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Mitochondrial Pseudogenes Suggest Repeated Inter-Species Hybridization in Hominid Evolution

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Mitochondrial Pseudogenes Suggest Repeated Inter-Species Hybridization in Hominid Evolution bioRxiv preprint doi: https://doi.org/10.1101/134502; this version posted May 9, 2017. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under Mitochondrial pseudogenes suggest aCC-BY repeated 4.0 International interlicense. -species hybridization in hominid evolution. Konstantin Popadin, Konstantin Gunbin, Leonid Peshkin, Sofia Annins, Yevgenya Kraytsberg, Natalya Markuzon, Rebecca R. Ackermann, Konstantin Khrapko. [email protected] Konstantin Popadin University of Lausanne [email protected] Konstantin Gunbin Novosibirsk State University [email protected] Leonid Peshkin Harvard Medical School [email protected] Sofia Annis Northeastern University Yevgenya Kraytsberg Beth Israel Deaconess Medical Center Harvard Medical School [email protected] Natalya Markuzon Draper Laboratory [email protected] Rebecca R. Ackermann University of Cape Town Corresponding Author: Konstantin Khrapko [email protected] Professor Department of Biology 134 Mugar Bldg 360 Huntington Avenue Northeastern University Boston MA 02115 bioRxiv preprint doi: https://doi.org/10.1101/134502; this version posted May 9, 2017. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 Internationallittle license information . on the presence or prevalence of Abstract: The hypothesis that the evolution of humans hybridization during earlier (pre-1Ma) periods in involved hybridization between diverged species has human evolution. A study (Patterson et al., 2006) been actively debated in recent years. We present concluded that the hominin lineage first significantly novel evidence in support of this hypothesis: the diverged from the chimpanzee lineage, but later analysis of nuclear pseudogenes of mtDNA (“NUMTs”). hybridized back, before finally diverging again. This NUMTs are considered “mtDNA fossils”, as they study prompted an intense debate (Barton, 2006) preserve sequences of ancient mtDNA and thus carry (Innan and Watanabe, 2006), (Wakeley, 2008), unique information about ancestral populations. Our (Patterson et al., 2008), (Presgraves and Yi, 2009), comparison of a NUMT sequence shared by humans, (Yamamichi et al., 2012), but has remained the sole chimpanzees, and gorillas with their mtDNAs implies piece of evidence for such an early admixture event. that, around the time of divergence between humans Although none of the subsequent studies fully rejected and chimpanzees, our evolutionary history involved or confirmed the hybridization scenario, most pointed the interbreeding of individuals whose mtDNA had to the lack of sufficient evidence to uphold it. The diverged as much as ~4.5Myr prior to the research presented here supports a similar early interbreeding event. This large divergence suggests a hybridization scenario using an entirely different distant interspecies hybridization. Additionally, approach. Moreover, our analyses suggest that distant analysis of two other NUMTs suggests that such events interbreedings occurred repeatedly among our distant occurred more than once. While it may seem ancestors. impossible, interspecies hybridizations of a similar The evidence for interspecies hybridization magnitude have been observed in other primates, e.g. presented here comes from special type of baboons and colobines. Our findings suggest a pseudogenes (“NUMTs”) that are fragments of complex pattern of speciation in primate human mitochondrial DNA (mtDNA) integrated into the ancestors and provide a potential explanation for the nuclear genome. There are hundreds of NUMT mosaic nature of fossil morphology found at the sequences in the human genome (Ramos et al.). emergence of the hominin lineage. NUMTs found in the present day human genome have been inserting into nuclear DNA since tens of millions years ago, and this process continues today Introduction: (Srinivasainagendra 2017) We have recently reported evidence that insertion of NUMTs into nuclear genome Increasingly, the emergence and evolution of our might have accelerated during the emergence of the species is being revealed as a period characterized by genus Homo (Gunbin 2016). NUMTs are considered genetic exchange between divergent lineages. For “DNA fossils”, since they preserve ancient mtDNA example, we now have evidence of hybridization sequences virtually unchanged due to significantly between Neanderthals and people expanding from lower mutational rate in the nuclear versus Africa (Sankararaman et al., 2012), (Vernot et al., mitochondrial