Publications by authors named "Sara De Fanti"

43 Publications

Y-chromosome variability and genetic history of Commons from Northern Italy.

Am J Phys Anthropol 2021 May 10. Epub 2021 May 10.

Department of Biological, Geological and Environmental Sciences, University of Bologna, Bologna, Italy.

Objectives: Genetic drift and admixture are driving forces in human evolution, but their concerted impact to population evolution in historical times and at a micro-geographic scale is poorly assessed. In this study we test a demographic model encompassing both admixture and drift to the case of social-cultural isolates such as the so-called "Commons."

Materials And Methods: Commons are peculiar institutions of medieval origins whose key feature is the tight relationship between population and territory, mediated by the collective property of shared resources. Here, we analyze the Y-chromosomal genetic structure of four Commons (for a total of 366 samples) from the Central and Eastern Padana plain in Northern Italy.

Results: Our results reveal that all these groups exhibit patterns of significant diversity reduction, peripheral/outlier position within the Italian/European genetic space and high frequency of Common-specific haplogroups. By explicitly testing different drift-admixture models, we show that a drift-only model is more probable for Central Padana Commons, while additional admixture (~20%) from external population around the same time of their foundation cannot be excluded for the Eastern ones.

Discussion: Building on these results, we suggest central Middle Ages as the most probable age of foundation for three of the considered Commons, the remaining one pointing to late antiquity. We conclude that an admixture-drift model is particularly useful for interpreting the genetic structure and recent demographic history of small-scale populations in which social-cultural features play a significant role.
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http://dx.doi.org/10.1002/ajpa.24302DOI Listing
May 2021

First Bronze Age Human Mitogenomes from Calabria (Grotta Della Monaca, Southern Italy).

Genes (Basel) 2021 Apr 25;12(5). Epub 2021 Apr 25.

Department of Cultural Heritage, University of Bologna, via Degli Ariani 1, 48121 Ravenna, Italy.

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.
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http://dx.doi.org/10.3390/genes12050636DOI Listing
April 2021

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

Evol Appl 2021 Feb 8;14(2):297-313. Epub 2020 Sep 8.

Laboratory of Molecular Anthropology & Centre for Genome Biology Department of Biological, Geological and Environmental Sciences University of Bologna Bologna Italy.

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.
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http://dx.doi.org/10.1111/eva.13090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7896717PMC
February 2021

Genetic history of Calabrian Greeks reveals ancient events and long term isolation in the Aspromonte area of Southern Italy.

Sci Rep 2021 Feb 4;11(1):3045. Epub 2021 Feb 4.

Department of Cultural Heritage, University of Bologna, Ravenna, Italy.

Calabrian Greeks are an enigmatic population that have preserved and evolved a unique variety of language, Greco, survived in the isolated Aspromonte mountain area of Southern Italy. To understand their genetic ancestry and explore possible effects of geographic and cultural isolation, we genome-wide genotyped a large set of South Italian samples including both communities that still speak Greco nowadays and those that lost the use of this language earlier in time. Comparisons with modern and ancient populations highlighted ancient, long-lasting genetic links with Eastern Mediterranean and Caucasian/Near-Eastern groups as ancestral sources of Southern Italians. Our results suggest that the Aspromonte communities might be interpreted as genetically drifted remnants that departed from such ancient genetic background as a consequence of long-term isolation. Specific patterns of population structuring and higher levels of genetic drift were indeed observed in these populations, reflecting geographic isolation amplified by cultural differences in the groups that still conserve the Greco language. Isolation and drift also affected the current genetic differentiation at specific gene pathways, prompting for future genome-wide association studies aimed at exploring trait-related loci that have drifted up in frequency in these isolated groups.
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http://dx.doi.org/10.1038/s41598-021-82591-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862261PMC
February 2021

Population Dynamics in Italian Canids between the Late Pleistocene and Bronze Age.

Genes (Basel) 2020 Nov 26;11(12). Epub 2020 Nov 26.

Department of Cultural Heritage, University of Bologna, Via Degli Ariani 1, 48121 Ravenna, Italy.

Dog domestication is still largely unresolved due to time-gaps in the sampling of regions. Ancient Italian canids are particularly understudied, currently represented by only a few specimens. In the present study, we sampled 27 canid remains from Northern Italy dated between the Late Pleistocene and Bronze Age to assess their genetic variability, and thus add context to dog domestication dynamics. They were targeted at four DNA fragments of the hypervariable region 1 of mitochondrial DNA. A total of 11 samples had good DNA preservation and were used for phylogenetic analyses. The dog samples were assigned to dog haplogroups A, C and D, and a Late Pleistocene wolf was set into wolf haplogroup 2. We present our data in the landscape of ancient and modern dog genetic variability, with a particular focus on the ancient Italian samples published thus far. Our results suggest there is high genetic variability within ancient Italian canids, where close relationships were evident between both a ~24,700 years old Italian canid, and Iberian and Bulgarian ancient dogs. These findings emphasize that disentangling dog domestication dynamics benefits from the analysis of specimens from Southern European regions.
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http://dx.doi.org/10.3390/genes11121409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761486PMC
November 2020

Haplotype data and forensic evaluation of 23 Y-STR and 12 X-STR loci in eight ethnic groups from Eritrea.

