Annotating conserved and novel features of primate transcriptomes using sequencing

See research article: http://genomebiology.com/2010/11/7/R78 webciteThe completion of the human genome was followed by sequencing of the genomes of closely related primate species, such as the chimpanzee and the rhesus macaque. The motivation was simple: as the genome provided the blueprint of an organism, comparisons between the human genome and the genomes of non-human primates should reveal genomic features underlying the human phenotype.One problem with this approach, however, is that a genome is not really a blueprint of a phenotype, but rather a well-scrambled message, in which functionally relevant sequences are lost in a sea of phenotypically neutral information. A seemingly straightforward way to identify functional sequences is to determine transcribed regions. This is not a simple task, however, as the transcriptome varies greatly across cell types and changes dramatically across an organism's lifespan. Thus, in the past decade, a large effort was put into annotating the human transcriptome, mainly by sequencing transcripts converted into cDNA libraries by conventional Sanger sequencing. As a result, it became clear that given enough sequencing coverage, almost any genomic sequence can be detected on the transcriptome level [1]. This is not entirely surprising, as human genes frequently contain long introns; moreover, RNA polymerase can generate spontaneous transcripts of no functional relevance. Still, this result indicated that dividing the genome into transcribed and non-transcribed parts to determine functionality was largely futile.These cDNA sequencing projects also showed that the boundaries of most human genes, including transcription start and termination sites and the splicing patterns of internal exons, are rather fuzzy [2-6]. In addition, many of the identified transcripts and gene isoforms turned out to be rare. This does not, however, mean that they are functionally irrelevant, as such transcripts may have important roles in a limited number