Reconstructing the Deep Population History of Central and South America.

We report genome-wide ancient DNA from 49 individuals forming four parallel time transects in Belize, Brazil, the Central Andes, and the Southern Cone, each dating to at least ∼9,000 years ago. The common ancestral population radiated rapidly from just one of the two early branches that contributed to Native Americans today. We document two previously unappreciated streams of gene flow between North and South America. One affected the Central Andes by ∼4,200 years ago, while the other explains an affinity between the oldest North American genome associated with the Clovis culture and the oldest Central and South Americans from Chile, Brazil, and Belize. However, this was not the primary source for later South Americans, as the other ancient individuals derive from lineages without specific affinity to the Clovis-associated genome, suggesting a population replacement that began at least 9,000 years ago and was followed by substantial population continuity in multiple regions.

Biogeographic Perspectives on Human Genetic Diversification.

Modern humans originated in Africa 300,000 yr ago, and before leaving their continent of origin, they underwent a process of intense diversification involving complex demographic dynamics. Upon exiting Africa, different populations emerged on the four other inhabited continents, shaped by the interplay of various evolutionary processes, such as migrations, founder effects, and natural selection. Within each region, continental populations, in turn, diversified and evolved almost independently for millennia. As a backdrop to this diversification, introgressions from archaic species contributed to establishing different patterns of genetic diversity in different geographic regions, reshaping our understanding of our species' variability. With the increasing availability of genomic data, it has become possible to delineate the subcontinental human population structure precisely. However, the bias toward the genomic research focused on populations from the global North has limited our understanding of the real diversity of our species and the processes and events that guided different human groups throughout their evolutionary history. This perspective is part of a series of articles celebrating 40 yr since our journal, Molecular Biology and Evolution, was founded (Russo et al. 2024). The perspective is accompanied by virtual issues, a selection of papers on human diversification published by Genome Biology and Evolution and Molecular Biology and Evolution.

Population-based change-point detection for the identification of homozygosity islands.

MOTIVATION: This work is motivated by the problem of identifying homozygosity islands on the genome of individuals in a population. Our method directly tackles the issue of identification of the homozygosity islands at the population level, without the need of analysing single individuals and then combine the results, as is made nowadays in state-of-the-art approaches. RESULTS: We propose regularized offline change-point methods to detect changes in the parameters of a multidimensional distribution when we have several aligned, independent samples of fixed resolution. We present a penalized maximum likelihood approach that can be efficiently computed by a dynamic programming algorithm or approximated by a fast binary segmentation algorithm. Both estimators are shown to converge almost surely to the set of change-points without the need of specifying a priori the number of change-points. In simulation, we observed similar performances from the exact and greedy estimators. Moreover, we provide a new methodology for the selection of the regularization constant which has the advantage of being automatic, consistent, and less prone to subjective analysis. AVAILABILITY AND IMPLEMENTATION: The data used in the application are from the Human Genome Diversity Project (HGDP) and is publicly available. Algorithms were implemented using the R software R Core Team (R: A Language and Environment for Statistical Computing. Vienna (Austria): R Foundation for Statistical Computing, 2020.) in the R package blockcpd, found at https://github.com/Lucas-Prates/blockcpd.

Deep genetic affinity between coastal Pacific and Amazonian natives evidenced by Australasian ancestry.

Different models have been proposed to elucidate the origins of the founding populations of America, along with the number of migratory waves and routes used by these first explorers. Settlements, both along the Pacific coast and on land, have been evidenced in genetic and archeological studies. However, the number of migratory waves and the origin of immigrants are still controversial topics. Here, we show the Australasian genetic signal is present in the Pacific coast region, indicating a more widespread signal distribution within South America and implicating an ancient contact between Pacific and Amazonian dwellers. We demonstrate that the Australasian population contribution was introduced in South America through the Pacific coastal route before the formation of the Amazonian branch, likely in the ancient coastal Pacific/Amazonian population. In addition, we detected a significant amount of interpopulation and intrapopulation variation in this genetic signal in South America. This study elucidates the genetic relationships of different ancestral components in the initial settlement of South America and proposes that the migratory route used by migrants who carried the Australasian ancestry led to the absence of this signal in the populations of Central and North America.

Human genetic determinants of COVID-19 in Brazil: challenges and future plans.

