Systematic identification of abundant A-to-I editing sites in the human transcriptome

RNA editing by members of the double-stranded RNA-specific ADAR family leads to site-specific conversion of adenosine to inosine (A-to-I) in precursor messenger RNAs. Editing by ADARs is believed to occur in all metazoa, and is essential for mammalian development. Currently, only a limited number of human ADAR substrates are known, while indirect evidence suggests a substantial fraction of all pre-mRNAs being affected. Here we describe a computational search for ADAR editing sites in the human transcriptome, using millions of available expressed sequences. 12,723 A-to-I editing sites were mapped in 1,637 different genes, with an estimated accuracy of 95%, raising the number of known editing sites by two orders of magnitude. We experimentally validated our method by verifying the occurrence of editing in 26 novel substrates. A-to-I editing in humans primarily occurs in non-coding regions of the RNA, typically in Alu repeats. Analysis of the large set of editing sites indicates the role of editing in controlling dsRNA stability.Comment: Pre-print version. See http://dx.doi.org/10.1038/nbt996 for a reprin

Alignment of flexible protein structures

Abstract We present two algorithms which align flexible prote3n structures. Both apply efficient structural pattern detection and graph theoretic techniques. The FlexProt algorithm simultaneously detects the hinge regions and aligns the rigid subparts of the molecules. It does it by cfficlently detecting maximal congruent rigid fragments in both molecules and calculating their optimal arrangement which does not violate the protein sequence order. The FlexMol algorithm is sequence order independent, yet requires as input the hypothesized hinge positions. Due its sequence order independence it can also be applied to proteln-protein interface matching and drug molecule alignment. It aligns the rigid parts of the molecule using the Geometric Hashing method and calculates optimal connectivity among these parts by graphtheoretic techniques. Both algorithms are highly efficient even compared with rigid structure alignment algorithms. Typical running times on a standard desl~op PC (400Mttz) are about 7 seconds for FlexProt and about 1 minute for FlexMol