Detailed analysis of 15q11-q14 sequence corrects errors and gaps in the public access sequence to fully reveal large segmental duplications at breakpoints for Prader-Willi, Angelman, and inv dup(15) syndromes

BACKGROUND: Chromosome 15 contains many segmental duplications, including some at 15q11-q13 that appear to be responsible for the deletions that cause Prader-Willi and Angelman syndromes and for other genomic disorders. The current version of the human genome sequence is incomplete, with seven gaps in the proximal region of 15q, some of which are flanked by duplicated sequence. We have investigated this region by conducting a detailed examination of the sequenced genomic clones in the public database, focusing on clones from the RP11 library that originates from one individual. RESULTS: Our analysis has revealed assembly errors, including contig NT_078094 being in the wrong orientation, and has enabled most of the gaps between contigs to be closed. We have constructed a map in which segmental duplications are no longer interrupted by gaps and which together reveals a complex region. There are two pairs of large direct repeats that are located in regions consistent with the two classes of deletions associated with Prader-Willi and Angelman syndromes. There are also large inverted repeats that account for the formation of the observed supernumerary marker chromosomes containing two copies of the proximal end of 15q and associated with autism spectrum disorders when involving duplications of maternal origin (inv dup[15] syndrome). CONCLUSION: We have produced a segmental map of 15q11-q14 that reveals several large direct and inverted repeats that are incompletely and inaccurately represented on the current human genome sequence. Some of these repeats are clearly responsible for deletions and duplications in known genomic disorders, whereas some may increase susceptibility to other disorders

Analysis of symmetrical region near the centromeric end of 15q to identify its likeliest arrangement in RP11

The region between the most proximal segments P ordered as in Figure 5 is indicated by the four rows of segments at the top. The first row, continuing to the third row, represents the upper RP11 haplotigs in Figure 5 and the second row, continuing to the fourth row, represents the lower haplotigs. The RP11 haplotigs are shown below the segments with the non-RP11 clones shown further below. Nine slices of 5 to 30 kilobases (kb), shown by alternating red or blue lines, were investigated, with each box showing the number of single nucleotide mismatches between each pair of RP11 haplotigs and non-RP11 clones in the slice.<p><b>Copyright information:</b></p><p>Taken from "Detailed analysis of 15q11-q14 sequence corrects errors and gaps in the public access sequence to fully reveal large segmental duplications at breakpoints for Prader-Willi, Angelman, and inv dup(15) syndromes"</p><p>http://genomebiology.com/2007/8/6/R114</p><p>Genome Biology 2007;8(6):R114-R114.</p><p>Published online 15 Jun 2007</p><p>PMCID:PMC2394762.</p><p></p

Evidence that RNA editing modulates splice site selection in the 5-HT2C receptor gene

Adenosine to inosine editing of mRNA from the human 5-HT2C receptor gene (HTR2C) occurs at five exonic positions (A–E) in a stable stem–loop that includes the normal 5′ splice site of intron 5 and is flanked by two alternative splice sites. Using in vitro editing, we identified a novel editing site (F) located in the intronic part of the stem–loop and demonstrated editing at this site in human brain. We have shown that in cell culture, base substitutions to mimic editing at different combinations of the six sites profoundly affect relative splicing at the normal and the upstream alternative splice site, but splicing at the downstream alternative splice site was consistently rare. Editing combinations in different splice variants from human brain were determined and are consistent with the effects of editing on splicing observed in cell culture. As RNA editing usually occurs close to exon/intron boundaries, this is likely to be a general phenomenon and suggests an important novel role for RNA editing