Human genetic disease caused by de novo mitochondrial-nuclear DNA transfer

Turner, Clesson; Killoran, Christina E.; Thomas, Nick; Rosenberg, Marjorie; Chuzhanova, Nadia; Johnston, Jennifer J.; Kemel, Yelena; Cooper, David Neil; Biesecker, Leslie G.

doi:10.1007/s00439-002-0892-2

Cited by 115 publications

(86 citation statements)

References 29 publications

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“…Several TSIPs disrupted the coding region of a gene (Onozawa et al, 2015). Furthermore, a recent report described a constitutional 72-bp insertion of mitochondrial sequence into the coding region of GLI3 , leading to Pallister-Hall syndrome (Turner et al, 2003). Of note, the conception of this patient was temporally and geographically associated with high-level radioactive contamination following the Chernobyl accident (Turner et al, 2003).…”

Section: Potential To Cause Genetic Diseasementioning

confidence: 99%

“…Furthermore, a recent report described a constitutional 72-bp insertion of mitochondrial sequence into the coding region of GLI3 , leading to Pallister-Hall syndrome (Turner et al, 2003). Of note, the conception of this patient was temporally and geographically associated with high-level radioactive contamination following the Chernobyl accident (Turner et al, 2003). Although speculative, it is conceivable that a DNA DSB in the germ cell, caused by ionizing radiation, was repaired by a TSI derived from mitochondrial DNA in this individual.…”

Section: Potential To Cause Genetic Diseasementioning

confidence: 99%

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Templated Sequence Insertion Polymorphisms in the Human Genome

Onozawa

Aplan

2016

Front. Chem.

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Templated Sequence Insertion Polymorphism (TSIP) is a recently described form of polymorphism recognized in the human genome, in which a sequence that is templated from a distant genomic region is inserted into the genome, seemingly at random. TSIPs can be grouped into two classes based on nucleotide sequence features at the insertion junctions; Class 1 TSIPs show features of insertions that are mediated via the LINE-1 ORF2 protein, including (1) target-site duplication (TSD), (2) polyadenylation 10–30 nucleotides downstream of a “cryptic” polyadenylation signal, and (3) preference for insertion at a 5′-TTTT/A-3′ sequence. In contrast, class 2 TSIPs show features consistent with repair of a DNA double-strand break (DSB) via insertion of a DNA “patch” that is derived from a distant genomic region. Survey of a large number of normal human volunteers demonstrates that most individuals have 25–30 TSIPs, and that these TSIPs track with specific geographic regions. Similar to other forms of human polymorphism, we suspect that these TSIPs may be important for the generation of human diversity and genetic diseases.

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Section: Potential To Cause Genetic Diseasementioning

confidence: 99%

Section: Potential To Cause Genetic Diseasementioning

confidence: 99%

Templated Sequence Insertion Polymorphisms in the Human Genome

Onozawa

Aplan

2016

Front. Chem.

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“…The frequency of the insertion events and the site of integration are therefore critical factors influencing genomic stability. In humans these two aspects have been investigated for mobile elements, including long and short interspersed elements and retroviruses (Li et al 2001; Batzer and Deininger 2002), but much less is known about nuclear DNA sequences of mitochondrial origin (NUMTs), which have been found associated with diseases in humans (Willett-Brozick et al 2001; Borensztajn et al 2002; Turner et al 2003). …”

Section: Introductionmentioning

confidence: 99%

Continued Colonization of the Human Genome by Mitochondrial DNA

2004

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Integration of mitochondrial DNA fragments into nuclear chromosomes (giving rise to nuclear DNA sequences of mitochondrial origin, or NUMTs) is an ongoing process that shapes nuclear genomes. In yeast this process depends on double-strand-break repair. Since NUMTs lack amplification and specific integration mechanisms, they represent the prototype of exogenous insertions in the nucleus. From sequence analysis of the genome of Homo sapiens, followed by sampling humans from different ethnic backgrounds, and chimpanzees, we have identified 27 NUMTs that are specific to humans and must have colonized human chromosomes in the last 4–6 million years. Thus, we measured the fixation rate of NUMTs in the human genome. Six such NUMTs show insertion polymorphism and provide a useful set of DNA markers for human population genetics. We also found that during recent human evolution, Chromosomes 18 and Y have been more susceptible to colonization by NUMTs. Surprisingly, 23 out of 27 human-specific NUMTs are inserted in known or predicted genes, mainly in introns. Some individuals carry a NUMT insertion in a tumor-suppressor gene and in a putative angiogenesis inhibitor. Therefore in humans, but not in yeast, NUMT integrations preferentially target coding or regulatory sequences. This is indeed the case for novel insertions associated with human diseases and those driven by environmental insults. We thus propose a mutagenic phenomenon that may be responsible for a variety of genetic diseases in humans and suggest that genetic or environmental factors that increase the frequency of chromosome breaks provide the impetus for the continued colonization of the human genome by mitochondrial DNA.

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“…NUMTs usually present themselves in three forms: a) continuous stretches of DNA that align linearly with the original mtDNA sequence, b) scrambled sequences derived from different regions of the mitochondrial genome, and c) re-arranged pieces of mtDNA different mitochondria [55]. Starting with the discovery of NUMTs in yeast [25], scattered reports of mitochondrial fragments in human DNA surfaced [57, 74, 98, 113] until sequencing of the human genome showed hundreds of NUMTs. The first analyses by Mourier et al [66] and Tourmen et al [96] revealed between 280 and 296 NUMTs in the human genome, of which 94 were 1000 bp or longer.…”

Section: Numtogenesis In Evolutionmentioning

confidence: 99%

Numtogenesis as a mechanism for development of cancer

Singh¹,

Choudhury

Tiwari

2017

Seminars in Cancer Biology

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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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Human genetic disease caused by de novo mitochondrial-nuclear DNA transfer

Cited by 115 publications

References 29 publications

Templated Sequence Insertion Polymorphisms in the Human Genome

Templated Sequence Insertion Polymorphisms in the Human Genome

Continued Colonization of the Human Genome by Mitochondrial DNA

Numtogenesis as a mechanism for development of cancer

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