Inbreeding & harmful mutations

In the last study from my PhD, Spencer Barrett, Mathieu Siol and I provide evidence that, as theory would predict, highly inbreeding populations may suffer from the build-up of bad (or 'deleterious') mutations.

In this study we build on our previous work assembling all of the expressed genes in the neotropical plant Eichhornia paniculata to test some long standing and critically important predictions about the genetic consequences of inbreeding. Commonly held beliefs that inbred organisms are unhealthy have a clear basis in genetics. There are two main forces at work to reduce the viability of inbred populations.

The first is called 'inbreeding depression', which is the extent to which inbreds are worse-off compared to their outbred relatives. The most widely accepted theory for why this happens comes from the fact that many organisms  humans includes, have two copies of every gene. This is fortunate because there are broken copies of important genes floating around in populations at low levels. But because you have two copies of each gene, you probably have one good copy to make up for the bad one, and will never know you're carrying this deleterious gene. Generally, if you're dad isn't your brother, uncle or grandfather and your wife isn't your sister, mother and aunt you're unlikely to pass on the same bad genes as your mate, ensuring that your offspring will also have at least one good copy of every gene.

The second factor that is predicted to reduce the long term survival of inbred populations is the accumulation of deleterious mutations. TO explain this will require some population genetics, so bear with me. Most people know that evolution is driven my natural selection, but there is another lesser-known force called genetic drift. Unlike selection, which favours the best variants, genetic drift is totally random. A simple coin toss analogy can be made -- a coin should flip 50% heads and 50% tails but if you flipped a coin 10 times and got 6 heads and 4 tails, no one would be surprised. These little deviations from what we expect are called sampling error, and the more coin tosses we do the closer we expect the ratio of heads and tails to reflect the 50:50 balance of the coin. Genetic drift is caused by this same sampling error occuring when genes are passed from one generation to the next. Large populations have less sampling error and we therefore expect the frequencies of alleles in the offspring to reflect the frequencies in the parental generation, plus any natural selection that has occurred.  This is important because, although natural selection acts deterministically, genetic drift is random and can counteract the efforts of selection -- back to inbreeding. Inbred populations are more often small, and therefore suffer from greater genetic drift than larger outbreeding populations. As a result, the force of genetic drift in inbred populations can be so great that it counteracts natural selection. When natural selection is interfered with deleterious mutations may rise in frequency and wipeout the competition, a process known as 'fixation of deleterious mutations'.

The neotropical plant, Eichhornia paniculata, is interesting because some populations have an extreme form of inbreeding, known as self-fertilization. Because these plants are hermaphroditic they can fertilize themselves, ensuring reproduction even when mates or pollinators are scarce. Not all of the populations use this form of mating, but  genetic evidence suggests that some of these 'selfing' populations have been inbreeding for thousands of years. In effect, this is a natural experiment where some populations are selfing, and highly inbred while others are outbred. We predicted that if the theory  is true, the small inbred populations should have started to accumulate bad mutations because genetic drift overwhelmed natural selection.

To test this prediction we sequenced thousands of genes in two self-fertilizing and one outcrossing Epaniculata. We categorized changes into those which negatively impact the protein they encode. What we found was that the two self-fertilizing plants had a significantly higher fraction of these deleterious mutations than the outcrossing plant. This suggests that either these mutations are more common or have fixed in the selfing populations. We also found some evidence that the fine tuning of how proteins are encoded has begun to erode in inbred populations. Until  recently these forces have been very difficult to identify because there may only be a  few deleterious mutations that have arisen. As a result, we need huge numbers of genes to detect this pattern. With new DNA sequencing technologies we have started to uncover these subtle patterns in the genome. The accumulation of deleterious mutations may, in part, explain the relatively short time that self-fertilizing and inbred species tend to persist before extinction.