Denisovan admixture facilitated environmental adaptation in Papua New Guinean populations.

Neandertals and Denisovans, having inhabited distinct regions in Eurasia and possibly Oceania for over 200,000 y, experienced ample time to adapt to diverse environmental challenges these regions presented. Among present-day human populations, Papua New Guineans (PNG) stand out as one of the few carrying substantial amounts of both Neandertal and Denisovan DNA, a result of past admixture events with these archaic human groups. This study investigates the distribution of introgressed Denisovan and Neandertal DNA within two distinct PNG populations, residing in the highlands of Mt Wilhelm and the lowlands of Daru Island. These locations exhibit unique environmental features, some of which may parallel the challenges that archaic humans once confronted and adapted to. Our results show that PNG highlanders carry higher levels of Denisovan DNA compared to PNG lowlanders. Among the Denisovan-like haplotypes with higher frequencies in highlander populations, those exhibiting the greatest frequency difference compared to lowlander populations also demonstrate more pronounced differences in population frequencies than frequency-matched nonarchaic variants. Two of the five most highly differentiated of those haplotypes reside in genomic areas linked to brain development genes. Conversely, Denisovan-like haplotypes more frequent in lowlanders overlap with genes associated with immune response processes. Our findings suggest that Denisovan DNA has provided genetic variation associated with brain biology and immune response to PNG genomes, some of which might have facilitated adaptive processes to environmental challenges.

Evolutionary and functional analyses of LRP5 in archaic and extant modern humans.

BACKGROUND: The human lineage has undergone a postcranial skeleton gracilization (i.e. lower bone mass and strength relative to body size) compared to other primates and archaic populations such as the Neanderthals. This gracilization has been traditionally explained by differences in the mechanical load that our ancestors exercised. However, there is growing evidence that gracilization could also be genetically influenced. RESULTS: We have analyzed the LRP5 gene, which is known to be associated with high bone mineral density conditions, from an evolutionary and functional point of view. Taking advantage of the published genomes of archaic Homo populations, our results suggest that this gene has a complex evolutionary history both between archaic and living humans and within living human populations. In particular, we identified the presence of different selective pressures in archaics and extant modern humans, as well as evidence of positive selection in the African and South East Asian populations from the 1000 Genomes Project. Furthermore, we observed a very limited evidence of archaic introgression in this gene (only at three haplotypes of East Asian ancestry out of the 1000 Genomes), compatible with a general erasing of the fingerprint of archaic introgression due to functional differences in archaics compared to extant modern humans. In agreement with this hypothesis, we observed private mutations in the archaic genomes that we experimentally validated as putatively increasing bone mineral density. In particular, four of five archaic missense mutations affecting the first ß-propeller of LRP5 displayed enhanced Wnt pathway activation, of which two also displayed reduced negative regulation. CONCLUSIONS: In summary, these data suggest a genetic component contributing to the understanding of skeletal differences between extant modern humans and archaic Homo populations.

Functional characterization of archaic-specific variants in mitonuclear genes: insights from comparative analysis in S. cerevisiae.

Neanderthal and Denisovan hybridisation with modern humans has generated a non-random genomic distribution of introgressed regions, the result of drift and selection dynamics. Cross-species genomic incompatibility and more efficient removal of slightly deleterious archaic variants have been proposed as selection-based processes involved in the post-hybridisation purge of archaic introgressed regions. Both scenarios require the presence of functionally different alleles across Homo species onto which selection operated differently according to which populations hosted them, but only a few of these variants have been pinpointed so far. In order to identify functionally divergent archaic variants removed in humans, we focused on mitonuclear genes, which are underrepresented in the genomic landscape of archaic humans. We searched for non-synonymous, fixed, archaic-derived variants present in mitonuclear genes, rare or absent in human populations. We then compared the functional impact of archaic and human variants in the model organism Saccharomyces cerevisiae. Notably, a variant within the mitochondrial tyrosyl-tRNA synthetase 2 (YARS2) gene exhibited a significant decrease in respiratory activity and a substantial reduction of Cox2 levels, a proxy for mitochondrial protein biosynthesis, coupled with the accumulation of the YARS2 protein precursor and a lower amount of mature enzyme. Our work suggests that this variant is associated with mitochondrial functionality impairment, thus contributing to the purging of archaic introgression in YARS2. While different molecular mechanisms may have impacted other mitonuclear genes, our approach can be extended to the functional screening of mitonuclear genetic variants present across species and populations.

