Why did Nature settle on just four nucleotides?


 The language of life has limited characters. Just four letters A, T, G and C (short for adenine, thymine, guanine and cytosine) make up the genetic material in every organism. Of course, U (uracil) replaces T in the RNA. It is not too hard to imagine the pre-biotic soup consisting of many such molecules, which could have been the contenders to carry genetic information. DNA would have been selected among these for obvious reasons. Many xeno-nucleotides (XNAs) have been synthesized in the lab and shown to be capable of heredity and evolution. There are also PNAs (peptide nucleic acids), which have proteins in their backbones and are heralded as a boon to nano-medicine. Why, then, nature settled on just four nucleotides? One thing that we can be sure of is that odd number of nucleotides are not feasible due to complementary base pairing.

“If you want to understand life, think not of throbbing gels, think of information technology”

Richard Dawkins

Parity-bit interpretation of nucleotides

Donall Mac Donaill, an Irish scientist, came up with a paper in 2002 that was too obvious to have been ignored this long. He represented each of the nucleotides in four bits. The first three bits represented the possible interactions a nucleotide can have with its complementary nucleotide and the fourth bit represented the ring. The hydrogen donating interactions were represented as 1 and accepting as 0. The pyrimidines got a 0 and the purines a 1. The nucleotides T, C, G, A were, hence, denoted as 0101, 1001, 0110 and 1010 respectively. The bits were also in accordance to complementary base pairing (for example A=T is 1010=0101). But, for four bits a nucleotide, there exist 24 = 16 possible nucleotides. These are also chemically possible.

Notice the nature of the bonds formed between the complementary bases
Notice the nature of the bonds formed between the complementary bases

Luckily, Donaill had a background in computers. He knew about a system developed in the Bell Labs in the ’50s which added to an extra bit to the end of each signal to make the sum of digits either odd or even (as agreed upon earlier by the sender and the receiver . Any error in the signal changed the sum of the signal and, hence, the receiver knew something had gone amiss. For instance, this is the signal to be sent is:

001 110 101 010 111 011

Adding a parity bit to make each signal subset evenly summed:

0011 1100 1010 0101 1111 0110

Any deviation from this and the reciever knows that the signal is erred. This system is employed in nearly everything from credit cards to online trading.

Donaill argued that nature had a similar check on nucleotides. But, wouldn’t it be easier to code the four nucleotides by 2 bits (00, 01, 11, 00) ?

DNA processing: relative speeds

Why would nature like more pairs of nucleotides? Why wouldn’t it so?

Greater the number of nucleotides, greater would be the diversity because of more permutations and combinations in the DNA sequence. But, more cumbersome would it be for the cells to manage relatively equal concentrations of each nucleotide (I know the nucleotides aren’t present in equal amounts in a DNA sequence, but the cell doesn’t know that and it must keep relatively equal amounts of each nucleotide at disposal). Does limiting the number of nucleotides to just four balance the diversity aspect to the cost? Yes.

Suppose there were only two nucleotides. They would be denoted as 0 and 1and their relative concentrations would be half. For any processing of DNA (anywhere the DNA sequence needs to be run linearly: replication, transcription or translation), the processing speed would be 1 bit X 0.5 relative concentration = 0.5 bit per unit time.

For the naturally occuring scenario, each nucleotide can be denoted by 2 bits and has a relative concentration of one-fourth. Thus, processing speed is 2 bits X 1/4 relative concentration = 0.5 bit per unit time. For 6 nucleotides, the processing speed would be log26 X 1/6 relative concentration = 0.43 bit per unit time. For 8 nucleotides, the processing speed would be log28 X 1/8 relative concentration = 0.37 bit per unit time. As the number of nucleotides increases, the processing speed drops gradually. The best speed was in the cases of 2 or 4 nucleotides. Of these, 4 nucleotides can accommodate greater diversity.

Conclusion

The balance between processing speed and possible variation seems to me the plausible reason why nature settled on just four nucleotides. I expressed the processing speed in per unit time and did not say anything on how much the unit was because that varies across species and the process concerned. This is something like Mendel’s factors in the late 1800s; deducted based on pure mathematical reasoning with physical proof yet to be validated. Also, for 2 bits per nucleotide, the entire human nuclear genome (with 3.2 billion base pairs) can be represented in just 756 MB of computer memory.

Read more here:

  1. Donaill, D. M., A parity code interpretation of nucleotide alphabet composition, Chemical Communications (Cambridge), Sep 21,2002
  2. “Why does DNA only use four nucleotides”? on Carl Brannen’s blog.
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5 thoughts on “Why did Nature settle on just four nucleotides?

    1. These encoding are not reflected by DNA methylation, but vice versa. DNA methylations are a way to increase protein diversity. There are only 30,000-100,000 genes while a lot many proteins.

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