Ered [161]. However, we already know that this kind of mutation is
Ered [161]. However, we already know that this kind of mutation is nonrandom because of the biological marking of the cytosine, which causes the mutation one way or the other. Notably, 24 of all point mutations in humans are due to this mutational process [156]. In addition, 18 of the human genome is within 10 bp of a CpG, and an 50 increase in single nucleotide polymorphisms (SNPs) has been observed within this distance in methylated regions [162]. It has been proposed that deamination of the methylated cytosine is followed by “error-prone repair” which not only establishes the CT mutation but also gives PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/27107493 rise to point mutations in nearby bases at the same time [162-164] (but of course, “error-prone repair” may also be called a “change-inducing mechanism”). Other short sequences also exist that have a substantial association with mutation rate. The sequences ATTG and ATAG have a mutation rate of TC in the second position that is 3.5- and 3.3-fold higher, respectively, than the genome-wide average TC mutation rate, and ACAA has a mutation rate of AC in the first position that is 3.4-fold higher than the average AC mutation rate,Livnat Biology Direct 2013, 8:24 http://www.biology-direct.com/content/8/1/Page 17 ofin humans [165] (compare to a 5.1-fold excess of CT mutations in CpGs in these data [165]). The average mutation rates of other short sequences also differ significantly amongst each other, and farther nucleotides also have a significant but ever smaller order PF-04418948 effect (reviewed in [155]). In addition, there are loci at the single-base resolution that undergo point mutation preferentially even though no simple sequences have been found yet in these loci [166-168]. We know of these loci from studies of coincident SNPs (cSNPs), where SNPs are observed in the same locations in related species [166-169] (understandably, they also tend to exist in the same loci where single nucleotide substitutions are observed in between-species comparisons; [166-168,170-172]). It has been said that traditional natural selection does not appear to explain these coincidences in the location of variance [168], and so we know that these mutations are guided, though we do not know how. According to Hodgkinson and Eyre-Walker [155], this part of the variance in the human mutation rate across loci that is accounted for by cSNPs unexplained by simple context, called “cryptic variance” [166], is as large as that of CpG mutations (the latter alone involving 24 of all point mutations in humans, as said). Thus, we already see that a large percentage of the total variance in the per-locus mutation rate in humans is accounted for by cSNPs and CpG mutations, two obviously nonrandom processes. It is also worthwhile mentioning that there is a strong association between meiotic recombination hotspots and mutation hotspots [173,174]. Meiotic recombination hotspots move rather quickly during evolution–i.e., they are not conserved between humans and chimpanzees– but they remain within a certain region for longer periods of time (in other words, they move quickly on the singlebase scale but more slowly on the Mb scale; [175,176]). Within these regions, substitution rates are elevated [173,176]. Importantly, meiotic recombination hotspots are clearly nonrandom: their locations involve DNA sequence motifs and, according to Wahls and Davidson [135], are determined by the combinatorial effect of the binding of multiple transcription factors at multiple transcription factor bind.
