1. "In the case of a population in which, as in many civilized nations, the birth rate is held down to an average of not much more than two per family, the upper or critical mutation rate, that beyond which any equilibrium is impossible, must be much lower than 0.5 and, as we have seen, perhaps lower than 0.1, even if natural selection were, within the-limits set by these conditions, to be given full scope. Since however it is not being given anything like full scope at present, we are not maintaining equilibrium anyhow, and under these circumstances any increase in u1 will simply accelerate, to a corresponding degree, the decline that must already be going on.", H. J. Muller, Our Load of Mutations, The American Journal of Human Genetics, June 1950, p.155-156
  2. Even beneficial mutations combine to cause problems: Negative Epistasis Between Beneficial Mutations in an Evolving Bacterial Population, Science, 2011. From the ScienceDaily's summary: "It was found that the beneficial mutations allowing the bacteria to increase in fitness didn't have a constant effect. The effect of their interactions depended on the presence of other mutations, which turned out to be overwhelmingly negative. 'These results point us toward expecting to see the rate of a population's fitness declining over time even with the continual addition of new beneficial mutations,' he said. 'As we sometimes see in sports, a group of individual stars doesn't necessarily make a great team.'". Also summarized in Mutations : when benefits level off, "Beneficial mutations within a bacterial population accumulate during evolution, but performance tends to reach a plateau. Consequently, theoretical evolutionary models need to take into account a 'braking effect' in expected benefits on the survival and the reproduction of organisms. ... They then noted that the benefit linked to the simultaneous presence of five mutations was less than the sum of the individual benefits conferred by each mutation individually."
  3. "the magic number appears to be 6 mutations per genome per generation -- a level beyond which species run the strong risk of extinction as their genomes lose stability.", ScienceDaily, Beyond A 'Speed Limit' On Mutations, Species Risk Extinction, Oct 1, 2007
  4. "It establishes a universal speed limit on rate of molecular evolution by predicting that populations go extinct (via lethal mutagenesis) when mutation rate exceeds approximately six mutations per essential part of genome per replication for mesophilic organisms", Konstantin B. Zeldovich et al, Protein stability imposes limits on organism complexity and speed of molecular evolution, PNAS, August 2007
  5. "each child inherits somewhere in the neighborhood of 30 to 50 new mutations.", ScienceNews, Human mutation rate slower than thought, June 2011
  6. "we identified 49 and 35 germline de novo mutations", Variation in genome-wide mutation rates within and between human families, Donald F Conrad et al., Nature Genetics, June 2011
  7. "the vast majority of the 3 billion 'letters' of the human genetic code are busily toiling at an array of previously invisible tasks.", Washington Post, Intricate Toiling Found In Nooks of DNA Once Believed to Stand Idle, June 2007
  8. "This new map reveals almost 3 million previously undetectable elements in non-coding regions that have been carefully preserved across all mammals, and whose disruptions appear to be associated with human disease.", Dark matter of the genome revealed through analysis of 29 mammals, October 2011
  9. "the combined deleterious effects of mutations were, on average, larger than expected from the multiplication of their individual effects. As observed in computational systems, negative epistasis was tightly associated with higher tolerance to mutations", S Bershtein et al., Robustness-epistasis link shapes the fitness landscape of a randomly drifting protein, Nature, November 2006
  10. "Our numerical simulations consistently show that deleterious mutations accumulate linearly across a large portion of the relevant parameter space. This appears to be primarily due to the predominance of nearly-neutral mutations. The problem of mutation accumulation becomes severe when mutation rates are high. Numerical simulations strongly support earlier theoretical and mathematical studies indicating that human mutation accumulation is a serious concern. Our simulations indicate that reduction of mutation rate is the most effective means for addressing this problem.", and "However, over long periods of time, even with intense selection, a significant number of deleterious mutations consistently become fixed.", and "The relentless accumulation of deleterious mutations is primarily due to the existence of un-selectable “nearlyneutral” mutations, but the genetic load problem is greatly amplified when mutation rates are high.Intensified natural selection only marginally slows the accumulation of deleterious mutations.", John Sanford, et al., Using computer Simulation to Understand Mutation Accumulation Dynamics and Genetic Load, Computational Science, 2007
  11. "The high deleterious mutation rate in humans presents a paradox. If mutations interact multiplicatively, the genetic load associated with such a high U would be intolerable in species with a low rate of reproduction", Michael W. Nachman & Susan L. Crowell, Estimate of the Mutation Rate per Nucleotide in Humans, Genetics, Sep 2000.
