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Alzheimer’s disease (AD) represents the most prevalent type of dementia in elderly people, primarily characterized by brain accumulation of beta-amyloid (Aβ) peptides, derived from Amyloid Precursor Protein (APP), in the extracellular space (amyloid plaques) and intracellular deposits of the hyperphosphorylated form of the protein tau (p-tau; tangles or neurofibrillary aggregates). The Nerve growth factor receptor (NGFR/p75NTR) represents a low-affinity receptor for all known mammalians neurotrophins (i.e., pro-NGF, NGF, BDNF, NT-3 e NT-4/5) and it is involved in pathways that determine both survival and death of neurons. Interestingly, also Aβ peptides can blind to NGFR/p75NTR making it the “ideal” candidate in mediating Aβ-induced neuropathology. Besides pathogenesis and neuropathology, several data indicated that NGFR/p75NTR could play a key role in AD also from a genetic perspective. Other studies suggested that NGFR/p75NTR could represent a good diagnostic tool, as well as a promising therapeutic target for AD. Here, we comprehensively summarize and review the current experimental evidence on this topic.

Over the course of the last two decades, the advancement of technological innovations in the field of Molecular Genetics has exponentially enhanced the ability to produce immense amounts of genomic data in a short time and at a fraction of the cost that was necessary to produce a single human genome at the beginning of the current millennium. This incessant progress has also changed the methods with which human genomic data are stored and handled, as well as the power of the analyses that can be carried out, allowing for a shift from the study of single loci linked to very specific phenotypes, to the possibility of dissecting the genomic background of entire populations by managing thousands of high-quality whole genome sequences. After an introduction to the discipline of Molecular Anthropology and an overview of the dispersal of Homo sapiens from Africa, the peopling of Europe and the migratory processes that involved the Italian peninsula, this thesis showcases up-to-date investigative methods, that allow for the analysis of both whole genome sequences and SNP-array data at different levels of detail (from single nucleotide polymorphisms to single genes, to gene networks, to biological pathways). Significant original contributions to knowledge in the fields of Molecular Anthropology and Human Population Genomics are highlighted. In particular, this thesis provides novel and exciting insights into the demography and adaptation events of the Italian population, in relation to the historical and pre-historic migratory waves that contributed to the peopling of Europe and the Mediterranean. Then, it focuses on the single APOE gene, exploring its worldwide variability, evolution and its contribution to a very complex phenotype, such as human longevity. Finally, it explores the demo-evolutionary context of isolated populations in Southern Italy, revealing unexpected neurological pathways as drivers of local differentiation in an innovative analytical perspective.

Additional file 1 : Figure S1. Procrustes analysis projecting genomic information summarized by first and second principal components onto geographic coordinates of Italian population samples. Figure S2. Decay of the length of chromosome chunks inherited by Italian population clusters from possible pairs of parental groups calculated with the GLOBETROTTER pipeline. Figure S3. PCA projecting variation of 559 ancient samples onto the genetic space defined by 239 individuals belonging to 40 modern Euro-Mediterranean populations. Figure S4. Outgroup f3 biplot comparing shared genetic drift between the N_ITA and S_ITA population clusters and, in turn, all ancient population groups included in the “modern + aDNA dataset”. Figure S5. Representation of the Insulin secretion pathway and of its components subjected to positive selection in the Italian population. Figure S6. Representation of the Mucin type O-glycan biosynthesis pathway and of its components subjected to positive selection in the S_ITA cluster. Figure S7. Representation of the Basal cell carcinoma pathway and of its components subjected to positive selection in the S_ITA cluster. Table S1. Admixture proportions inferred for N_ITA and S_ITA population clusters with the GLOBETROTTER method. Table S2. Admixture dates inferred for N_ITA and S_ITA population clusters with the GLOBETROTTER method. Table S3. Gene networks showing significant signatures of positive selection according to signet analysis performed on the obtained genome-wide distribution of DIND scores. Table S4. Gene networks showing significant signatures of positive selection according to signet analysis performed on the obtained genome-wide distribution of nSL scores. Table S5. Gene networks showing significant signatures of balancing selection according to signet analysis performed on the obtained genome-wide distribution of BALLET scores. Supplementary Results.

