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Prebiotically plausible mechanisms increase compositional diversity of nucleic acid sequences.

Derr J, Manapat ML, Rajamani S, Leu K, Xulvi-Brunet R, Joseph I, Nowak MA, Chen IA - Nucleic Acids Res. (2012)

Bottom Line: However, ribonucleotides vary greatly in synthetic yield, reactivity and degradation rate, and their non-enzymatic polymerization results in compositionally biased sequences.Our work suggests that prebiotically plausible chemical mechanisms of nucleic acid polymerization and ligation could predispose toward a diverse pool of longer, potentially structured molecules.Such mechanisms could have set the stage for the appearance of functional activity very early in the emergence of life.

View Article: PubMed Central - PubMed

Affiliation: FAS Center for Systems Biology, Harvard University, Cambridge, MA 02138, USA.

ABSTRACT
During the origin of life, the biological information of nucleic acid polymers must have increased to encode functional molecules (the RNA world). Ribozymes tend to be compositionally unbiased, as is the vast majority of possible sequence space. However, ribonucleotides vary greatly in synthetic yield, reactivity and degradation rate, and their non-enzymatic polymerization results in compositionally biased sequences. While natural selection could lead to complex sequences, molecules with some activity are required to begin this process. Was the emergence of compositionally diverse sequences a matter of chance, or could prebiotically plausible reactions counter chemical biases to increase the probability of finding a ribozyme? Our in silico simulations using a two-letter alphabet show that template-directed ligation and high concatenation rates counter compositional bias and shift the pool toward longer sequences, permitting greater exploration of sequence space and stable folding. We verified experimentally that unbiased DNA sequences are more efficient templates for ligation, thus increasing the compositional diversity of the pool. Our work suggests that prebiotically plausible chemical mechanisms of nucleic acid polymerization and ligation could predispose toward a diverse pool of longer, potentially structured molecules. Such mechanisms could have set the stage for the appearance of functional activity very early in the emergence of life.

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Proposed prebiotic scenario. Monomers first concatenate into compositionally biased short oligomers. When the oligomers are long enough to act as templates, template-directed ligation produces relatively long, compositionally diverse sequences. These sequences can fold into stable structures, some of which may be catalytically active, leading to the RNA world.
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gks065-F4: Proposed prebiotic scenario. Monomers first concatenate into compositionally biased short oligomers. When the oligomers are long enough to act as templates, template-directed ligation produces relatively long, compositionally diverse sequences. These sequences can fold into stable structures, some of which may be catalytically active, leading to the RNA world.

Mentions: While it may be possible to imagine scenarios where different biases cancel one another to produce complex pools, such finely tuned rates are unlikely in real systems. Based on our results using two-letter simulations and template-dependent DNA ligation, we can suggest the following prebiotic scenario (Figure 4). Initially the sequence pool would consist of short, highly compositionally biased sequences resulting from differences in reactivity among the nucleotides. However, once these sequences become long enough to serve as templates (length ≥ 6), the general mechanism of template-directed ligation would favor propagation of internally diverse sequences. A small increase in diversity would correspond to an exponentially large increase in the fraction of sequence space that would be explored. One should note that the optimal compositional diversity for forming secondary structures may be less than the maximum possible. For example, compositional bias toward GC-rich sequences may be a reasonable criterion for identifying non-coding RNAs in the genome due to the effect on folding stability (67), although formal structure itself does not appear to be a good criterion (perhaps because the compositional diversity of a genome tends to be fairly high, giving a relatively large probability of forming structures). Nevertheless, it is unclear whether the bias from prebiotic processes would be in the correct direction to favor structures, and it would still be desirable to increase diversity over the substantial ∼10-fold initial compositional bias estimated for prebiotic reactions. As the compositional bias disappeared, well-folded sequences could emerge. In addition, template-directed ligation would rapidly stitch together short sequences to produce a qualitative shift toward long sequences. The combined effects on diversity and length would enable the generation of ribozymes. These first inefficient ribozymes could then ‘jump-start’ the evolution of sequences with greater function and complexity through natural selection, especially within a spatially restricted context (44,63,68).Figure 4.