Int J Legal Med 2021 Mar 22;135(2):449-453. Epub 2020 Oct 22.

Department of Biological, Geological and Environmental Sciences-Lab. of Molecular Anthropology & Centre for Genome Biology, University of Bologna, Via Selmi 3, 40126, Bologna, Italy.

Eritrea is a multi-ethnic country of over 3 million of people consisting of different ethnic groups, having each its own language and cultural tradition. Due to the lack of population genetic data for markers of forensic interest, in this study, we analyzed the genetic polymorphisms of 23 Y-chromosome STR loci and of 12 X-chromosome STR loci in a sample of 255 unrelated individuals from 8 Eritrean ethnic groups, with the aim to generate a reference haplotype database for anthropological and forensic applications. X- and Y-chromosomes markers may indeed offer information especially in personal identification and kinship testing, when relying on the availability of large local population data to derive sufficiently accurate frequency estimates. The population genetic analyses in the Eritrean sample for both the two set of Y- and X-STR markers showed high power of discrimination both at country-based and population levels. Comparison population results highlight the importance of considering the ethnic composition within the analyzed country and the necessity of increasing available data especially when referring to heterogeneous populations such as the African ones.
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http://dx.doi.org/10.1007/s00414-020-02446-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7870587PMC
March 2021

Gene Panel Analysis in a Large Cohort of Patients With Autosomal Dominant Polycystic Kidney Disease Allows the Identification of 80 Potentially Causative Novel Variants and the Characterization of a Complex Genetic Architecture in a Subset of Families.

Front Genet 2020 7;11:464. Epub 2020 May 7.

Nephrology, Dialysis and Transplantation Unit, Department of Experimental, Diagnostic and Specialty Medicine (DIMES), S. Orsola-Malpighi University Hospital, Bologna, Italy.

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common inherited disorders in humans and the majority of patients carry a variant in either or . Genetic testing is increasingly required for diagnosis, prognosis, and treatment decision, but it is challenging due to segmental duplications of , genetic and allelic heterogeneity, and the presence of many variants hypomorphic or of uncertain significance. We propose an NGS-based testing strategy for molecular analysis of ADPKD and its phenocopies, validated in a diagnostic setting. Our protocol is based on high-throughput simultaneous sequencing of and after long range PCR of coding regions, followed by a masked reference genome alignment, and MLPA analysis. A further screening of additional 14 cystogenes was performed in negative cases. We applied this strategy to analyze 212 patients with a clinical suspicion of ADPKD. We detected causative variants (interpreted as pathogenic/likely pathogenic) in 61.3% of our index patients, and variants of uncertain clinical significance in 12.5%. The majority (88%) of genetic variants was identified in , 12% in . Among 158 distinct variants, 80 (50.6%) were previously unreported, confirming broad allelic heterogeneity. Eleven patients showed more than one variant. Segregation analysis indicated biallelic disease in five patients, digenic in one, variant with unknown phase in two. Furthermore, our NGS protocol allowed the identification of two patients with somatic mosaicism, which was undetectable with Sanger sequencing. Among patients without / variants, we identified three with possible alternative diagnosis: a patient with biallelic mutations in , confirming the overlap between recessive and dominant PKD, and two patients with variants in and , respectively. Genotype-phenotype correlations showed that patients with variants predicted to truncate (T) the protein experienced end-stage renal disease 9 years earlier than patients with non-truncating (NT) mutations and >13 years earlier than patients with mutations. ADPKD- cases showed a disease onset significantly earlier than ADPKD- and ADPK-, as well as a significant earlier diagnosis. These data emphasize the need to combine clinical information with genetic data to achieve useful prognostic predictions.
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http://dx.doi.org/10.3389/fgene.2020.00464DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7224062PMC
May 2020

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

BMC Biol 2020 05 22;18(1):51. Epub 2020 May 22.

Interdepartmental Centre Alma Mater Research Institute on Global Challenges and Climate Change, University of Bologna, Bologna, Italy.

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.
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http://dx.doi.org/10.1186/s12915-020-00778-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7243322PMC
May 2020

Gut microbiota composition in Himalayan and Andean populations and its relationship with diet, lifestyle and adaptation to the high-altitude environment.

J Anthropol Sci 2019 Dec 25;96:189-208. Epub 2019 Nov 25.

Institute of Biology and Agrarian Biotechnology (IBBA), National Research Council (CNR), Pisa, Italy,

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.
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http://dx.doi.org/10.4436/JASS.97007DOI Listing
December 2019

Estimating Y-Str Mutation Rates and Tmrca Through Deep-Rooting Italian Pedigrees.

Sci Rep 2019 06 21;9(1):9032. Epub 2019 Jun 21.

Dipartimento di Beni Culturali, Università di Bologna, 48121, Ravenna, Italy.