Lithuanian polyphonic songs sutartines: the archaic nature of their musical language in the context of global music.

Lithuanian traditional polyphonic songs, known as sutartines, are characterized by a distinctive musical language and have almost no analogues in world music. The aim of this article is to explore the peculiarities of their musical language and the socio-cultural context of their performance tradition in order to reveal their archaic origins. The archaic nature of sutartines songs is shown not by individual features of their musical language, but by the totality of these features, the peculiarities of their poetics, and performance traditions. An examination of the musical elements and poetry of these songs, and their juxtaposition against examples of archaic vocal polyphony from other cultures, leads to the convergence of arguments in favour of the very ancient origins of these songs, possibly dating back to Old Europe (c. 3 millennium BC). A deeper insight into sutartines songs significantly enriches our understanding of the origin and development of traditional vocal polyphony.

Late History of Cattle Breeds in Central Europe in Light of Genetic and Archaeogenetic Sources-Overview, Thoughts, and Perspectives.

Although Europe was not a primary centre of cattle domestication, its expansion from the Middle East and subsequent development created a complex pattern of cattle breed diversity. Many isolated populations of local historical breeds still carry the message about the physical and genetic traits of ancient populations. Since the way of life of human communities starting from the eleventh millennium BP was strongly determined by livestock husbandry, the knowledge of cattle diversity through the ages is helpful in the interpretation of many archaeological findings. Historical cattle diversity is currently at the intersection of two leading directions of genetic research. Firstly, it is archaeogenetics attempting to recover and interpret the preserved genetic information directly from archaeological finds. The advanced archaeogenetic approaches meet with the population genomics of extant cattle populations. The immense amount of genetic information collected from living cattle, due to its key economic role, allows for reconstructing the genetic profiles of the ancient populations backwards. The present paper aims to place selected archaeogenetic, genetic, and genomic findings in the picture of cattle history in Central Europe, as suggested by archaeozoological and historical records. Perspectives of the methodical connection between the genetic approaches and the approaches of traditional archaeozoology, such as osteomorphology and osteometry, are discussed. The importance, actuality, and effectiveness of combining different approaches to each archaeological find, such as morphological characterization, interpretation of the historical context, and molecular data, are stressed.

Adaptive Selection of Cis-regulatory Elements in the Han Chinese.

Cis-regulatory elements have an important role in human adaptation to the living environment. However, the lag in population genomic cohort studies and epigenomic studies, hinders the research in the adaptive analysis of cis-regulatory elements in human populations. In this study, we collected 4,013 unrelated individuals and performed a comprehensive analysis of adaptive selection of genome-wide cis-regulatory elements in the Han Chinese. In total, 12.34% of genomic regions are under the influence of adaptive selection, where 1.00% of enhancers and 2.06% of promoters are under positive selection, and 0.06% of enhancers and 0.02% of promoters are under balancing selection. Gene ontology enrichment analysis of these cis-regulatory elements under adaptive selection reveals that many positive selections in the Han Chinese occur in pathways involved in cell-cell adhesion processes, and many balancing selections are related to immune processes. Two classes of adaptive cis-regulatory elements related to cell adhesion were in-depth analyzed, one is the adaptive enhancers derived from neanderthal introgression, leads to lower hyaluronidase level in skin, and brings better performance on UV-radiation resistance to the Han Chinese. Another one is the cis-regulatory elements regulating wound healing, and the results suggest the positive selection inhibits coagulation and promotes angiogenesis and wound healing in the Han Chinese. Finally, we found that many pathogenic alleles, such as risky alleles of type 2 diabetes or schizophrenia, remain in the population due to the hitchhiking effect of positive selections. Our findings will help deepen our understanding of the adaptive evolution of genome regulation in the Han Chinese.

