title: Polymorphic tandem repeats within gene promoters act as modifiers of gene expression and DNA methylation in humans.
abstract: Despite representing an important source of genetic variation, tandem repeats (TRs) remain poorly studied due to technical difficulties. We hypothesized that TRs can operate as expression (eQTLs) and methylation (mQTLs) quantitative trait loci. To test this we analyzed the effect of variation at 4849 promoter-associated TRs, genotyped in 120 individuals, on neighboring gene expression and DNA methylation. Polymorphic promoter TRs were associated with increased variance in local gene expression and DNA methylation, suggesting functional consequences related to TR variation. We identified >100 TRs associated with expression/methylation levels of adjacent genes. These potential eQTL/mQTL TRs were enriched for overlaps with transcription factor binding and DNaseI hypersensitivity sites, providing a rationale for their effects. Moreover, we showed that most TR variants are poorly tagged by nearby single nucleotide polymorphisms (SNPs) markers, indicating that many functional TR variants are not effectively assayed by SNP-based approaches. Our study assigns biological significance to TR variations in the human genome, and suggests that a significant fraction of TR variations exert functional effects via alterations of local gene expression or epigenetics. We conclude that targeted studies that focus on genotyping TR variants are required to fully ascertain functional variation in the genome.
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Javier
authors.initials: J
authors.lastname: Quilez
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Audrey
authors.initials: A
authors.lastname: Guilmatre
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Paras
authors.initials: P
authors.lastname: Garg
authors.affiliation: Virginia Bioinformatics Institute and Department of Biological Sciences, Virginia Tech, Blacksburg, VA 24061, USA.
authors.forename: Gareth
authors.initials: G
authors.lastname: Highnam
authors.affiliation: Harvard-MIT Division of Health Sciences and Technology, MIT, Cambridge, MA 02139, USA Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA New York Genome Center, New York, NY 10038, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Gymrek
authors.affiliation: Harvard-MIT Division of Health Sciences and Technology, MIT, Cambridge, MA 02139, USA Department of Computer Science, Fu Foundation School of Engineering, Columbia University, New York, NY 10027, USA.
authors.forename: Yaniv
authors.initials: Y
authors.lastname: Erlich
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Ricky S
authors.initials: RS
authors.lastname: Joshi
authors.affiliation: Virginia Bioinformatics Institute and Department of Biological Sciences, Virginia Tech, Blacksburg, VA 24061, USA.
authors.forename: David
authors.initials: D
authors.lastname: Mittelman
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA andrew.sharp@mssm.edu.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Sharp
mesh_terms: D019175:DNA Methylation; D005786:Gene Expression Regulation; D060005:Genotyping Techniques; D006801:Humans; D015810:Linkage Disequilibrium; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D040641:Quantitative Trait Loci; D017422:Sequence Analysis, DNA; D020080:Tandem Repeat Sequences