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.

Fig. 1

A high percentage of STRs in genomes and genomes probably tend to produce repeats. a STR percentages of 55 randomly-selected reported segments and the control group, which were the sequences generated with the same nucleotide numbers and components as those of the 55 selected reported segments but the random nucleotide orders by a program written in C language. b Contradiction analysis of disappearance and high percentage of STRs in the genomes

Fig. 2

Straight strand models of semi-conservative replication and slippage. a The space of a nucleotide was drawn. * indicates that those number is the theoretical values (top); The stable straight model of semi-conservative replication (middle); The comparison of hydrogen bond and 3′-5′ phosphodiester bonds (bottom) [–57]. ^# indicates the strength ratio was calculated by the strength of hydrogen bond dividing that of phosphodiester bond. b The impossible straight slippage models of mononucleotide, dinucleotide and trinucleotide repeats according to the strict geometric calculation of the space of a nucleotide and the stability of hydrogen and phosphodiester bonds

Fig. 3

The DNA chain is highly curved or folded in the nucleus and the impossible curved slippage model. a Schematic diagram of the size of the nuclear space (top) [61]; The normal replicating enzymes complex straighten the DNA chain, while the disturbed replicating enzymes complex may cause the DNA molecule return to curved state (bottom). b Impossible curved template slippage model according to the strict geometric calculation of the space of a nucleotide and the stability of hydrogen and phosphodiester bonds (top); Mono- and dinucleotide repeats may be impossibly produced in curved replicating strands (middle and bottom)

Fig. 4

Stable folded slippage models of mononucleotide to hexanucleotide repeats amplification according to the strict geometric calculation of the space of a nucleotide and the stability of hydrogen and phosphodiester bonds. Repeat units tend to be expanded in the replicating strands when the template strands are on the inner side of the folded slippage models respectively. The bottom 3 sub-figures were the folded slippage models in three-dimensional helix form

Fig. 5

Stable folded slippage models of mononucleotide to hexanucleotide repeats contraction according to the strict geometric calculation of the space of a nucleotide and the stability of hydrogen and phosphodiester bonds. Repeat units tend to be subtracted in the replicating strands when the template strands are on the outside of the folded slippage models respectively. The bottom 3 sub-figures were the folded slippage models in three-dimensional helix form

Fig. 6

Repeat production incline to expansion. F^o, Fⁱ refer to the force required for the two template strands to bend, respectively. F^o > Fⁱ means that the force of the template strand bending downward is greater than the bending upward, and P^e > P^c means that the possibility of the template strand bending upward is greater than the downward bending