Genome Digging: Insight into the Mitochondrial Genome of Homo

Abstract

BackgroundA fraction of the Neanderthal mitochondrial genome sequence has a similarity with a 5,839-bp nuclear DNA sequence of mitochondrial origin (numt) on the human chromosome 1. This fact has never been interpreted. Although this phenomenon may be attributed to contamination and mosaic assembly of Neanderthal mtDNA from short sequencing reads, we explain the mysterious similarity by integration of this numt (mtAncestor-1) into the nuclear genome of the common ancestor of Neanderthals and modern humans not long before their reproductive split.Principal FindingsExploiting bioinformatics, we uncovered an additional numt (mtAncestor-2) with a high similarity to the Neanderthal mtDNA and indicated that both numts represent almost identical replicas of the mtDNA sequences ancestral to the mitochondrial genomes of Neanderthals and modern humans. In the proteins, encoded by mtDNA, the majority of amino acids distinguishing chimpanzees from humans and Neanderthals were acquired by the ancestral hominins. The overall rate of nonsynonymous evolution in Neanderthal mitochondrial protein-coding genes is not higher than in other lineages. The model incorporating the ancestral hominin mtDNA sequences estimates the average divergence age of the mtDNAs of Neanderthals and modern humans to be 450,000–485,000 years. The mtAncestor-1 and mtAncestor-2 sequences were incorporated into the nuclear genome approximately 620,000 years and 2,885,000 years ago, respectively.ConclusionsThis study provides the first insight into the evolution of the mitochondrial DNA in hominins ancestral to Neanderthals and humans. We hypothesize that mtAncestor-1 and mtAncestor-2 are likely to be molecular fossils of the mtDNAs of Homo heidelbergensis and a stem Homo lineage. The dN/dS dynamics suggests that the effective population size of extinct hominins was low. However, the hominin lineage ancestral to humans, Neanderthals and H. heidelbergensis, had a larger effective population size and possessed genetic diversity comparable with those of chimpanzee and gorilla.

Polymorphic NumtS trace human population relationships

“…As a result, the here presented compilation demands to be a comprehensive list of reference humanspeciWc NumtS. Insertion of the majority of analysed human-speciWc NumtS very probably occurred in ancestral African groups before modern humans migrated out of Africa and thus before the several bottlenecks undergone by H. sapiens populations during colonization of the Eurasian and American continents, as already reported for various human NumtS (Bensasson et al 2003;Ricchetti et al 2004;Ovchinnikov and Kholina 2010). Some human NumtS have been shown to be highly similar to the Neanderthal mtDNA, and this has been explained by their integration into the nuclear genome of a common ancestor of Neanderthals and modern humans (Ovchinnikov and Kholina 2010).…”

“…Therefore, the most ancient NumtS have been described as true "molecular fossils", whereas the most recent ones may be regarded as "snapshots" of mtDNAs coexisting at the time of insertion (Hazkani-Covo et al 2010). This property of NumtS sequences to resemble ancestral mtDNA has been successfully used for phylogenetic classiWcation in very diVerent taxonomic groups (Schmitz et al 2005;Ovchinnikov and Kholina 2010;Baldo et al 2011), oVering the opportunity to study the correlation between mitochondrial and nuclear genome evolutions.…”

“…Although phylogenetic studies have generally examined NumtS sequences (Schmitz et al 2005;Ovchinnikov and Kholina 2010), in the present work we analysed their property as indels, thanks to the recent implementation of NumtS tracks on the University of California Santa Cruz (UCSC) human genome browser build hg18 (http:// genome.ucsc.edu; Kent et al 2002;Simone et al 2011), a powerful tool which allowed us to identify a very large number of human-speciWc NumtS. By applying bioinformatics analyses to the 1000 Genomes Project sequence data, and providing in vitro validation of the observed polymorphic loci, we did succeed in depicting the landscape of variation of a series of NumtS in several ethnic groups worldwide, making an advance in their identiWcation as useful markers in the study of human population genetics.…”

Comparison of detection methods and genome quality when quantifying nuclear mitochondrial insertions in vertebrate genomes

“…The accumulation of mutations in older numt insertions can alter the transferred sequence so that it is no longer perceived as a mtDNA fragment. When numts are co-amplified with mtDNA during PCR-based studies or misaligned during similarity searches, they can compromise studies involving heteroplasmy ( Maude et al, 2019 ), DNA barcoding ( Song et al, 2008 ), ancient DNA ( Ovchinnikov and Kholina, 2010 ) and phylogenetics ( Lucas et al, 2022 ). Numts have also incorrectly supported the bi-parental inheritance of mtDNA ( Luo et al, 2018 ).…”