title: Allele frequencies of variants in ultra conserved elements identify selective pressure on transcription factor binding.
abstract: Ultra-conserved genes or elements (UCGs/UCEs) in the human genome are extreme examples of conservation. We characterized natural variations in 2884 UCEs and UCGs in two distinct populations; Singaporean Chinese (n = 280) and Italian (n = 501) by using a pooled sample, targeted capture, sequencing approach. We identify, with high confidence, in these regions the abundance of rare SNVs (MAF<0.5%) of which 75% is not present in dbSNP137. UCEs association studies for complex human traits can use this information to model expected background variation and thus necessary power for association studies. By combining our data with 1000 Genome Project data, we show in three independent datasets that prevalent UCE variants (MAF>5%) are more often found in relatively less-conserved nucleotides within UCEs, compared to rare variants. Moreover, prevalent variants are less likely to overlap transcription factor binding site. Using SNPfold we found no significant influence of RNA secondary structure on UCE conservation. All together, these results suggest UCEs are not under selective pressure as a stretch of DNA but are under differential evolutionary pressure on the single nucleotide level.
authors.affiliation: Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, Singapore, Singapore.
authors.forename: Toomas
authors.initials: T
authors.lastname: Silla
authors.affiliation: Human Genetics, Genome Institute of Singapore, Singapore, Singapore.
authors.forename: Katrin
authors.initials: K
authors.lastname: Kepp
authors.affiliation: Department of Medicine, National University of Singapore, Singapore, Singapore; Cardiovascular & Metabolic Disorders Program, Duke-NUS Graduate Medical School, Singapore, Singapore.
authors.forename: E Shyong
authors.initials: ES
authors.lastname: Tai
authors.affiliation: Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, Singapore, Singapore.
authors.forename: Liang
authors.initials: L
authors.lastname: Goh
authors.affiliation: Human Genetics, Genome Institute of Singapore, Singapore, Singapore.
authors.forename: Sonia
authors.initials: S
authors.lastname: Davila
authors.affiliation: Experimental Therapeutics & Cancer Genetics, MD Anderson Cancer Center, Texas State University, Houston, Texas, United States of America; Division of Molecular Medicine, Ruder Boskovic Institute, Zagreb, Croatia.
authors.forename: Tina
authors.initials: T
authors.lastname: Catela Ivkovic
authors.affiliation: Experimental Therapeutics & Cancer Genetics, MD Anderson Cancer Center, Texas State University, Houston, Texas, United States of America.
authors.forename: George A
authors.initials: GA
authors.lastname: Calin
authors.affiliation: Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, Singapore, Singapore.
authors.forename: P Mathijs
authors.initials: PM
authors.lastname: Voorhoeve
mesh_terms: D017124:Conserved Sequence / Q000235:genetics*; D005787:Gene Frequency; D015894:Genome, Human; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D009690:Nucleic Acid Conformation; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding; D012313:RNA / Q000737:chemistry / Q000378:metabolism; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000737:chemistry* / Q000378:metabolism
chemical_list: D014157:Transcription Factors; D012313:RNA