Ülevaade Põhja-Euraasias laialt levinud Y-kromosoomaalse haplogrupi N fülogeneesist ja fülogeograafiast ning Euroopa kahe keeleliselt erandliku rahva – ungarlaste ja kalmõkkide – populatsiooniuuringud

Väitekirja elektrooniline versioon ei sisalda publiktasiooneInimkonna evolutsioon ja demograafiline ajalugu on jätnud jälje põlvest-põlve päranduvasse genoomi. Geneetilisi andmeid on inimpopulatsioonide uurimisel kasutatud juba sadakond aastat, kuid alles viimase kümnekonna aasta tehnoloogilised arengud on avanud tee inimkonna genoomse varieeruvuse arengu terviklikkuse jälgimiseks. Käesolev töö uurib meeste Y-kromosoomi geneetilist varieeruvust. Y-kromosoomi täisjärjestustest rekonstrueeritakse meesliinide fülogeneetilisi puid ning hinnatakse liinide lahknemisaegu. Väitekiri keskendub Põhja-Euraasia meestel levinud Y-kromosoomi liini haplogrupp (hg) N uuringutele. Hinnatakse hg N alam-klaadide topoloogiat, lahknemisaegu, levikumustreid ja sagedusi erinevatel Põhja-Euraasia rahvastel. Eraldi analüüsitakse hg N olemasolu Kesk-Euroopas elavatel uurali keeli kõnelevatel ungarlastel ning geograafiliselt kaugetel Uurali mäestiku ümbruses elavatel populatsioonidel, k.a. keelesugulastel. Seni teadaolevalt oli geneetiline seos tänapäeva ungarlasete ja teiste uurali keeli rääkivate rahvaste vahel kasin. Leidsime, et siiski avaldub marginaalne seos Y-kromosoomi variandi N3a4 kaudu ja ungarlastel esinev N3a4 on kladistiliselt sama, mis ob-ugridel – hantide ja mansidel – ning mitmetel teistel Uurali/Lääne-Siberi rahvastel. Läänemere-soomlaste sõsarliinist lahknes antud liin umbes 4-5 aastatuhande eest. Lisaks analüüsime meesliine oirat-mongoli keelt rääkivatel kalmõkkidel, kelle esiisad ~400 aasta eest liikusid Lääne-Mongooliast Ida-Euroopa lauskmaa kaguossa. Kalmõkkide isaliine võrreldakse Mongoolias, Kõrgõzstanis ja Hiinas elavate keelesugulaste omadega. Neil hõimudel on levinud hg C3, mille fülogeneetilise puu topoloogia ja teiste hg-de sagedused viitavad kalmõkkide ning keelesugulaste geneetilisele sarnasusele sõltumata lahusolekust. Veidi esineb neil N3a varianti, mis on rohke mitmetel mongoli hõimudel. See näitab Holotseeni keskajast pärinevate meesliinide, kohati ulatuslikku kattuvust uurali ja mongoli keelte rääkijate vahel.Human evolution and demographic history have left a mark into our genome, passed on through generations. Genetic information has been applied to compare peoples for nearly a century. Yet the technological advances of the past decade have opened a path to whole human genomic variation. Current thesis studies the genetic variation of the paternally inherited Y chromosome. Whole Y chromosome sequences are used in the construction of phylogenetic trees and estimation of lineage split times. The thesis focuses on a Y chromosome lineage haplogroup (hg) N that is prevalent in North Eurasian men. A high-resolution phylogenetic tree reveals new sub-lineages; their spread patterns and frequencies are assessed in various North Eurasian populations. Also, the occurrence of hg N is examined in Uralic speaking Hungarians of Central Europe and geographically distant peoples, including linguistic relatives, living around the Ural Mountains. Hungarians are genetically similar to their geographic neighbours. Genetic affinity with other Uralic speakers has been deemed elusive. Here we report that such a link, albeit limited, manifests in Y-chromosomal hg N3a4 bringing Hungarians together with Ob-Ugric Khanty and Mansi and several other Ural Mountain/West Siberian populations. Its sister clade, rich among Baltic-Finnic peoples, split from the former ~4-5 millennia ago. The study also analyses paternal lineages of Oirat-Mongolic-speaking Kalmyks, whose ancestors ~400 years ago migrated from West Mongolia to East European Plain. Male lineages of Kalmyks and their linguistic relatives living in Mongolia, Kyrgyzstan and China are compared. A common hg in these populations is C3. Its phylogenetic tree and frequencies of other hgs show genetic similarity among studied populations despite the separation. Meanwhile, hg N3a, scarce in Kalmyks and frequent in some Mongol tribes, depicts an occasional extensive overlap of Y chromosomes between Uralic- and Mongolic speakers, dating to mid-Holocene.https://www.ester.ee/record=b535927

Y-chromosomal connection between Hungarians and geographically distant populations of the Ural Mountain region and West Siberia

Hungarians who live in Central Europe today are one of the westernmost Uralic speakers. Despite of the proposed Volga-Ural/West Siberian roots of the Hungarian language, the present-day Hungarian gene pool is highly similar to that of the surrounding Indo-European speaking populations. However, a limited portion of specific Y-chromosomal lineages from haplogroup N, sometimes associated with the spread of Uralic languages, link modern Hungarians with populations living close to the Ural Mountain range on the border of Europe and Asia. Here we investigate the paternal genetic connection between these spatially separated populations. We reconstruct the phylogeny of N3a4-Z1936 clade by using 33 high-coverage Y-chromosomal sequences and estimate the coalescent times of its sub-clades. We genotype close to 5000 samples from 46 Eurasian populations to show the presence of N3a4-B539 lineages among Hungarians and in the populations from Ural Mountain region, including Ob-Ugricspeakers from West Siberia who are geographically distant but linguistically closest to Hungarians. This sub-clade splits from its sister-branch N3a4-B535, frequent today among Northeast European Uralic speakers, 4000–5000 ya, which is in the time-frame of the proposed divergence of Ugric languages

Causes and Timing of Mortality and Morbidity Among Late Presenters Starting Antiretroviral Therapy in the REALITY Trial.