In the population genomics era, the study of Y-chromosome variability is still of the greatest interest for several fields ranging from molecular anthropology to forensics and genetic genealogy. In particular, mutation rates of Y-chromosomal Short Tandem Repeats markers (Y-STRs) are key parameters for different interdisciplinary applications. Among them, testing the patrilineal relatedness between individuals and calculating their Time of Most Recent Common Ancestors (TMRCAs) are of the utmost importance. To provide new valuable estimates and to address these issues, we typed 47 Y-STRs (comprising Yfiler, PowerPlex23 and YfilerPlus loci, the recently defined Rapidly Mutating [RM] panel and 11 additional markers often used in genetic genealogical applications) in 135 individuals belonging to 66 deep-rooting paternal genealogies from Northern Italy. Our results confirmed that the genealogy approach is an effective way to obtain reliable Y-STR mutation rate estimates even with a limited number of samples. Moreover, they showed that the impact of multi-step mutations and backmutations is negligible within the temporal scale usually adopted by forensic and genetic genealogy analyses. We then detected a significant association between the number of mutations within genealogies and observed TMRCAs. Therefore, we compared observed and expected TMRCAs by implementing a Bayesian procedure originally designed by Walsh (2001) and showed that the method yields a good performance (up to 96.72%), especially when using the Infinite Alleles Model (IAM).
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http://dx.doi.org/10.1038/s41598-019-45398-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6588691PMC
June 2019

Multi-analytic study of a probable case of fibrous dysplasia (FD) from certosa monumental cemetery (Bologna, Italy).

Int J Paleopathol 2019 06 23;25:1-8. Epub 2019 Mar 23.

Department of Cultural Heritage, University of Bologna, via degli Ariani 1, 48121, Ravenna, Italy; Department of Human Evolution, Max Planck Institute for Evolutionary Anthropology, Deutscher Platz 6, 04103, Leipzig, Germany.

Objective: To evaluate, via a multidisciplinary approach, a distinctive paleopathological condition believed to be fibrous dysplasia, found on a 19th/20th century skeleton from Certosa Monumental Cemetery, Bologna, Italy.

Materials: A skeletonized cranium and mandible recovered from an ossuary in 2014.

Methods: Pathological alterations were analysed by radiological examination, dental macrowear, histopathological and genetic analyses.

Result: The skeleton is believed to be an adult male. Differential diagnoses include Paget's disease, McCune-Albright syndrome, osteochondroma and osteosarcoma. The radiographic findings, along with the solitary nature of the lesions, are strong evidence for the diagnosis of fibrous dysplasia (FD). Genetic analysis further revealed a frequency of ˜1% of mutant alleles with the R201C substitution, one of the post-zygotic activating mutation frequently associated with FD.

Conclusions: The multi-analytical method employed suggests a diagnosis of monostotic form of FD. The diagnostic design incorporates multiple lines of evidence, including macroscopic, histopathological, and genetic analyses.

Significance: Through the use of a multi-analytic approach, robust diagnoses can be offered. This case serves as one of the oldest examples of FD from an historical context. The genetic mutation detected, associated with FD, has not been previously reported in historical/ancient samples.
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http://dx.doi.org/10.1016/j.ijpp.2019.03.003DOI Listing
June 2019

Dissecting the Pre-Columbian Genomic Ancestry of Native Americans along the Andes-Amazonia Divide.

Mol Biol Evol 2019 06;36(6):1254-1269

Laboratory of Molecular Anthropology and Centre for Genome Biology, Department of Biological, Geological and Environmental Sciences, University of Bologna, Bologna, Italy.

Extensive European and African admixture coupled with loss of Amerindian lineages makes the reconstruction of pre-Columbian history of Native Americans based on present-day genomes extremely challenging. Still open questions remain about the dispersals that occurred throughout the continent after the initial peopling from the Beringia, especially concerning the number and dynamics of diffusions into South America. Indeed, if environmental and historical factors contributed to shape distinct gene pools in the Andes and Amazonia, the origins of this East-West genetic structure and the extension of further interactions between populations residing along this divide are still not well understood. To this end, we generated new high-resolution genome-wide data for 229 individuals representative of one Central and ten South Amerindian ethnic groups from Mexico, Peru, Bolivia, and Argentina. Low levels of European and African admixture in the sampled individuals allowed the application of fine-scale haplotype-based methods and demographic modeling approaches. These analyses revealed highly specific Native American genetic ancestries and great intragroup homogeneity, along with limited traces of gene flow mainly from the Andes into Peruvian Amazonians. Substantial amount of genetic drift differentially experienced by the considered populations underlined distinct patterns of recent inbreeding or prolonged isolation. Overall, our results support the hypothesis that all non-Andean South Americans are compatible with descending from a common lineage, while we found low support for common Mesoamerican ancestors of both Andeans and other South American groups. These findings suggest extensive back-migrations into Central America from non-Andean sources or conceal distinct peopling events into the Southern Continent.
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http://dx.doi.org/10.1093/molbev/msz066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6526910PMC
June 2019

Response of high-risk MDS to azacitidine and lenalidomide is impacted by baseline and acquired mutations in a cluster of three inositide-specific genes.

Leukemia 2019 09 20;33(9):2276-2290. Epub 2019 Feb 20.

Cellular Signalling Laboratory, Human Anatomy Section, Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.

