Neighboring-nucleotide effects on single nucleotide polymorphisms: a study of 2.6 million polymorphisms across the human genome.

We investigated substitution patterns and neighboring-nucleotide effects for 2,576,903 single nucleotide polymorphisms (SNPs) publicly available through the National Center for Biotechnology Information (NCBI). The proportions of substitutions were A/G, 32.77%; C/T, 32.81%; A/C, 8.98%; G/T, 9.06%; A/T, 7.46%; and C/G, 8.92%. The two nucleotides immediately neighboring the variable site showed major deviation from genome-wide and chromosome-specific expectations, although lesser biases extended as far as 200 bp. On the 5' side, the biases for A, C, G, and T were 1.43%, 4.91%, -1.70%, and -4.62%, respectively. These biases were -4.44%, -1.59%, 5.05%, and 0.99%, respectively, on the 3' side. The neighboring-nucleotide patterns for transitions were dominated by the hypermutability effects of CpG dinucleotides. Transitions were more common than transversions, and the probability of a transversion increased with increasing A + T content at the two adjacent sites. Neighboring-nucleotide biases were not consistent among chromosomes, with Chromosomes 19 and 22 standing out as different from the others. These data provide genome-wide information about the effects of neighboring nucleotides on mutational and evolutionary processes giving rise to contemporary patterns of nucleotide occurrence surrounding SNPs.

[1]  S. Hess,et al.  The influence of nearest neighbors on the rate and pattern of spontaneous point mutations , 1992, Journal of Molecular Evolution.

[2]  D. Cooper,et al.  The mutational spectrum of single base-pair substitutions causing human genetic disease: patterns and predictions , 1990, Human Genetics.

[3]  T B Kepler,et al.  Statistical inference of sequence-dependent mutation rates. , 2001, Current opinion in genetics & development.

[4]  Pui-Yan Kwok,et al.  Single-nucleotide polymorphisms in the public domain: how useful are they? , 2001, Nature Genetics.

[5]  A. Morrison,et al.  Linkage Disequilibrium Structure and Its Impact on the Localization of a Candidate Functional Mutation , 2001, Genetic epidemiology.

[6]  L. Jin,et al.  Worldwide Dna Sequence Variation in a 10-kilobase Noncoding Region on Human Chromosome 22 Materials and Methods Dna Samples. Sixty-four Individuals Were Collected Worldwide from 16 Populations in Four Major Geographic Areas, including 20 , 2022 .

[7]  M Krawczak,et al.  Neighboring-nucleotide effects on the rates of germ-line single-base-pair substitution in human genes. , 1998, American journal of human genetics.

[8]  M. Clegg,et al.  The Influence of Specific Neighboring Bases on Substitution Bias in Noncoding Regions of the Plant Chloroplast Genome , 1997, Journal of Molecular Evolution.

[9]  N Risch,et al.  The Future of Genetic Studies of Complex Human Diseases , 1996, Science.

[10]  B. Morton,et al.  Neighboring base composition and transversion/transition bias in a comparison of rice and maize chloroplast noncoding regions. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[11]  A. Bird CpG-rich islands and the function of DNA methylation , 1986, Nature.