November 18, 2008

Heterozygote Instability and Population-size dependent autosomal microsatellite mutation rate

From the paper:
Instead of population size interacting with a fixed mutation rate to determine an equilibrium heterozygosity, our analysis suggests that a feedback loop can operate causing heterozygosity to increase over time, each increase also increasing the mutation rate which in turn raises heterozygosity. Within this framework, changes in population size may act to modulate the rate of change of heterozygosity, with population expansion causing acceleration and population contraction causing a slowdown. For example, population decline erodes genetic variability through drift, reducing heterozygosity and hence potentially lowering the genome-wide mutation rate relative to a related population that has not declined.
Microsatellite mutations seem to occur more often if the two alleles (we're talking about autosomal microsatellites) differ in length. Thus, heterozygosity affects the mutation rate. Populations differ in their heterozygosity, hence their microsatellites evolve at different rates. Moreover, these rates fluctuate with population size. In a growing population, heterozygosity increases, while small populations tend to be more homozygous. Since mutation rates are used to infer the ages of population splits and other events, this has important implications about human history, although these are not exactly spelled out in the paper.

BMC Genetics 2008, 9:72doi:10.1186/1471-2156-9-72

Heterozygosity increases microsatellite mutation rate, linking it to demographic history

William Amos et al.

Abstract (provisional)


Biochemical experiments in yeast suggest a possible mechanism that would cause heterozygous sites to mutate faster than equivalent homozygous sites. If such a process operates, it could undermine a key assumption at the core of population genetic theory, namely that mutation rate and population size are indpendent, because population expansion would increase heterozygosity that in turn would increase mutation rate. Here we test this hypothesis using both direct counting of microsatellite mutations in human pedigrees and an analysis of the relationship between microsatellite length and patterns of demographically-induced variation in heterozygosity.


We find that microsatellite alleles of any given length are more likely to mutate when their homologue is unusually different in length. Furthermore, microsatellite lengths in human populations do not vary randomly, but instead exhibit highly predictable trends with both distance from Africa, a surrogate measure of genome-wide heterozygosity, and modern population size. This predictability remains even after statistically controlling for non-independence due to shared ancestry among populations.


Our results reveal patterns that are unexpected under classical population genetic theory, where no mechanism exists capable of linking allele length to extrinsic variables such as geography or population size. However, the predictability of microsatellite length is consistent with heterozygote instability and suggest that this has an important impact on microsatellite evolution. Whether similar processes impact on single nucleotide polymorphisms remains unclear.


1 comment:

terryt said...

Of course I find most of your posts interesting but this one is especially so. It means the genetic disadvantages through inbreeding are much greater even than we've imagined ("while small populations tend to be more homozygous").

As a bird and animal breeder I'm aware that inbreeding has a huge effect on economic productivity. However I've often heard breeders of ornamental birds maintain that inbreeding is not a problem. In fact I believe that inbreeding is an extremely important element in species' evolution (including the human species).