Specific myeloid-related and inositide-specific gene mutations can be linked to myelodysplastic syndromes (MDS) pathogenesis and therapy. Here, 44 higher-risk MDS patients were treated with azacitidine and lenalidomide and mutations analyses were performed at baseline and during the therapy. Results were then correlated to clinical outcome, overall survival (OS), leukemia-free-survival (LFS) and response to therapy. Collectively, 34/44 patients were considered evaluable for response, with an overall response rate of 76.25% (26/34 cases): 17 patients showed a durable response, 9 patients early lost response and 8 patients never responded. The most frequently mutated genes were ASXL1, TET2, RUNX1, and SRSF2. All patients early losing response, as well as cases never responding, acquired the same 3 point mutations during therapy, affecting respectively PIK3CD (D133E), AKT3 (D280G), and PLCG2 (Q548R) genes, that regulate cell proliferation and differentiation. Moreover, Kaplan-Meier analyses revealed that this mutated cluster was significantly associated with a shorter OS, LFS, and duration of response. All in all, a common mutated cluster affecting 3 inositide-specific genes is significantly associated with loss of response to azacitidine and lenalidomide therapy in higher risk MDS. Further studies are warranted to confirm these data and to further analyze the functional role of this 3-gene cluster.
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http://dx.doi.org/10.1038/s41375-019-0416-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6733710PMC
September 2019

The genetic legacy of the Yaghnobis: A witness of an ancient Eurasian ancestry in the historically reshuffled central Asian gene pool.

Am J Phys Anthropol 2019 04 29;168(4):717-728. Epub 2019 Jan 29.

Laboratories of Physical Anthropology and Ancient DNA, Department of Cultural Heritage, University of Bologna, Ravenna, Italy.

Objectives: The Yaghnobis are an ethno-linguistic minority historically settled along the Yaghnob River in the Upper-Zarafshan Valley in Tajikistan. They speak a language of Old Sogdian origin, which is the only present-day witness of the Lingua Franca used along the Silk Road in Late Antiquity. The aim of this study was to reconstruct the genetic history of this community in order to shed light on its isolation and genetic ancestry within the Euro-Asiatic context.

Materials And Methods: A total of 100 DNA samples were collected in the Yaghnob and Matcha Valleys during several expeditions and their mitochondrial, Y-chromosome and autosomal genome-wide variation were compared with that from a large set of modern and ancient Euro-Asiatic samples.

Results: Findings from uniparental markers highlighted the long-term isolation of the Yaghnobis. Mitochondrial DNA ancestry traced an ancient link with Middle Eastern populations, whereas Y-chromosome legacy showed more tight relationships with Central Asians. Admixture, outgroup-f3, and D-statistics computed on autosomal variation corroborated Y-chromosome evidence, pointing respectively to low Anatolian Neolithic and high Steppe ancestry proportions in Yaghnobis, and to their closer affinity with Tajiks than to Iranians.

Discussion: Although the Yaghnobis do not show evident signs of recent admixture, they could be considered a modern proxy for the source of gene flow for many Central Asian and Middle Eastern groups. Accordingly, they seem to retain a peculiar genomic ancestry probably ascribable to an ancient gene pool originally wide spread across a vast area and subsequently reshuffled by distinct demographic events occurred in Middle East and Central Asia.
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http://dx.doi.org/10.1002/ajpa.23789DOI Listing
April 2019

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

Sci Rep 2019 01 24;9(1):753. Epub 2019 Jan 24.

Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.

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.
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http://dx.doi.org/10.1038/s41598-018-37277-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6345742PMC
January 2019

First evidence of association between past environmental exposure to dioxin and DNA methylation of CYP1A1 and IGF2 genes in present day Vietnamese population.

Environ Pollut 2018 Nov 17;242(Pt A):976-985. Epub 2018 Jul 17.

Medical Genetics Unit, S. Orsola Hospital, University of Bologna, Italy and European School of Genetic Medicine, Italy.

During the Vietnam War, the United States military sprayed over 74 million litres of Agent Orange (AO) to destroy forest cover as a counterinsurgency tactic in Vietnam, Laos and Cambodia. The main ingredient was contaminated by 2,3,7,8-tetrachlorodibenzo-paradioxin (TCDD). DNA methylation (DNAm) differences are potential biomarker of environmental toxicants exposure. The aim of this study was to perform a preliminary investigation of the DNAm levels from peripheral blood of the present-day Vietnamese population, including individuals whose parents, according to historical data, were exposed to AO/TCDD during the war. 94 individuals from heavily sprayed areas (cases) and 94 individuals from non-sprayed areas (controls) were studied, and historical data on alleged exposure of parents collected. 94 cases were analysed considering those whose father/parents participated in the war (N = 29) and considering the place of residence of both parents (64 living in sprayed areas versus 30 in non-contaminated areas). DNAm levels in CYP1A1 and IGF2 genes were measured (MALDI-TOF technology). The analyses showed that: 1) one CpG site in the CYP1A1 and one in the IGF2 gene showed significant differences in DNAm levels between cases and controls; 2) the CYP1A1 region resulted to be hypomethylated (in 9 out of 16 sites/units; p-val<0.01) in 29 individuals whose father/parents participated in the war in the spray zones; 3) we showed that the place of residence of both parents influenced methylation levels of the CYP1A1 and IGF2 genes (p-val<0.05). In conclusion this study indicates that past environmental exposure to dioxin (AO/TCDD) shapes the DNAm profile of CYP1A1 and that the place of living for parents in former spray zones influences DNAm of CYP1A1 and IGF2 genes. These results open the way to new applications of DNAm as potential biomarker(s) of past human exposure to dioxin.
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http://dx.doi.org/10.1016/j.envpol.2018.07.015DOI Listing
November 2018

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

Genome Biol Evol 2018 11 1;10(11):2919-2930. Epub 2018 Nov 1.

