Dietary, Cultural, and Pathogens-Related Selective Pressures Shaped Differential Adaptive Evolution among Native Mexican Populations

Native American genetic ancestry has been remarkably implicated with increased risk of diverse health issues in several Mexican populations, especially in relation to the dramatic changes in environmental, dietary, and cultural settings they have recently undergone. In particular, the effects of these ecological transitions and Westernization of lifestyles have been investigated so far predominantly on Mestizo individuals. Nevertheless, indigenous groups, rather than admixed Mexicans, have plausibly retained the highest proportions of genetic components shaped by natural selection in response to the ancient milieu experienced by Mexican ancestors during their pre-Columbian evolutionary history. These formerly adaptive variants have the potential to represent the genetic determinants of some biological traits that are peculiar to Mexican people, as well as a reservoir of loci with possible biomedical relevance. To test such a hypothesis, we used genome-wide genotype data to infer the unique adaptive evolution of Native Mexican groups selected as reasonable descendants of the main pre-Columbian Mexican civilizations. A combination of haplotype-based and gene-network analyses enabled us to detect genomic signatures ascribable to polygenic adaptive traits plausibly evolved by the main genetic clusters of Mexican indigenous populations to cope with local environmental and/or cultural conditions. Some of these adaptations were found to play a role in modulating the susceptibility/resistance of these groups to certain pathological conditions, thus providing new evidence that diverse selective pressures have contributed to shape the current biological and disease-risk patterns of present-day Native and Mestizo Mexican populations

Evidence of Polygenic Adaptation to High Altitude from Tibetan and Sherpa Genomes

Although Tibetans and Sherpa present several physiological adjustments evolved to cope with selective pressures imposed by the high-altitude environment, especially hypobaric hypoxia, few selective sweeps at a limited number of hypoxia related genes were confirmed by multiple genomic studies. Nevertheless, variants at these loci were found to be associated only with downregulation of the erythropoietic cascade, which represents an indirect aspect of the considered adaptive phenotype. Accordingly, the genetic basis of Tibetan/Sherpa adaptive traits remains to be fully elucidated, in part due to limitations of selection scans implemented so far and mostly relying on the hard sweep model.In order to overcome this issue, we used whole-genome sequence data and several selection statistics as input for gene network analyses aimed at testing for the occurrence of polygenic adaptation in these high-altitude Himalayan populations. Being able to detect also subtle genomic signatures ascribable to weak positive selection at multiple genes of the same functional subnetwork, this approach allowed us to infer adaptive evolution at loci individually showing small effect sizes, but belonging to highly interconnected biological pathways overall involved in angiogenetic processes.Therefore, these findings pinpointed a series of selective events neglected so far, which likely contributed to the augmented tissue blood perfusion observed in Tibetans and Sherpa, thus uncovering the genetic determinants of a key biological mechanism that underlies their adaptation to high altitude

Genomic adaptations to cereal-based diets contribute to mitigate metabolic risk in some human populations of East Asian ancestry

Adoption of diets based on some cereals, especially on rice, signified an iconic change in nutritional habits for many Asian populations and a relevant challenge for their capability to maintain glucose homeostasis. Indeed, rice shows the highest carbohydrates content and glycemic index among the domesticated cereals and its usual ingestion represents a potential risk factor for developing insulin resistance and related metabolic diseases. Nevertheless, type 2 diabetes and obesity epidemiological patterns differ among Asian populations that rely on rice as a staple food, with higher diabetes prevalence and increased levels of central adiposity observed in people of South Asian ancestry rather than in East Asians. This may be at least partly due to the fact that populations from East Asian regions where wild rice or other cereals such as millet have been already consumed before their cultivation and/or were early domesticated have relied on these nutritional resources for a period long enough to have possibly evolved biological adaptations that counteract their detrimental side effects. To test such a hypothesis, we compared adaptive evolution of these populations with that of control groups from regions where the adoption of cereal-based diets occurred many thousand years later and which were identified from a genome-wide dataset including 2,379 individuals from 124 East Asian and South Asian populations. This revealed selective sweeps and polygenic adaptive mechanisms affecting functional pathways involved in fatty acids metabolism, cholesterol/triglycerides biosynthesis from carbohydrates, regulation of glucose homeostasis, and production of retinoic acid in Chinese Han and Tujia ethnic groups, as well as in people of Korean and Japanese ancestry. Accordingly, long-standing rice- and/or millet-based diets have possibly contributed to trigger the evolution of such biological adaptations, which might represent one of the factors that play a role in mitigating the metabolic risk of these East Asian populations

Gut microbiota composition in himalayan and andean populations and its relationship with diet, lifestyle and adaptation to the high-altitude environment

