In the world, there is one group of scientific researchers, which named Molecular evolutionist, these people have a fascinate magic that can ascertain the divergence age between two species based on the DNA sequences. Using the divergence time between Human and Chimpanzee as an example, Chen and Li1 estimate the divergence time is 4.6 to 6.2 million years ago (MYs), while Glazko and Nei2 infer the divergence time is around 6 MYs (with a range of 5–7). These two different researches come to an almost same result; in addition, around 1000 different researches cited these two papers, imply this result convinced most scientists and should be a truth.
Molecular evolutionist can never siting nearby, watching the Human and Chimpanzee diverge from the common ancestor at 6MYA, so, how can they get their magic play on the story, how can they know the reality based on these tiny molecular material? The answer is the substitution rate, which is just like a clock, set to the same pace as the time itself, measuring the evolution force working on the genomic DNA in stillness. In 1968, Kimura Motoo3 published his famous Neutral theory of molecular evolution, which was considered to be a big challenge to the Darwin’s Nature selection theory at first, but finally, most scientist are convinced that this theory is a specific scope based on the molecular level, and is compatible to the Darwin’s Nature selection theory, and then, this neutral theory become a solid foundation for the substitution rate theory and molecular clock theory, and make this molecular evolution field become one of the prosperous scientific aspects. Through the 1980s and 1990s, dozens models and tests are presented to evaluated to substitution rate and to detect the genes which are not belong to neutral evolution, like the simplest JC69 model4, K80 model5 and HKY85 model6, like the Tajima’s D test7, Fu and Li test8 and MK-test9. Although more than 30 years have passed, people still are full of enthusiasm about using these models and tests, especially when using them to detect positive selected genes.
Generally, people believe that when the substitution ratio Ka/Ks >>1, the compared gene is under positive selection10, which means that this gene allele has some advantageous compare to ancient copy that will help the organism to adaptive the environment. That also means that these positive selected genes have a larger probability to be an essential gene during the evolution. The molecular evolutionists are so successful on introducing their outcomes to other filed researchers, and especially to the functional research scientists, most of these functional scientists are willing to use these models and tests to confirm their own cases, however, the molecular evolutionists failed at attracting the functional scientists to understand the complex formula and the complex parameters, to a certain extent, the functional scientists, even few of the molecular evolutionist, are not so clear about some items, like the Ka/Ks vs dN/dS.
Including me, except the moments that just finish checking the literature, I always will feels chaos about these two substitution rate ratio. Generally, I will consider they are totally the same; they are just using the different characters to denote the same meaning. But meanwhile, some scientists insist they have some subtle differences. Finally, I felt boredom to this question, and then go to check the very original paper, to check out the truth.
The “Wikipedia” define the Ka/Ks ratio (or ω) and the dN/dS as a same item, which is the ratio of the number of Nonsynonymous substitutions per non-synonymous site (Ka, dN) to the number of synonymous substitutions per synonymous site (Ks, dS).
And also, I accidentally download a mid-term test and answer from the website, which has the question “What is the difference between the Ka/Ks ratio and the Dn/Ds ratio”, and the answer is “Ka/Ks is the ratio of the numbers of nonsynonymous to synonymous substitution since divergence of two sequences while Dn/Ds is the ratio of the rate of nonsynonymous to synonymous substitution since divergence of two sequences”.
I tried to trace back to the initial papers which used these characters, and the results turn out the Ka/Ks was presented at 198511 (LWL85) and dN/ds was presented at 198612 (NG86), whit the clear definition: “Let Ks be the number of (synonymous) substitutions per synonymous site and Ka the number of (nonsynonymous) substitutions per nonsynonymous site” and “the number of synonymous substitutions (dS) and nonsynonymous substitutions (dN) per site”. Although, I noticed that Takashi Miyata and Teruo Yasunaga13 had used the Ka and Ks in their paper in 1980, but the definition inside is “Amino acid difference (Ka) and synonymous difference (Ks)”, which is not the same as we used in present. So, the definition in LWL8511 and the definition in NG8612 are the original definition for the Ka/Ks and dN/dS, which formula is:
Based on these complex calculation formulas, and based on the mutation rate estimated from well-known proteins, and the fossil adjustment on the molecular clock, the molecular evolutionist can play their magic, to tell us the divergence time between any species.
Reference:
1. Chen, F. C. & Li, W. H. Genomic divergences between humans and other hominoids and the effective population size of the common ancestor of humans and chimpanzees. American journal of human genetics 68, 444–56 (2001).
2. Glazko, G. V. Estimation of Divergence Times for Major Lineages of Primate Species. Molecular Biology and Evolution 20, 424–434 (2003).
3. Kimura, M. Evolutionary rate at the molecular level. Nature 217, 624–6 (1968).
4. Jukes, T. & Cantor, C. Evolution of Protein Molecules. (1969). at <http://www.citeulike.org/user/adijr/article/1673661>
5. Kimura, M. A simple method for estimating evolutionary rates of base substitutions through comparative studies of nucleotide sequences. Journal of molecular evolution 16, 111–20 (1980).
6. Hasegawa, M., Kishino, H. & Yano, T. Dating of the human-ape splitting by a molecular clock of mitochondrial DNA. Journal of molecular evolution 22, 160–74 (1985).
7. Tajima, F. Statistical method for testing the neutral mutation hypothesis by DNA polymorphism. Genetics 123, 585–95 (1989).
8. Fu, Y. X. & Li, W. H. Statistical tests of neutrality of mutations. Genetics 133, 693–709 (1993).
9. McDonald, J. H. & Kreitman, M. Adaptive protein evolution at the Adh locus in Drosophila. Nature 351, 652–4 (1991).
10. Hurst, L. D. The Ka/Ks ratio: diagnosing the form of sequence evolution. Trends in genetics : TIG 18, 486 (2002).
11. Li, W. H., Wu, C. I. & Luo, C. C. A new method for estimating synonymous and nonsynonymous rates of nucleotide substitution considering the relative likelihood of nucleotide and codon changes. Molecular biology and evolution 2, 150–74 (1985).
12. Nei, M. & Gojobori, T. Simple methods for estimating the numbers of synonymous and nonsynonymous nucleotide substitutions. Molecular biology and evolution 3, 418–26 (1986).
13. Miyata, T. & Yasunaga, T. Molecular evolution of mRNA: a method for estimating evolutionary rates of synonymous and amino acid substitutions from homologous nucleotide sequences and its application. Journal of molecular evolution 16, 23–36 (1980).