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. 2022 May 1;13(5):810.
doi: 10.3390/genes13050810.

Mitochondrial Pseudogenes Suggest Repeated Inter-Species Hybridization among Direct Human Ancestors

Konstantin Popadin  1   2   3 , Konstantin Gunbin  4 , Leonid Peshkin  5 , Sofia Annis  6 , Zoe Fleischmann  6 , Melissa Franco  6 , Yevgenya Kraytsberg  7 , Natalya Markuzon  8 , Rebecca R Ackermann  9 , Konstantin Khrapko  6
Affiliations

Mitochondrial Pseudogenes Suggest Repeated Inter-Species Hybridization among Direct Human Ancestors

Konstantin Popadin et al. Genes (Basel). .

Abstract

The hypothesis that the evolution of humans involves hybridization between diverged species has been actively debated in recent years. We present the following novel evidence in support of this hypothesis: the analysis of nuclear pseudogenes of mtDNA ("NUMTs"). NUMTs are considered "mtDNA fossils" as they preserve sequences of ancient mtDNA and thus carry unique information about ancestral populations. Our comparison of a NUMT sequence shared by humans, chimpanzees, and gorillas with their mtDNAs implies that, around the time of divergence between humans and chimpanzees, our evolutionary history involved the interbreeding of individuals whose mtDNA had diverged as much as ~4.5 Myr prior. This large divergence suggests a distant interspecies hybridization. Additionally, analysis of two other NUMTs suggests that such events occur repeatedly. Our findings suggest a complex pattern of speciation in primate/human ancestors and provide one potential explanation for the mosaic nature of fossil morphology found at the emergence of the hominin lineage. A preliminary version of this manuscript was uploaded to the preprint server BioRxiv in 2017 (10.1101/134502).

Keywords: NUMT; human evolution; hybridization; mtDNA.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
A joint phylogenetic tree of the hominine mtDNA and the ps5 pseudogene of mtDNA. (A) 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 because of the low mutation rates in nuclear DNA compared to mtDNA). The length of the “ps5 stem” implies ~4.5 My of evolution. The intriguing question is how did ps5 get back into the Homo-Pan-Gorilla clade after its precursor had been diverging from this clade for millions of years. Orangutan, gibbon, and baboon outgroups were omitted for simplicity (see Supplementary Notes SN2, SN4 and Figure S3 for tree building approach and stability analysis). (B) Interpretation of the mtDNA/ps5 tree of Figure 1A. Blue hazy branches represent species, rather than individual loci, and blue haze schematically symbolizes the superposition of the phylogenetic trajectories of all the nuclear genetic loci. Because the ps5 stem branch is essentially mitochondrial, it must have been evolving within a continuous maternal lineage, which, to accommodate the very long ps5 stem, should have been diverging for ~4.5 My. The long separation period implies that this maternal lineage was a part of a separate species. That species should have eventually gone extinct and is thus labeled “extinct Hominine”. The ps5 pseudogene was created in the extinct Hominine (half blue/half green circle) and transferred to the Homo-Pan-Gorilla clade via interspecies hybridization (thin blue arrow). Solid lines represent lineages currently extant lineages, dotted lines—extinct lineages.
Figure 2
Figure 2
The divergence of hominine taxa from their common ancestors with sister taxa (a.k.a. branch lengths) is compared to the divergence of the ps5 precursor mtDNA (mtDNA of the hypothetical extinct Hominine) from its common ancestor with living hominines at the time of the ps5 formation (turquoise). Note that divergence of the ps5 precursor is intermediate between the divergences of congeneric species (P. troglodytes and P. paniscus; G. gorilla and G. beringei) and the divergences of genera (Homo and Pan). Divergences were estimated from the common ancestor with a sister taxon (e.g., for Homo—from the common ancestor with Pan, for P. troglodytes—from the common ancestor with P. paniscus, and for Ps5 precursor mtDNA—from the common ancestor with the Homo-Pan-Gorilla clade). The curves represent the distribution of estimates by the jackknife procedure (Supplementary Note SN3); the ps5 data has been corrected by the fraction of mtDNA mutations in the ps5 stem (i.e., multiplied by 0.75, Supplementary Note SN5).
Figure 3
Figure 3
Phylogenetics of the pseudogene Ps11 and Hominine mtDNA. PhyML GTR. Note that this tree is still under construction; there are some unresolved problems in topology. In fact, this particular region of mtDNA is generally not apt for genealogical analysis because of high conservation and high selective pressures (as it is an rRNA coding region).
Figure 4
Figure 4
Phylogenetics of the pseudogene Ps7 and old-world monkey mtDNA.
Figure 5
Figure 5
Comparison of the NUMT transfer (right) and the mtDNA introgression (left) scenarios of hybridization. (A) represents the inferred events, (B) represents the resulting observed phylogenies. Blue arrows represent the NUMTs, and light blue lines depict the superposition of the phylogenetic trajectories of all the nuclear genetic loci, as in Figure 1B. The mtDNA genealogies are green. Horizontal arrows represent introgression of mtDNA (green) or transfer of the NUMT locus between extinct hominine and the HCG mitochondrial (blue). Extinct hominine mtDNA lineage is neon green, the HCG mtDNA lineage is forest green.
See this image and copyright information in PMC

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