Additional file 1 : Figure S1. Procrustes analysis projecting genomic information summarized by first and second principal components onto geographic coordinates of Italian population samples. Figure S2. Decay of the length of chromosome chunks inherited by Italian population clusters from possible pairs of parental groups calculated with the GLOBETROTTER pipeline. Figure S3. PCA projecting variation of 559 ancient samples onto the genetic space defined by 239 individuals belonging to 40 modern Euro-Mediterranean populations. Figure S4. Outgroup f3 biplot comparing shared genetic drift between the N_ITA and S_ITA population clusters and, in turn, all ancient population groups included in the “modern + aDNA dataset”. Figure S5. Representation of the Insulin secretion pathway and of its components subjected to positive selection in the Italian population. Figure S6. Representation of the Mucin type O-glycan biosynthesis pathway and of its components subjected to positive selection in the S_ITA cluster. Figure S7. Representation of the Basal cell carcinoma pathway and of its components subjected to positive selection in the S_ITA cluster. Table S1. Admixture proportions inferred for N_ITA and S_ITA population clusters with the GLOBETROTTER method. Table S2. Admixture dates inferred for N_ITA and S_ITA population clusters with the GLOBETROTTER method. Table S3. Gene networks showing significant signatures of positive selection according to signet analysis performed on the obtained genome-wide distribution of DIND scores. Table S4. Gene networks showing significant signatures of positive selection according to signet analysis performed on the obtained genome-wide distribution of nSL scores. Table S5. Gene networks showing significant signatures of balancing selection according to signet analysis performed on the obtained genome-wide distribution of BALLET scores. Supplementary Results.

Mutation A713T in the amyloid precursor protein (APP) has been linked to cases of Alzheimer’s disease (AD), cerebral amyloid angiopathy (CAA) and cerebrovascular disease. Despite its rarity, it has been observed in several families from the same geographical area, in the Calabria region in Southern Italy. Genotyping of 720,000 genome-wide SNPs with the HumanOmniExpress BeadChip was performed for six patients that were representative of apparently unrelated Calabrian families, as well as a Belgian subject of Italian descent (all with the same A713T mutation and disease). Their genomic structure and genetic relationships were analyzed. Demographic reconstruction and coalescent theory were applied to estimate the time of the most recent common ancestor (tMRCA) among patients. Results show that all A713T carriers fell into the genetic variability of Southern Italy and were not more closely related to each other than to any other healthy Calabrian individual. However, five out of seven patients shared a 1.7 Mbp-long DNA segment centered on the A713T mutation, making it possible to estimate a tMRCA for its common origin in the Calabrian region dating back over 1000 years. The analysis of affected individuals with methodologies based on human population genomics thus provides informative insights in support of clinical observations and biomedical research.

The aim of this work was to collect and harmonize the results of several studies achieved over the years, in order to obtain a database of georeferenced observations on polycyclic aromatic hydrocarbons (PAHs) in Western and Central Mediterranean seafood. For each observation, some information on the taxonomy and the ecology of the sampled species are reported, as well as details on the investigated hydrocarbon, and spatial and temporal information on sampling. Moreover, two health risk indexes were calculated for each record and included in the database. Through several statistical methods, we conducted a meta-analysis of the data on some of the species in this database, identifying trends that could be related to the biology of the investigated organisms, as well as to the physico-chemical properties of each hydrocarbon and to the oceanographic characteristic of this part of the Mediterranean. The analysis of the data showed that, at a consumption rate like the one typical of the Italian population, seafood caught from the area considered in the present work seems to pose a minimal risk to health. However, we also found evidence of an increasing trend of PAH concentrations in Mediterranean mussels, pointing to the need for constant monitoring. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.

Retrotransposons are genetic elements with the ability to replicate in the genome using reverse transcriptase: they have been associated with the development of different biological structures, such as the Central Nervous System (CNS), and their high mutagenic potential has been linked to various diseases, including cancer and neurological disorders. Throughout evolution and over time, Primates and Homo had to cope with infections from viruses and bacteria, and also with endogenous retroelements. Therefore, host genomes have evolved numerous methods to counteract the activity of endogenous and exogenous pathogens, and the APOBEC3 family of mutators is a prime example of a defensive mechanism in this context.In most Primates, there are seven members of the APOBEC3 family of deaminase proteins: among their functions, there is the ability to inhibit the mobilization of retrotransposons and the functionality of viruses. The evolution of the APOBEC3 proteins found in Primates is correlated with the expansion of two major families of retrotransposons, i.e. ERV and LINE-1.In this review, we will discuss how the rapid expansion of the APOBEC3 family is linked to the evolution of retrotransposons, highlighting the strong evolutionary arms race that characterized the history of APOBEC3s and endogenous retroelements in Primates. Moreover, the possible role of this relationship will be assessed in the context of embryonic development and brain-associated diseases.

