Are mutations truly random?

Do genetic mutations really occur at random spots along the genome, as researchers have long supposed? Maybe not, according to a study published online today (January 13) in Proceedings of the Royal Society B, which proposes a mechanism for how new mutations might preferentially form around existing ones. Image: Wikimedia commons, Jerome Walker, Dennis Myts"The idea is quite interesting,"

By | January 13, 2010

Do genetic mutations really occur at random spots along the genome, as researchers have long supposed? Maybe not, according to a study published online today (January 13) in Proceedings of the Royal Society B, which proposes a mechanism for how new mutations might preferentially form around existing ones.
Image: Wikimedia commons,
Jerome Walker, Dennis Myts
"The idea is quite interesting," said evolutionary geneticist linkurl:Maud Tenaillon; of the University of California, Irvine, who was not involved in the research. "I think it could be a good explanation for [mutational] hotspots." But, she cautioned, the support for this hypothesis so far falls solely on a somewhat incomplete theoretical model. Single nucleotide polymorphisms (SNPs) exist in clusters of varying size and density across the genome. Despite this non-random distribution, scientists believed for many years that these so-called mutational hotspots were the product of natural selection and other post-mutational processes, and that the mutations occurred at random. However, "in last two decades, the large amount of both genomic and polymorphic data has changed the way of thinking in the field," Dacheng Tian of linkurl:Nanjing University; in China, who did not participate in the work, wrote in an email to The Scientist. "[This] idea provides a self-increasing hypothesis, which may be useful to rethink the formation of such non-randomness." In the Royal Society study, evolutionary geneticist linkurl:William Amos; of Cambridge University suggested one of the first mechanisms by which mutations may occur non-randomly. In this theoretical paper, Amos proposed that SNPs may form more commonly around pre-existing mutations as a result of a DNA repair system. When the repair system encounters a mismatch in the genome, which may occur at heterozygous regions where SNPs already exist, the repair machinery rips up the mistake and relays the DNA to correct it. Because mutations can occur when DNA replicates, the extra rounds of DNA replication associated with the DNA repair system could potentially cause mutations to cluster. Using SNP data from the HapMap website for human chromosome 1, Amos calculated the average size and density of existing mutational clusters. He then ran simulations under the assumption of either this new, non-random mechanism of mutation formation or that of randomly occurring mutations. He found that the non-random model more closely predicted the frequency and density of the mutational clusters on the chromosome. "My theory is going to shake things up majorly," Amos said. "The concept of non-independent mutations simply wasn't thought of before -- this is completely new and it really changes how we think of DNA evolving." One interesting implication of this mechanism of SNP formation is that "it attracts mutations to where polymorphisms already exists, where it is likely to be tolerated [or even] beneficial," and vice versa, Amos said. "If you bias the mutations that do occur to where other mutations [already exist], you're more likely to do good than" if mutations occurred randomly. This mechanism, Amos added, may thus provide a way for the genome to reduce the overall number of deleterious mutations that occur. While the idea is interesting and "it may be true," Tenaillon said, "I'm not convinced." There are several factors known to contribute to the non-random distribution of SNPs that Amos did not include in his simplified model, such as natural selection and demography. The HapMap data Amos used, for example, come from a European population, which is widely believed to have undergone a major bottleneck about 30,000 years ago, Tenaillon said. Such a bottleneck can significantly alter the SNP distribution, causing enormous increases in the numbers of SNPs in certain areas of the genome, she explained. Furthermore, this data set included both coding and noncoding regions, which are known to vary in the density of mutations since natural selection acts more potently on coding regions. "It's not easy to discriminate between all these mechanisms," Tenaillon said. "It would have been nice if they could have taken into account all the things we know can create mutational hotspots and show that [the] effect [of self-perpetuating SNP formation] was [still] significant." More rigorously testing this hypothesis could include creating a more comprehensive theoretical model, as well as using genomic data from noncoding regions only and from a more "worldwide" population, she said. Still, the idea warrants further exploration, Tenaillon added. "It's nice to have a paper where you have an idea it gives you material to discuss something," she said. "It's an interesting [concept] to test." Clarification: In the original version of this story, a quote from Amos could have been misinterpreted to mean that mutations occurring under the proposed nonrandom mechanism were more likely to be beneficial than deleterious. Rather, the chance of being beneficial will be higher under this mechanism than if mutations occurred randomly.
**__Related stories:__***linkurl:Phase I of HapMap Complete;
[26th October 2005]*linkurl:Whole-Genome SNP Genotyping;
[2nd June 2003]*linkurl:SNPs as Windows on Evolution;
[7th January 2002]


Avatar of: ROBERT Fowler


Posts: 15

January 13, 2010

It has been known for decades in bacteria and phage that mutations can occur in clusters and in hotspots that occur in particular sequence contexts. We have not always understood the molecular explanations for why hotspots occur where they do but several hypotheses have been offered.\n\nWhat is usually meant by randomness with respect to mutagenesis is that mutations occur without regard to their immediate adaptive value. Their location and frequency has been long known to be nonrandom.

