Fitness effects of mutations in humans

I'm not at all familiar with the methods in this paper, but the conclusion sounds interesting, namely that "it will be difficult to locate the majority of mutations involved in genetic disease unless the disease is completely un-associated with fitness, or some of the mutations have been subject to positive selection."

The Distribution of Fitness Effects of New Deleterious Amino Acid Mutations in Humans
Adam Eyre-Walker, Meg Woolfit, Ted Phelps

Genetics, March 17, 2006, Epub ahead of print.

Abstract: The distribution of fitness effects of new mutations is a fundamental parameter in genetics. Here we present a new method by which the distribution can be estimated. The method is fairly robust to changes in population size and admixture, and it can be corrected for any residual effects if a model of the demography is available . We apply the method to extensively sampled single nucleotide polymorphism data from humans and estimate the distribution of fitness effects for amino acid changing mutations. We show that a gamma distribution with a shape parameter of 0.23 provides a good fit to the data and we estimate that more than 50% of mutations are likely to have mild effects, such that they reduce fitness by between 1/1000 and 1/10. We also infer that fewer than 15% of new mutations are likely to have strongly deleterious effects. We estimate that on average a non-synonymous mutation reduces fitness by ~4.3% and that the average strength of selection acting against a non-synonymous polymorphism is ~9 x 10-5. We argue that the relaxation of natural selection due to modern medicine and reduced variance in family size is not likely to lead to a rapid decline in genetic quality, but that it will be very difficult to locate most of the genes involved in complex genetic diseases.