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Evolution@home predicts Muller's ratchet in human mtDNA

Today the first biological results paper of evolution@home was published in Genetical Research by Cambridge University Press. It analyses deleterious mutation accumulation from Muller's ratchet in human mitochondrial DNA, a vital part of mankind's genetic makeup.

Mitochondria are our power plants ...

Mitochondria are tiny parts of a cell that act like power plants to supply every cell in the body with life-giving energy. They come with their own densely packed genome and nature goes a long way to ensure that its vital information is transmitted as error-free as possible from one generation to another.
This is more complicated than with normal genes, because mitochondria in humans reproduce asexually and it is not clear whether there are even rare exceptions to this rule in the human germ line. Asexual reproduction means in this case that the mitochondrial DNA (mtDNA) of a child comes only from the mother and does not contain contributions from the father as well, which would allow harmful mutations in either contributions to be repaired by the other. Before we inherit our mtDNA, very strict quality controls ensure that only the very best mitochondria make it into the next generation.

... but not immune to failures in their molecular machinery.

However, sometimes a harmful DNA change still makes it into the next generation. The rate at which this occurs can be observed by comparing sequences in known pedigrees and is in rough agreement with estimates from population genetical methods. Newer methods even allowed obtaining rough estimates of the sizes of the effects on fitness that these deleterious mutations have.
If these estimates are combined with the known effective population size of humans, then the so called theory of Muller's ratchet should tell us how many generations it takes on average until a harmful mutation is irreversibly fixed in the whole population. However, Muller's ratchet is a hard nut to crack: while it is simple to explain as a mathematical problem, it turns out to be extremely hard to solve.

evolution@home predicts harmful mutation accumulation

In the first computing project of evolution@home I used globally distributed computing over the Internet to solve the problem by simulation for the case of human mitochondrial DNA. I compiled the most credible values for mutation rate, mutational effects and population size to predict the rate of accumulation of harmful mutations in the human population. Combining these predictions with a multiplicative fitness model allows predicting rough estimates of extinction times for the human evolutionary line.
The results come as a surprise to conventional wisdom. As reported in "Genetical Research", some biologically realistic combinations of mutation rates and effects suggest that the human line should have gone extinct within the last 20 million years, if our current best estimates apply to the past as well. This apparent genomic decay paradox calls for further investigations and mtDNA is by no means the only system where biologists have encountered it. Future research will have to look carefully at the various potential solutions to the genomic decay paradox to help us understand what is really going on. High on this list of potential solutions that should be checked are back mutations and inhomogeneities in the mutation rate that may result in even more back mutations. Extremely rare recombination events that might have escaped the scrutiny of the scientific community so far will also have to be considered. These issues will have to be addressed eventually with new simulators for evolution@home and other research.

Practical implications

The new research has some practical implications as well. It documents the enormous influence of the mutation rate on the rate of accumulation of harmful mutations. This implies that everything that increases mutation rates will also increase the accumulation of mitochondrial genetic diseases up to the point where infertility endangers human survival. The easiest way to escape these dangers is to keep the mutation rate as low as possible. Even the most optimistic scenarios of future medical biotechnology are not likely to reverse the damage that is constantly being done by mutagenic pollution and other human activities that lead to an increase in mutation rates above normal levels. There are many reasons why we should reduce man-made increases of mutation rates to a minimum, including cancer and Mendelian genetic diseases, like cystic fibrosis. The long-term perspectives just add to the incentive to act.


Apologies for the delay in the publication of this entry (technical reasons).

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