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.

Genetic Variations of Ultraconserved Elements in the Human Genome

“…Remarkably, our results indeed show that a vast majority of UCE polymorphisms exhibit extremely low MAFs-less than 6% occur at a frequency of >1%. Depletion of prevalent polymorphisms from UCEs has also been confirmed by Silla et al (2014). It may be assumed that recurrent polymorphisms are less likely associated with fitness, while those occurring at lower MAFs more likely have deleterious consequences.…”

“…At present, UCEs are among the most popular DNA markers for phylogenomic analysis (Tagliacollo and Lanfear, 2018). They might also be good candidates for targeted sequencing projects and association studies (Silla et al, 2014) and might present valuable and easily detectable disease biomarkers. Bao et al (2016) for example found association between rs8004379 and prostate cancer-specific mortality.…”

Conserved non-coding elements: developmental gene regulation meets genome organization

“…Furthermore, it is unclear whether overlapping binding sites would be sufficient to explain extreme non-coding conservation, given promiscuity of binding sites and binding site divergence between species ( 76 ). A recent paper also proposed that CNEs are not under selective pressure as a whole DNA segment but are under various evolutionary constraints on the single nucleotide level ( 77 ), suggesting that overlapping TFBS likely do not account for the degree of conservation characteristic of CNEs.…”

Introduction of ‘Generalized Genomic Signatures’ for the quantification of neighbour preferences leads to taxonomy- and functionality-based distinction among sequences

“…This view explains the gradual increase of the δ-distance of a series of CNE collections from their surrogate sequences, when these CNE datasets are produced by gradual increase of the conservation thresholds (see Table 2). Moreover, the high performance of GGSs in distinguishing among all examined CNE classes, for all considered lengths n , does not support the suggestion that the selective pressure shaping CNEs, and especially the more extremely conserved ones (mentioned as Ultra-Conserved Elements or UCEs in that work), is exerted on the single nucleotide level 37 , since GGSs capture nucleotide correlations extending along whole stretches of DNA.…”