Department of Biology, Indiana University, Bloomington, IN 47405, USA.
Proc Natl Acad Sci U S A. 2010 Jan 19;107(3):961-8. doi: 10.1073/pnas.0912629107. Epub 2010 Jan 4.
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.
虽然突变提供了表型进化的燃料,但它也通过产生主要是有害等位基因对适应性造成了巨大负担,这是从人类健康角度出发值得关注的问题。在这里,新建立的用于单基因疾病的新生突变数据库被用于估计自发突变的速率和分子谱,并对真核基因组进化得出一些推论。尽管人类每代的突变率非常高,但在每个细胞分裂的基础上,人类生殖系的突变率低于其他任何物种记录的突变率。与其他物种的数据进行比较表明,存在普遍的偏向 A/T 组成的突变偏向,这导致了这样一种假设,即全基因组核苷酸组成通常进化到有利于 G/C 的选择力与随机遗传漂变的力大致平衡的程度,使得平衡全基因组核苷酸组成的变化主要由突变偏向的变化来定义。对与内含子相关的危险的量化揭示出,关键剪接位点残基的突变是人类死亡的主要原因。最后,考虑到当前人类行为对有害突变积累的长期后果,除非开发出新的遗传干预手段,否则在未来几个世纪内,工业化社会的人类适应性将大幅下降。