Laboratory of Molecular Anthropology & Centre for Genome Biology, Department of Biological, Geological and Environmental Sciences, University of Bologna, Bologna, Italy.

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.
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http://dx.doi.org/10.1093/gbe/evy233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6239493PMC
November 2018

Three Reportedly Unrelated Families With Liddle Syndrome Inherited From a Common Ancestor.

Hypertension 2018 02 11;71(2):273-279. Epub 2017 Dec 11.

From the Department of Biology (L.P.) and Endocrinology Unit, Department of Medicine (F.M.), University of Padova, Italy; Estonian Biocentre, Tartu (L.P.); Research Department of Genetics, Evolution and Environment, University College London, United Kingdom (Y.D., M.G.T.); Department of Biological Geological and Environmental Sciences (M.S., S.D.F., D.L.) and Department of Experimental, Diagnostic and Specialty Medicine (P.G.), University of Bologna, Italy; IRCCS Centro Cardiologico Monzino, Milano, Italy (M.R.); Department of Oncology and Advanced Technologies, Laboratory of Molecular Biology (E.F., B.C.) and Department of Internal Medicine (E.R.), IRCCS Santa Maria Nuova Hospital, Reggio Emilia, Italy; Department of Endocrinology and Metabolic Diseases, San Raffaele Scientific Institute, Milano, Italy (A.C.); and Department of Molecular Medicine, University of Pavia, Italy (F.N., O.Z.).

Liddle syndrome is considered a rare Mendelian hypertension. We have previously described 3 reportedly unrelated families, native of an Italian area around the Strait of Messina, carrying the same mutation (βP617L) of the epithelial sodium channel. The aims of our study were (1) to evaluate whether a close genomic relationship exists between the 3 families through the analysis of mitochondrial DNA and Y chromosome; and (2) to quantify the genomic relatedness between the patients with Liddle syndrome belonging to the 3 families and assess the hypothesis of a mutation shared through identity by descent. HVRI (the hypervariable region I) of the mitochondrial DNA genome and the Y chromosome short tandem repeats profiles were analyzed in individuals of the 3 families. Genotyping 542 585 genome-wide single nucleotide polymorphisms was performed in all the patients with Liddle syndrome of the 3 families and some of their relatives. A panel of 780 healthy Italian adult samples typed for the same set of markers was used as controls. espite different lineages between the 3 families based on the analysis of mitochondrial DNA and Y chromosome, the 3 probands and their 6 affected relatives share the same ≈5 Mbp long haplotype which encompasses the mutant allele. Using an approach based on coalescent theory, we estimate that the 3 families inherited the mutant allele from a common ancestor ≈13 generations ago and that such an ancestor may have left ≈20 carriers alive today. The prevalence of Liddle syndrome in the region of origin of the 3 families may be much higher than that estimated worldwide.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.117.10491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5767121PMC
February 2018

Iron Age Italic population genetics: the Piceni from Novilara (8th-7th century BC).

Ann Hum Biol 2018 Feb;45(1):34-43

b Department of Cultural Heritage , University of Bologna , Ravenna , Italy.

Background: Archaeological data provide evidence that Italy, during the Iron Age, witnessed the appearance of the first communities with well defined cultural identities. To date, only a few studies report genetic data about these populations and, in particular, the Piceni have never been analysed.

Aims: To provide new data about mitochondrial DNA (mtDNA) variability of an Iron Age Italic population, to understand the contribution of the Piceni in shaping the modern Italian gene pool and to ascertain the kinship between some individuals buried in the same grave within the Novilara necropolis.

Subjects And Methods: In a first set of 10 individuals from Novilara, we performed deep sequencing of the HVS-I region of the mtDNA, combined with the genotyping of 22 SNPs in the coding region and the analysis of several autosomal markers.

Results: The results show a low nucleotide diversity for the inhabitants of Novilara and highlight a genetic affinity of this ancient population with the current inhabitants of central Italy. No family relationship was observed between the individuals analysed here.

Conclusions: This study provides a preliminary characterisation of the mtDNA variability of the Piceni of Novilara, as well as a kinship assessment of two peculiar burials.
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http://dx.doi.org/10.1080/03014460.2017.1414876DOI Listing
February 2018

The genomic landscape of Nepalese Tibeto-Burmans reveals new insights into the recent peopling of Southern Himalayas.

Sci Rep 2017 Nov 14;7(1):15512. Epub 2017 Nov 14.

Laboratory of Molecular Anthropology & Centre for Genome Biology, Dept. of Biological, Geological and Environmental Sciences, University of Bologna, Bologna, Italy.

