapiens into Asia remain unknown1,5-7. Here we describe Xiamabei, a well-preserved, approximately 40,000-year-old archaeological site in northern China, which includes the earliest known ochre-processing feature in east Asia, a distinctive miniaturized lithic assemblage with bladelet-like tools bearing traces of hafting, and a bone tool. The cultural assembly of traits at Xiamabei is unique for Eastern Asia and does not correspond with those found at other archaeological site assemblages inhabited by archaic populations or those generally associated with the expansion of H. sapiens, such as the Initial Upper Palaeolithic8-10. The record of northern Asia supports a process of technological innovations and cultural diversification emerging in a period of hominin hybridization and admixture2,3,6,11.
Subject(s)
Archaeology , Hominidae , Tool Use Behavior , Animals , Bone and Bones , China , History, Ancient , Humans , NeanderthalsABSTRACT
Changes in gene regulatory elements play critical roles in human phenotypic divergence. However, identifying the base-pair changes responsible for the distinctive morphology of Homo sapiens remains challenging. Here, we report a noncoding single-nucleotide polymorphism (SNP), rs41298798, as a potential causal variant contributing to the morphology of the skull base and vertebral structures found in Homo sapiens. Screening for differentially regulated genes between Homo sapiens and extinct relatives revealed 13 candidate genes associated with basicranial development, with TBX1, implicated in DiGeorge syndrome, playing a pivotal role. Epigenetic markers and in silico analyses prioritized rs41298798 within a TBX1 intron for functional validation. CRISPR editing revealed that the 41-base-pair region surrounding rs41298798 modulates gene expression at 22q11.21. The derived allele of rs41298798 acts as an allele-specific enhancer mediated by E2F1, resulting in increased TBX1 expression levels compared to the ancestral allele. Tbx1-knockout mice exhibited skull base and vertebral abnormalities similar to those seen in DiGeorge syndrome. Phenotypic differences associated with TBX1 deficiency are observed between Homo sapiens and Neanderthals (Homo neanderthalensis). In conclusion, the regulatory divergence of TBX1 contributes to the formation of skull base and vertebral structures found in Homo sapiens.
Subject(s)
Polymorphism, Single Nucleotide , T-Box Domain Proteins , T-Box Domain Proteins/genetics , T-Box Domain Proteins/metabolism , Humans , Animals , Mice , DiGeorge Syndrome/genetics , Neanderthals/genetics , Mice, Knockout , Skull/anatomy & histology , Alleles , Spine/anatomy & histology , Spine/abnormalities , Chromosomes, Human, Pair 22/genetics , PhenotypeABSTRACT
New finds in the palaeoanthropological and genomic records have changed our view of the origins of modern human ancestry. Here we review our current understanding of how the ancestry of modern humans around the globe can be traced into the deep past, and which ancestors it passes through during our journey back in time. We identify three key phases that are surrounded by major questions, and which will be at the frontiers of future research. The most recent phase comprises the worldwide expansion of modern humans between 40 and 60 thousand years ago (ka) and their last known contacts with archaic groups such as Neanderthals and Denisovans. The second phase is associated with a broadly construed African origin of modern human diversity between 60 and 300 ka. The oldest phase comprises the complex separation of modern human ancestors from archaic human groups from 0.3 to 1 million years ago. We argue that no specific point in time can currently be identified at which modern human ancestry was confined to a limited birthplace, and that patterns of the first appearance of anatomical or behavioural traits that are used to define Homo sapiens are consistent with a range of evolutionary histories.