The low frequency of recessive disease: insights from ENU mutagenesis, severity of disease phenotype, GWAS associations, and demography: an analytical review.

A survey of a select panel of 14 genetic diseases with mixed inheritance confirms that, while autosomal recessive (AR) disease genes are more numerous than autosomal dominant (AD) or X-linked (XL) ones, they make a smaller average contribution to disease. Data collected from N-ethyl-N-nitrosourea (ENU) mutagenesis studies show a similar excess of AR mutations. The smaller AR contribution may partially reflect disease severity, but only in the comparison of AR with AD mutations. On the contrary, XL mutations for the 14 diseases are generally more severe. Genome-wide associations studies (GWAS) data provide fresh insight into the shortage, with a limited negative selection effect mediated by the pleiotropic expression of recessive disease genes in other deleterious phenotypes. Genomic data provide further evidence of purging selection in a past European population bottleneck followed by a dramatic population explosion, now more clearly associated with past climate change. We consider these likely to be the main factors responsible for the low AR to AD/XL inheritance ratio.