COVID-19 pandemic represented a worldwide major challenge in different areas, and efforts undertaken by the scientific community led to the understanding of some of the genetic determinants that influence the different COVID-19 outcomes. In this paper, we review the studies about the role of human genetics in COVID-19 severity and how Brazilian studies also contributed to those findings. Rare variants in genes related to Inborn Errors of Immunity (IEI) in the type I interferons pathway, and its phenocopies, have been described as being causative of severe outcomes. IEI and its phenocopies are present in Brazil, not only in COVID-19 patients, but also in autoimmune conditions and severe reactions to yellow fever vaccine. In addition, studies focusing on common variants and GWAS studies encompassing worldwide patients have found several loci associated with COVID-19 severity. A GWAS study including only Brazilian COVID-19 patients identified a new locus 1q32.1 associated with COVID-19 severity. Thus, more comprehensive studies considering the Brazilian genomic diversity should be performed, since they can help to reveal not only what are the genetic determinants that contribute to the different outcomes for COVID-19 in the Brazilian population, but in the understanding of human genetics in different health conditions.

Population Histories and Genomic Diversity of South American Natives.

South America is home to one of the most culturally diverse present-day native populations. However, the dispersion pattern, genetic substructure, and demographic complexity within South America are still poorly understood. Based on genome-wide data of 58 native populations, we provide a comprehensive scenario of South American indigenous groups considering the genomic, environmental, and linguistic data. Clear patterns of genetic structure were inferred among the South American natives, presenting at least four primary genetic clusters in the Amazonian and savanna regions and three clusters in the Andes and Pacific coast. We detected a cline of genetic variation along a west-east axis, contradicting a hard Andes-Amazon divide. This longitudinal genetic variation seemed to have been shaped by both serial population bottlenecks and isolation by distance. Results indicated that present-day South American substructures recapitulate ancient macroregional ancestries and western Amazonia groups show genetic evidence of cultural exchanges that led to language replacement in precontact times. Finally, demographic inferences pointed to a higher resilience of the western South American groups regarding population collapses caused by the European invasion and indicated precontact population reductions and demic expansions in South America.

Disentangling Signatures of Selection Before and After European Colonization in Latin Americans.

Throughout human evolutionary history, large-scale migrations have led to intermixing (i.e., admixture) between previously separated human groups. Although classical and recent work have shown that studying admixture can yield novel historical insights, the extent to which this process contributed to adaptation remains underexplored. Here, we introduce a novel statistical model, specific to admixed populations, that identifies loci under selection while determining whether the selection likely occurred post-admixture or prior to admixture in one of the ancestral source populations. Through extensive simulations, we show that this method is able to detect selection, even in recently formed admixed populations, and to accurately differentiate between selection occurring in the ancestral or admixed population. We apply this method to genome-wide SNP data of ∼4,000 individuals in five admixed Latin American cohorts from Brazil, Chile, Colombia, Mexico, and Peru. Our approach replicates previous reports of selection in the human leukocyte antigen region that are consistent with selection post-admixture. We also report novel signals of selection in genomic regions spanning 47 genes, reinforcing many of these signals with an alternative, commonly used local-ancestry-inference approach. These signals include several genes involved in immunity, which may reflect responses to endemic pathogens of the Americas and to the challenge of infectious disease brought by European contact. In addition, some of the strongest signals inferred to be under selection in the Native American ancestral groups of modern Latin Americans overlap with genes implicated in energy metabolism phenotypes, plausibly reflecting adaptations to novel dietary sources available in the Americas.

Roadmap for Establishing Large-Scale Genomic Medicine Initiatives in Low- and Middle-Income Countries.

In the post-genomic era, genomic medicine interventions as a key component of personalized medicine and tailored-made health care are greatly anticipated following recent scientific and technological advances. Indeed, large-scale sequencing efforts that explore human genomic variation have been initiated in several, mostly developed, countries across the globe, such as the United States, the United Kingdom, and a few others. Here, we highlight the successful implementation of large-scale national genomic initiatives, namely the Genome of Greece (GoGreece) and the DNA do Brasil (DNABr), aiming to emphasize the importance of implementing such initiatives in developing countries. Based on this experience, we also provide a roadmap for replicating these projects in other low-resource settings, thereby bringing genomic medicine in these countries closer to clinical fruition.

Genomic insight into the origins and dispersal of the Brazilian coastal natives.

