mutation

Lynch M 2016 Mutation and human exceptionalism: our future genetic load. Genetics 202:869-875.

• the human germline mutation rate is higher than that in any other well-studied species
• human somatic mutation rates are substantially elevated above those in the germline
• this is also seen in other species
• what is exceptional about humans is the recent detachment from the challenges of the natural environment and the ability to modify phenotypic traits in ways that mitigate the fitness effects of mutations
• this results in a relaxation of selection against mildly deleterious mutations, including those magnifying the mutation rate itself
• the long-term consequence of such effects is an expected genetic deterioration in the baseline human condition
• because the brain is a particularly large mutational target, this is of particular concern
• the price will have to be covered by further investment in various forms of medical intervention

• the average human mutation rate is in the range of 1.1–1.7 × 10⁻⁸ per nucleotide site per generation for base-substitution mutations alone
• the mutation rate to small insertion/deletions is ~ 8% of the base-substitution rate
• large structural changes (involving mobile-element insertions and interchromosomal exchanges) arise at a rate of ~ 0.08 per haploid genome per generation
• an average newborn contains ~ 100 de novo mutations

• the mutation rate per generation increases by a factor of 2 between males of age 20 and 40 years
• a convincing example of variation in the human mutation rate on a large geographic scale is a 1.6-fold increase in the incidence of one particular point-mutation type in Europeans relative to African and Asian populations
• the contribution of environmental differences to this effect is unknown

• despite 3 billion years of natural selection, in no known organism has the base-substitution mutation rate evolved to < 10⁻¹¹ per nucleotide site per cell division

• Tomasetti and Vogelstein (2015) argued that the majority of cancers are unavoidable consequences of the stochastic arrival of background replication errors in normal, otherwise healthy cells (rather than responses to exogenous and avoidable carcinogenic factors)
• Tomasetti and Vogelstein's conclusion that most cancers are unpredictable (and therefore unpreventable) elicited considerable controversy

• we know little to nothing about the effects on DNA stability at the nucleotide level in eukaryotic host cells

• in all organisms, the majority of mutations with effects on fitness reduce viability/fecundity by something on the order of 1% per mutation
• this class is thought to constitute 1–10% of all human mutations, the remainder being essentially neutral
• taking the lower end of the latter range suggests that the recurrent load of mutations imposed on the human population drags fitness down by ~ 100 × 0.01 × 1% = 1% per generation, more so if the fraction of deleterious mutations exceeds 0.01 or if the environment is mutagenic, and less so if the average fitness effect of a mutation were to be < 1%
• a less conservative calculation suggests that the recurrent load could be as high as 5% per generation

• human brain function is governed by the expression of thousands of genes
• the germline mutation rate to psychological disorders may be unusually high
• at least 30% of individuals with autism spectrum disorders appear to acquire such behaviors by de novo mutation
• notably, human brain cells also incur up to dozens of mobile-element insertions per cell

• there has been a slow decline in intelligence in the United States and the United Kingdom over the past century
• again the underlying issues with respect to environmental factors have not been fully resolved