Abstract
BackgroundIn recent years it has been demonstrated that structural variations, such as indels (insertions and deletions), are common throughout the genome, but the implications of structural variations are still not clearly understood. Long tandem repeats (e.g. microsatellites or simple repeats) are known to be hypermutable (indel-rich), but are rare in exons and only occasionally associated with diseases. Here we focus on short (imperfect) tandem repeats (STRs) which fall below the radar of conventional tandem repeat detection, and investigate whether STRs are targets for disease-related mutations in human exons. In particular, we test whether they share the hypermutability of the longer tandem repeats and whether disease-related genes have a higher STR content than non-disease-related genes.ResultsWe show that validated human indels are extremely common in STR regions compared to non-STR regions. In contrast to longer tandem repeats, our definition of STRs found them to be present in exons of most known human genes (92%), 99% of all STR sequences in exons are shorter than 33 base pairs and 62% of all STR sequences are imperfect repeats. We also demonstrate that STRs are significantly overrepresented in disease-related genes in both human and mouse. These results are preserved when we limit the analysis to STRs outside known longer tandem repeats.ConclusionBased on our findings we conclude that STRs represent hypermutable regions in the human genome that are linked to human disease. In addition, STRs constitute an obvious target when screening for rare mutations, because of the relatively low amount of STRs in exons (1,973,844 bp) and the limited length of STR regions.
Highlights
In recent years it has been demonstrated that structural variations, such as indels, are common throughout the genome, but the implications of structural variations are still not clearly understood
The identified Short Tandem Repeats (STR) make up 4.02% of the human genome, and the majority of the identified STR segments (62.1%) are imperfect repeats regions, i.e. they contain polymorphic base-pairs or basepairs that do not match the periodic pattern
It appeared that 92.23% of all known human genes have STRs in their exons and 99% of STR regions are shorter than 33 bp
Summary
In recent years it has been demonstrated that structural variations, such as indels (insertions and deletions), are common throughout the genome, but the implications of structural variations are still not clearly understood. Long tandem repeats (e.g. microsatellites or simple repeats) are known to be hypermutable (indel-rich), but are rare in exons and only occasionally associated with diseases. A striking feature of the human genome is its plasticity, which is illustrated by the many occurrences of structural variations such as indels and copy number variations [16]. In an earlier paper we studied STRs (originally called periodic DNA; see Figure 1 and Methods for a definition) and demonstrated that STRs, in contrast to longer tandem repeats, are common in exonic regions, and that SNPs are more frequent in STRs compared with non-STRs [7]. Long intergenic tandem repeats are well known targets for structural variation, and in this study we investigate whether exonic STRs share this property, and may serve as a probable target for exonic disease causing mutations.
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