In the 15th century, ∼900,000 Native Americans, mostly Tupí speakers, lived on the Brazilian coast. By the end of the 18th century, the coastal native populations were declared extinct. The Tupí arrived on the east coast after leaving the Amazonian basin ∼2,000 y before present; however, there is no consensus on how this migration occurred: toward the northern Amazon and then directly to the Atlantic coast, or heading south into the continent and then migrating to the coast. Here we leveraged genomic data from one of the last remaining putative representatives of the Tupí coastal branch, a small, admixed, self-reported Tupiniquim community, as well as data of a Guaraní Mbyá native population from Southern Brazil and of three other native populations from the Amazonian region. We demonstrated that the Tupiniquim Native American ancestry is not related to any extant Brazilian Native American population already studied, and thus they could be considered the only living representatives of the extinct Tupí branch that used to settle the Atlantic Coast of Brazil. Furthermore, these data show evidence of a direct migration from Amazon to the Northeast Coast in pre-Columbian time, giving rise to the Tupí Coastal populations, and a single distinct migration southward that originated the Guaraní people from Brazil and Paraguay. This study elucidates the population dynamics and diversification of the Brazilian natives at a genomic level, which was made possible by recovering data from the Brazilian coastal population through the genomes of mestizo individuals.

A genomic perspective on South American human history.

It has generally been accepted that the current indigenous peoples of the Americas are derived from ancestors from northeastern Asia. The latter were believed to have spread into the American continent by the end of the Last Glacial Maximum. In this sense, a joint and in-depth study of the earliest settlement of East Asia and the Americas is required to elucidate these events accurately. The first Americans underwent an adaptation process to the Americas' vast environmental diversity, mediated by biological and cultural evolution and niche construction, resulting in enormous cultural diversity, a wealth of domesticated species, and extensive landscape modifications. Afterward, in the Late Holocene, the advent of intensive agricultural food production systems, sedentism, and climate change significantly reshaped genetic and cultural diversity across the continent, particularly in the Andes and Amazonia. Furthermore, starting around the end of the 15th century, European colonization resulted in massive extermination of indigenous peoples and extensive admixture. Thus, the present review aims to create a comprehensive picture of the main events involved in the formation of contemporary South American indigenous populations and the dynamics responsible for shaping their genetic diversity by integrating current genetic data with evidence from archeology, linguistics and other disciplines.

Genetic evidence for two founding populations of the Americas.

Genetic studies have consistently indicated a single common origin of Native American groups from Central and South America. However, some morphological studies have suggested a more complex picture, whereby the northeast Asian affinities of present-day Native Americans contrast with a distinctive morphology seen in some of the earliest American skeletons, which share traits with present-day Australasians (indigenous groups in Australia, Melanesia, and island Southeast Asia). Here we analyse genome-wide data to show that some Amazonian Native Americans descend partly from a Native American founding population that carried ancestry more closely related to indigenous Australians, New Guineans and Andaman Islanders than to any present-day Eurasians or Native Americans. This signature is not present to the same extent, or at all, in present-day Northern and Central Americans or in a ∼12,600-year-old Clovis-associated genome, suggesting a more diverse set of founding populations of the Americas than previously accepted.

Adaptation and co-adaptation of skin pigmentation and vitamin D genes in native Americans.

We carried out an exhaustive review regarding human skin color variation and how much it may be related to vitamin D metabolism and other photosensitive molecules. We discuss evolutionary contexts that modulate this variability and hypotheses postulated to explain them; for example, a small amount of melanin in the skin facilitates vitamin D production, making it advantageous to have fair skin in an environment with little radiation incidence. In contrast, more melanin protects folate from degradation in an environment with a high incidence of radiation. Some Native American populations have a skin color at odds with what would be expected for the amount of radiation in the environment in which they live, a finding challenging the so-called "vitamin D-folate hypothesis." Since food is also a source of vitamin D, dietary habits should also be considered. Here we argue that a gene network approach provides tools to explain this phenomenon since it indicates potential alleles co-evolving in a compensatory way. We identified alleles of the vitamin D metabolism and pigmentation pathways segregated together, but in different proportions, in agriculturalists and hunter-gatherers. Finally, we highlight how an evolutionary approach can be useful to understand current topics of medical interest.

Genetic signature of natural selection in first Americans.

When humans moved from Asia toward the Americas over 18,000 y ago and eventually peopled the New World they encountered a new environment with extreme climate conditions and distinct dietary resources. These environmental and dietary pressures may have led to instances of genetic adaptation with the potential to influence the phenotypic variation in extant Native American populations. An example of such an event is the evolution of the fatty acid desaturases (FADS) genes, which have been claimed to harbor signals of positive selection in Inuit populations due to adaptation to the cold Greenland Arctic climate and to a protein-rich diet. Because there was evidence of intercontinental variation in this genetic region, with indications of positive selection for its variants, we decided to compare the Inuit findings with other Native American data. Here, we use several lines of evidence to show that the signal of FADS-positive selection is not restricted to the Arctic but instead is broadly observed throughout the Americas. The shared signature of selection among populations living in such a diverse range of environments is likely due to a single and strong instance of local adaptation that took place in the common ancestral population before their entrance into the New World. These first Americans peopled the whole continent and spread this adaptive variant across a diverse set of environments.

