Three separate mitochondrial DNA sequences are contiguous in human genomic DNA

doi:10.1016/0022-2836(89)90103-4

Journal of Molecular Biology

Volume 210, Issue 4, 20 December 1989, Pages 703-707

https://doi.org/10.1016/0022-2836(89)90103-4 Get rights and content

Abstract

We isolated from a HeLa genomic library 38 plaques that hybridized to total mitochondrial (mt) DNA isolated from human placenta. One clone (HLmt-17·8) hybridized to a 740 base-pair (12 S ribosomal RNA gene and displacement loop) mtDNA probe and was characterized in more detail. Within its 17·8 × 10³ base-pair insert a 1·6 × 10³ base-pair mtDNA fragment was similar to three non-sequential coding genes of human mtDNA, including a part of the 12 S ribosomal RNA (684–971), the cytochrome oxidase I (6553–7302), and two NADH dehydrogenase [ $ND 4 L ND 4$ ] (10,606–11,159). The similarity to human mtDNA sequences was 92·0%, 92·3% and 92·4%, respectively, the highest degree of similarity to human mtDNA so far reported. This is also the first report of several adjacent mtDNA-like sequences in cellular chromosomes. The mtDNA-like sequences in HLmt-17·8 was found in the DNAs of human placenta, freshly isolated human leukocytes, foreskin and several human cell lines; but it was not present in other primates or lower organisms. The HLmt-17.8 mtDNA-like region appears to be a pseudogene that transferred into the nucleus in humans more recently than nine million years ago.

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Based on this recognition, blasting human genome data against mtDNA provides a simplified transgenic human analysis, which we term mitochromics. Human mtDNA has migrated into chromosomes throughout evolution [14-18]. Once integrated, fragments of mitochondrial origin (mtDNA-like) may experience a slower mutation rate than their counterparts in the mitochondria.
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A slow and steady accumulation of mtDNA in the nuclear genome could lead to progressive changes in the overall cellular proteome and cause cancer [87]. An early indication of the role of mitochondrial insertions in tumorigenesis came from the experiments by Kamimura et al. on HeLa cells [48]. They hybridized the entire HeLa genomic library to the total human mtDNA and focused on three nuclear fragments that showed homology to parts of mitochondrial 12s rRNA, cytochrome oxidase I, and NADH dehydrogenase.
Transfer of genetic material from cytoplasmic organelles to the nucleus, an ongoing process, has implications in evolution, aging, and human pathologies such as cancer. The transferred mitochondrial DNA (mtDNA) fragments in the nuclear genome are called nuclear mtDNA or NUMTs. We have named the process numtogenesis, defining the term as the transfer of mtDNA into the nuclear genome, or, less specifically, the transfer of mitochondria or mitochondrial components into the nucleus. There is increasing evidence of the involvement of NUMTs in human biology and pathology. Although information pertaining to NUMTs and numtogenesis is sparse, the role of this aspect of mitochondrial biology to human cancers is apparent. In this review, we present available knowledge about the origin and mechanisms of numtogenesis, with special emphasis on the role of NUMTs in human malignancies. We describe studies undertaken in our laboratory and in others and discuss the influence of NUMTs in tumor initiation and progression and in survival of cancer patients. We describe suppressors of numtogenesis and evolutionary conserved mechanisms underlying numtogenesis in cancer. An understanding the emerging field of numtogenesis should allow comprehension of this process in various malignancies and other diseases and, more generally, in human health.
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Indeed, BLAST search showed that mtDNA (NC_001807) exhibited sequence similarity with some chromosomal sequences including a contig (NT_034772) of chromosome 5, for which nuclear mitochondrial DNA-like sequences were not included among BAC clones of our array. Mitochondrial DNA-like nuclear fragments have been documented in various eukaryotic species [29–33]. Such nuclear copies of mtDNA can confound phylogenetic and population genetic studies [34].
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The study of mitochondrial DNA (mtDNA) has helped to demonstrate the African origin of our species and the relationship between living humans and the Neanderthals. mtDNA data have also been used to establish the time and route of major events in human history, such as the expansion of Neolithic farmers into Europe, and the settlement of the Pacific and the New World. However, it is becoming apparent that mtDNA evolution is more complex than previously believed. Anomalous mutation patterns perturb phylogenetic assumptions based on mtDNA data. Although they are frequently dismissed as sequencing errors or mutation hotspots, some of the anomalies have no satisfactory explanation. The mechanisms behind apparent mutation rate heterogeneity, or even possible mtDNA recombination, remain unknown. These issues need to be addressed, as they have profound consequences for the interpretation of mtDNA data.
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Malfunction of mismatch repair (MMR) genes produces nuclear genome instability (NGI) and plays an important role in the origin of some hereditary and sporadic human cancers. The appearance of non-inherited microsatellite alleles in tumor cells (microsatellite instability, MSI) is one of the expressions of NGI. We present here data showing mitochondrial genome instability (mtGI) in most of the human cancers analyzed so far. The mtDNA markers used were point mutations, length-tract instability of mono- or dinucleotide repeats, mono- or dinucleotide insertions or deletions, and long deletions. Comparison of normal and tumoral tissues from the same individual reveals that mt-mutations may show as homoplasmic (all tumor cells have the same variant haplotype) or as heteroplasmic (tumor cells are a mosaic of inherited and acquired variant haplotypes). Breast, colorectal, gastric and kidney cancers exhibit mtGI with a pattern of mt-mutations specific for each tumor. No correlation between NGI and mtGI was found in breast, colorectal or kidney cancers, while a positive correlation was found in gastric cancer. Conversely, germ cell testicular cancers lack mtGI. Damage by reactive oxygen species (ROS), slipped-strand mispairing (SSM) and deficient repair are the causes explaining the appearance of mtGI. The replication and repair of mtDNA are controlled by nuclear genes. So far, there is no clear evidence linking MMR gene malfunction with mtGI. Polymerase γ (POLγ) carries out the mtDNA synthesis. Since this process is error-prone due to a deficiency in the proofreading activity of POLγ, this enzyme has been assumed to be involved in the origin of mt-mutations. Somatic cells have hundreds to thousands of mtDNA molecules with a very high rate of spontaneous mutations. Accordingly, most somatic cells probably have a low frequency of randomly mutated mtDNA molecules. Most cancers are of monoclonal origin. Hence, to explain the appearance of mtGI in tumors we have to explain why a given variant mt-haplotype expands and replaces part of (heteroplasmy) or all (homoplasmy) wild mt-haplotypes in cancer cells. Selective and/or replicative advantage of some mutations combined with a severe bottleneck during the mitochondrial segregation accompanying mitosis are the mechanisms probably involved in the origin of mtGI.
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^☆: This work was supported by Public Health Service grants CA40065 and CA50195 from the National Institutes of Health and by CD-347A from the American Cancer Society.

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Journal of Molecular Biology

Three separate mitochondrial DNA sequences are contiguous in human genomic DNA☆

Abstract

J. Mol. Biol.

Mutat. Res.

J. Mol. Biol.

Nature (London)

Nature (London)