Molecular Biology and Evolution 18:523-529 (2001)
© 2001 Society for Molecular Biology and Evolution
ARTICLE |
Positive and Negative Selection in the DAZ Gene Family
Department of Biology, Galton Laboratory, University College London, London, England
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Abstract |
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Because a microdeletion containing the DAZ gene is the most frequently observed deletion in infertile men, the DAZ gene was considered a strong candidate for the azoospermia factor. A recent evolutionary analysis, however, suggested that DAZ was free from functional constraints and consequently played little or no role in human spermatogenesis. The major evidence for this surprising conclusion is that the nonsynonymous substitution rate is similar to the synonymous rate and to the rate in introns. In this study, we reexamined the evolution of the DAZ gene family by using maximum-likelihood methods, which accommodate variable selective pressures among sites or among branches. The results suggest that DAZ is not free from functional constraints. Most amino acids in DAZ are under strong selective constraint, while a few sites are under diversifying selection with nonsynonymous/ synonymous rate ratios (dN/dS) well above 1. As a result, the average dN/dS ratio over sites is not a sensible measure of selective pressure on the protein. Lineage-specific analysis indicated that human members of this gene family were evolving by positive Darwinian selection, although the evidence was not strong.
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Introduction |
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TOPAbstract IntroductionMaterials and MethodsResultsDiscussionAcknowledgementsliterature cited |
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Azoospermia is the most common form of infertility in human males (Shinka and Nakahori 1996
). A locus on the human Y chromosome, the azoospermic factor (AZF), is believed to contain a gene, or genes, crucial to proper differentiation of male germ cells. The observation that microdeletions at three different loci of AZF occur in 5%–15% of infertile men supports this hypothesis (Ferlin et al. 1999
). One of these loci (AZFc) encodes the Deleted in AZoospermia (DAZ) gene. Because AZFc is the most frequently observed deletion in infertile men, it was considered a strong candidate for the azoospermia factor (Ferlin et al. 1999
). Genes from a number of different pathways, however, are required for normal spermatogenesis (Elliott and Cooke 1997
).
DAZ is located on the Y chromosome, but it is closely related to the autosomal gene DAZL1. While DAZL1 is present in all vertebrates, DAZ is found only in Old World Monkeys. Thus, DAZ [Yq11.23 ] is believed to have evolved via translocation of DAZL1 [3p24] to the Y chromosome (Saxena et al. 1996
; Gromoll et al. 1999
) some time after the divergence of Old and New World monkeys; Kumar and Hedges (1998)
dated that divergence to about 40 MYA. After the translocation event, DAZ underwent a series of rearrangements and a modified copy was amplified, yielding a Y gene cluster.
DAZ and DAZL1 have a functional role in fertility. Both DAZ and DAZL1 are expressed exclusively in germ cells (Cooke et al. 1996
; Ruggiu et al. 1997
; Gromoll et al. 1999
), and in humans DAZ expression is highest in spermatogonia (Menke, Mutter, and Page 1997
). Experimental elimination of DAZL1 in mice results in termination of germ cell development beyond the spermatoginial stage (Ruggiu et al. 1997
). Moreover, Y-encoded human DAZ can compliment the sterile phenotype of DAZL1 null mice, yielding a partial recovery of spermatogenesis, which suggests the same or similar target mRNA for DAZ and DAZL1 during spermatogenesis (Slee et al. 1999
). Although the specific functions of DAZ and DAZL1 are unknown, the presence of RNA recognition motifs suggests that these genes could be involved in controlling the cell cycle switch from mitotic to meiotic cell division (Gromoll et al. 1999
); this cell cycle switch is controlled by RNA-binding proteins in yeast (Watanabe et al. 1997
).
Surprisingly, a recent evolutionary analysis of the DAZ family (DAZ and DAZL1 genes) indicated a lack of functional constraints on DAZ. Agulnik et al. (1998)
found a high rate of nonsynonymous substitution, similar rates between exons and introns, and similar rates among the three codon positions. They concluded that there were no functional constraints on evolution of DAZ and that patterns of sequence divergence were due to neutral drift. They hypothesized that Y-linked DAZ played little role in human spermatogenesis.
