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Human Molecular Genetics Advance Access published online on October 20, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddh326
© 2004 by Oxford University Press
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Article

Heterologous mitochondrial DNA recombination in human cells

Marilena D'Aurelio 1, Carl D. Gajewski 1, Michael T. Lin 1, William M. Mauck 1, Leon Z. Shao 1, Giorgio Lenaz 2, Carlos T. Moraes 3, and Giovanni Manfredi MD, PhD4*

1 Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, New York
2 Dipartimento di Biochimica G. Moruzzi, Università di Bologna, Italy
3 Department of Neurology, University of Miami School of Medicine, Miami, Florida
4 Department of Neurology and Neuroscience, Weill Medical College of Cornell University, 525 E 68th Street, A-505, New York, 10021 New York

* To whom correspondence should be addressed.
Giovanni Manfredi, E-mail: gim2004{at}mail.med.cornell.edu


  Abstract

Inter-molecular heterologous mitochondrial DNA (mtDNA) recombination is known to occur in yeast and plants. Nevertheless, its occurrence in human cells is still controversial. To address this issue we have fused two human cybrid cell lines, each containing a distinct pathogenic mtDNA mutation and specific sets of genetic markers. In this hybrid model, we found direct evidence of recombination between these two mtDNA haplotypes. Recombinant mtDNA molecules in the hybrid cells were identified using three independent experimental approaches. First, recombinant molecules containing genetic markers from both parental alleles were demonstrated with PCR-RFLP analyses, by measuring the relative frequencies of each marker. Second, fragments of recombinant mtDNA were cloned and sequenced to identify the regions involved in the recombination events. Finally, recombinant molecules were demonstrated directly by Southern blot using appropriate combinations of polymorphic restriction sites and probes. This combined approach confirmed the existence of heterogeneous species of recombinant mtDNA molecules in the hybrid cells. These findings have important implications for mtDNA-related diseases, the interpretation of human evolution and population genetics, as well as forensic analyses based on mtDNA genotyping.


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