While much research attention has focused on demographic processes that enabled human diffusion on the Tibetan plateau, little is known about more recent colonization of Southern Himalayas. In particular, the history of migrations, admixture and/or isolation of populations speaking Tibeto-Burman languages, which is supposed to be quite complex and to have reshaped patterns of genetic variation on both sides of the Himalayan arc, remains only partially elucidated. We thus described the genomic landscape of previously unsurveyed Tibeto-Burman (i.e. Sherpa and Tamang) and Indo-Aryan communities from remote Nepalese valleys. Exploration of their genomic relationships with South/East Asian populations provided evidence for Tibetan admixture with low-altitude East Asians and for Sherpa isolation. We also showed that the other Southern Himalayan Tibeto-Burmans derived East Asian ancestry not from the Tibetan/Sherpa lineage, but from low-altitude ancestors who migrated from China plausibly across Northern India/Myanmar, having experienced extensive admixture that reshuffled the ancestral Tibeto-Burman gene pool. These findings improved the understanding of the impact of gene flow/drift on the evolution of high-altitude Himalayan peoples and shed light on migration events that drove colonization of the southern Himalayan slopes, as well as on the role played by different Tibeto-Burman groups in such a complex demographic scenario.
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http://dx.doi.org/10.1038/s41598-017-15862-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5686152PMC
November 2017

Genetic variability of CYP2D6, CYP2B6, CYP2C9 and CYP2C19 genes across the Italian Peninsula.

Ann Hum Biol 2018 Feb 3;45(1):66-71. Epub 2017 Oct 3.

a Department of Medical and Surgical Sciences , University of Bologna. Institute of Legal Medicine , Bologna , Italy.

Background: Environmental conditions and past migratory events may have shaped genetic heterogeneity of clinically relevant enzymes involved in the phase I metabolism of the most common therapeutic drugs.

Aim: To investigate the genetic variability of CYP2D6, CYP2B6, CYP2C19 and CYP2C9 across the Italian Peninsula, by sampling only ancestrally and geographically homogeneous individuals from northern, central and southern Italy.

Subjects And Methods: A total of 25 SNPs were genotyped in 174 unrelated Italian individuals by means of multiplex PCR and minisequencing reactions. CYP2D6 genotypic data were used to predict phenotypes and the phylogenetic relationships among reconstructed haplotypes were represented by means of a Median Joining Network.

Results: Pairwise Fisher Exact tests revealed significant differences between northern and southern Italy in the distribution of CYP2C19 genotypes, with the CYP2C19*2 allele appearing over-represented in northern Italy. Likewise, significant differences in the distribution of CYP2D6 genotypes (*4/*3, *4/*4 and *6/*4) responsible for the poor metabolizer phenotype were observed in northern with respect to both central and southern Italy.

Conclusions: The north-south structuring pattern showed by CYP2D6 and CYP2C19 underline how a deeper knowledge of the geographic distribution of alleles may improve clinical practice and help to avoid hypothetical bias in drug trials.
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http://dx.doi.org/10.1080/03014460.2017.1378368DOI Listing
February 2018

Lactase persistence in Tunisia as a result of admixture with other Mediterranean populations.

Genes Nutr 2017 24;12:20. Epub 2017 Aug 24.

Laboratory of Molecular Anthropology and Centre for Genome Biology, Department of Biological, Geological and Environmental Sciences (BiGeA), University of Bologna, 40126 Bologna, Italy.

Background: The ability to digest lactose after weaning, namely, lactase persistence (LP), is encoded by polymorphisms in the gene and varies widely in frequency among different human populations. Although, evolution of LP-related genetic variants was investigated in many groups of Sub-Saharan African, Middle Eastern, and European ancestry, only few studies have focused on populations from North Africa and no data are especially available from the Tunisian one. For this reason, there is an urgent need to investigate the frequency patterns at these loci in Tunisia since this adaptive trait is implicated in health.

Methods: Forty SNPs covering the genes and including the two functional variants - 13,910 C > T and - 22,018 G > A were genotyped in 117 Tunisian individuals using the Sequenom Mass Array technology. The observed nucleotide and haplotype patterns of variation were then compared with those of several African, European, and Mediterranean human groups for which comparable data were publicly available. Admixture analysis on a 5 Mb genomic region surrounding the loci was also performed by extracting genotypes from a previously generated genome-wide dataset in order to deepen the reconstruction of the evolutionary history of these loci.

Results: We found that lactase non-persistence (LNP)-related alleles and haplotypes were predominantly present in the examined population. A clear differentiation between Tunisian, African, and North European/North Italian samples was found, while the Tunisian population showed more genetic affinity to Central and South Italian groups.

Conclusions: Our study provided a first report of LP-associated alleles and haplotypes in the Tunisian population. We highlighted a gradient followed by LP diffusion from Europe to North Africa. Based on the rich historic background of Tunisia, we suggest that this adaptive trait was introduced in that geographic region by a relatively recent gene flow.
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http://dx.doi.org/10.1186/s12263-017-0573-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5571577PMC
August 2017

Reply: Purifying selection on mitochondrial DNA: a strategy for the oocyte to preserve competence.