The nonsynonymous-to-synonymous rate ratio (dN/ dS) provides a sensitive measure of selective pressure on the protein. However, when selection pressure varies among amino acid sites, the average dN/dS ratio might not be very informative about the evolutionary processes affecting the gene. The objective of this study was to investigate the role of both purifying and positive selection on the DAZ gene family by using maximum-likelihood methods that accommodate differences in selective pressures among sites (Nielsen and Yang 1998
; Yang et al. 2000
). Our findings indicated that DAZ was not free of functional constraints and that other explanations for its rapid rate of nonsynonymous evolution must be considered. There has been considerable debate as to whether rapid evolution in gene families is caused by positive Darwinian selection after gene duplication (Ohta 1993
) or by relaxation, but not complete loss, of functional constraints in redundant genes (Kimura 1983
; Li 1985
). In the latter case, a new function might evolve when formerly neutral substitutions convey a selective advantage in a novel environment or genetic background (Dykhuizen and Hartl 1980
). We also examined variable selective pressures among lineages (Yang 1998
; Yang and Nielsen 1998
), and our findings suggest that both models could have played a role in the evolution of the DAZ gene family.
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Materials and Methods |
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TOPAbstract IntroductionMaterials and MethodsResultsDiscussionAcknowledgementsliterature cited |
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Sequence Data
Two data sets were compiled, reflecting a trade-off between more characters versus more taxa. Data set 1 was composed of 618 bp of DNA sequence (after exclusion of gaps) from five representatives of the DAZ gene family (fig. 1 ). Sequences of DAZL1 were from Homo sapiens (GenBank accession number U066078), Macaca mulatta (AF053608), and Mus musculus (U046694), and sequences of DAZ were from H. sapiens (NM004081) and Macaca fascicularis (AJ012216). Sequences included exons 1–6, A7, C8, and 10. Macaca fascicularis DAZ (AJ012216) contains an intragenic duplication of exons 2–6 and multiple copies of exons 7 and 8. We sampled the 3' copy of exons 2–6, which is 99% similar to the 5' copy. The "A" copy of exon 7 and the "C" copy of exon 8 were sampled because each predates divergence of the human and Macaca lineages (Gromoll et al. 1999
). Data set 1 was used to investigate variation in selective pressure among lineages. To study variation in selective pressure among sites, however, more sequences were needed. Hence, a second data set was compiled consisting of 11 members of the DAZ gene family (fig. 2
), but only 291 bp of DNA sequence. Included in data set 2 were exons 3–5 and portions of exons 2 and 6. This data set was composed almost entirely of the RNA recognition domain, which spans exons 2–5. Data set 2 included DAZL1 from Cebua apella (AF053608), H. sapiens (U066078), M. mulatta (AF053608), and Papio hamadryas (AF053607); a single copy of DAZ from H. sapiens (NM004081), Pan troglodytes (AF072324), and M. fascicularis (AJ012216); and two DAZ clones (C1 and C2) from P. hamadryas (C1: AF07230; C2: AF07321) and M. mulatta (C1: AF072322; C2: AF072323). Clones from P. hamadryas and M. mulatta were divergent copies from a multicopy DAZ array on the Y chromosome (Agulnick et al. 1998
). Saxena et al. (2000)
recently reported that human DAZ genes occur as a four-copy array in the AZFc region of the Y chromosome. However, they found that the four copies differed by only a single, silent, transition in exon 7A, so only one copy was included in our analysis.
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Data Analysis
Tree topologies were estimated using maximum likelihood (ML) under the general time-reversible (GTR) model with a discrete gamma model (d
) of rate variation among sites (Yang 1994a, 1994b
). Trees also were estimated by least-squares from synonymous divergences estimated by ML under a codon model of evolution (Goldman and Yang 1994
). The PAUP* computer program (Swofford 2000
) was used for conducting tree searches.
We implemented four nested models of variable selective pressures among branches (Yang 1998
; Yang and Nielsen 1998
). Model A was the simplest and assumed the same 
ratio for all branches. Models B and C were based on the prediction that a gene family evolves under different selective pressures following gene duplication. Model B assumed two ratios: one for the branch predating the translocation to the Y chromosome (fig. 1
; branch a), and a second for branches postdating the translocation (branches b–g). Model C assumed three ratios: one for branch a, one for DAZL1 branches postdating the translocation (branches b–d), and one for all DAZ branches (branches e–g). Model D (free ratios) assumed an independent ratio for each branch of a topology and was employed to evaluate the potential for positive selection in any one branch of the tree.