January 13, 2010

It is really not easy to believe that mutations are not random. We all know that usually mutations are there and once the specific stress develops, then the mutation makes the individual better fit to survive or less fit depending upon the consequences of the mutation. To think in not randomness implies that mutations is being designed by the genome and I do not believe that is true, although it will be nice a mechanism able to design mutations in a specifi way.
Avatar of: Mike Brennan

Mike Brennan

Posts: 11

January 13, 2010

It is entirely possible for mutations to occur more often at certain places at a chromosome level, but cause non-related changes in traits in the organism. One mutation could, for example, cause a change in eye color, and another mutation at the same "hotspot" could cause a change in the absorbtion of a certain sugar. These would be random from the whol organism point of vier.


Posts: 10

January 14, 2010

Does the local secondary structure of the DNA strand play any role in the fidelity of its replication by the polymerase? How would this impact on clustering of mutations?
Avatar of: anonymous poster

anonymous poster

Posts: 1

January 14, 2010

This is actually not a question now. There have been a number of research publications to reveal that mutations are not random but preferential. Inside DNA, strengths of chemical bonds and atomic binding are not equal at not and some are more vulnerable than others. This is the basic reason for nonrandom mutations.
Avatar of: Antoine Danchin

Antoine Danchin

Posts: 5

January 14, 2010

Apparently, memory fades away extremely rapidly, especially when media communication takes the place of science. Do you remember the definition of what a cistron is? Do you remember Seymour Benzer? Well, in his demonstration of the nature of gene organisation in bacteria he accumulated mutations, and mapped them precisely (in the lysogenic lambda rex genes, which confer resistance of the host cells to T-even virulent phages). He clearly observed big clusters, with hot spots (the term remains).\n\nSubsequently it was found in a wealth of studies that mutations were never uniformly distributed. This is to be expected in a random process anyway, but the very process of creation of mutations is not random, as the physics of DNA and all its wielding processes differ considerably with each other. When the double helix is opened, the local mutation rate increases considerably (and this is why there exists often a repair system associated to the transcription machinery). Mutations are more frequent as the replication fork moves, and this is the basis for a use of nitrosoguanidine mutagenesis, where investigators purposedly accumulated mutations at a given locus. Mismatch repair systems tend to be associated to particular subtypes of mutations, etc etc. Alteration of the methylation capacity of the cell (which can be caused by metabolic alterations) results in clusters of mutations (this is visible around the dam methylation sites in E. coli). And the list can be extended at will.\n\nThe important point is not that mutations are clustered, but that they are not directed. Please do not invent novelty when it is not there!
Avatar of: Arlin Stoltzfus

Arlin Stoltzfus

Posts: 1

January 14, 2010

Several people have pointed out that the finding that mutation is not "random" is not new. Antoine Danchin pointed out that "hotspots" were clearly apparent in Benzer's work (1). \n\nAnother classic work is Drake's 1970 book "The Molecular Basis of Mutation" (2). Table 1 of this book shows literally 7 orders of magnitude difference in the rates of specific point mutations in the same genome. \n\nThose publications take us back 40 or 50 years, but the finding of non-random mutation goes back even further and is referenced in works of Morgan and Muller. \n\nThus, a more interesting issue for discussion is "why does the non-randomness of mutation keep getting ignored?". \n\nBarbara McClintock's findings about transposable elements were ignored for decades. This was not because her work was suppressed or that she was dismissed for being a woman, as some misguided feminists have argued. Though McClintock suffered job discrimination, she also won grants and honors and was elected president of the genetics society of america in the 1940s-- proof that she had earned respect and recognition from her peers long before her work was "rediscovered". \n\nThe McClintock story suggests that one possible reason a scientific finding gets ignored is that it has little significance-- it does not solve important scientific problems or have practical applications. Only when the field had "ripened" and there were several scientific problems in different organisms (flies, corn, bacteria) that called for genome instability-- only then did the world recognize the importance of McClintock's results, and then she won a Nobel prize. \n\nAnother reason that a scientific finding gets ignored is that it runs counter to deeply entrenched doctrines or habits of thought. In this case, there are so many scientists devoted to the Darwinian catechism that mutation is "random" that they have continued to repeat this long after it was known to be untrue, and they will even change the definition of "random" to provide more wiggle room to continue saying that mutation is "random". \n\nArlin\n\n(1) Benzer, S. 1961. On the Topography of the Genetic Fine Structure. Proc. Natl. Acad. Sci., U.S.A. 47:403-415\n(2) Drake, J. W. 1970. The Molecular Basis of Mutation. Holden-Day, San Francisco.\n
Avatar of: Dov Henis

