Biparental Inheritance of Mitochondrial DNA


The general rule of mitochondrial inheritance is:

‘ 37 genes mitochondrial DNA of maternal origin’

Nothing more and nothing less. What would we do without it? This well-supported assumption about mitochondrial inheritance has formed the frameworks for decades of calculations that then went on to inform the bulk of modern ancestral analyses. Recognised as one of the most reliable methods for understanding phylogeny, due to its reliable and slow rate of mutation, small changes in mitochondrial DNA among isolated groups signposted the split from a mother and thus revealed details on evolutionary origins and likely historical migration patterns.

Though, in the same way that the organisms we study themselves evolve, our understanding is once more on the brink of a revolution.

Beliefs in the background

In 2002, danish researchers challenged this widely-held understanding after studying a male patient whose DNA was sequenced in the hopes of finding the origins of his mitochondrial disorder. To the researcher’s surprise, the 37 mitochondrial genes were in no way maternal in origin. His mtDNA sequence appeared to be of purely parental origin. Verified by independent researchers at Harvard University, this groundbreaking finding sparked an international debate over the existence of recombinant mitochondrial DNA.

However since, then, despite an exhaustive search for new subjects, no new cases have emerged for study. The controversy circulating the possibility of biparental inheritance of mtDNA remained a debate within highly specialized circles.

The Recombinant mtDNA Discovery

Fast forward, however, to last thursday. On October 29th 2018, a group of international researchers, working in the Children’s Hospital of Philadelphia and the University of Philadelphia, published in the journal PNAS, compelling evidence for the transmission of paternal mitochondrial DNA (mtDNA) in humans after sequencing the mtDNA of a four year old patient who suffered from a mitochondrial disorder.

After sequencing his genome as well as those of his close female relatives, researchers found he had a highly peculiar pattern of mutant genes. Upon further analysis, the peculiar pattern was found predictably congruent to that of his mother and sister, neither of whom had his mitochondrial disorder. Though origins of his disorder remained unidentified, his mtDNA pattern was so peculiar, researchers went on to test the patient’s grandparents too.

An unexpected discovery was found: his mother’s mutation pattern matched only certain regions of his grandmother’s mitochondrial sequence, whereas others were traced to that of the boy’s grandfather. Further sequencing of his grandfather’s female relatives revealed that he too inherited a recombinant pattern of similarly biparental origin.

The study then progressed. mtDNA samples were taken from multiple members of two other unrelated multigenerational families who were suspected to have mitochondrial disorders. Astonishingly, similarly recombinant mtDNA patterns were revealed even after genome sequences were sequenced in other laboratories for verification.


So what is the mechanism for biparental mtDNA?

The international research team at philadelphia already have an hypothesis. At first, both gametes contribute mitochondrial DNA to a developing foetus, but once fertilization is complete, a mitochondrial-killing mechanism is activated. This mechanism theoretically destroys any traces of paternal mtDNA. The Philadelphian researchers believe that a mutation in nuclear gene inhibits the killing mechanism and results in recombinant mtDNA in offspring. The mutation of the nuclear gene appears to be inherited and expressed in an autosomal dominant.

What does this mean for humanity?

Though the setbacks caused by this discovery are obvious (i.e. the decades worth of what was previously considered as well-supported hypotheses may now have to be re-investigated), the potential positive implications are astounding. A more accurate and advanced model of mechanisms governing mitochondrial inheritance could potentially lead to a novel field of mitochondrial medicine, and solutions for the mitochondrial disorders that have puzzled us for decades.

Thanks for reading!

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