title: An expanded sequence context model broadly explains variability in polymorphism levels across the human genome.
abstract: The rate of single-nucleotide polymorphism varies substantially across the human genome and fundamentally influences evolution and incidence of genetic disease. Previous studies have only considered the immediately flanking nucleotides around a polymorphic site--the site's trinucleotide sequence context--to study polymorphism levels across the genome. Moreover, the impact of larger sequence contexts has not been fully clarified, even though context substantially influences rates of polymorphism. Using a new statistical framework and data from the 1000 Genomes Project, we demonstrate that a heptanucleotide context explains >81% of variability in substitution probabilities, highlighting new mutation-promoting motifs at ApT dinucleotide, CAAT and TACG sequences. Our approach also identifies previously undocumented variability in C-to-T substitutions at CpG sites, which is not immediately explained by differential methylation intensity. Using our model, we present informative substitution intolerance scores for genes and a new intolerance score for amino acids, and we demonstrate clinical use of the model in neuropsychiatric diseases.
authors.affiliation: Genomics and Computational Biology Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Varun
authors.initials: V
authors.lastname: Aggarwala
authors.affiliation: Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.|Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Voight
mesh_terms: D001321:Autistic Disorder / Q000235:genetics; D001483:Base Sequence; D001499:Bayes Theorem; D018899:CpG Islands; D019175:DNA Methylation; D021901:DNA, Intergenic / Q000235:genetics; D015894:Genome, Human; D006801:Humans; D008957:Models, Genetic; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D012044:Regression Analysis; D017422:Sequence Analysis, DNA
chemical_list: D021901:DNA, Intergenic