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

- Relatively semi-conservative replication and a folded slippage model for short tandem repeats.
- 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.
- Short tandem repeats (STRs), also referred as simple se- quence repeats (SSRs), have attracted increasingly great interests in recent decades [1 – 7], and have been widely analyzed in the sequences of eukaryotic, prokaryotic and.
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- Though STRs have been comprehensively researched, there is actually no precise definition or wide-convinced standard for the extraction of STRs all the time, which is usually based on setting the minimum numbers of the iterations for the mononucleotide to hexanucleotide repeats based on empirical criterion .
- It was suggested that the STRs are most possibly born in the process of replication [5].
- and proposed a folded replication slippage model for explaining repeats occurrence, which seems more reasonable to explain the remaining of high percentage short repeats in genomes, and also to explain the frequent STR expan- sion and contraction.
- and proposed a folded replication slippage model for explaining repeats occurrence, which seems more reasonable to explain the remaining of high percentage short repeats in genomes, and also to explain the frequent STR expansion and contraction.
- Since all these segments were randomly selected from their genomes, our results suggested that the high content of short STRs is a general feature of all organism genomes after long time evolution, and that the few formerly well-studied repeats may only stand for the proverbial tip of the iceberg .
- The null hypothesis test demonstrated that the percentages of STRs in the generated segments are all lower than those in the reported segments, indicating that the high percentages of short STRs preserved valu- able signals in all reported segments..
- According to the former stated theories, any ordered sequences such as STRs would mutate into disordered sequences in the long evolutionary history without the presence of selective pressure.
- This theory alone would result in the dilution of STRs and cannot explain the universal presence of preserved high content of STRs in genomes.
- Some of the longer STRs also possibly mutate into short STRs by contraction and point mutation as debated by many evolutionists and these debates are possible because most short repeats were not considered in their statistics.
- 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.
- It is well known that each base pair of DNA is a one-to- one correspondence without other extra residue during replication in the double-helix model [38, 39].
- And Meselson and Stahl have verified that the replication of DNA chains is semi-conservative by sedimentation tech- niques based on the diversity differential of DNA with different isotopes, implicating that the number of nucle- otides in the replicating strand is consistent with that in the template strand during a complete replication.
- However, if the preserved high content of short repeats is produced during replication as described above, the number of nucleotides in the replication strand would be one or several nucleotides/motifs higher than that in the template strand.
- In vitro experiments also revealed the presence of repeats during DNA repli- cation, and the nascent replication chain has an increase in the number of nucleobases .
- In the case of our relatively semi-conservative replication model, the replication process can be described as the following formula:.
- ¼ int ½ N 0 f i λ i ð 1 þ f 1 λ 1 Þ ð 1 þ f 2 λ 2 Þ… ð 1 þ f i − 1 λ i − 1 Þ ≥ 0 ð 2 Þ N 0 : The number of nucleotides in the initial template strand;.
- N i : The number of nucleotides in the replicating strand during No.
- ΔN i : The difference of the nucleotide numbers between N i and N i-1.
- In general, the number of nucleotides in the replicat- ing strand is likely to have exactly equal to that in the template strand.
- For example, the total number of nucleotides in the initial template strand for stable PCR is up to two to three thousand nucleotides.
- Nevertheless, when the observed strand is long enough to result in a ΔN i of larger than 1, our model would explain how the number of nucleotides in the replicating strand changes from that in the template strand.
- For instance, when we suppose N λ f 1 = 1, the value of ΔN 1 would be 10, which could result in the increase of 10 nucleotides (or repeat- motifs) in the replicating strands when compared with the template strand.
- Table 1 The lengths (bp) of STRs with different repeat unit types and different iterations in the segment of the reported human reference X chromosomal sequence at the location of bp.
- We use f i to represent the fixation pos- sibility of the nascent repeats under selective pressure.
- 1 indi- cates that the nascent STRs are deleterious but still can be fixed in the genome with survived offspring, like Hunting- ton’s disease [14].
- This suggests that the replication process may be relatively semi-conservative..
- Folded slippage model.
- The existing slippage model is indeed a straight template strand model, with no plausible consideration regarding the space required for the nascent nucleobase, the much stronger phosphodiester bonds when compared with hydrogen bonds (Fig.
- The straight replication slippage model suggests that the STRs possibly occurred by slippage occasionally but is rather ambiguous about further details in the mechan- ism.
- 33, T: 33, G: 34, C which possess a certain phys- ical space in the molecule.
- We re- constructed the linear replication slippage model with a CAD geometric calculation by considering the space of bases (Fig.
- Since it is impossible to form a slippage bubble by a larger elong- ation of the phosphodiester bonds to accommodate the nascent repeat unit, the straight slippage model is insuffi- cient to explain to the occurrence of short repeats and a more sophisticated slippage model should be proposed..
- Actually existing replication slippage studies has largely overlooked the validity of the straight template strand as- sumption in the replication process – the template strands are thought to be perfectly straight in all replication models.
- It is well known that the dimension of fully unfolded and extended genomic DNA chains are sev- eral magnitudes higher than the dimension of the nucleus (Fig.
- Therefore, the gen- omic DNA chains are generally highly compacted and folded in the nucleus.
- However, environmental factors such as temperature, viral proteins or diseases may disrupt the normal works of the enzyme complexes.
