Topics: Amino acid, Gene, Evolution Pages: 24 (5125 words) Published: February 23, 2013
The Nonsynonymous/Synonymous Substitution Rate Ratio versus the Radical/ Conservative Replacement Rate Ratio in the Evolution of Mammalian Genes Kousuke Hanada,*  Shin-Han Shiu,  and Wen-Hsiung Li*

*Department of Ecology and Evolution, University of Chicago; and  Department of Plant Biology, Michigan State University There are 2 ways to infer selection pressures in the evolution of protein-coding genes, the nonsynonymous and synonymous substitution rate ratio (KA/KS) and the radical and conservative amino acid replacement rate ratio (KR/KC). Because the KR/KC ratio depends on the definition of radical and conservative changes in the classification of amino acids, we develop an amino acid classification that maximizes the correlation between KA/KS and KR/KC. An analysis of 3,375 orthologous gene groups among 5 mammalian species shows that our classification gives a significantly higher correlation coefficient between the 2 ratios than those of existing classifications. However, there are many orthologous gene groups with a low KA/KS but a high KR/KC ratio. Examining the functions of these genes, we found an overrepresentation of functional categories related to development. To determine if the overrepresentation is stage specific, we examined the expression patterns of these genes at different developmental stages of the mouse. Interestingly, these genes are highly expressed in the early middle stage of development (blastocyst to amnion). It is commonly thought that developmental genes tend to be conservative in evolution, but some molecular changes in developmental stages should have contributed to morphological divergence in adult mammals. Therefore, we propose that the relaxed pressures indicated by the KR/KC ratio but not by KA/KS in the early middle stage of development may be important for the morphological divergence of mammals at the adult stage, whereas purifying selection detected by KA/KS occurs in the early middle developmental stage.

Selection pressure on protein-coding sequences is
commonly estimated by the ratio of the nonsynonymous
substitution rate (KA) to the synonymous substitution rate
(KS) (Li and Gojobori 1983; Hughes and Nei 1988). If the
KA/KS ratio is higher than 1, positive selection is assumed to have occurred during the evolution of the sequence. The
ratio of the radical replacement rate (KR) to the conservative replacement rate (KC) has also been used to detect positive
selection (Hughes et al. 1990). The KR/KC ratio is useful for examining selection pressure in distantly related proteincoding sequences because the KA/KS ratio cannot be accurately estimated in this case due to saturation of KS

(Gojobori 1983; Smith JM and Smith NH 1996). Because
there are 2 ways of inferring selection pressure on a sequence, an open question is whether these 2 approaches give the same conclusion or not. Zhang (2000) and Smith
(2003) found that KA/KS is correlated with KR/KC based on
the amino acid classification that considers polarity and
volume using 47 mammalian and 25 Drosophila genes.
However, there are several types of amino acid classifications, and it is not known which classification gives a KR/KC measure that best correlates with the KA/KS ratio. Therefore, we do not know the degree of correlation between the 2 ratios in general.

In the present study, we searched for an amino acid
classification that gives the best correlation between the
2 ratios. This amino acid classification is useful because
the KR/KC ratio based on this classification can identify
genes undergoing similar selection pressures inferred by
the KA/KS ratio between distant protein-coding sequences.
Another issue is that it is likely that the 2 ratios are not completely correlated even if the amino acid classification Key words: positive selection, radical substitution, conservative substitution, classification of amino acids, development.

Mol. Biol. Evol. 24(10):2235–2241. 2007...

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Takashi Gojobori, Associate Editor
Accepted July 16, 2007
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