The influence of nearest neighbors on the rate and pattern of spontaneous point mutations

Abstract

The numbers and local sequence environments of the two types of substitution mutation plus additions and deletions have been obtained directly in this study from differences between a large number of extant primate gene and pseudogene sequences. A total of 3786 mutations were scored in regions where similarities between pseudogene and corresponding gene sequences is greater than or equal to 85%, comprising approximately 30% of the pseudogene database of 80,584 bp. The pattern of mutations obtained in this fashion is almost identical to that obtained by Li et al. (1984) using a slightly different, more direct approach and with a smaller database. When mutations were scored, the neighbor pairs on the 5' and 3' sides were also noted, leading to a large 16 x 12 matrix of transitions and transversions. Biases of varying magnitude are found in the rates of substitution of the same base pair in different local sequence environments. The overall order for the effect of the 5' neighbor on the rates of substitution mutation of a pyrimidine is A greater than C much greater than T greater than G, and G greater than A greater than T greater than C for the 3' neighbor; where these results represent the average of substitution rates for the complement purine with complement neighbors of bases ordered above. The order for the 3' neighbor is essentially the same for the two transitions and most of the four transversions as well; however, the order for the 5' neighbor is more variable. The overall rate for the C.G----T.A transition is not unusual, however the presence of a 3' neighboring G.C pair boosts the rate substantially, presumably due to specific cytosine methylation of the CG doublet in primate DNAs. The rate of the T.A----C.G transition is also well above average when the 3' neighbor is an A.T, and to a lesser extent a G.C, pair. The latter bias is typical in that it reflects the association of alternating pyrimidine-purine sequences with increasing mutation rates. The substitution of the pyrimidine in a 5'purine-pyrimidine-purine3' sequence generally occurs much faster than in a pyrimidine tract and points to the local conformation as a major determining factor of the substitution rate. An apparent inverse relationship is found between starting and product doublet frequencies of base pairs undergoing mutations with specific 3' neighbors, indicating that differences in intrinsic substitution rates of base pairs with specific neighbors are a key factor in producing the familiar biases of nearest-neighbor frequencies.

Neighboring-Nucleotide Effects on Single Nucleotide Polymorphisms: A Study of 2.6 Million Polymorphisms Across the Human Genome

“…This order is different from that calculated from 3243 substitutions in gene and pseudogene sequences published by Blake et al (1992), which had C ≈ A ӷ t > g at the ‫1מ‬ site and G ӷ A > t ӷ c at the +1 site after being normalized by the average nucleotide proportion in the gene sequences. The GC content of their gene and pseudogene sequences was 57%, compared with 41% for the genome average.…”

Human Triallelic Sites: Evidence for a New Mutational Mechanism?

“…It has previously been shown that the mutation rate varies as a function of local context effects, particularly depending upon the adjacent nucleotides (Blake et al 1992;Zhao et al 2003;Hwang and Green 2004). Such variation in the mutation rate could lead to an increased number of triallelic SNPs if some sites have an elevated mutation in two or more pathways, e.g., if both C / T and C / A occur at higher rates.…”

“…The mutation rate of a site is known to depend upon the adjacent nucleotides, the best known example being the CpG dinucleotide (Coulondre et al 1978;Bird 1980) at which the frequency of both transition and transversion mutations is elevated. However, other adjacent nucleotides also influence the mutation rate (Blake et al 1992;Zhao et al 2003;Hwang and Green 2004). Furthermore, we have recently shown that there is variation in the mutation rate that does not depend upon the identity of the adjacent nucleotides or any specific context (Hodgkinson et al 2009).…”

Mutation patterns in cancer genomes

“…Transition mutations occur at a significantly higher rate than transversion mutations (6)(7)(8). Substitution rates depend on flanking nucleotides, a notable example being cytosine in CpG dinucleotides which, in mammals, is usually methylated at the 5-carbon and undergoes hydrolytic deamination to thymine at a relatively high rate (8)(9)(10).…”

“…Transition mutations occur at a significantly higher rate than transversion mutations (6)(7)(8). Substitution rates depend on flanking nucleotides, a notable example being cytosine in CpG dinucleotides which, in mammals, is usually methylated at the 5-carbon and undergoes hydrolytic deamination to thymine at a relatively high rate (8)(9)(10). The germline mutation rate at CpGs is much lower within CpG islands (regions enriched in CpGs surrounding or near the transcription start sites of many genes) reflecting, at least in part, the fact that most islands are likely unmethylated in the germline (10).…”