ML models (Yang and Nielsen 2000
; Yang et al. 2000
) also permit testing and identification of selective pressures at individual codon sites. We implemented three such models: M3 (discrete), M7 (beta), and M8 (beta&). M3 assumed two site classes with the proportions f0 and f1 and ratios 0 and 1 estimated from the data. M7 assumed that ratios were distributed among sites according to a beta distribution. Depending on parameters p and q, the beta distribution can take a variety of shapes within the interval (0, 1). M8, an extension of M7, added an extra class of sites having an parameter freely estimated from the data. Positive selection was indicated when an parameter of M3 or M8 was >1. The likelihood ratio test was used to compare a one-ratio model (M0) with M3 and to compare M7 with M8. If there were sites with > 1, Bayesian methods were used to calculate the posterior probability that a site fell into each site class; sites with high probabilities for > 1 were likely to be under positive Darwinian selection (Yang et al. 2000
).
All ML analyses of codon models were performed using the codeml program of the PAML package (Yang 1999
). The models employed correction for transition/ transversion rate bias and codon usage bias, features of DNA sequence evolution that have a significant effect on the estimation of substitution rates (Yang and Nielsen 1998, 2000
).
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Results |
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TOPAbstract IntroductionMaterials and MethodsResultsDiscussionAcknowledgementsliterature cited |
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Variable Selection Pressure Among Lineages
Phylogenetic analyses of data set 1 by different tree reconstruction methods yielded the same tree topology (fig. 1 ), and this topology was used to analyze variable selective pressures among lineages. Four models (A–D) were fitted by ML to data set 1 (table 1 ). The estimate of
for model A ( = 0.295) represented an average over all codon sites and branches. Model A was then compared with model B, which assumed that selective constraints changed after translocation of DAZL1 to the Y chromosome. Twice the difference in their likelihood scores (2
) was compared with a 
2 distribution with degrees of freedom equal to the difference between models in number of parameters. This likelihood ratio test indicated that model B provided a significantly better fit to these data (2 = 17.8, df = 1, P = 0.000025). The dN/dS ratio after the translocation, 1 = 0.51, is significantly higher than that prior to the translocation, 0 = 0.10.
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Model B assumed that both autosomal DAZL1 and the copy that was translocated to the Y chromosome (DAZ) experienced the same change in selective constraints after the translocation event. This simple model was compared with a more complex model (model C) in which changes in selective constraints after the translocation were allowed to differ between DAZL1 and DAZ (table 1 ). Estimates under model C indicate very different
values for DAZ and DAZL1 after duplication (table 1
). However, the likelihood of model C was not significantly better than that of model B (2 = 1.12, df = 1, P = 0.29).
Because positive selection at any one point in the phylogeny could have affected our results, we applied the free-ratios model (model D) to the same data. The likelihood score under model D was significantly better than that obtained for model B (2 = 14.2, df = 5, P = 0.014). Branches b, d, and g exhibited values >1 (table 1
). Use of the simpler but less realistic F3x4 model, which calculates codon frequencies by using base composition at the three codon positions, produced similar results. Note that for branch g was slightly less than 1 under the F3x4 model (6 = 0.99), whereas it was greater than 1 under the F61 model (6 = 1.144).
Variable Selection Pressure Among Sites
Phylogenetic analysis of data set 2 under the nucleotide model GTR+d recovered a topology in which divergent copies of DAZ from the same species were not monophyletic, indicating that divergent copies of DAZ originated in an early amplification event and persisted in multiple lineages (fig. 2A
). This result is similar to that obtained in a previous analysis of the DAZ gene family (Agulnik et al. 1998
). We also inferred a tree topology from synonymous divergences (fig. 2B
). This tree, although different from the tree obtained from the nucleotide analysis, also indicated that some copies of DAZ originated from an early amplification event and persisted to the present day. Both trees also indicate a clear bifurcation between all DAZL1 and DAZ sequences, supporting the hypothesis that a single translocation event gave rise to the Y-encoded DAZ. To investigate the impact of tree topology, models of variable values among sites were analyzed using both topologies in figure 2
(table 2 ). The small size of data set 2 (291 bp; 97 codons) prevented use of the parameter-rich model of empirical codon frequencies (the F61 model), and the F3x4 model was used instead.
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The discrete model (M3), which allowed two site classes with independent
ratios, provided a significant improvement over the one-ratio model (M0) regardless of the tree topology assumed (table 3
). The selective pressure is not uniform among amino acid sites. Estimates of parameters under M3 suggest that most sites (95%–97%) are under selective constraint, with 0 = 0.35–0.37, while a few sites (3%–5%) are evolving by positive selection, with 1 close to 6. Both models, M3 and M8, which allowed for the presence of positively selected sites indicated that some variation in selective pressure was due to positive selection (table 2
). Likelihood ratio tests indicated that these models fit the data better than models in which positively selected sites were not allowed (table 3
). It is also noteworthy that regardless of model or topology, values for sites not subject to positive Darwinian selection were well below 1 (table 2 ), indicating evolution by purifying selection.
