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      Impact of demography and population dynamics on the genetic architecture of human longevity

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          Abstract

          The study of the genetics of longevity has been mainly addressed by GWASs that considered subjects from different populations to reach higher statistical power. The "price to pay" is that population-specific evolutionary histories and trade-offs were neglected in the investigation of gene-environment interactions. We propose a new “diachronic” approach that considers processes occurred at both evolutionary and lifespan timescales. We focused on a well-characterized population in terms of evolutionary history ( i.e. Italians) and we generated genome-wide data for 333 centenarians from the peninsula and 773 geographically-matched healthy individuals. Obtained results showed that: (i) centenarian genomes are enriched for an ancestral component likely shaped by pre-Neolithic migrations; (ii) centenarians born in Northern Italy unexpectedly clustered with controls from Central/Southern Italy suggesting that Neolithic and Bronze Age gene flow did not favor longevity in this population; (iii) local past adaptive events in response to pathogens and targeting arachidonic acid metabolism became favorable for longevity; (iv) lifelong changes in the frequency of several alleles revealed pleiotropy and trade-off mechanisms crucial for longevity. Therefore, we propose that demographic history and ancient/recent population dynamics need to be properly considered to identify genes involved in longevity, which can differ in different temporal/spatial settings.

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          Most cited references34

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          The genetic history of Ice Age Europe

          Modern humans arrived in Europe ~45,000 years ago, but little is known about their genetic composition before the start of farming ~8,500 years ago. We analyze genome-wide data from 51 Eurasians from ~45,000-7,000 years ago. Over this time, the proportion of Neanderthal DNA decreased from 3–6% to around 2%, consistent with natural selection against Neanderthal variants in modern humans. Whereas the earliest modern humans in Europe did not contribute substantially to present-day Europeans, all individuals between ~37,000 and ~14,000 years ago descended from a single founder population which forms part of the ancestry of present-day Europeans. A ~35,000 year old individual from northwest Europe represents an early branch of this founder population which was then displaced across a broad region, before reappearing in southwest Europe during the Ice Age ~19,000 years ago. During the major warming period after ~14,000 years ago, a new genetic component related to present-day Near Easterners appears in Europe. These results document how population turnover and migration have been recurring themes of European pre-history.
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            Network medicine--from obesity to the "diseasome".

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              Paleogenomics. Genomic structure in Europeans dating back at least 36,200 years.

              The origin of contemporary Europeans remains contentious. We obtained a genome sequence from Kostenki 14 in European Russia dating from 38,700 to 36,200 years ago, one of the oldest fossils of anatomically modern humans from Europe. We find that Kostenki 14 shares a close ancestry with the 24,000-year-old Mal'ta boy from central Siberia, European Mesolithic hunter-gatherers, some contemporary western Siberians, and many Europeans, but not eastern Asians. Additionally, the Kostenki 14 genome shows evidence of shared ancestry with a population basal to all Eurasians that also relates to later European Neolithic farmers. We find that Kostenki 14 contains more Neandertal DNA that is contained in longer tracts than present Europeans. Our findings reveal the timing of divergence of western Eurasians and East Asians to be more than 36,200 years ago and that European genomic structure today dates back to the Upper Paleolithic and derives from a metapopulation that at times stretched from Europe to central Asia.
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                Author and article information

                Journal
                Aging (Albany NY)
                Aging (Albany NY)
                Aging
                Aging (Albany NY)
                Impact Journals
                1945-4589
                August 2018
                08 August 2018
                : 10
                : 8
                : 1947-1963
                Affiliations
                [1 ]Department of Biological, Geological, and Environmental Sciences (BiGeA), Laboratory of Molecular Anthropology and Centre for Genome Biology, University of Bologna , Bologna, , Italy
                [2 ]School of Anthropology and Museum Ethnography, University of Oxford , Oxford, , UK
                [3 ]Interdepartmental Center "L. Galvani," (CIG), University of Bologna , Bologna, , Italy
                [4 ]IRCCS, Institute of Neurological Sciences of Bologna , Bologna, , Italy
                [5 ]Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna , Bologna, , Italy
                [6 ]Applied Biomedical Research Center (CRBA), S. Orsola-Malpighi Polyclinic, Bologna, , Italy
                [7 ]Biodemography of Aging Research Unit, Social Science Research Institute, Duke University , Durham, , NC, 27708, USA
                [8 ]Istituto Auxologico Italiano IRCCS, Cusano Milanino, Milan, , Italy
                [9 ]Department of Biology, Ecology and Earth Sciences, University of Calabria , Rende, , Italy
                [10 ]Geriatric Unit, Department of Medical Sciences and Community Health, University of Milan , Milan, Italy
                [11 ]Fondazione Ca' Granda, IRCCS Ospedale Maggiore Policlinico, Milan, , Italy
                [12 ]Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence , Florence, , Italy
                [13 ]Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence , Florence, , Italy
                [14 ]IRCCS Don Gnocchi, Florence, , Italy
                [15 ]Azienda Ospedaliera-IRCCS, Reggio Emilia, , Italy
                [16 ]Department of Surgical, Medical, Dental and Morphological Sciences with Interest transplant, Oncological and Regenerative Medicine, Università di Modena e Reggio Emilia , Italy
                [17 ]Department for the Cultural Heritage (DBC), University of Bologna , Ravenna, , Italy
                [18 ]Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet at Huddinge University Hospital, S-141 86 Stockholm, Sweden
                [19 ]CNR Institute of Molecular Genetics, Unit of Bologna, Bologna, , Italy
                [20 ]Rizzoli Orthopaedic Institute, Laboratory of Cell Biology , Bologna, , Italy
                [21 ]Co-senior authors
                [* ]Equal contribution
                Author notes
                Correspondence to: Cristina Giuliani; email: cristina.giuliani2@ 123456unibo.it
                Correspondence to: Paolo Garagnani; email: paolo.garagnani2@ 123456unibo.it
                Article
                101515
                10.18632/aging.101515
                6128422
                30089705
                535174e4-0109-42b3-a026-9ac2345bddf9
                Copyright © 2018 Giuliani et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution (CC BY) 3.0 License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 20 July 2018
                : 26 July 2018
                Categories
                Research Paper

                Cell biology
                centenarians,population dynamics,longevity,human genetics
                Cell biology
                centenarians, population dynamics, longevity, human genetics

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