Timing the first human migration into eastern Asia

A recent report in BMC Biology indicates that modern humans first arrived in southern East Asia 60,000 years ago and settled the rest of East Asia from there. This early date and migration route has significant implications for our understanding of the origins of present-day human populations

From the Alps to the Mediterranean and beyond: genetics, environment, culture and the "impossible beauty" of Italy

Since prehistoric times, Italy has represented a bridge between peoples, genes and cultures. Its peculiar geographical position explains why: it is located in the center of the Mediterranean Sea, flanked by the Balkans and the Hellenic Peninsula to the east, Iberia to the west and surrounded by North Africa to the south and central Europe to the north. This makes Italy of extraordinary interest for the study of some different aspects of human diversity. Here we overview current knowledge regarding the relationships between the structure of the genetic variation of Italian populations and the geographical, ecological and cultural factors that have characterized their evolutionary history. Human presence in Italian territory is deeply rooted in the past. Lithic artifacts produced by the genus Homo and remains of Homo sapiens are among the earliest to have been found on the continent, as shown by the lithic industry of Pirro Nord (between 1.3 and 1.6 Mya) and the dental remains of the "Grotta del Cavallo" (between 45 and 43 Kya). Genetic and genomic studies relating to existing and extinct human groups have shed light on the migrations from Europe, Africa and Asia that created the ancient layers of the genetic structure of today's Italian populations, especially before the Iron Age. The important role of isolation (genetic and cultural) in shaping genetic structure is clearly visible in the patterns of intra- and inter-population diversity observed among Italian ethno-linguistic minorities that settled on the peninsula and on the major islands until the 19th century. Finally, selective pressures have likely driven the distribution of originally adaptive variants and haplotypes that now confer protection or susceptibility to major diseases such as diabetes and cardiovascular disease (in northern Italy) and tuberculosis and leprosy (in the south). What emerges is a picture where the combined effects of migration, isolation and natural selection generated by the interplay of geography, environment and culture have shaped a complex pattern of human diversity that is unique in Europe and which goes hand in hand with today's rich animal and plant biodiversity. In a nutshell, scientific evidence and cultural heritage paint Italy as a place with extremely diverse environments where distant peoples have met since the deep past, bringing and sharing genes and ideas

Epigenetic Variability across Human Populations: A Focus on DNA Methylation Profiles of the KRTCAP3, MAD1L1 and BRSK2 Genes

Natural epigenetic diversity has been suggested as a key mechanism in microevolutionary processes due to its capability to create phenotypic variability within individuals and populations. It constitutes an important reservoir of variation potentially useful for rapid adaptation in response to environmental stimuli. The analysis of population epigenetic structure represents a possible tool to study human adaptation and to identify external factors that are able to naturally shape human DNA methylation variability. The aim of this study is to investigate the dynamics that create epigenetic diversity between and within different human groups. To this end, we first used publicly available epigenome-wide data to explore population-specific DNA methylation changes that occur at macro-geographic scales. Results from this analysis suggest that nutrients, UVA exposure and pathogens load might represent the main environmental factors able to shape DNA methylation profiles. Then, we evaluated DNA methylation of candidate genes (KRTCAP3, MAD1L1, and BRSK2), emerged from the previous analysis, in individuals belonging to different populations from Morocco, Nigeria, Philippines, China, and Italy, but living in the same Italian city. DNA methylation of the BRSK2 gene is significantly different between Moroccans and Nigerians (pairwise t-test: CpG 6 P-value = 5.2*10 (-) (3); CpG 9 P-value = 2.6*10 (-) (3); CpG 10 P-value = 3.1*10 (-) (3); CpG 11 P-value = 2.8*10 (-) (3)). Comprehensively, these results suggest that DNA methylation diversity is a source of variability in human groups at macro and microgeographical scales and that population demographic and adaptive histories, as well as the individual ancestry, actually influence DNA methylation profiles

A Combined Targeted and Whole Exome Sequencing Approach Identified Novel Candidate Genes Involved in Heritable Pulmonary Arterial Hypertension