BACKGROUND: In sub-Saharan Africa, 20%-25% of people starting antiretroviral therapy (ART) have severe immunosuppression; approximately 10% die within 3 months. In the Reduction of EArly mortaLITY (REALITY) randomized trial, a broad enhanced anti-infection prophylaxis bundle reduced mortality vs cotrimoxazole. We investigate the contribution and timing of different causes of mortality/morbidity. METHODS: Participants started ART with a CD4 count .3); and reduced nonfatal/fatal tuberculosis and cryptococcosis (P .2). CONCLUSIONS: Enhanced prophylaxis reduced mortality from cryptococcosis and unknown causes and nonfatal tuberculosis and cryptococcosis. High early incidence of fatal/nonfatal events highlights the need for starting enhanced-prophylaxis with ART in advanced disease. CLINICAL TRIALS REGISTRATION: ISRCTN43622374

Genetic characterization of populations in the Marquesas Archipelago in the context of the Austronesian expansion

Our exploration of the genetic constitution of Nuku Hiva (n = 51), Hiva Oa (n = 28) and Tahuata (n = 8) of the Marquesas Archipelago based on the analyses of genome-wide autosomal markers as well as high-resolution genotyping of paternal and maternal lineages provides us with information on the origins and settlement of these islands at the fringe of the Austronesian expansion. One widespread theme that emerges from this study is the genetic uniformity and relative isolation exhibited by the Marquesas and Society populations. This genetic homogeneity within East Polynesia groups is reflected in their limited average heterozygosity, uniformity of constituents in the Structure analyses, reiteration of complete mtDNA sequences, marked separation from Asian and other Oceanic populations in the PC analyses, limited differentiation in the PCAs and large number of IBD segments in common. Both the f3 and the Outgroup f3 results provide indications of intra-East Polynesian gene flow that may have promoted the observed intra-East Polynesia genetic homogeneity while ALDER analyses indicate that East Polynesia experienced two gene flow episodes, one relatively recent from Europe that coincides roughly with the European incursion into the region and an early one that may represent the original settlement of the islands by Austronesians. Median Network analysis based on high-resolution Y-STR loci under C2a-M208 generates a star-like topology with East Polynesian groups (especially from the Society Archipelago) in central stem positions and individuals from the different populations radiating out one mutational step away while several Samoan and outlier individuals occupy peripheral positions. This arrangement of populations is congruent with dispersals of C2a-M208 Y chromosomes from East Polynesia as a migration hub signaling dispersals in various directions. The equivalent ages of the C2a-M208 lineage of the populations in the Network corroborate an east to west flow of the most abundant Polynesian Y chromosome

Recommendations for defining preventable HIV-related mortality for public health monitoring in the era of Getting to Zero: an expert consensus

Getting to Zero is a commonly cited strategic aim to reduce mortality due to both HIV and avoidable deaths among people with HIV. However, no clear definitions are attached to these aims with regard to what constitutes HIV-related or preventable mortality, and their ambition is limited. This Position Paper presents consensus recommendations to define preventable HIV-related mortality for a pragmatic approach to public health monitoring by use of national HIV surveillance data. These recommendations were informed by a comprehensive literature review and agreed by 42 international experts, including clinicians, public health professionals, researchers, commissioners, and community representatives. By applying the recommendations to 2019 national HIV surveillance data from the UK, we show that 30% of deaths among people with HIV were HIV-related or possibly HIV-related, and at least 63% of these deaths were preventable or potentially preventable. The application of these recommendations by health authorities will ensure consistent monitoring of HIV elimination targets and allow for the identification of inequalities and areas for intervention

Phylogenetic history of patrilineages rare in northern and eastern Europe from large-scale re-sequencing of human Y-chromosomes

The most frequent Y-chromosomal (chrY) haplogroups in northern and eastern Europe (NEE) are well-known and thoroughly characterised. Yet a considerable number of men in every population carry rare paternal lineages with estimated frequencies around 5%. So far, limited sample-sizes and insufficient resolution of genotyping have obstructed a truly comprehensive look into the variety of rare paternal lineages segregating within populations and potential signals of population history that such lineages might convey. Here we harness the power of massive re-sequencing of human Y chromosomes to identify previously unknown population-specific clusters among rare paternal lineages in NEE. We construct dated phylogenies for haplogroups E2-M215, J2-M172, G-M201 and Q-M242 on the basis of 421 (of them 282 novel) high-coverage chrY sequences collected from large-scale databases focusing on populations of NEE. Within these otherwise rare haplogroups we disclose lineages that began to radiate similar to 1-3 thousand years ago in Estonia and Sweden and reveal male phylogenetic patterns testifying of comparatively recent local demographic expansions. Conversely, haplogroup Q lineages bear evidence of ancient Siberian influence lingering in the modern paternal gene pool of northern Europe. We assess the possible direction of influx of ancestral carriers for some of these male lineages. In addition, we demonstrate the congruency of paternal haplogroup composition of our dataset with two independent population-based cohorts from Estonia and Sweden

Investigating the origins of eastern Polynesians using genome-wide data from the Leeward Society Isles

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