Hum Reprod 2017 09;32(9):1949-1950

Reproductive Medicine Unit, S.I.S.Me.R., Via Mazzini, 12, Bologna 40138, Italy.

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http://dx.doi.org/10.1093/humrep/dex255DOI Listing
September 2017

Multiple selective events at the PRDM16 functional pathway shaped adaptation of western European populations to different climate conditions.

J Anthropol Sci 2017 12 10;95:235-247. Epub 2017 Jul 10.

Laboratory of Molecular Anthropology, Department of Biological, Geological and Environmental Sciences, University of Bologna, Bologna, 40126, Italy; Centre for Genome Biology, Department of Biological, Geological and Environmental Sciences, University of Bologna, Bologna, 40126, Italy.

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.
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http://dx.doi.org/10.4436/JASS.95011DOI Listing
December 2017

Ancient and recent admixture layers in Sicily and Southern Italy trace multiple migration routes along the Mediterranean.

Sci Rep 2017 05 16;7(1):1984. Epub 2017 May 16.

Laboratory of Molecular Anthropology, Department of Biological, Geological and Environmental Sciences, University of Bologna, Bologna, Italy.

The Mediterranean shores stretching between Sicily, Southern Italy and the Southern Balkans witnessed a long series of migration processes and cultural exchanges. Accordingly, present-day population diversity is composed by multiple genetic layers, which make the deciphering of different ancestral and historical contributes particularly challenging. We address this issue by genotyping 511 samples from 23 populations of Sicily, Southern Italy, Greece and Albania with the Illumina GenoChip Array, also including new samples from Albanian- and Greek-speaking ethno-linguistic minorities of Southern Italy. Our results reveal a shared Mediterranean genetic continuity, extending from Sicily to Cyprus, where Southern Italian populations appear genetically closer to Greek-speaking islands than to continental Greece. Besides a predominant Neolithic background, we identify traces of Post-Neolithic Levantine- and Caucasus-related ancestries, compatible with maritime Bronze-Age migrations. We argue that these results may have important implications in the cultural history of Europe, such as in the diffusion of some Indo-European languages. Instead, recent historical expansions from North-Eastern Europe account for the observed differentiation of present-day continental Southern Balkan groups. Patterns of IBD-sharing directly reconnect Albanian-speaking Arbereshe with a recent Balkan-source origin, while Greek-speaking communities of Southern Italy cluster with their Italian-speaking neighbours suggesting a long-term history of presence in Southern Italy.
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http://dx.doi.org/10.1038/s41598-017-01802-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5434004PMC
May 2017

Intra-individual purifying selection on mitochondrial DNA variants during human oogenesis.

Hum Reprod 2017 05;32(5):1100-1107

Medical Genetics Unit, S. Orsola Hospital, University of Bologna, Bologna 40126, Italy.

Study Question: Does selection for mtDNA mutations occur in human oocytes?

Summary Answer: We provide statistical evidence in favor of the existence of purifying selection for mtDNA mutations in human oocytes acting between the expulsion of the first and second polar bodies (PBs).

What Is Known Already: Several lines of evidence in Metazoa, including humans, indicate that variation within the germline of mitochondrial genomes is under purifying selection. The presence of this internal selection filter in the germline has important consequences for the evolutionary trajectory of mtDNA. However, the nature and localization of this internal filter are still unclear while several hypotheses are proposed in the literature.

Study Design, Size, Duration: In this study, 60 mitochondrial genomes were sequenced from 17 sets of oocytes, first and second PBs, and peripheral blood taken from nine women between 38 and 43 years of age.

Participants/materials, Setting, Methods: Whole genome amplification was performed only on the single cell samples and Sanger sequencing was performed on amplicons. The comparison of variant profiles between first and second PB sequences showed no difference in substitution rates but displayed instead a sharp difference in pathogenicity scores of protein-coding sequences using three different metrics (MutPred, Polyphen and SNPs&GO).

Main Results And The Role Of Chance: Unlike the first, second PBs showed no significant differences in pathogenic scores with blood and oocyte sequences. This suggests that a filtering mechanism for disadvantageous variants operates during oocyte development between the expulsion of the first and second PB.

Large Scale Data: N/A.

Limitations, Reasons For Caution: The sample size is small and further studies are needed before this approach can be used in clinical practice. Studies on a model organism would allow the sample size to be increased.

Wider Implications Of The Findings: This work opens the way to the study of the correlation between mtDNA mutations, mitochondrial capacity and viability of oocytes.

Study Funding/competing Interest(s): This work was supported by a SISMER grant. Laboratory facilities and skills were freely provided by SISMER, and by the Alma Mater Studiorum, University of Bologna. The authors have no conflict of interest to disclose.
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http://dx.doi.org/10.1093/humrep/dex051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5850138PMC
May 2017

Massive parallel sequencing of human whole mitochondrial genomes with Ion Torrent technology: an optimized workflow for Anthropological and Population Genetics studies.

Mitochondrial DNA A DNA Mapp Seq Anal 2017 11 8;28(6):843-850. Epub 2016 Nov 8.

a Laboratory of Molecular Anthropology, Department of Biological, Geological & Environmental Sciences (BiGeA) , University of Bologna , Bologna , Italy.

