Rate, molecular spectrum, and consequences of human mutation

Abstract

Although mutation provides the fuel for phenotypic evolution, it also imposes a substantial burden on fitness through the production of predominantly deleterious alleles, a matter of concern from a human-health perspective. Here, recently established databases on de novo mutations for monogenic disorders are used to estimate the rate and molecular spectrum of spontaneously arising mutations and to derive a number of inferences with respect to eukaryotic genome evolution. Although the human per-generation mutation rate is exceptionally high, on a per-cell division basis, the human germline mutation rate is lower than that recorded for any other species. Comparison with data from other species demonstrates a universal mutational bias toward A/T composition, and leads to the hypothesis that genome-wide nucleotide composition generally evolves to the point at which the power of selection in favor of G/C is approximately balanced by the power of random genetic drift, such that variation in equilibrium genome-wide nucleotide composition is largely defined by variation in mutation biases. Quantification of the hazards associated with introns reveals that mutations at key splice-site residues are a major source of human mortality. Finally, a consideration of the long-term consequences of current human behavior for deleterious-mutation accumulation leads to the conclusion that a substantial reduction in human fitness can be expected over the next few centuries in industrialized societies unless novel means of genetic intervention are developed.

Fig. 1.

The size-frequency spectrum of insertion and deletion mutations in human genes, summed over autosomal-dominant and X-linked genes. The scaling of frequency (f) with length of the mutation (L) is f = 0.56L^−1.82 (r² = 0.957) and f = 0.67L^−1.82 (r² = 0.973) for insertions and deletions, respectively. These regressions exclude the plotted data points for mutations with size changes that are multiples of 3, which leave the reading frame intact and in some cases have minimal phenotypic effects (and therefore go undetected), and also only employ mutations in size classes up to L = 20, beyond which sample sizes are very small and sporadic. For the latter reason, the data beyond L = 10 are also pooled into windows of three base sizes and divided by 3 to retain the appropriate scale.

Fig. 2.

The cost of introns in human genes in units of the cost of coding nucleotides. The solid diagonal line denotes the average ratio of the values on the vertical and horizontal axes, 30.8. The dashed lines, for reference, denote ratios of 10 (lower) and 100 (upper). Thus, the mutational cost of an intron in a typical human gene is equivalent to adding 30.8 coding nucleotides, and for the vast majority of loci this cost falls within the range of 10 to 100.