Human populations living at high altitude evolved a number of biological adjustments to cope with a challenging environment characterised especially by reduced oxygen availability and limited nutritional resources. This condition may also affect their gut microbiota composition. Here, we explored the impact of exposure to such selective pressures on human gut microbiota by considering different ethnic groups living at variable degrees of altitude: the high-altitude Sherpa and low-altitude Tamang populations from Nepal, the high-altitude Aymara population from Bolivia, as well as a low-altitude cohort of European ancestry, used as control. We thus observed microbial profiles common to the Sherpa and Aymara, but absent in the low-altitude cohorts, which may contribute to the achievement of adaptation to high-altitude lifestyle and nutritional conditions. The collected evidences suggest that microbial signatures associated to these rural populations may enhance metabolic functions able to supply essential compounds useful for the host to cope with high altitude-related physiological changes and energy demand. Therefore, these results add another valuable piece of the puzzle to the understanding of the beneficial effects of symbiosis between microbes and their human host even from an evolutionary perspective

Ancient genomic time transect from the Central Asian Steppe unravels the history of the Scythians

The Scythians were a multitude of horse-warrior nomad cultures dwelling in the Eurasian steppe during the first millennium BCE. Because of the lack of first-hand written records, little is known about the origins and relations among the different cultures. To address these questions, we produced genome-wide data for 111 ancient individuals retrieved from 39 archaeological sites from the first millennia BCE and CE across the Central Asian Steppe. We uncovered major admixture events in the Late Bronze Age forming the genetic substratum for two main Iron Age gene-pools emerging around the Altai and the Urals respectively. Their demise was mirrored by new genetic turnovers, linked to the spread of the eastern nomad empires in the first centuries CE. Compared to the high genetic heterogeneity of the past, the homogenization of the present-day Kazakhs gene pool is notable, likely a result of 400 years of strict exogamous social rules.Introduction Results - The IA transition in the Kazakh Steppe - Admixture modeling of IA steppe populations - Post-IA genetic turnovers in the Kazakh Steppe - Dating ancient admixture - Present-day Kazakhs Discussion Material and methods - Radiocarbon dating - DNA extraction, library preparations, and sequencing - Modern DNA genotyping and quality controls - Ancient DNA data processing -- Raw data -- Authentication and contamination estimate -- Genotyping -- Sex determination -- Genetic relatedness estimation - Uniparental haplogroup assignment - Population structure analyses - Individual labeling and population grouping criteria - F-statistics and ancestry modeling - Admixture dating - CHROMOPAINTER and fineSTRUCTURE analyse

Genomic history of the Italian population recapitulates key evolutionary dynamics of both Continental and Southern Europeans

Background: The cline of human genetic diversity observable across Europe is recapitulated at a micro-geographic scale by variation within the Italian population. Besides resulting from extensive gene flow, this might be ascribable also to local adaptations to diverse ecological contexts evolved by people who anciently spread along the Italian Peninsula. Dissecting the evolutionary history of the ancestors of present-day Italians may thus improve the understanding of demographic and biological processes that contributed to shape the gene pool of European populations. However, previous SNP array-based studies failed to investigate the full spectrum of Italian variation, generally neglecting low-frequency genetic variants and examining a limited set of small effect size alleles, which may represent important determinants of population structure and complex adaptive traits. To overcome these issues, we analyzed 38 high-coverage whole-genome sequences representative of population clusters at the opposite ends of the cline of Italian variation, along with a large panel of modern and ancient Euro-Mediterranean genomes. Results: We provided evidence for the early divergence of Italian groups dating back to the Late Glacial and for Neolithic and distinct Bronze Age migrations having further differentiated their gene pools. We inferred adaptive evolution at insulin-related loci in people from Italian regions with a temperate climate, while possible adaptations to pathogens and ultraviolet radiation were observed in Mediterranean Italians. Some of these adaptive events may also have secondarily modulated population disease or longevity predisposition. Conclusions: We disentangled the contribution of multiple migratory and adaptive events in shaping the heterogeneous Italian genomic background, which exemplify population dynamics and gene-environment interactions that played significant roles also in the formation of the Continental and Southern European genomic landscapes

A Loss-of-Function HCN4 Mutation Associated With Familial Benign Myoclonic Epilepsy in Infancy Causes Increased Neuronal Excitability

