Hypothesis: BK virus subtype IV that is now prevalent in East Asia originated in Denisovans, archaic humans inhabiting East Eurasia

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On the origin of modern humans: Asian perspectives science.sciencemag.org/content/358/63…

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Multiple Deeply Divergent Denisovan Ancestries in Papuans cell.com/cell/fulltext/…

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<Title> Hypothesis: BK virus subtype IV that is now prevalent in East Asia originated in Denisovans, archaic humans inhabiting East Eurasia <Introduction> Approximately 60,000 years ago, the ancestors of modern humans left Africa and headed for Europe and Asia. At that time,

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archaic humans (e.g., Neanderthals and Denisovans) inhabited Europe and Asia. The ancestors of modern humans encountered and fought against these archaic humans who were defeated and eliminated from Europe and Asia. This is the accepted theory. However, technological advances in

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gene extraction and analysis using excavated bones and teeth of ancient human beings led to the discovery that the ancestors of modern humans crossbred with the archaic humans. If the ancestors of modern humans were sufficiently intimate with the archaic humans to crossbreed,

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viruses that infected the archaic humans may have been transmitted to the ancestors of modern humans. Probably, BK virus subtype IV is the best candidate for such a virus, as detailed below. <About BKV> The BK virus (BKV) is a small DNA virus belonging to the polyomavirus family

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Each member of this family has a strict host specificity; thus, BKV infects only humans. Most humans are infected with BKV during childhood, without notable symptoms. In immunocompetent hosts, BKV asymptomatically persists in the kidney and urinary tract, but it may cause BKV

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nephropathy in renal transplant recipients under immunosuppression. It should be noted that JC virus (JCV), a virus closely related to BKV, has been used as a marker to trace human migrations. <Epidemiology of BKV> Based on antigenic differences, BKV has been classified into four

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subtypes, I to IV. The relative incidences of the four subtypes are shown in the pie charts for each geographic region in Fig. 1. (1) Subtype I is distributed throughout the world, including Africa. Thus, it can be inferred that subtype I was present in modern humans born in pic.twitter.com/FMpCSj5arc

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Africa and that it co-migrated with modern humans not only during out-of-Africa dispersal but also during subsequent dispersals in Europe and Asia. (2) Both subtypes II and III are not or rarely detected worldwide. Our recent study based on a molecular phylogenetic analysis

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revealed that subtypes II and III constitute a single group, subtype II/III. (3) Subtype IV is rarely detected in Africa, is prevalent in Europe, with a biased distribution in north (Finland, Sweden), central (Hungary), and south countries (Italy and Greece), and highly prevalent

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throughout East Asia <Phylogenetic analysis> We assumed that BKV subtype IV originated in East Asia, and that the distribution of subtype IV in Europe, biased in north, central and south areas, was caused by recent migrations of East Asians. To examine this hypothesis, we

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performed a phylogenetic analysis based on whole genome sequencing. Our approach consisted of four steps: (1) extraction of DNA (genetic material) from urine samples collected around the world; (2) selective amplification of BKV DNA using the PCR method; (3) determination of the

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nucleotide sequences of BKV DNA using an automatic DNA sequencer; and (4) construction of a phylogenetic tree based on sequence differences between BKV isolates using appropriate software. <Phylogenetic tree> A phylogenetic tree relating different subtype IV isolates was

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constructed based on complete nucleotide sequences, and its schematic is presented in Fig. 2. We identified six subgroups (a1, a2, b1, b2, c1, and c2) that formed a tree represented by the formula: “(a1, a2), ((b1, b2), (c1, c2)).” The ancestral subtype IV diverged into two pic.twitter.com/oIU7NOmucY

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branches A and B. Branch A generated subgroups (a1 and a2), whereas branch B further diverged into two subbranches, B1 and B2, the former generating subgroups (b1 and b2) and the latter generating subgroups (c1 and c2) (Fig. 2).<Geographic distribution> We next evaluated the

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geographic distribution of each subgroup. The relative incidence of individual subgroups is shown in the pie charts for each geographic region in Fig. 3. The geographic regions where each subgroup was detected are indicated in Fig. 2. In short, many subgroups are distributed in pic.twitter.com/NeF3CRcwW5

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East Asia, whereas only a single subtype (c2) is spread in Europe. The Asian region where c2 is mainly distributed is Mongolia. Thus, we concluded that subtype IV of BKV, which is now prevalent among modern humans, originated from a virus or a few viruses that infected ancestral

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East Asians. To visualize our conclusion, the distribution of subtype IV subgroups on Eurasia is illustrated in Fig. 4. In this figure, red, blue, and green circles represent the areas where subtype IV subgroups (a1, a2), (b1, b2), and (c1, c2) may have been generated,. pic.twitter.com/DdC1JHewiX

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respectively. Arrows from these circles represent the migration of indicated subgroups. This figure was prepared based on the phylogenetic tree relating different subgroups and the geographic distribution of individual subgroups (see Figs. 2 and 3). <Hypothesis> Twelve years ago,

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we introduced a hypothesis that may explain the origin of subtype IV BKV that initially infected ancestral East Asians. This hypothesis assumes that the natural host of BKV subtype IV was a primate living in Asia. When ancestral Asians entered an area inhabited by the subtype IV-

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infected primate, they may have acquired subtype IV shed by the primate. Indeed, polyomaviruses were reported to occasionally change hosts, although they generally co-evolve with their hosts. Here, we propose a new version of our previous hypothesis: subtype IV BKV was

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transmitted from Denisovans, a species of archaic humans inhabiting East Eurasia. This hypothesis is based on the possible contact between ancestors of East Asians and Denisovans, as described above. <Closing remark> We propose the hypothesis that subtype IV BKV was transmitted

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from Denisovans, a species of archaic humans living in East Eurasia, to ancestors of East Asians. It may be impossible to gain direct evidence for our hypothesis because BKV cannot be detected from excavated bones or teeth (BKV exists in the kidney and urinary tract). Our

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hypothesis will be further supported, if similar to subtype IV BKV, other viruses or parasites are found to have been transmitted from Denisovans or other archaic humans to modern humans. <Acknowledgment>I am grateful to Drs. Tadaichi Kitamura, Chie Sugimoto, and Souichi Nukuzuma