title: Evidence for evolutionary and nonevolutionary forces shaping the distribution of human genetic variants near transcription start sites.
abstract: The regions surrounding transcription start sites (TSSs) of genes play a critical role in the regulation of gene expression. At the same time, current evidence indicates that these regions are particularly stressed by transcription-related mutagenic phenomena. In this work we performed a genome-wide analysis of the distribution of single nucleotide polymorphisms (SNPs) inside the 10 kb region flanking human TSSs by dividing SNPs into four classes according to their frequency (rare, two intermediate classes, and common). We found that, in this 10 kb region, the distribution of variants depends on their frequency and on their localization relative to the TSS. We found that the distribution of variants is generally different for TSSs located inside or outside of CpG islands. We found a significant relationship between the distribution of rare variants and nucleosome occupancy scores. Furthermore, our analysis suggests that evolutionary (purifying selection) and nonevolutionary (biased gene conversion) forces both play a role in determining the relative SNP frequency around TSSs. Finally, we analyzed the potential pathogenicity of each class of variant using the Combined Annotation Dependent Depletion score. In conclusion, this study provides a novel and detailed view of the distribution of genomic variants around TSSs, providing insight into the forces that instigate and maintain variability in such critical regions.
authors.affiliation: Gruppo Interdipartimentale di Bioinformatica e Biologia Computazionale, Università degli Studi di Napoli "Federico II", Naples, Italy; Dipartimento di Fisica, Università degli Studi di Napoli "Federico II", Naples, Italy; Istituto Nazionale di Fisica Nucleare, Sezione di Napoli, Naples, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Scala
authors.affiliation: Gruppo Interdipartimentale di Bioinformatica e Biologia Computazionale, Università degli Studi di Napoli "Federico II", Naples, Italy; Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli "Federico II", Naples, Italy; Istituto di Endocrinologia ed Oncologia Sperimentale (IEOS), CNR, Naples, Italy.
authors.forename: Ornella
authors.initials: O
authors.lastname: Affinito
authors.affiliation: Gruppo Interdipartimentale di Bioinformatica e Biologia Computazionale, Università degli Studi di Napoli "Federico II", Naples, Italy; Dipartimento di Fisica, Università degli Studi di Napoli "Federico II", Naples, Italy; Istituto Nazionale di Fisica Nucleare, Sezione di Napoli, Naples, Italy.
authors.forename: Gennaro
authors.initials: G
authors.lastname: Miele
authors.affiliation: Gruppo Interdipartimentale di Bioinformatica e Biologia Computazionale, Università degli Studi di Napoli "Federico II", Naples, Italy; Istituto di Endocrinologia ed Oncologia Sperimentale (IEOS), CNR, Naples, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Monticelli
authors.affiliation: Gruppo Interdipartimentale di Bioinformatica e Biologia Computazionale, Università degli Studi di Napoli "Federico II", Naples, Italy; Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli "Federico II", Naples, Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Cocozza
mesh_terms: D018899:CpG Islands; D019143:Evolution, Molecular; D005787:Gene Frequency; D006801:Humans; D008957:Models, Genetic; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D017422:Sequence Analysis, DNA; D024363:Transcription Initiation Site; D014158:Transcription, Genetic