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 splicesite 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.base substitutions | human genetic disorders | introns | mutation rate | mutational spectrum D espite its central significance to matters of health and phenotypic evolution, many uncertainties still remain about the rate and spectrum of mutations spontaneously arising in the human genome (1-3). How frequently do germline and somatic mutations arise, and to what extent does this vary between the sexes? What is the relative incidence of various forms of mutations, e.g., missense and nonsense base substitutions, insertions, duplications, and deletions, especially among alterations having major phenotypic effects? How does the mutational spectrum in humans compare with that in other species? And most importantly, what are the consequences of mutation for the long-term genetic well-being of our species?In the near future, it should be possible to provide refined answers to these and many more questions by sequencing the complete genomes of well defined pedigrees and somatic tissues (4, 5). However, it is already possible to achieve a relatively complete picture of the point-mutation process from databases on mutations at loci known to underlie monogenic disorders with major phenotypic effects. In the case of autosomal-dominant and X-linked disorders, affected individuals can generally be identified as de novo mutants by comparison with the parental phenotypes, thereby providing a nearly unbiased view of the rate and spectrum of locus-specific mutations, similar to what has been achieved ...

DNA replication timing and selection shape the landscape of nucleotide variation in cancer genomes

“…First, there are likely to be additional layers of repair mechanisms in germ cells, which would buffer replication timingdependent accumulation of mutations. Supporting this, germ-line mutation rates are known to be lower than somatic mutation rates 16 . The exact mechanism would become clear with advances in our understanding of the DNA repair in germ and somatic cells.…”

“…Furthermore, somatic mutations would be restricted to the progeny of the mutated cells, but germ-line mutations would be propagated to all cells in an organism, increasing the chance of exerting deleterious effects in some cell types. The observation that the somatic mutation rate per generation is higher than the germ-line mutation rate 16 raises an interesting notion that multicellular organisms have evolved to optimize somatic and germ-line mutation rates, so that an organism can keep individual cells viable during its lifetime while passing sufficiently intact genetic information to its offspring.…”

“…The evolutionary framework has improved our understanding of the genetic basis of cancer [13][14][15] . Although the somatic evolution of cancer cells is reminiscent of the evolution of organisms, the two differ in many ways, such as timescale, effective population size, mutation rate, and outcome of the evolution 15,16 . Understanding differences between the two can improve our understanding of the genetic basis of cancer.…”

Rate and molecular spectrum of spontaneous mutations in the bacteriumEscherichia colias determined by whole-genome sequencing

“…Our data confirm and extend these results to the entire genome. Mutational data from a variety of sources have confirmed that in almost all organisms spontaneous mutations are dominated by G:C > A:T transitions, a bias that tends to drive genomes toward greater A:T content (28). However, the G:C content of genomes varies widely, so some selective pressure or nonadaptive mechanism must drive genomes back toward G:C-richness.…”

Longer time scale for human evolution

“…This procedure allows very precise estimates, but introduces systematic bias toward higher substitution rates and longer branch lengths because a new lineage can leave a fossil record only after its origin, never beforehand (1). Now, widespread resequencing, initially of de novo Mendelian genetic disorders (2,3) and later of whole genomes in parent-offspring trios (4), has allowed direct comparisons of parent and offspring genomes. The most commonly used, but now outdated, estimate of the mutation rate was 2.4 × 10 −8 changes per nucleotide per generation (5).…”