Reconstructing Native American population history.

The peopling of the Americas has been the subject of extensive genetic, archaeological and linguistic research; however, central questions remain unresolved. One contentious issue is whether the settlement occurred by means of a single migration or multiple streams of migration from Siberia. The pattern of dispersals within the Americas is also poorly understood. To address these questions at a higher resolution than was previously possible, we assembled data from 52 Native American and 17 Siberian groups genotyped at 364,470 single nucleotide polymorphisms. Here we show that Native Americans descend from at least three streams of Asian gene flow. Most descend entirely from a single ancestral population that we call 'First American'. However, speakers of Eskimo-Aleut languages from the Arctic inherit almost half their ancestry from a second stream of Asian gene flow, and the Na-Dene-speaking Chipewyan from Canada inherit roughly one-tenth of their ancestry from a third stream. We show that the initial peopling followed a southward expansion facilitated by the coast, with sequential population splits and little gene flow after divergence, especially in South America. A major exception is in Chibchan speakers on both sides of the Panama isthmus, who have ancestry from both North and South America.

A tale of agriculturalists and hunter-gatherers: Exploring the thrifty genotype hypothesis in native South Americans.

OBJECTIVES: To determine genetic differences between agriculturalist and hunter-gatherer southern Native American populations for selected metabolism-related markers and to test whether Neel's thrifty genotype hypothesis (TGH) could explain the genetic patterns observed in these populations. MATERIALS AND METHODS: 375 Native South American individuals from 17 populations were genotyped using six markers (APOE rs429358 and rs7412; APOA2 rs5082; CD36 rs3211883; TCF7L2 rs11196205; and IGF2BP2 rs11705701). Additionally, APOE genotypes from 39 individuals were obtained from the literature. AMOVA, main effects, and gene-gene interaction tests were performed. RESULTS: We observed differences in allele distribution patterns between agriculturalists and hunter-gatherers for some markers. For instance, between-groups component of genetic variance (FCT ) for APOE rs429358 showed strong differences in allelic distributions between hunter-gatherers and agriculturalists (p = 0.00196). Gene-gene interaction analysis indicated that the APOE E4/CD36 TT and APOE E4/IGF2BP2 A carrier combinations occur at a higher frequency in hunter-gatherers, but this combination is not replicated in archaic (Neanderthal and Denisovan) and ancient (Anzick, Saqqaq, Ust-Ishim, Mal'ta) hunter-gatherer individuals. DISCUSSION: A complex scenario explains the observed frequencies of the tested markers in hunter-gatherers. Different factors, such as pleotropic alleles, rainforest selective pressures, and population dynamics, may be collectively shaping the observed genetic patterns. We conclude that although TGH seems a plausible hypothesis to explain part of the data, other factors may be important in our tested populations.

Admixture in Latin America: geographic structure, phenotypic diversity and self-perception of ancestry based on 7,342 individuals.

The current genetic makeup of Latin America has been shaped by a history of extensive admixture between Africans, Europeans and Native Americans, a process taking place within the context of extensive geographic and social stratification. We estimated individual ancestry proportions in a sample of 7,342 subjects ascertained in five countries (Brazil, Chile, Colombia, México and Perú). These individuals were also characterized for a range of physical appearance traits and for self-perception of ancestry. The geographic distribution of admixture proportions in this sample reveals extensive population structure, illustrating the continuing impact of demographic history on the genetic diversity of Latin America. Significant ancestry effects were detected for most phenotypes studied. However, ancestry generally explains only a modest proportion of total phenotypic variation. Genetically estimated and self-perceived ancestry correlate significantly, but certain physical attributes have a strong impact on self-perception and bias self-perception of ancestry relative to genetically estimated ancestry.

Self-assessment of color categories and its relationship with HLA profiling in Brazilian bone marrow donors.

