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. 1998 Mar 31;95(7):3708-13.
doi: 10.1073/pnas.95.7.3708.

Positive Darwinian selection after gene duplication in primate ribonuclease genes

J Zhang  1 , H F Rosenberg, M Nei
Affiliations

Positive Darwinian selection after gene duplication in primate ribonuclease genes

J Zhang et al. Proc Natl Acad Sci U S A. .

Abstract

Evolutionary mechanisms of origins of new gene function have been a subject of long-standing debate. Here we report a convincing case in which positive Darwinian selection operated at the molecular level during the evolution of novel function by gene duplication. The genes for eosinophil cationic protein (ECP) and eosinophil-derived neurotoxin (EDN) in primates belong to the ribonuclease gene family, and the ECP gene, whose product has an anti-pathogen function not displayed by EDN, was generated by duplication of the EDN gene about 31 million years ago. Using inferred nucleotide sequences of ancestral organisms, we showed that the rate of nonsynonymous nucleotide substitution was significantly higher than that of synonymous substitution for the ECP gene. This strongly suggests that positive Darwinian selection operated in the early stage of evolution of the ECP gene. It was also found that the number of arginine residues increased substantially in a short period of evolutionary time after gene duplication, and these amino acid changes probably produced the novel anti-pathogen function of ECP.

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Figures

Figure 1
Figure 1
Evolutionary tree of primate ECP and EDN genes. The root of this tree is located on the branch linking node a and the NW monkey tamarin if we use mouse sequences (54, 55) as outgroups. The gene duplication occurred at node a. (A) The b̂N and b̂S for each branch are presented as b̂N (×100)/b̂S (×100) above the branch. The standard errors of b̂N and b̂S are 0.0176 and 0.0151 for the branch a–b and 0.0108 and 0.0056 for the branch d–e, respectively. The statistical significance of the positiveness of b̂N − b̂S was determined by one-tailed Z test and is indicated by asterisks (∗∗, 1%). (B) The numbers of nonsynonymous (n) and synonymous (s) substitutions per sequence per branch are presented as n/s above each branch. The N/S ratio for the sequences is given above the tree. The statistical significance of the difference between n/s and N/S was tested by Fisher’s exact test (Table 1).
Figure 2
Figure 2
Amino acid sequences of present-day and ancestral ECP and EDN proteins. Amino acids are presented by single-letter codes, and dots show the same amino acids as those of the sequence at node a. The arginine (R) residues of ECP and EDN are shown in bold type when they are not identical with those of the ancestral protein at node a. Ambiguous amino acid sites of ancestral sequences at nodes a, b, and c are underlined, where the posterior probability of the most likely amino acid is lower than twice the probability of the second most likely amino acid. The alternative amino acids at the underlined sites were K, R, M, T, Q, N, and T for sites 28, 72, 87, 88, 104, 111, and 113, respectively. These ambiguities occurred almost always at the sites where the orangutan ECP and EDN have the same amino acids but different ones from those of the other orthologous sequences. The overall accuracies (posterior probabilities) of the ancestral proteins were 0.96, 0.97, and 0.98, for nodes a, b, and c, respectively.
Figure 3
Figure 3
Evolution of the novel anti-pathogen toxicity and arginine changes in ECP. Each circle represents one arginine residue in ECP or EDN sequences (see Fig. 2). For the present-day proteins, only the numbers of arginines for human sequences are presented. The average number of arginines for OW monkeys and hominoids is 18.2 for ECP and 7.6 for EDN. The pI value for each protein is also presented. The numbers of amino acid changes to arginines in the branches a–b and a–c in Fig. 1 are given alongside the arrow signs. The numbers of changes from arginines to other amino acids are given in parentheses. MY, million years.
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