The pathogenesis of idiopathic and heritable forms of pulmonary arterial hypertension is still not completely understood, even though several causative genes have been proposed, so that a third of patients remains genetically unresolved. Here we applied a multistep approach to extend identification of the genetic bases of such a disease by searching for novel candidate genes/pathways. Twenty-eight patients belonging to 18 families were screened for BMPR2 mutations and BMPR2-negative samples were tested for 12 additional candidate genes by means of a specific massive parallel sequencing-based assay. Finally, whole exome sequencing was performed on four patients showing no mutations at known disease genes, as well as on their unaffected parents. In addition to EIF2AK4, which has been already suggested to be associated with pulmonary veno-occlusive disease, we identified the novel candidate genes ATP13A3, CD248, EFCAB4B, involved in lung vascular remodeling that represent reliable drivers contributing to the disease according to their biological functions/inheritance patterns. Therefore, our results suggest that combining gene panel and whole exome sequencing provides new insights useful for the genetic diagnosis of familial and idiopathic pulmonary arterial hypertension, as well as for the identification of biological pathways that will be potentially targeted by new therapeutic strategies

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

Ancient pathogen-driven adaptation triggers increased susceptibility to non-celiac wheat sensitivity in present-day European populations

Details of sequence profiles for each NCWS subject. (XLSX 47 kb

Complex interplay between neutral and adaptive evolution shaped differential genomic background and disease susceptibility along the Italian peninsula

The Italian peninsula has long represented a natural hub for human migrations across the Mediterranean area, being involved in several prehistoric and historical population movements. Coupled with a patchy environmental landscape entailing different ecological/cultural selective pressures, this might have produced peculiar patterns of population structure and local adaptations responsible for heterogeneous genomic background of present-day Italians. To disentangle this complex scenario, genome-wide data from 780 Italian individuals were generated and set into the context of European/Mediterranean genomic diversity by comparison with genotypes from 50 populations. To maximize possibility of pinpointing functional genomic regions that have played adaptive roles during Italian natural history, our survey included also ∼250,000 exomic markers and ∼20,000 coding/regulatory variants with well-established clinical relevance. This enabled fine-grained dissection of Italian population structure through the identification of clusters of genetically homogeneous provinces and of genomic regions underlying their local adaptations. Description of such patterns disclosed crucial implications for understanding differential susceptibility to some inflammatory/autoimmune disorders, coronary artery disease and type 2 diabetes of diverse Italian subpopulations, suggesting the evolutionary causes that made some of them particularly exposed to the metabolic and immune challenges imposed by dietary and lifestyle shifts that involved western societies in the last centuries

Pai Hsien-yung, Crystal Boys and Taipei's Memories : View from 'Metropolis Spaces' of the 1970s(Summaries : International Symposium "People's Transportation and Cultural Diversity in East Asia")

Genetic signatures from the Paleolithic inhabitants of Eurasia can be traced from the early divergent mitochondrial DNA lineages still present in contemporary human populations. Previous studies already suggested a pre-Neolithic diffusion of mitochondrial haplogroup HV*(xH,V) lineages, a relatively rare class of mtDNA types that includes parallel branches mainly distributed across Europe and West Asia with a certain degree of structure. Up till now, variation within haplogroup HV was addressed mainly by analyzing sequence data from the mtDNA control region, except for specific sub-branches, such as HV4 or the widely distributed haplogroups H and V. In this study, we present a revised HV topology based on full mtDNA genome data, and we include a comprehensive dataset consisting of 316 complete mtDNA sequences including 60 new samples from the Italian peninsula, a previously underrepresented geographic area. We highlight points of instability in the particular topology of this haplogroup, reconstructed with BEAST-generated trees and networks. We also confirm a major lineage expansion that probably followed the Late Glacial Maximum and preceded Neolithic population movements. We finally observe that Italy harbors a reservoir of mtDNA diversity, with deep-rooting HV lineages often related to sequences present in the Caucasus and the Middle East. The resulting hypothesis of a glacial refugium in Southern Italy has implications for the understanding of late Paleolithic population movements and is discussed within the archaeological cultural shifts occurred over the entire continent