Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2013;8(2):e54710.
doi: 10.1371/journal.pone.0054710. Epub 2013 Feb 6.

Microsatellite tandem repeats are abundant in human promoters and are associated with regulatory elements

Sterling Sawaya  1 , Andrew Bagshaw, Emmanuel Buschiazzo, Pankaj Kumar, Shantanu Chowdhury, Michael A Black, Neil Gemmell
Affiliations

Microsatellite tandem repeats are abundant in human promoters and are associated with regulatory elements

Sterling Sawaya et al. PLoS One. 2013.

Abstract

Tandem repeats are genomic elements that are prone to changes in repeat number and are thus often polymorphic. These sequences are found at a high density at the start of human genes, in the gene's promoter. Increasing empirical evidence suggests that length variation in these tandem repeats can affect gene regulation. One class of tandem repeats, known as microsatellites, rapidly alter in repeat number. Some of the genetic variation induced by microsatellites is known to result in phenotypic variation. Recently, our group developed a novel method for measuring the evolutionary conservation of microsatellites, and with it we discovered that human microsatellites near transcription start sites are often highly conserved. In this study, we examined the properties of microsatellites found in promoters. We found a high density of microsatellites at the start of genes. We showed that microsatellites are statistically associated with promoters using a wavelet analysis, which allowed us to test for associations on multiple scales and to control for other promoter related elements. Because promoter microsatellites tend to be G/C rich, we hypothesized that G/C rich regulatory elements may drive the association between microsatellites and promoters. Our results indicate that CpG islands, G-quadruplexes (G4) and untranslated regulatory regions have highly significant associations with microsatellites, but controlling for these elements in the analysis does not remove the association between microsatellites and promoters. Due to their intrinsic lability and their overlap with predicted functional elements, these results suggest that many promoter microsatellites have the potential to affect human phenotypes by generating mutations in regulatory elements, which may ultimately result in disease. We discuss the potential functions of human promoter microsatellites in this context.

PubMed Disclaimer

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Distribution of microsatellites around promoters.
The total number of microsatellites present in each 100 base-pair bin are provided for all microsatellites within 10 kb of the TSS. Also shown are the total number of only coding microsatellites (blue) or only 5′ UTR microsatellites (red).
Figure 2
Figure 2. Kendall rank correlations between wavelet coefficients.
The pairwise correlations between smooth coefficients are in the top right, and detail coefficients are the bottom left. The diagonal displays the normalized power spectrum for the wavelet coefficients, which can be interpreted as a measure of the variation of each signal at each scale. Note that the majority of factors examined here have most of their variation at the finest scales, while GC content and G4 elements contain a large amount of variation at the largest scales. Abbreviations for each element are “msat” for microsatellite, “G4” for predicted G4 regions, “CpG” for CpG islands, and “GC” for G/C content. Associations with a p-value above 0.001 are shown in red if positive, blue if negative. The smallest scale examined was 1 kb in size, and each successive scale increases by a factor of two.
Figure 3
Figure 3. Linear model of wavelet results, displaying p-values.
The top figure shows the results of the smooth coefficients, the bottom shows the results of the detail coefficients. Positive relationships are shown in red, negative in blue. The formula image value is shown at the bottom of the figure. The largest scales were not included in this figure for simplicity.
Figure 4
Figure 4. Strand-specific densities for the motifs A/T and AC/GT around promoters.
These figures show the cubic spline of the densities of each strand-specific motif for bins of size 1kb (solid) and 100 base-pair (dashed) for the entire 5 kb promoter region.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Warren WC, Hillier LW, Marshall Graves JA, Birney E, Ponting CP, et al. (2008) Genome analysis of the platypus reveals unique signatures of evolution. Nature 453: 175–183. - PMC - PubMed
    1. Ellegren H (2004) Microsatellites: simple sequences with complex evolution. Nature Reviews Genetics 5: 435–445. - PubMed
    1. Sun JX, Helgason A, Masson G, Ebenesersdottir SS, Li H, et al. (2012) A direct characterization of human mutation based on microsatellites. Nat Genet 44: 1161–1165. - PMC - PubMed
    1. Payseur BA, Jing P, Haasl RJ (2011) A genomic portrait of human microsatellite variation. Mol Biol Evol 28: 303–312. - PMC - PubMed
    1. Buschiazzo E, Gemmell N (2006) The rise, fall and renaissance of microsatellites in eukaryotic genomes. Bioessays 28: 1040–1050. - PubMed

Publication types

Grants and funding

SS and NG were partially funded by Royal Society of New Zealand Marsden Grant (UOO 0721) and Minority Health International Research Training grant (National Institutes of Health). AB was funded by a Royal Society of New Zealand Marsden Grant (UOO 085). PK was funded by a Sr. Research Fellowship from the Indian Council of Medical Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.