The role of farming and fishing in the rise of social complexity in the Central Andes: a stable isotope perspective.

For many years, the rise of stratified societies along the Central Andean coast, known as the birthplace of Andean civilization, has been closely linked to a marine-oriented economy. This hypothesis has recently been challenged by increasing evidence of plant management and cultivation among Andean populations long before the emergence of complex societies and monumental architecture. The extent to which marine and plant-based economies were integrated and their contributions to early sedentism, population growth, and intra-community stratification, however, remain subjects of ongoing and contentious debate. Using Bayesian Mixing Models we reanalyze the previously published stable isotopes (δ15Ncollagen, δ13Ccollagen, δ13Capatite) values of 572 human individuals from 39 archaeological sites in the Central Andes dated between ca. 7000 BCE and 200 CE to reconstruct dietary regimes in probabilistic terms. Our results reveal that fish, terrestrial fauna, and cultivated plants variably contributed to the diet of prehistoric Andean populations; in coastal and middle valley settlements plant cultivation, not fishing, fueled the development of the earliest complex societies during the Formative Period (from 3000 BCE). Similarly, in the highlands the societies that built ceremonial centers show a plant-based economy. Our findings also show that maize only became a staple food (> 25% dietary contribution) in more recent phases of Andean prehistory, around 500 BCE.

Pharmacogenetic Variation in Neanderthals and Denisovans and Implications for Human Health and Response to Medications.

Modern humans carry both Neanderthal and Denisovan (archaic) genome elements that are part of the human gene pool and affect the life and health of living individuals. The impact of archaic DNA may be particularly evident in pharmacogenes-genes responsible for the processing of exogenous substances such as food, pollutants, and medications-as these can relate to changing environmental effects, and beneficial variants may have been retained as modern humans encountered new environments. However, the health implications and contribution of archaic ancestry in pharmacogenes of modern humans remain understudied. Here, we explore 11 key cytochrome P450 genes (CYP450) involved in 75% of all drug metabolizing reactions in three Neanderthal and one Denisovan individuals and examine archaic introgression in modern human populations. We infer the metabolizing efficiency of these 11 CYP450 genes in archaic individuals and find important predicted phenotypic differences relative to modern human variants. We identify several single nucleotide variants shared between archaic and modern humans in each gene, including some potentially function-altering mutations in archaic CYP450 genes, which may result in altered metabolism in living people carrying these variants. We also identified several variants in the archaic CYP450 genes that are novel and unique to archaic humans as well as one gene, CYP2B6, that shows evidence for a gene duplication found only in Neanderthals and modern Africans. Finally, we highlight CYP2A6, CYP2C9, and CYP2J2, genes which show evidence for archaic introgression into modern humans and posit evolutionary hypotheses that explain their allele frequencies in modern populations.

The origins and function of musical performance.

Music is widely recognised as a human universal, yet there is no agreed explanation for its function, or why and when it evolved. I summarise experimental evidence that the primary function of musicking lies in social bonding, both at the dyadic and community levels, via the effect that performing any form of music has on the brain's endorphin system (the principal neurohormonal basis for social bonding in primates). The many other functions associated with music-making (mate choice, pleasure, coalition signalling, etc) are all better understood as derivative of this, either as secondary selection pressures or as windows of evolutionary opportunity (exaptations). If music's function is primarily as an adjunct of the social bonding mechanism (a feature it shares with laughter, feasting, storytelling and the rituals of religion), then reverse engineering the problem suggests that the capacity for music-making most likely evolved with the appearance of archaic humans. This agrees well with anatomical evidence for the capacity to sing.