Investigation of human mitochondrial DNA variation patterns and phylogeny has been extensively used in Anthropological and Population Genetics studies and sequencing the whole mitochondrial genome is progressively becoming the gold standard. Among the currently available massive parallel sequencing technologies, Ion Torrent™ semiconductor sequencing represents a promising approach for such studies. Nevertheless, an experimental protocol conceived to enable the achievement of both as high as possible yield and of the most homogeneous sequence coverage through the whole mitochondrial genome is still not available. The present work was thus aimed at improving the overall performance of whole mitochondrial genomes Ion Torrent™ sequencing, with special focus on the capability to obtain robust coverage and highly reliable variants calling. For this purpose, a series of cost-effective modifications in standard laboratory workflows was fine-tuned to optimize them for medium- and large-scale population studies. A total of 54 human samples were thus subjected to sequencing of the whole mitochondrial genome with the Ion Personal Genome Machine™ System in four distinct experiments and using Ion 314 chips. Seven of the selected samples were also characterized by means of conventional Sanger sequencing for the sake of comparison. Obtained results demonstrated that the implemented optimizations had definitely improved sequencing outputs in terms of both variants calling efficiency and coverage uniformity, enabling to setup an effective and accurate protocol for whole mitochondrial genome sequencing and a considerable reduction in experimental time consumption and sequencing costs.
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http://dx.doi.org/10.1080/24701394.2016.1197218DOI Listing
November 2017

Mutation Rates and Discriminating Power for 13 Rapidly-Mutating Y-STRs between Related and Unrelated Individuals.

PLoS One 2016 1;11(11):e0165678. Epub 2016 Nov 1.

Dipartimento di Scienze Mediche e Chirurgiche, Università di Bologna, Bologna, Italy.

Rapidly Mutating Y-STRs (RM Y-STRs) were recently introduced in forensics in order to increase the differentiation of Y-chromosomal profiles even in case of close relatives. We estimate RM Y-STRs mutation rates and their power to discriminate between related individuals by using samples extracted from a wide set of paternal pedigrees and by comparing RM Y-STRs results with those obtained from the Y-filer set. In addition, we tested the ability of RM Y-STRs to discriminate between unrelated individuals carrying the same Y-filer haplotype, using the haplogroup R-M269 (reportedly characterised by a strong resemblance in Y-STR profiles) as a case study. Our results, despite confirming the high mutability of RM Y-STRs, show significantly lower mutation rates than reference germline ones. Consequently, their power to discriminate between related individuals, despite being higher than the one of Y-filer, does not seem to improve significantly the performance of the latter. On the contrary, when considering R-M269 unrelated individuals, RM Y-STRs reveal significant discriminatory power and retain some phylogenetic signal, allowing the correct classification of individuals for some R-M269-derived sub-lineages. These results have important implications not only for forensics, but also for molecular anthropology, suggesting that RM Y-STRs are useful tools for exploring subtle genetic variability within Y-chromosomal haplogroups.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0165678PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5089551PMC
June 2017

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

Sci Rep 2016 09 1;6:32513. Epub 2016 Sep 1.

Laboratory of Molecular Anthropology and Centre for Genome Biology, Department of Biological, Geological and Environmental Sciences, University of Bologna, Bologna, Italy.

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.
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http://dx.doi.org/10.1038/srep32513DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5007512PMC
September 2016

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

Genes Nutr 2016 23;11:15. Epub 2016 May 23.

Laboratory of Molecular Anthropology, Department of Biological, Geological and Environmental Sciences, 40126 Bologna, Italy.

Background: Non-celiac wheat sensitivity is an emerging wheat-related syndrome showing peak prevalence in Western populations. Recent studies hypothesize that new gliadin alleles introduced in the human diet by replacement of ancient wheat with modern varieties can prompt immune responses mediated by the CXCR3-chemokine axis potentially underlying such pathogenic inflammation. This cultural shift may also explain disease epidemiology, having turned European-specific adaptive alleles previously targeted by natural selection into disadvantageous ones.

Methods: To explore this evolutionary scenario, we performed ultra-deep sequencing of genes pivotal in the CXCR3-inflammatory pathway on individuals diagnosed for non-celiac wheat sensitivity and we applied anthropological evolutionary genetics methods to sequence data from worldwide populations to investigate the genetic legacy of natural selection on these loci.

Results: Our results indicate that balancing selection has maintained two divergent CXCL10/CXCL11 haplotypes in Europeans, one responsible for boosting inflammatory reactions and another for encoding moderate chemokine expression.

Conclusions: This led to considerably higher occurrence of the former haplotype in Western people than in Africans and East Asians, suggesting that they might be more prone to side effects related to the consumption of modern wheat varieties. Accordingly, this study contributed to shed new light on some of the mechanisms potentially involved in the disease etiology and on the evolutionary bases of its present-day epidemiological patterns. Moreover, overrepresentation of disease homozygotes for the dis-adaptive haplotype plausibly accounts for their even more enhanced CXCR3-axis expression and for their further increase in disease risk, representing a promising finding to be validated by larger follow-up studies.
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http://dx.doi.org/10.1186/s12263-016-0532-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4968434PMC
August 2016