Genetic discoveries related to Alzheimer’s disease and other dementias have been performed using either large cohorts of affected subjects or multiple individuals from the same pedigree, therefore disregarding mutations in the context of healthy groups. Moreover, a large portion of studies so far have been performed on individuals of European ancestry, with a remarkable lack of epidemiological and genomic data from underrepresented populations. The present study aims at scanning 70 single-point mutations on the APP gene in a publicly available genetic dataset including 2.504 healthy individuals from 26 populations, and analyzing their distribution. Moreover, after gametic phase reconstruction, a pairwise comparison of the segments surrounding the mutations was performed to reveal patterns of haplotype sharing that could point to specific cross-population and cross-ancestry admixture events. Eight mutations have been detected in the worldwide dataset, with several of them being specific for a single individual, population or macroarea. Patterns of segment sharing reflect recent historical events of migration and admixture possibly linked to colonization campaigns. These observations reveal the population dynamics of the considered APP mutations in worldwide human groups, and support the development of ancestry-informed screening practices for the improvement of precision and personalized approaches to neurodegeneration and dementias.

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.

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.

The Italian peninsula was host to a strong history of migration processes that shaped its genomic variability since prehistoric times. During the Metal Age, Sicily and Southern Italy were the protagonists of intense trade networks and settlements along the Mediterranean. Nonetheless, ancient DNA studies in Southern Italy are, at present, still limited to prehistoric and Roman Apulia. Here, we present the first mitogenomes from a Middle Bronze Age cave burial in Calabria to address this knowledge gap. We adopted a hybridization capture approach, which enabled the recovery of one complete and one partial mitochondrial genome. Phylogenetic analysis assigned these two individuals to the H1e and H5 subhaplogroups, respectively. This preliminary phylogenetic analysis supports affinities with coeval Sicilian populations, along with Linearbandkeramik and Bell Beaker cultures maternal lineages from Central Europe and Iberia. Our work represents a starting point which contributes to the comprehension of migrations and population dynamics in Southern Italy, and highlights this knowledge gap yet to be filled by genomic studies.

Several studies highlighted the role of climate in shaping many human evolutionary processes. This occurred even in relatively recent times, having affected various human phenotypic traits, among which metabolic processes that orchestrate absorption and accumulation of substances to maintain energy homeostasis, that is critical for the survival of individuals in high energy-expenditure environments. To date, most researches have focalized on detection of climatic influence on SNPs' frequency in populations exposed to extreme environmental conditions or by comparing variation patterns between populations from different continents. In this study, we instead explored the genetic background of distinct western European human groups at loci involved in nutritional and thermoregulation processes, to test whether patterns of differential local adaptation to environmental conditions could be appreciated also at a lower geographical scale. Taking advantage from the 1000 Genomes Project data, genetic information for 21 genes involved in nutritional and thermoregulation processes was analysed for three western European populations. The applied Anthropological Genetics methods pointed to appreciable differentiation between the examined groups especially for the PRDM16 gene. Moreover, several neutrality tests suggested that balancing selection has acted on different regions of the gene in people from Great Britain, as well as that more recent positive selection could have also targeted some PRDM16 SNPs in Finn and Italian populations. These series of adaptive footprints are plausibly related to climate variability in both ancient and relatively recent times. Since this locus is involved in thermoregulation mechanisms and adipogenesis, local adaptations mediated by a pathway related to the brown adipose tissue activity could have evolved in response to changing cold temperature exposures of such populations.

Transposable Elements (TEs) are mobile genetic elements that constitute half of the human genome. Recent studies suggest that polymorphic non-reference TEs (nrTEs) may contribute to cognitive diseases, such as schizophrenia, through a cis-regulatory effect. The aim of this work is to identify sets of nrTEs putatively linked to an increased risk of developing schizophrenia. To do so, we inspected the nrTE content of genomes from the Dorsolateral Prefrontal Cortex of schizophrenic and control individuals, and identified 38 nrTEs which possibly contribute to the emergence of this psychiatric disorder. Furthermore, we performed in silico functional inferences and found, for instance, that 9 of the 38 nrTEs act as expression/alternative splicing quantitative trait loci (eQTLs/sQTLs) in the brain, suggesting a possible role in shaping the human cognitive genome structure. Therefore, to our knowledge, this is the first attempt at identifying polymorphic nrTEs that can contribute to the functionality of the brain. Finally, we suggest that a neurodevelopmental genetic mechanism, which involves evolutionarily young nrTEs, can be the key to understanding the ethiopathogenesis of this complex disorder.