All organisms suffer from mutation and at least some of those mutations are harmful. We have been interested in estimating the rate at which harmful mutations occur, how harmful they are and what they do to us. We showed many years ago that humans have a surprisingly high rate of harmful mutation – each of us receives at least two new harmful mutations from our parents (Eyre-Walker and Keightley 1999; Lecesque, et al. 2012). These harmful mutations mean that some individuals die or fail to reproduce. Puzzlingly initial calculations suggested that these harmful mutations would cause 88% of the population to fail to reproduce, and that each female would therefore have to have more than 16 offspring. Clearly humans do not have that level of reproductive excess. We have recently shown however, that this “load” can be significantly reduced if selection acts via competition (Lecesque, et al. 2012).

We have also developed methods to estimate how harmful mutations are (Eyre-Walker, et al. 2006; Keightley and Eyre-Walker 2007). Estimates vary between species, but it is evident that all humans carry around a large number of mildly harmful mutations. These may contribute to diseases with a strong genetic basis, such as heart disease, type II diabetes and schizophrenia. These diseases are caused both by “bad” genes and the environment. A central question is whether most of the genetic variation underlying these traits are common variants with small effects, or rare mutations with large effects. Using population genetic theory we have shown that we might expect most variation to be rare (Eyre-Walker 2010). However, genome wide association studies suggest a mixed picture in which both common and rare mutations contribute to disease. What this tells us about the nature of selection upon these traits is unclear at the moment.

Eyre-Walker A 2010. Genetic architecture of a complex trait and its implications for fitness and genome-wide association studies. Proceedings of the National Academy of Sciences of the United States of America 107 Suppl 1: 1752-1756. doi: 10.1073/pnas.0906182107

Eyre-Walker A, Keightley PD 1999. High genomic deleterious mutation rates in hominids. Nature 397: 344-347.

Eyre-Walker A, Woolfit M, Phelps T 2006. The distribution of fitness effects of new deleterious amino acid mutations in humans. Genetics 173: 891-900.

Keightley PD, Eyre-Walker A 2007. Joint inference of the distribution of fitness effects of deleterious mutations and population demography based on nucleotide polymrophism frequencies. Genetics 177: 1-11.

Lecesque Y, Keightley PD, Eyre-Walker A 2012. A resolution of the mutation load paradox in humans. Genetics 191: 1321-1330.