Long-range heterogeneity at the 3' ends of human mRNAs

Abstract

The publication of a draft of the human genome and of large collections of transcribed sequences has made it possible to study the complex relationship between the transcriptome and the genome. In the work presented here, we have focused on mapping mRNA 3' ends onto the genome by use of the raw data generated by the expressed sequence tag (EST) sequencing projects. We find that at least half of the human genes encode multiple transcripts whose polyadenylation is driven by multiple signals. The corresponding transcript 3' ends are spread over distances in the kilobase range. This finding has profound implications for our understanding of gene expression regulation and of the diversity of human transcripts, for the design of cDNA microarray probes, and for the interpretation of gene expression profiling experiments.

Figure 1

Examples of extended and overlapping 3′ untranslated region (UTR). Alignments of transcripts to the genome (yellow bar) were visualized using ACEDB. The direction of transcription is bottom to top on the left and top to bottom on the right. The direction of transcription of unspliced expressed sequence tags (ESTs) was based on their annotation, except for the unspliced ORESTES sequences, which were arbitrarily assigned to the right-hand strand. The orientation of 3′ tags was deduced from the polarity of the poly(A) tract. Light blue: RefSeq sequences; dark blue: full-length cDNA sequences; green: ORESTES sequences; and red: EST sequences. 3′ tags are represented by black boxes, with one box per cluster member. Regions covered by UniGene clusters are indicated on the right. (A) 3′ terminal exons of the NCAM2 gene. (B) Overlapping 3′ ends of the COL18A1 and SCL19A1 genes. Many ESTs derived from the COL18A1 gene were omitted for clarity.