Thursday, 4 February 2016

Segregation of naturally occurring mitochondrial DNA variants in a mini-pig model

Gael Cagnone, Te-Sha Tsai, Kanokwan Srirattana, Fernando Rossello, David R. Powell, Gary Rohrer, Lynsey Cree, Ian A. Trounce, Justin St. John
Recent work in mice has shown that different mitochondrial sequences (haplotypes) will tend to accumulate in different tissues, and this segregation depends on the sequence in question.

In this study, the authors study four mtDNA mutations, over three generations of mini-pigs. These mutations were: Del A376 affecting 12 rRNA; Del A1302 affecting 16s rRNA; Del A1394 affecting 16s rRNA; and Del A9725 affecting NADH3 (a protein of the electron transport chain). The authors investigated which tissues had variable mutant load, and found that mutant load is significantly reduced in diaphragm (4/4 mutants), muscle (3/4 mutants), brain (2/4 mutants) and fat (2/4 mutants). 
They then go on to correlate the variation with mtDNA copy number, across all tissues, and all generations. In one of the four cases, no correlation was observed. However, in Del A376 and Del 1302, variant load had a fairly strong negative correlation with mtDNA copy number; in Del 1394, the correlation was weaker and also negative.
The authors therefore suggest that mutant load is lowered in high-respiratory tissue, such as brain, diaphragm, muscle, liver, heart and fat.

Thoughts: Are these mutants deleterious to respiratory activity? I imagine so, since they are all deletion mutations, so cause frameshifts. If that is the case, I wonder if the mutations could be ranked by how much they inhibit OXPHOS? I wonder whether the strongest inhibitors either have i) the strongest gradient with mtDNA copy number or ii) lowest overall abundance in all tissues?

I also find it pretty surprising that frameshift mutations can be found in healthy pig tissues, even 2-15%. I wonder whether there is a complementation effect happening here: several different mutants producing transcription products that the others cannot?