Prebiotically plausible mechanisms increase compositional diversity of nucleic acid sequences.

Derr J, Manapat ML, Rajamani S, Leu K, Xulvi-Brunet R, Joseph I, Nowak MA, Chen IA - Nucleic Acids Res. (2012)

Proposed prebiotic scenario. Monomers first concatenate into compositionally biased short oligomers. When the oligomers are long enough to act as templates, template-directed ligation produces relatively long, compositionally diverse sequences. These sequences can fold into stable structures, some of which may be catalytically active, leading to the RNA world.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3378899&req=5

gks065-F4: Proposed prebiotic scenario. Monomers first concatenate into compositionally biased short oligomers. When the oligomers are long enough to act as templates, template-directed ligation produces relatively long, compositionally diverse sequences. These sequences can fold into stable structures, some of which may be catalytically active, leading to the RNA world.
Mentions: While it may be possible to imagine scenarios where different biases cancel one another to produce complex pools, such finely tuned rates are unlikely in real systems. Based on our results using two-letter simulations and template-dependent DNA ligation, we can suggest the following prebiotic scenario (Figure 4). Initially the sequence pool would consist of short, highly compositionally biased sequences resulting from differences in reactivity among the nucleotides. However, once these sequences become long enough to serve as templates (length ≥ 6), the general mechanism of template-directed ligation would favor propagation of internally diverse sequences. A small increase in diversity would correspond to an exponentially large increase in the fraction of sequence space that would be explored. One should note that the optimal compositional diversity for forming secondary structures may be less than the maximum possible. For example, compositional bias toward GC-rich sequences may be a reasonable criterion for identifying non-coding RNAs in the genome due to the effect on folding stability (67), although formal structure itself does not appear to be a good criterion (perhaps because the compositional diversity of a genome tends to be fairly high, giving a relatively large probability of forming structures). Nevertheless, it is unclear whether the bias from prebiotic processes would be in the correct direction to favor structures, and it would still be desirable to increase diversity over the substantial ∼10-fold initial compositional bias estimated for prebiotic reactions. As the compositional bias disappeared, well-folded sequences could emerge. In addition, template-directed ligation would rapidly stitch together short sequences to produce a qualitative shift toward long sequences. The combined effects on diversity and length would enable the generation of ribozymes. These first inefficient ribozymes could then ‘jump-start’ the evolution of sequences with greater function and complexity through natural selection, especially within a spatially restricted context (44,63,68).Figure 4.

Bottom Line: However, ribonucleotides vary greatly in synthetic yield, reactivity and degradation rate, and their non-enzymatic polymerization results in compositionally biased sequences.Our work suggests that prebiotically plausible chemical mechanisms of nucleic acid polymerization and ligation could predispose toward a diverse pool of longer, potentially structured molecules.Such mechanisms could have set the stage for the appearance of functional activity very early in the emergence of life.

View Article: PubMed Central - PubMed

Affiliation: FAS Center for Systems Biology, Harvard University, Cambridge, MA 02138, USA.

ABSTRACT
During the origin of life, the biological information of nucleic acid polymers must have increased to encode functional molecules (the RNA world). Ribozymes tend to be compositionally unbiased, as is the vast majority of possible sequence space. However, ribonucleotides vary greatly in synthetic yield, reactivity and degradation rate, and their non-enzymatic polymerization results in compositionally biased sequences. While natural selection could lead to complex sequences, molecules with some activity are required to begin this process. Was the emergence of compositionally diverse sequences a matter of chance, or could prebiotically plausible reactions counter chemical biases to increase the probability of finding a ribozyme? Our in silico simulations using a two-letter alphabet show that template-directed ligation and high concatenation rates counter compositional bias and shift the pool toward longer sequences, permitting greater exploration of sequence space and stable folding. We verified experimentally that unbiased DNA sequences are more efficient templates for ligation, thus increasing the compositional diversity of the pool. Our work suggests that prebiotically plausible chemical mechanisms of nucleic acid polymerization and ligation could predispose toward a diverse pool of longer, potentially structured molecules. Such mechanisms could have set the stage for the appearance of functional activity very early in the emergence of life.

Show MeSH
Related in: MedlinePlus