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Mitochondrial Genome Diversity Unexpectedly High, Study Finds

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – Mitochondrial genomes — even those in normal cells — are more heterogeneous than previously believed, according to a new paper published online in Nature.

Researchers from Johns Hopkins and Case Western Universities used high-throughput sequencing to assess mtDNA from normal and cancerous cells. They found variability in the mitochondrial sequences within normal cells and between different tissue types from the same individual. This variation was even more pronounced in cancer cells, which contained mitochondrial mutations that could also be detected in patient blood samples.

"These studies provide insights into the nature and variability of mtDNA sequences and have implications for mitochondrial processes during embryogenesis, cancer biomarker development and forensic analysis," co-corresponding author Nickolas Papadopoulos, a cancer biology researcher and director of translational genetics at Johns Hopkins' Kimmel Cancer Center, and colleagues wrote. "In particular, they demonstrate that individual humans are characterized by a complex mixture of related mitochondrial genotypes rather than a single genotype."

Mitochondria are responsible for providing energy to eukaryotic cells. Roughly 50 to 100 of these organelles, inherited from an individual's mother, are found in each human cell, Papadopoulos and his co-workers explained. Each contains between five and ten mitochondrial genomes. But it's unclear how much variability, if any, exists within each individual's mtDNA.

Past studies suggest mtDNA is the same within and between cells, the team noted, though "[t]he presence of multiple copies of mtDNA per cell leaves open the possibility that all the copies are not identical."

To address such questions, the researchers used massively parallel sequencing with the Illumina Genome Analyzer II platform to sequence mtDNA libraries made from normal cells from one individual, generating sequence that covered each base an average of 16,700 times.

After accounting for sequence errors introduced during PCR and sequencing, the researchers still detected 28 so-called homoplasmic mutations not found in the human mitochondrial reference genome and eight heteroplasmic alleles — alleles that varied within cells from the same individual.

The researchers not only verified these sequences using independent approaches but also detected both homoplasmic and heteroplasmic variants in their follow-up experiments of normal cells and tissues from other individuals.

For instance, they detected an average of 28 homoplasmic and four heteroplasmic alleles when they sampled nine other individuals, focusing on the same cell type assessed initially.

Meanwhile, when the researchers tested ten autopsy tissues from one individual, they found variation not only within cells from the same tissue but also from one tissue to the next — a pattern that the verified by testing five tissues from yet another individual.

In an effort to determine how and when such heteroplasmic variants arise, the team compared mtDNA sequences within two families, each containing parents and two children.

Results from those experiments suggest that most of these variations are a consequence of tissue-specific mutations arising during development.

"A small fraction of the heteroplasmic variants were clearly inherited from the mother," the researchers explained, "but the remainder were apparently somatic mutations that probably occurred during very early development."

Interestingly, such mtDNA variation appears to be even more common in cancerous cells. When they compared matched cancer and normal cells from the same cell type for 10 individuals, the team found that 90 percent of the cancers not only contained variants present in normal cells but also additional mutations. Compared with variants in normal cells, these cancer-associated mtDNA mutations were far more likely to fall in protein- or RNA-coding regions.

As such, the researchers suggested, cancer specific mtDNA may prove useful as cancer biomarkers. Indeed, when they tested blood samples from two individuals with colorectal cancer before and after surgery, they were able to detect differences in the levels of cancer-related mtDNA mutations. And, they noted, mtDNA was more concentrated and easier to detect in the blood than nuclear DNA sequences associated with the tumor.

Based on such findings, they argued that mtDNA variation may have diagnostic — as well as forensic — applications down the road.

"[A]n individual, and perhaps even a single cell, does not have a single mtDNA genotype," Papadopoulos and his co-authors concluded. "This suggests caution in excluding identity on the basis of a single or small number of mismatched alleles when the tissue in evidence (such as sperm) is not the same as the reference tissue of the suspect (such as blood or hair)."

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