Allele Frequencies of Variants in Ultra Conserved Elements Identify Selective Pressure on Transcription Factor Binding

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 (MAF5%) 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.

人类基因组中的超保守基因或元件（Ultra-conserved genes or elements, UCGs/UCEs）是保守性极强的典型范例。本研究采用混合样本靶向捕获测序方法，对两个不同人群——新加坡华裔群体（n=280）与意大利裔群体（n=501）——的2884个UCGs/UCEs区域内的自然变异进行了表征。我们以高置信度在上述区域中鉴定到：相较于罕见变异，次要等位基因频率≤5%的罕见单核苷酸变异（single nucleotide variant, SNV）在UCEs内相对保守性较弱的核苷酸位点中更为常见。此外，常见变异与转录因子结合位点（transcription factor binding site, TFBS）重叠的概率更低。借助SNPfold工具分析后，我们发现RNA二级结构对UCE保守性无显著影响。综合以上结果，本研究表明，UCEs并非作为一段DNA序列受到选择压力，而是在单核苷酸水平上受到差异化的进化选择压力。