Main morphological characteristics and sexual dimorphism of hominin adult femora from the Sima de los Huesos Middle Pleistocene site (Sierra de Atapuerca, Spain).

The excellent fossil record from Sima de los Huesos (SH) includes three well-known complete adult femora and several partial specimens that have not yet been published in detail. This fossil record provides an opportunity to analyze the morphology of European pre-Neandertal adult femur and its variation with different evolution patterns. Currently, there are a minimum of five adult individuals (males or females). In this study, we compiled previously published basic anatomical and biometric characteristics of SH adult femora, emphasizing the most relevant features compared to other recent and fossil hominins. The SH femora exhibited a primitive morphological pattern common to all non-Homo sapiens femora, as well as most of the Neandertal traits. Therefore, the complete Upper Pleistocene Neandertal pattern was well-established in Middle Pleistocene ancestors long before the proper Neandertals appeared. Additionally, we highlight that the SH and Neandertal femora share some morphological traits and proportions with modern humans that hold sexual significance in our species, regardless of size. Keeping this in mind, we discussed the sex determination of the complete SH specimens and re-evaluated sex allocation in two of them.

Diverse African genomes reveal selection on ancient modern human introgressions in Neanderthals.

Comparisons of Neanderthal genomes to anatomically modern human (AMH) genomes show a history of Neanderthal-to-AMH introgression stemming from interbreeding after the migration of AMHs from Africa to Eurasia. All non-sub-Saharan African AMHs have genomic regions genetically similar to Neanderthals that descend from this introgression. Regions of the genome with Neanderthal similarities have also been identified in sub-Saharan African populations, but their origins have been unclear. To better understand how these regions are distributed across sub-Saharan Africa, the source of their origin, and what their distribution within the genome tells us about early AMH and Neanderthal evolution, we analyzed a dataset of high-coverage, whole-genome sequences from 180 individuals from 12 diverse sub-Saharan African populations. In sub-Saharan African populations with non-sub-Saharan African ancestry, as much as 1% of their genomes can be attributed to Neanderthal sequence introduced by recent migration, and subsequent admixture, of AMH populations originating from the Levant and North Africa. However, most Neanderthal homologous regions in sub-Saharan African populations originate from migration of AMH populations from Africa to Eurasia ∼250 kya, and subsequent admixture with Neanderthals, resulting in ∼6% AMH ancestry in Neanderthals. These results indicate that there have been multiple migration events of AMHs out of Africa and that Neanderthal and AMH gene flow has been bi-directional. Observing that genomic regions where AMHs show a depletion of Neanderthal introgression are also regions where Neanderthal genomes show a depletion of AMH introgression points to deleterious interactions between introgressed variants and background genomes in both groups-a hallmark of incipient speciation.

Genetic Origins and Adaptive Evolution of the Deng People on the Tibetan Plateau.

The Tibetan Plateau is populated by diverse ethnic groups, but most of them are underrepresented in genomics studies compared with the Tibetans (TIB). Here, to gain further insight into the genetic diversity and evolutionary history of the people living in the Tibetan Plateau, we sequenced 54 whole genomes of the Deng people with high coverage (30-60×) and analyzed the data together with that of TIB and Sherpas, as well as 968 ancient Asian genomes and available archaic and modern human data. We identified 17.74 million novel single-nucleotide variants from the newly sequenced genomes, although the Deng people showed reduced genomic diversity and a relatively small effective population size. Compared with the other Tibetan highlander groups which are highly admixed, the Deng people are dominated by a sole ancestry that could be traced to some ancient northern East Asian populations. The divergence between Deng and Tibetan people (∼4,700-7,200 years) was more recent than that between highlanders and the Han Chinese (Deng-HAN, ∼9,000-14,000 years; TIB-HAN, 7,200-10,000 years). Adaptive genetic variants (AGVs) identified in the Deng are only partially shared with those previously reported in the TIB like HLA-DQB1, whereas others like KLHL12 were not reported in TIB. In contrast, the top candidate genes harboring AGVs as previously identified in TIB, like EPAS1 and EGLN1, do not show strong positive selection signals in Deng. Interestingly, Deng also showed a different archaic introgression scenario from that observed in the TIB. Our results suggest that convergent adaptation might be prevalent on the Tibetan Plateau.