Dov Henis

Posts: 97

January 15, 2010

Predeluvian Adnauseam Genetic Mantras\nWhich I Dispelled Years Ago\n\n\nA. "Are mutations truly random?"\n\n\nAccidental mutations are accidents, not normal evolutionary factors.\n\nIt's cultural feedback to the genes that effects normal, which is BIASED, genetic evolution, nothing to do with mutation. Genes' expressions modifications are initiated by cultural changes that have demonstrated improved survival of the genome, thus increase the constrained energy of the genome. This is THE plain and simple evolution mechanism.\n\nOccasionally accidental mutations are, rationally and in fact, starting states for a new evolutionary route. Occasionally, accidentally.\n\n\nB. "New clues to Y evolution"\n\n\nQuote: "New findings challenge researchers' understanding of how the Y chromosome evolved"\n\nMy old findings were that it's not sex, but culture. See\n\n"Seed of Human-Chimp Genomes Diversity"\n\n\n\nDov Henis\n(Comments From The 22nd Century)
Avatar of: Grant Cooper

Grant Cooper

Posts: 1

January 17, 2010

Time-dependent, replication-independent mutations, CpG --> TpG, are operational at the DNA level in mammalian systems [1] and the rate of CpG --> TpG is ~ 15-fold greater when cytosine is methylated [2]. This form of time-dependent mutation, C --> *C --> T & G --> *G --> A, represents two of the 4 time-dependent substitutions exhibited by T4 bacteriophage [3,4], i.e., G' --> T, G' --> C, *G --> A & *C --> T in addition to A-T --> *A-*T --> deletion, indicating a modest evolutionary shift favoring A-T richness. Agreement between the biology, chemistry and physics [3,4] implies that time-dependent events exhibited by T4 phage are applicable to all duplex DNA systems. \n\n\nCITATIONS\n\n[1] Hwang, D.G., Green, P., 2004. Bayesian Markov chain Monte Carlo sequence analysis reveals varying neutral substitution patterns in mammalian evolution. Proc. Natl. Acad. Sci. USA 101, 13994-14001. \n\n[2] Elango, N., Kim, S-H., NICS Program, Vigoda, E., Yi, S.V., 2008. Mutations of different molecular origins exhibit contrasting patterns of regional substitution rate variation, PLoS Comput. Biol. 4, e1000015. doi: 10.1371/journal.pcbi.1000015.\n\n[3] Cooper, W.G, 2009a. Necessity of quantum coherence to account for the spectrum of time-dependent mutations exhibited by bacteriophage T4. Biochem. Genet. 47, 892-410. DOI: 10.1007/s10528-009-9293-8.\n\n[4] Cooper, W.G, 2009b. Evidence for transcriptase quantum processing implies entanglement and decoherence of superposition proton states. BioSystems 97, 73-89. DOI: 10.1016/j.biosystems.2009.04.010 \n\n
Avatar of: Al Bradbury

Al Bradbury

Posts: 7

February 8, 2010

The theorist proposes that no one has ever proposed anything like this before. I have. I long suspected and have written on line that cells keep a record of where mutations could occur without risk, and thereby create more reactive 'zones' where mutations are not catastrophic, and allows these areas to be susceptible to more mutation. Others have suggested more sophisticated and exotic abilities. Somewhere down the line this would involve repair mecahnisms because they are also involved in mutation. If a physical change in the code that also causes mutability is also inherited, it allows certain areas to be 'played with' whilst key genes are 'put' in safe areas or protected by other means/a change in the way they are tagged/Surrounding DNA/Location ie in which chromosome or even in euchromatin or heterochromatin. I argued that this is actually a requirement of eukaryotes and is connected to why we have so much DNA. If one thought in terms of man made machines, like a nuclear reactor, we can see that some changes in the design would be capable of catastrophy. As a result, only a few bits could be safely modified. If we were to introduce mutations in each design and allow these to inherit, we would learn that only some parts can be mutated once a 'good' design is reached, without a higher chance of destruction than competitive benefit. Contrary to many assumptions, life does not want to evolve, it wishes to retain a working formula. To obtain and vitally maintain a mutatable formula that is also very complex and sophisticated, is completely impossible unless you put mutations where they aren't catastrophic, or else, as this thought experiment will prove, parents who produce non-mutatable young will gain a large advantage over parents who indroduce what will likely merely impair the design. This creates an evolutionary pressure towards extreme conservation of a design, not evolution. Prokaryotes dont do this, and eukaryotes generally introduce a lot of change between generations. This could only be possible with 'mutation impact management' built into the genetic system, including the ability to ignore mutations, revert or switch to alternatives.\n\nEukaryotes are basically designs that are libraries of adaptation so the real action is in the active control of expression and how this is inherited. As far as this new theory proposes, I consider it inherently obvious as a natural requirement of any complex changing machine that is expected to actually work. Over time, not only the DNA, but the various components that control the DNA replication and expression, are sunject to evolution and increasing sophistication, a relationship that is in fact necessary (you must have both as complexity increases)

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