predicting the effects of frameshifting indels预测移码indels的影响.pdf

Hu and Ng Genome Biology 2012, 13:R9 /2012/13/2/R9 METHOD Open Access Predicting the effects of frameshifting indels Jing Hu 1 and Pauline C Ng2* Abstract Each human has approximately 50 to 280 frameshifting indels, yet their implications are unknown. We created SIFT Indel, a prediction method for frameshifting indels that has 84% accuracy. The percentage of human frameshifting indels predicted to be gene-damaging is negatively correlated with allele frequency. We also show that although the first frameshifting indel in a gene causes loss of function, there is a tendency for the second frameshifting indel to compensate and restore protein function. SIFT Indel is available at /www/SIFT_indels2.html Background degraded by nonsense-mediated or non-stop-mediated Small insertions/deletions (indels of 20 bp or less) mRNA decay [11-13]. Researchers tend to assume these account for nearly 24% of known Mendelian disease frameshifting (FS) indels are loss-of-function variants. mutations. It is the second largest class of mutation type However, we and other researchers have identified some that leads to disease following amino acid substitutions, trends for FS indel variants observed in the human which account for over half of known Mendelian disease population. For example, polymorphic indels tend to mutations [1]. There exist many bioinformatics algo- cluster towards the end of a protein, thereby avoiding rithms that predict whether an amino acid substitution nonsense-mediated decay [14,15]. They also tend to affects protein function (for example, SIFT [2], PolyPhen occur in hypothetical and