Ghost introgression facilitates genomic divergence of a sympatric cryptic lineage in Cycas revoluta.

A cryptic lineage is a genetically diverged but morphologically unrecognized variant of a known species. Clarifying cryptic lineage evolution is essential for quantifying species diversity. In sympatric cryptic lineage divergence compared with allopatric divergence, the forces of divergent selection and mating patterns override geographical isolation. Introgression, by supplying preadapted or neutral standing genetic variations, can promote sympatric cryptic lineage divergence via selection. However, most studies concentrated on extant species introgression, ignoring the genetic legacy of introgression from extinct or unsampled lineages ("ghost introgression"). Cycads are an ideal plant for studying the influence of ghost introgression because of their common interspecific gene flow and past high extinction rate. Here, we utilized reference-based ddRADseq to clarify the role of ghost introgression in the evolution of a previously identified sympatric cryptic lineage in Cycas revoluta. After re-evaluating the evolutionary independency of cryptic lineages, the group-wise diverged single-nucleotide polymorphisms among sympatric and allopatric lineages were compared and functionally annotated. Next, we employed an approximate Bayesian computation method for hypothesis testing to clarify the cryptic lineage evolution and ghost introgression effect. SNPs with the genomic signatures of ghost introgression were further annotated. Our results reconfirmed the evolutionary independency of cryptic lineage among C. revoluta and demonstrated that ghost introgression to the noncryptic lineage facilitated their divergence. Gene function related to heat stress and disease resistance implied ecological adaptation of the main extant populations of C. revoluta.

Large-scale functional screen identifies genetic variants with splicing effects in modern and archaic humans.

Humans coexisted 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 5,169 alleles tested in this massively parallel splicing reporter assay (MaPSy), we report 962 exonic splicing mutations 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 that 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 unique tissue-specific alternative splicing variant at the adaptively introgressed innate immunity gene TLR1, as well as a unique 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 unique 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.

The Impact of Modern Admixture on Archaic Human Ancestry in Human Populations.

Admixture, the genetic merging of parental populations resulting in mixed ancestry, has occurred frequently throughout the course of human history. Numerous admixture events have occurred between human populations across the world, which have shaped genetic ancestry in modern humans. For example, populations in the Americas are often mosaics of different ancestries due to recent admixture events as part of European colonization. Admixed individuals also often have introgressed DNA from Neanderthals and Denisovans that may have come from multiple ancestral populations, which may affect how archaic ancestry is distributed across an admixed genome. In this study, we analyzed admixed populations from the Americas to assess whether the proportion and location of admixed segments due to recent admixture impact an individual's archaic ancestry. We identified a positive correlation between non-African ancestry and archaic alleles, as well as a slight increase of Denisovan alleles in Indigenous American segments relative to European segments in admixed genomes. We also identify several genes as candidates for adaptive introgression, based on archaic alleles present at high frequency in admixed American populations but low frequency in East Asian populations. These results provide insights into how recent admixture events between modern humans redistributed archaic ancestry in admixed genomes.

Whole-genome sequencing reveals a complex African population demographic history and signatures of local adaptation.

We conduct high coverage (>30×) whole-genome sequencing of 180 individuals from 12 indigenous African populations. We identify millions of unreported variants, many predicted to be functionally important. We observe that the ancestors of southern African San and central African rainforest hunter-gatherers (RHG) diverged from other populations >200 kya and maintained a large effective population size. We observe evidence for ancient population structure in Africa and for multiple introgression events from "ghost" populations with highly diverged genetic lineages. Although currently geographically isolated, we observe evidence for gene flow between eastern and southern Khoesan-speaking hunter-gatherer populations lasting until ∼12 kya. We identify signatures of local adaptation for traits related to skin color, immune response, height, and metabolic processes. We identify a positively selected variant in the lightly pigmented San that influences pigmentation in vitro by regulating the enhancer activity and gene expression of PDPK1.

