* Department of Genome Sciences, University of Washington
Departments of Biology and Genetics, University of California, Riverside
Department of Biological Statistics and Computational Biology, Cornell University
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Abstract |
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Key Words: positive Darwinian selection sexual conflict fertilization likelihood ratio test speciation
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Introduction |
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We compiled gene alignments from GenBank for several male and female mammalian reproductive proteins (table 1). We analyzed Zonadhesin (Zen, Hardy and Garbers 1995), PH20 (SPAM1, Lin et al. 1993), Fertilin ß (Adam2, Zhu, Bansal, and Evans 2000), Fertilin (Adam1, Wong et al. 2001), CD9 (Miyado et al. 2000), Acrosin (Acr, Baba et al. 1994), Sperm protein 17 (SP17, Richardson, Yamasaki, and O'rand 1994), and ß- galactosyltransferase (gt, Miller, Macek, and Shur 1992). Some of these genes were extremely divergent, and we deleted regions that did not align reliably. The number of sequences we analyzed ranged from 5 to 10 per gene. All alignments are available from the authors on request, and the protein alignments used are available on the Molecular Biology and Evolution journal website as supplementary material (http://www.molbiolevol.org).
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Materials and Methods |
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We, therefore, implemented a new version of the LRT which is robust to the assumptions regarding the distribution of in (0, 1). It has the additional advantage that the asymptotic distribution of the test statistic follows from standard theory in contrast to test I. The test is performed by adding a category of sites with
s = 1 to the null model. The new modified null model M8A then specifies that the distribution of
follows a mixture between a beta-distribution and a point mass at
= 1. Model M8A is then compared with a version of model M8, constrained such that
s
1, using an LRT. The only difference between the models is that under the null model (M8A)
s = 1, whereas in the more general model (M8)
s
1. From standard theory (Chernoff 1954), it follows that the log-likelihood ratio statistic is asymptotically distributed as a 50:50 mixture of a point mass at zero and a
12-distribution.
Test II may in some cases have more power than test I because of the reduction in the degrees of freedom and because the true asymptotic distribution, and not an ad hoc approximation, is used. However, it may in other cases have less power if there exists a category of positively selected sites with a value of that is only slightly larger than one.
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Results and Discussion |
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Sites predicted to be the targets of positive Darwinian selection were identified using an empirical Bayes approach (Nielsen and Yang 1998; Yang et al. 2000). In a few of the proteins studied, the active sites implicated to be involved in sperm-egg interaction have been identified. For example, a disintegrin-like domain in fertilin ß has been implicated in sperm-egg binding (Zhu, Bansal, and Evans 2000). Remarkably, the majority (>90%) of the sites in our analysis predicted to be under positive Darwinian selection with posterior probabilities greater than 0.90 fall in the C-terminal portion of the molecule containing this putative sperm-egg binding domain (see supplementary material: http://www.molbiolevol.org). A similar result was obtained for fertilin (Wong et al. 2001). Although the selective pressure remains unknown, the observation that the sites predicted to be subjected to positive selection fall in putative sperm-eggbinding domains suggests a selective force relating to male-female interaction, in this case fertilization. These results combined with those of earlier studies (Swanson et al. 2001) suggest that evolutionary analyses such as those described in this study may be a powerful way to identify regions with putative functional significance, which could be tested in functional assays.
The finding of a large number of mammalian reproductive proteins being subjected to positive Darwinian selection may have profound implications on studies of fertility. For example, rapidly evolving reproductive molecules could lead to a mismatch in sperm-egg proteins, which could contribute to infertility. This would be analogous to matches in class I major histocompatibility complex molecules necessary for successful skin grafts or matching blood-type groups for blood transfusions. In sea urchins, there is a significant effect of the genotype of reproductive proteins and the success of individual crosses within a population of one species (Palumbi 1999). The sites predicted to be subjected to positive Darwinian selection in this study could be involved directly in sperm-egg interaction and thus may be good targets to develop nonhormonal means of contraception aimed at disrupting sperm-egg interaction. Finally, inclusion of evolutionary diversification may help clarify some of the controversies in mammalian fertilization that have arisen due to diverse experimental observations (Wassarman 1999). Our results suggest that analyses for the coevolution of rapidly evolving male- female reproductive proteins may provide evidence that is consistent with interaction between some of the proposed, yet controversial, sperm-eggbinding pairs. Currently, sufficient data are not available to perform these coevolution analyses.
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Acknowledgements |
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Footnotes |
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Literature Cited |
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