HCN channels are highly expressed and functionally relevant in neurons and increasing evidence demonstrates their involvement in the etiology of human epilepsies. Among HCN isoforms, HCN4 is important in cardiac tissue, where it underlies pacemaker activity. Despite being expressed also in deep structures of the brain, mutations of this channel functionally shown to be associated with epilepsy have not been reported yet. Using Next Generation Sequencing for the screening of patients with idiopathic epilepsy, we identified the p.Arg550Cys (c.1648C>T) heterozygous mutation on HCN4 in two brothers affected by benign myoclonic epilepsy of infancy. Functional characterization in heterologous expression system and in neurons showed that the mutation determines a loss of function of HCN4 contribution to activity and an increase of neuronal discharge, potentially predisposing to epilepsy. Expressed in cardiomyocytes, mutant channels activate at slightly more negative voltages than wild-type (WT), in accordance with borderline bradycardia. While HCN4 variants have been frequently associated with cardiac arrhythmias, these data represent the first experimental evidence that functional alteration of HCN4 can also be involved in human epilepsy through a loss-of-function effect and associated increased neuronal excitability. Since HCN4 appears to be highly expressed in deep brain structures only early during development, our data provide a potential explanation for a link between dysfunctional HCN4 and infantile epilepsy. These findings suggest that it may be useful to include HCN4 screening to extend the knowledge of the genetic causes of infantile epilepsies, potentially paving the way for the identification of innovative therapeutic strategies

The origin and legacy of the Etruscans through a 2000-year archeogenomic time transect

The origin, development, and legacy of the enigmatic Etruscan civilization from the central region of the Italian peninsula known as Etruria have been debated for centuries. Here we report a genomic time transect of 82 individuals spanning almost two millennia (800 BCE to 1000 CE) across Etruria and southern Italy. During the Iron Age, we detect a component of Indo-European–associated steppe ancestry and the lack of recent Anatolian-related admixture among the putative non–Indo-European–speaking Etruscans. Despite comprising diverse individuals of central European, northern African, and Near Eastern ancestry, the local gene pool is largely maintained across the first millennium BCE. This drastically changes during the Roman Imperial period where we report an abrupt population-wide shift to ~50% admixture with eastern Mediterranean ancestry. Last, we identify northern European components appearing in central Italy during the Early Middle Ages, which thus formed the genetic landscape of present-day Italian populations

Ancient genomes reveal origin and rapid trans-Eurasian migration of 7^th century Avar elites

The Avars settled the Carpathian Basin in 567/68 CE, establishing an empire lasting over 200 years. Who they were and where they came from is highly debated. Contemporaries have disagreed about whether they were, as they claimed, the direct successors of the Mongolian Steppe Rouran empire that was destroyed by the Turks in ∼550 CE. Here, we analyze new genome-wide data from 66 pre-Avar and Avar-period Carpathian Basin individuals, including the 8 richest Avar-period burials and further elite sites from Avar’s empire core region. Our results provide support for a rapid long-distance trans-Eurasian migration of Avar-period elites. These individuals carried Northeast Asian ancestry matching the profile of preceding Mongolian Steppe populations, particularly a genome available from the Rouran period. Some of the later elite individuals carried an additional non-local ancestry component broadly matching the steppe, which could point to a later migration or reflect greater genetic diversity within the initial migrant population.- Introduction - Results -- Ancient DNA dataset and quality control -- The genomic structure of the pre-Avar-period population -- The genomic structure of the Avar-period population -- Modeling the eastern steppe ancestry of the elites in the core of the Avar empire -- The heterogeneous ancestry in the regions surrounding the Avar empire’s core - Discussion -- Limitations of the study - Star Method

Ancient DNA reveals admixture history and endogamy in the prehistoric Aegean (advance online)

The Neolithic and Bronze Ages were highly transformative periods forthe genetic history of Europe but for the Aegean—a region fundamentalto Europe’s prehistory—the biological dimensions of cultural transitionshave been elucidated only to a limited extent so far. We have analysed newlygenerated genome-wide data from 102 ancient individuals from Crete, theGreek mainland and the Aegean Islands, spanning from the Neolithic tothe Iron Age. We found that the early farmers from Crete shared the sameancestry as other contemporaneous Neolithic Aegeans. In contrast, the endof the Neolithic period and the following Early Bronze Age were marked by‘eastern’ gene flow, which was predominantly of Anatolian origin in Crete.Confirming previous findings for additional Central/Eastern Europeanancestry in the Greek mainland by the Middle Bronze Age, we additionallyshow that such genetic signatures appeared in Crete gradually from theseventeenth to twelfth centuries bc, a period when the influence of themainland over the island intensified. Biological and cultural connectednesswithin the Aegean is also supported by the finding of consanguineousendogamy practiced at high frequencies, unprecedented in the globalancient DNA record. Our results highlight the potential of archaeogenomicapproaches in the Aegean for unravelling the interplay of genetic admixture,marital and other cultural practice