genome (Zischler et al., 1995). NUMTs 2016), between Denisovans and humans (Meyer et al., therefore offer an opportunity to peek into the distant 2012), between Neanderthals and Denisovans (Prufer past of populations (Bensasson et al., 2001), (Baldo et et al., 2014), and between Denisovans and an al., 2011), (Wang et al., 2015). Here, we demonstrate unidentified hominin (Prufer et al., 2014). Hominin that a NUMT on chromosome 5 descends from a here denotes human lineage upon its separation from mitochondrial genome that had been highly divergent the chimpanzee. The term Hominine, in contrast, from our ancestors’ mtDNA at the time of becoming a denotes the human, chimpanzee and gorilla clade, pseudogene. This implies that this pseudogene should upon its separation from the orangutan lineage (Ref have been created in an individual from a (hominine) needed). Denisovan-like mtDNA has also been species that at the time of insertion was highly detected in earlier (ca. 400,000ya) hominins (Meyer et diverged from our direct ancestor. For this al. 2014), implying mtDNA introgression or pseudogene to end up in our genome, this (now hybridization. Evidence also exists for gene flow (ca. extinct) hominine should have hybridized with our 35Kya) between African populations that diverged direct ancestors. Moreover, our analysis of additional 700,000 years ago (Hammer et al., 2011). These NUMTs with similar phylogenic history, implies that studies indicate that hybridization was prevalent this scenario was not unique. during the period of emergence of Homo sapiens, and suggest that it may be the rule rather than the exception in hominin evolution. However, we have 1 bioRxiv preprint doi: https://doi.org/10.1101/134502; this version posted May 9, 2017. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under Results. aCC-BY 4.0 Internationaltree should resemble the license. mtDNA sub-tree, which is a A NUMT on chromosome 5 originated from a good representation of the great ape evolution. One highly divergent mitochondrial genome. may expect, though, that all branches of the NUMT tree In an early screen of human pseudogenes of should be shorter than those of mtDNA tree, as mtDNA (Li-Sucholeiki et al., 1999) we discovered a mutation rate in the nuclear DNA is expected to be pseudogene sequence on chromosome 5 which later lower than in mtDNA. Contrary to these expectations, turned out to be a large (~9kb) NUMT called here the NUMT has a very different shape: a very long stem “ps5”. We then discovered close homologs of ps5 in (“ps5 stem”) and short branches. Even more the chimpanzee and gorilla genomes, i.e. in all intriguingly, phylogenetic mutational analysis (Suppl. contemporary hominines, but absent in orangutan and Note 6) showed that the mutations of the ps5 stem more distant primates (see Suppl. Note 1). This contain a very high proportion of synonymous NUMT turned out to have an extraordinary changes, similar to mtDNA branches. In contrast, evolutionary history. mutations in the outer pseudogene branches (Fig. 1A, A joint phylogenetic tree of the 3 ps5 NUMTs colored blue) contain a significantly higher proportion and the mtDNA sequences of great apes (Fig. 1A) has a of non-synonymous changes (p<0.00005,), as expected very surprising shape. One would expect that, as for a truly pseudogenic, dysfunctional sequence. Thus selectively neutral loci, pseudogenes should ps5 sequence has been evolving under mitochondrial approximately follow the evolutionary paths of the selective constraints, i.e. as a part of a functional species in which they reside. That is, the NUMT sub- mitochondrial genome, until it gave rise to a pseudogene which then split into the Homo, Pan, and Gorilla variants. The impressive length of the ps5 stem implies that at the time of it’s insertion in to the nuclear genome, the mtDNA predecessor of ps5 NUMT was highly divergent from the Homo/Pan/Gorilla ancestral mtDNA. Because the rate of evolution of mtDNA is relatively stable and well- documented, this divergence can be evaluated quantitatively with reasonable confidence. Figure 1 A. A joint phylogenetic tree of the hominine mtDNA and the ps5 pseudogene of mtDNA. Green and blue lines depict the mitochondrial and the pseudogene lineages respectively, diverging from their mitochondrial common ancestor (green circle). The common pseudogene stem (“Ps5 stem”) is colored green because, remarkably, mutations of the “ps5 stem” are mostly synonymous changes that must have occurred in a functional mitochondrial genome. This contrasts with a low fraction of synonymous changes in the pseudogene branches (blue). Note that the pseudogene branches are short,
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