The Brazil Ministry of Health maintains a Registry of Bone Marrow Donors that corresponds to approximately 12% of the Bone Marrow Donors Worldwide registry. This registry contains information on ethnicity (by self-assessment of color) and HLA-A, -B, and -DRB1 type. The self-assessment of color tool has been extensively used for admixed population characterization. In this context, Brazil represents a highly admixed population, resulting from 5 centuries of colonization and interbreeding, mainly, but not exclusively, among Native Americans, Europeans, and Africans. Here we evaluated self-assessed skin color and HLA genetic information from 71,291 bone marrow donors of southern Brazil to verify how likely is the HLA profiling correspondence within and between self-assessed color groups. We found that HLA itself was a better ancestry indicator than was self-assessed color. Therefore, self-assessment of color in highly admixed populations, such as that of Brazil, is not indicative of higher correspondence in the HLA profiles within skin color groups.

Ancient remains and the first peopling of the Americas: Reassessing the Hoyo Negro skull.

OBJECTIVE: A noticeably well-preserved ∼12.500 years-old skeleton from the Hoyo Negro cave, Yucatán, México, was recently reported, along with its archaeological, genetic and skeletal characteristics. Based exclusively on an anatomical description of the skull (HN5/48), Chatters and colleagues stated that this specimen can be assigned to a set of ancient remains that differ from modern Native Americans, the so called "Paleoamericans". Here, we aim to further explore the morphological affinities of this specimen with a set of comparative cranial samples covering ancient and modern periods from Asia and the Americas. METHODS: Images published in the original article were analyzed using geometric morphometrics methods. Shape variables were used to perform Principal Component and Discriminant analysis against the reference samples. RESULTS: Even thought the Principal Component Analysis suggests that the Hoyo Negro skull falls in a subregion of the morphospace occupied by both "Paleoamericans" and some modern Native Americans, the Discriminant analyses suggest greater affinity with a modern Native American sample. DISCUSSION: These results reinforce the idea that the original population that first occupied the New World carried high levels of within-group variation, which we have suggested previously on a synthetic model for the settlement of the Americas. Our results also highlight the importance of developing formal classificatory test before deriving settlement hypothesis purely based on macroscopic descriptions.

Facial asymmetry and genetic ancestry in Latin American admixed populations.

Fluctuating and directional asymmetry are aspects of morphological variation widely used to infer environmental and genetic factors affecting facial phenotypes. However, the genetic basis and environmental determinants of both asymmetry types is far from being completely known. The analysis of facial asymmetries in admixed individuals can be of help to characterize the impact of a genome's heterozygosity on the developmental basis of both fluctuating and directional asymmetries. Here we characterize the association between genetic ancestry and individual asymmetry on a sample of Latin-American admixed populations. To do so, three-dimensional (3D) facial shape attributes were explored on a sample of 4,104 volunteers aged between 18 and 85 years. Individual ancestry and heterozygosity was estimated using more than 730,000 genome-wide markers. Multivariate techniques applied to geometric morphometric data were used to evaluate the magnitude and significance of directional and fluctuating asymmetry (FA), as well as correlations and multiple regressions aimed to estimate the relationship between facial FA scores and heterozygosity and a set of covariates. Results indicate that directional and FA are both significant, the former being the strongest expression of asymmetry in this sample. In addition, our analyses suggest that there are some specific patterns of facial asymmetries characterizing the different ancestry groups. Finally, we find that more heterozygous individuals exhibit lower levels of asymmetry. Our results highlight the importance of including ancestry-admixture estimators, especially when the analyses are aimed to compare levels of asymmetries on groups differing on socioeconomic levels, as a proxy to estimate developmental noise.

Cultural diversification promotes rapid phenotypic evolution in Xavánte Indians.

Shifts in social structure and cultural practices can potentially promote unusual combinations of allele frequencies that drive the evolution of genetic and phenotypic novelties during human evolution. These cultural practices act in combination with geographical and linguistic barriers and can promote faster evolutionary changes shaped by gene-culture interactions. However, specific cases indicative of this interaction are scarce. Here we show that quantitative genetic parameters obtained from cephalometric data taken on 1,203 individuals analyzed in combination with genetic, climatic, social, and life-history data belonging to six South Amerindian populations are compatible with a scenario of rapid genetic and phenotypic evolution, probably mediated by cultural shifts. We found that the Xavánte experienced a remarkable pace of evolution: the rate of morphological change is far greater than expected for its time of split from their sister group, the Kayapó, which occurred around 1,500 y ago. We also suggest that this rapid differentiation was possible because of strong social-organization differences. Our results demonstrate how human groups deriving from a recent common ancestor can experience variable paces of phenotypic divergence, probably as a response to different cultural or social determinants. We suggest that assembling composite databases involving cultural and biological data will be of key importance to unravel cases of evolution modulated by the cultural environment.