Mitochondrial genetic heterogeneity in normal and cancerous cells

Mitochondrial genetic heterogeneity in normal and cancerous cells
11 March 2010 | By Dr Caroline Wright

Whilst the vast majority of human DNA is located in the nucleus, a small amount is also present in the mitochondria – the ‘power houses’ of the cell – and mutations in one of the mitochondrial DNA (‘mtDNA’) is responsible for several serious rare inherited disorders (see previous news). Unlike the nuclear genome, however, which is usually only present as a single copy per cell, there are generally around 50-100 mitochondria per cell, and around 5-10 copies of mtDNA per mitochondrion. The rate of mutation is also much higher in mitochondrial DNA than nuclear DNA, due to the absence of proof reading and correcting enzymes. Therefore, in addition to having multiple copies of identical mtDNA in a cell (homoplasmy), cells may also have multiple alternative copies (heteroplasmy) which may also vary between different cells and tissues.

The advent of massively parallel sequencing methodologies makes it technically feasible to investigate mitochondrial genetic heterogeneity, as is allows very rare variants to be detected. A new paper in Nature reports the sequencing of mtDNA samples from both normal and cancerous human cells [He Y et al. Nature (2010) doi: 10.1038/nature08802]. In the non-cancerous cells, an average of 28 novel mtDNA homoplasmic alleles were identified in a single individual which were not present in the mtDNA reference sequence (see the MitoMap database). In addition, in areas of known variation, an average of 4 heteroplasmic alleles were identified per sample, which were either maternally inherited or arose as de novo somatic mutations early in development, and had tissue-specific allele frequencies of between 7-91%.

As expected, the cancerous cells (derived from colorectal tumours) had higher mitochondrial genetic heterogeneity, with 20 cancer-specific variants detected, most of which were heteroplasmic. Interestingly, the heteroplasmic variants detected in the normal colon tissue were either entirely absent from the cancer cells or present in homoplasmy, supporting the hypothesis that cancer cells evolve from aberrant stem cells across many cellular generations over many years. The authors suggest that these cancer-specific mtDNA mutations could prove to be excellent biomarkers to track cancer progression because, unlike genetic rearrangements that are characteristic of nuclear DNA in cancer cells (see previous news), they are 500-1,000 fold more numerous in the cells. Moreover, minor changes are easier to detect because of the relatively small size of mtDNA.

Keywords: DNA Technologies
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