Evolutionary relevance of single nucleotide variants within the forebrain exclusive human accelerated enhancer regions.

BACKGROUND: Human accelerated regions (HARs) are short conserved genomic sequences that have acquired significantly more nucleotide substitutions than expected in the human lineage after divergence from chimpanzees. The fast evolution of HARs may reflect their roles in the origin of human-specific traits. A recent study has reported positively-selected single nucleotide variants (SNVs) within brain-exclusive human accelerated enhancers (BE-HAEs) hs1210 (forebrain), hs563 (hindbrain) and hs304 (midbrain/forebrain). By including data from archaic hominins, these SNVs were shown to be Homo sapiens-specific, residing within transcriptional factors binding sites (TFBSs) for SOX2 (hs1210), RUNX1/3 (hs563), and FOS/JUND (hs304). Although these findings suggest that the predicted modifications in TFBSs may have some role in present-day brain structure, work is required to verify the extent to which these changes translate into functional variation. RESULTS: To start to fill this gap, we investigate the SOX2 SNV, with both forebrain expression and strong signal of positive selection in humans. We demonstrate that the HMG box of SOX2 binds in vitro with Homo sapiens-specific derived A-allele and ancestral T-allele carrying DNA sites in BE-HAE hs1210. Molecular docking and simulation analysis indicated highly favourable binding of HMG box with derived A-allele containing DNA site when compared to site carrying ancestral T-allele. CONCLUSION: These results suggest that adoptive changes in TF affinity within BE-HAE hs1210 and other HAR enhancers in the evolutionary history of Homo sapiens might. have brought about changes in gene expression patterns and have functional consequences on forebrain formation and evolution. METHODS: The present study employ electrophoretic mobility shift assays (EMSA) and molecular docking and molecular dynamics simulations approaches.

Extraordinary selection on the human X chromosome associated with archaic admixture.

The X chromosome in non-African humans shows less diversity and less Neanderthal introgression than expected from neutral evolution. Analyzing 162 human male X chromosomes worldwide, we identified fourteen chromosomal regions where nearly identical haplotypes spanning several hundred kilobases are found at high frequencies in non-Africans. Genetic drift alone cannot explain the existence of these haplotypes, which must have been associated with strong positive selection in partial selective sweeps. Moreover, the swept haplotypes are entirely devoid of archaic ancestry as opposed to the non-swept haplotypes in the same genomic regions. The ancient Ust'-Ishim male dated at 45,000 before the present (BP) also carries the swept haplotypes, implying that selection on the haplotypes must have occurred between 45,000 and 55,000 years ago. Finally, we find that the chromosomal positions of sweeps overlap previously reported hotspots of selective sweeps in great ape evolution, suggesting a mechanism of selection unique to X chromosomes.

Insights into brain evolution through the genotype-phenotype connection.

It has recently become possible to start exploring how the genotype translates into human brain morphology and behavior by combining detailed genomic and phenotypic data from thousands of present-day people with archaic genomes of extinct humans, and gene expression data. As a starting point into this emerging interdisciplinary domain, we highlight current debates about which aspects of the modern human brain are unique. We review recent developments from (1) comparative primate neuroscience-a fast-growing field offering an invaluable framework for understanding general mechanisms and the evolution of human-specific traits. (2) paleoanthropology-based on evidence from endocranial imprints in fossil skulls, we trace the evolution from the ape-like brain phenotype of early hominins more than 3 million years ago to the unusual globular brain shape of present-day people. (3) Genomics of present-day and extinct humans. The morphological and genetic differences between modern humans and our closest extinct cousins, the Neandertals, offer important clues about the genetic underpinnings of brain morphology and behavior. The functional consequences of these genetic differences can be tested in animal models, and brain organoids.