Relatively semi-conservative replication and a folded slippage model for short tandem repeats

Abstract

Background The ubiquitous presence of short tandem repeats (STRs) in virtually all genomes implicates their functional relevance, while a widely-accepted definition of STR is yet to be established. Previous studies majorly focus on relatively longer STRs, while shorter repeats were generally excluded. Herein, we have adopted a more generous criteria to define shorter repeats, which has led to the definition of a much larger number of STRs that lack prior analysis. Using this definition, we analyzed the short repeats in 55 randomly selected segments in 55 randomly selected genomic sequences from a fairly wide range of species covering animals, plants, fungi, protozoa, bacteria, archaea and viruses. Results Our analysis reveals a high percentage of short repeats in all 55 randomly selected segments, indicating that the universal presence of high-content short repeats could be a common characteristic of genomes across all biological kingdoms. Therefore, it is reasonable to assume a mechanism for continuous production of repeats that can make the replicating process relatively semi-conservative. We have proposed a folded replication slippage model that considers the geometric space of nucleotides and hydrogen bond stability to explain the mechanism more explicitly, with improving the existing straight-line slippage model. The folded slippage model can explain the expansion and contraction of mono- to hexa- nucleotide repeats with proper folding angles. Analysis of external forces in the folding template strands also suggests that expansion exists more commonly than contraction in the short tandem repeats. Conclusion The folded replication slippage model provides a reasonable explanation for the continuous occurrences of simple sequence repeats in genomes. This model also contributes to the explanation of STR-to-genome evolution and is an alternative model that complements semi-conservative replication.

Microsatellite Density Landscapes Illustrate Short Tandem Repeats Aggregation in The Complete Reference Human Genome

“…The first construction of the locus maps of HDMA peaks clearly revealed that these HDMA peaks are distributed regularly along every human chromosome in both the reference (GRCh38) and first complete (CHM13) human genome, suggesting that the high-density microsatellites accumulation is probably the necessary fundamental elements in human genome. We formerly presented a folded slippage model for repeats occurring mechanism, predicting that micro-disturbing in the process of replication may provide a lot of chances for the template chain folded to produce repeats, which are possibly selected fixation for different biological significance in the long-history evolution [44]. Among all motif types of HDMA peaks, more than half of HDMA peaks are AT n motif type in the GRC38 and CHM13 human genome, suggesting that AT n motif is the most specific STRs motif among all STRs motifs and tend to accumulate in human genome.…”

“…Among all motif types of HDMA peaks, more than half of HDMA peaks are AT n motif type in the GRC38 and CHM13 human genome, suggesting that AT n motif is the most specific STRs motif among all STRs motifs and tend to accumulate in human genome. The folded slippage replication possibly explain why short and A/T repeat-motifs occur much more frequently than long and C/G repeat-motifs [44], however, there is no A n and T n motif accumulation peak but many AT n motif accumulation peaks (Fig 2C -2E, Table S6), further indicating that AT n motifs might have been specifically selected as very essential elements for genome structures and functions to fix and accumulate in these chromosomes. And the comparison of HDMA peaks between the GRCh38 and CHM13 human genomes clarified that the sequence of HDMA peaks are higher variable with exhibiting repeat motifs expanding or contacting dramatically, this is consistent with many former observation that STRs are liable to mutation through repeat units expanding or contacting [45][46][47], indicating that the variation of HDMA peaks probably affect regulatory and then related to variation of gene expression profiles, and further may act to human phenotypes and human variation.…”

“…Microsatellites are increasingly realized to have biological significance in human genome and health, and are reported to involve in more than 30 disorders and several cancers (Kim et al 2013; Hause et al 2016; Priestley et al 2019; van Wietmarschen et al 2020), regulate gene expression in healthy genomes (Gymrek et al 2016; Quilez et al 2016), and also be related to genetic plasticity and missing heritability (Verstrepen et al 2005; Fondon et al 2008; Hannan 2010; Nasrallah et al 2012; Willems et al 2014; Mallick et al 2016; Gymrek et al 2017; Willems et al 2017). Slipped-strand mispairing was suggested as a major mechanism for tandem repeat occurrence (Levinson and Gutman 1987; Schlötterer and Tautz 1992), and we formerly presented a folded slippage model for short tandem repeats occurring mechanism, predicting that micro-disturbing in the process of replication may provide a lot of chances for the template chain folded to produce short tandem repeats, which are possibly selected and fixated for different biological significance in the long-history evolution (Zhang et al 2020).…”

ULTRA-Effective Labeling of Repetitive Genomic Sequence

“…Biological sequences are complex and full of subtle patterns; however, one of the most common patterns is not subtle at all: tandem repeats. Tandem repeats are a class of biological sequences that, for various reasons [1][2][3][4], consist of multiple adjacent copies of some core repetitive unit. "AACAACAACAACAACAACAACAAC" is an example of a short tandem repeat composed of an "AAC" unit repeated 8 times.…”

“…An assortment of repeat expansion mechanisms is responsible for the various classes of tandem repeats. Short tandem repeats [ 5 ] are primarily caused by replication slippage [ 1 , 6 ] and have small repetitive units from 1 to 6 bp, which can repeat to span up to hundreds of bp [ 7 , 8 ]. Minisatellites [ 9 ] are a larger sort of tandem repeat, having units between 6–60 bp and occupying regions as large as 20 kb [ 10 ].…”