  12. "If substitutions at 10% of all nucleotide sites have selection coefficients within this range with the mean 10 , an average individual carries ~ 100 lethal equivalents.", A.S. Kondrashov, Contamination of the genome by very slightly deleterious mutations: why have we not died 100 times over?, 1995
  13. "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.", and "Possible solutions to this problem, including multigenerational cryogenic storage and utilization of gametes and/or embryos, will raise significant ethical conflicts between short-term and long-term considerations.", and "per-generation reduction in fitness due to recurrent mutation is at least 1% in humans and quite possibly as high as 5%", and "1–50-bp deletions are approximately three times as common as insertions of the same size", Michael Lynch, Rate, molecular spectrum, and consequences of human mutation, PNAS, Dec. 2009
  14. "Since most mutations, if they have any effect at all, are harmful, the overall impact of the mutation process must be deleterious." and "If war or famine force our descendants to return to a stone-age life they will have to contend with all the problems that their stone-age ancestors had plus mutations that have accumulated in the meantime.", James F. Crow, The high spontaneous mutation rate: Is it a health risk?, PNAS, 1997
  15. "Each one of us receives approximately 60 new mutations in our genome from our parents.", Science Daily,We Are All Mutants: First Direct Whole-Genome Measure of Human Mutation Predicts 60 New Mutations in Each of Us, 2011
  16. Francis Collins is head of the NIH, and formerly head of the human genome project. He has departed from his previous position on junk DNA from 4 years earlier: "The discoveries of the past decade, little known to most of the public, have completely overturned much of what used to be taught in high school biology. If you thought the DNA molecule comprised thousands of genes but far more 'junk DNA', think again.", and "The exons and introns of protein-coding genes add up together to about 30 percent of the genome. Of that 30 percent, 1.5 percent are coding exons and 28.5 percent are removable introns. What about the rest? It appears there are also long 'spacer' segments of DNA that lie between genes and that don't crowd for protein. In some instances, these regions extend across hundreds of thousands or even millions of base pairs, in which case they are referred to rather dismissively as 'gene deserts.' These regions are not just filler, however. They contain many of the signals that are needed to instruct a nearby gene about whether it should be on or off at a given developmental time in a given tissue. Furthermore, we are learning that there may be thousands of genes hanging out in these so-called deserts that don't code for protein at all. They are copied into RNA, but those RNA molecules are never translated--instead, they serve some other important functions.", and "It turns out that only about 1.5 percent of the human genome is involved in coding for protein. But that doesn't mean the rest is "junk DNA." A number of exciting new discoveries about the human genome should remind us not to become complacent in our understanding of this marvelous instruction book. For instance, it has recently become clear that there is a whole family of RNA molecules that do not code for protein. These so-called non-coding RNAs are capable of carrying out a host of important functions, including modifying the efficiency by which other RNAs are translated. In addition, our understanding of how genes are regulated is undergoing dramatic revision, as the signals embedded in the DNA molecule and the proteins that bind to them are rapidly being elucidated. The complexity of this network of regulatory information is truly mind-blowing, and has given rise to a whole new branch of biomedical research, sometimes referred to as 'systems biology.'" Francis Collins, The Language of Life: DNA and the Revolution in Personalized Medicine, p. 5-6, 9 293, 2010
  17. The reduction in fitness (i.e., the genetic load) due to deleterious mutations with multiplicative effects is given by 1 - e-U Kimura and Maruyama 1966. For U=3, the average fitness is reduced to 0.05, or put differently, each female would need to produce 40 offspring for 2 to survive and maintain the population at constant size. This assumes that all mortality is due to selection and so the actual number of offspring required to maintain a constant population size is probably higher. With U=30 (the lower bound of human mutation), 1013 offspring are needed per female to prevent degeneration.
  18. Geneticist James F. Crow: "Every deleterious mutation must eventually be eliminated from the population by premature death or reduced relative reproductive success, a 'genetic death'. That implies three genetic deaths per person! Why aren't we extinct?", Under the junk DNA view that dominated in 1999 when Crow wrote, he reasoned strong selection was enough to overcome it. Interestingly, he also speculates, "Are some of our headaches, stomach upsets, weak eyesight and other ailments the result of mutation accumulation? Probably, but in our present state of knowledge, we can only speculate." The odds of losing at genetic roulette, Nature, 1999
  19. "This new map reveals almost 3 million previously undetectable elements in non-coding regions carefully preserved across all mammals, whose disruptions appear to be associated with human disease.", "The scientists were able to suggest possible functions for more than half of the 360 million DNA letters contained in the conserved elements" Dark matter of the genome revealed through analysis of 29 mammals, Oct 2011