- We speculate that such disruption of the enzyme complex may cause both the replicating strand and the template strand to regain their curved or folded state, resulting in the emergence of provisional kinked strands..
- First, we proposed a curved template slippage model for the replication process.
- O [55], with a strength at about 3% of the 3′, 5′-phosphodiester bonds .
- While the distance between the bases is fixed at the backbone, the strengths of the hydrogen bonds are negatively correlated to the distance between every base pair.
- The curved slippage model partially explains the spaces that form slippage bubble, yet at the cost of forming unstable hydrogen bonds double- chain structures (Arm1 and Arm2) on both sides of the slippage bubble (Fig.
- Then we proposed a folded slippage model.
- The phosphodiester bonds are fixed and the bases are well paired with stable hydrogen bonds on both sides of the slippage bubble (Fig.
- Actually, there are two variations of the folded slip- page models: When template strand is on the inner side, the repeat unit duplicates to produce new repetitive unit or repeat expansion (Fig.
- The features of this folded slippage model can explain the widely observed STR mutations with expansion and contraction of repeat.
- 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.
- In addition, replication slippage of template strands with different folding angles may result in the expansion or contraction of repeat units with differ- ent sizes.
- These features of our folded slippage model can explain the emergence of short tandem repeats which usually refers to the tandem repeats with repeat units from mono- to hexanucleotides .
- Such long tandem repetitive sequences are unlikely to occur since the energy to break off 14–30 hydrogen bonds are on the same scale as the energy to break off one phosphodiester bond, which explains the observations that they are often much less abundant in the genomes [59, 67].
- Our folded slippage model can also explain how the (A m T n ) repeats tend to grow faster than (G m C n ) repeats.
- 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].
- 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).
- because smaller number of broken hydrogen bonds in the (A m T n ) repeats impose lower energy barrier for repeat ex- pansion .
- We also build a simplified double- helical model in three-dimensional forms to show the folded slippage model more intuitively (Figs.
- When compared with the straight template slippage model, the folded template model exhibits enough geo- metric space in the slippage bubble to accommodate re- peat nucleotides without stretching the phosphodiester bonds.
- When compared with the curved template model, the folded model has two sides of the slippage bubble stably paired, and has Arm1 and Arm2 similar to the straight template replication model at both sides (Figs.
- The folded model takes full account of the space required by nucleotides, the stability of phosphodiester bonds, and the strength comparison between.
- This model can explain STR mutations with repeat unit expansion and contraction, and provides a plausible explanation for the production of short repeats production in the repli- cating process which otherwise neither the straight slip- page model nor the curved slippage model can explain..
- The folded template strand slippage model may be re- sponsible for the continual production of repeat se- quences and the retention of high percentage of repeat sequences in genomes..
- 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 high content of repeat sequences is still in a stable state in the genome of each species, implicating a higher rate for repeat expansion when compared with repeat con- traction, which is also reported in many other studies .
- while it is on the outer side, the base in the folding position is squeezed inward.
- Compre- hensive consideration of the small difference of the.
- F i suggests that the probability for the template strand folded on the inner side is higher than that on the outer side.
- Our folded slippage model suggested that the repeats tend to expand when the template strand is on inner side and tend to contract when the tem- plate strand is on the outer side.
- When the template strand on the outer side, repeats tend to contract, so λ c <.
- 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.
- When the template strand on the inner side, repeats tend to expand, so λ e >.
- F i 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.
- We improved the straight slippage model to a folded slippage model by fully considering the geometric spaces of nucleotide bases, the relationship between phosphodiester and hydrogen bond, and the stability of these bonds.
- though the long unit repeats may be ex- plained by the former slippage model [33, 59]..
- Most of the emerging repeats should be lethal mutation and may have been negatively selected to lost.
- and some beneficial repeat expansions may promote the emer- gence of different new properties or functions – all of which lead to the abundance of repeat sequences in the genomes with a diversified set of roles as reported in the literature .
- the longer genomes pos- sibly evolved from the short genomes in the long evolu- tionary replicating process..
- We proposed a folded replication slippage model, which provides a reasonable explanation for the continuous occurrences of STRs and their high contents in genomes with improving the exist- ing straight-line slippage model, and this folded replica- tion slippage model also suggests that expansion exists more commonly than contraction in the STRs without the presence of selective pressure.
- We also extracted perfect mono- to hexanucleotide re- peats under the above threshold in the sequences that were generated by a program written in C language (Program S1).
- The nucleotide compositions and num- bers of the generate segments were the same as those of the selected segments, however, the nucleotide orders of the generate segments were randomly rearranged in the C program.
- Then, the validating test, which can verify that the short STRs extracted in those 55 reported seg- ments are not randomly occurred, was based on the comparison of the STR percentages in the reported seg- ments and the generated segments..
- Then we applied AutoCAD [82] to draw the straight, curved and folded slippage models ac- cording to the strict geometric calculation of the spaces of nucleotides and different strengths between hydrogen bonds and phosphodiester bonds.
- And the slippage.
- The information including accession number of 55 analyzed sequence segments is listed in Table S1 and also available in the following git-hub web link.
- Table S2 is the dataset of STRs with different repeat units and dif- ferent iterations in 55 analyzed segmental sequences under the standard of which are also available in the following git-hub web link.
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