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Agulnick et al. (1998)
hypothesized that there were no functional constraints on DAZ sequences. To test this hypothesis specifically, we reanalyzed only the DAZ sequences of data set 2. The results were consistent with the previous analysis of data set 2; values for those sites not subject to positive Darwinian selection were well below 1 (e.g., tree 1—discrete model: 0 = 0.43, f0 = 0.93, 1 = 3.4, f1 = 0.07; beta& model—p = 98, q = 122, f0 = 0.94, 1 = 4.1, f1 = 0.06). |
Discussion |
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TOPAbstract IntroductionMaterials and MethodsResultsDiscussionAcknowledgementsliterature cited |
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Maximum-likelihood analysis of the DAZ gene family revealed significant variation in selective pressures among lineages and among sites. The majority of sites are clearly subject to purifying selection, with the nonsynonymous rate being well below the synonymous rate. A small fraction of sites exhibit nonsynonymous rates almost six times the synonymous rate, indicating the action of positive Darwinian selection. Lineage-specific analyses indicated that following the translocation of an autosomal copy of DAZL1 to the Y chromosome, both loci experienced increased rates of nonsynonymous substitution. In DAZL1 this was due, at least in part, to early evolution by positive Darwinian selection. Later, DAZL1 of M. fascicularis returned to evolution by purifying selection, whereas DAZL1 of humans continued to evolve by positive Darwinian selection. Although there was also an increase in nonsynonymous substitution in DAZ, its early evolution was most consistent with purifying selection. Nevertheless, more recent evolution in DAZ shows the same pattern as DAZL1, with human evolution by positive Darwinian selection and M. fascicularis evolution by purifying selection.
Based on an evolutionary analysis of the DAZ gene family, Agulnik et al. (1998)
concluded that there were no functional constraints on the evolution of DAZ in primates and questioned the role of DAZ in human spermatogenesis. Our findings, however, indicate that the majority of sites in DAZ are subject to purifying selection. This notion is supported by the observation of intact reading frames for all the sampled exons of DAZ; there are no frameshift mutations or premature stop codons. Moreover, complementation of sterile-phenotype DAZL1 mice by human DAZ strongly suggests a functional role for human DAZ in spermatogenesis (Slee et al. 1999
). These observations, taken together with expression patterns of DAZ, lead us to conclude that DAZ is not free from functional constraints in primates and that the DAZ gene is likely to have functional importance in human spermatogenesis.
The pairwise approach used by Agulnick et al. (1998)
is the most common method of computing synonymous and nonsynonymous rates. This approach, however, averages rates over all sites and also over the entire time interval that separates a pair of sequences. Agulnick et al. (1998)
did not observe dN/dS ratios in excess of 1 in most comparisons because evolution by positive selection occurred at a subset of sites and only in certain lineages of DAZ. This example is not unique, as the pairwise approach also failed to detect positive selection in HIV (Leigh Brown 1997
; Crandall et al. 1999
; Zanotto et al. 1999
). Moreover, the same effect led to the incorrect conclusion that the 
-casein gene was free from functional constraint (Ward, Honeycutt, and Derr 1997
). These studies indicate that for some proteins the traditional approach to estimating the dN/dS ratio might not provide a sensible measure of selective pressure.
Gene duplication is considered an important mechanism for functional divergence (Ohno 1970
; Ohta 1993
). However, the process by which duplicated genes acquire new functions is less clear. There is often an acceleration of the rate of evolution following gene duplication (Li 1985
; Ohta 1993, 1994
). Accelerated rates could initially be driven by positive Darwinian selection for functional divergence (Ohta 1993, 1994
) or by relaxation of selective constraints. In the latter case, it is thought that random fixation of neutral changes eventually leads to a novel function in one or both copies. This model was referred to as the "Dykhuizen-Hartl effect" by Zhang, Rosenberg, and Nei (1998)
. Our findings are consistent with both models. The elevated rate of nonsynonymous substitution in autosomal DAZL1 following its duplication appears to result from the action of positive Darwinian selection. However, elevated rates of nonsynonymous substitution in DAZ immediately following its origin via the translocation event appear to result from decreased levels of purifying selection, suggesting a possible role for the Dykhuizen-Hartl effect in the early stages of DAZ evolution.
Our findings are consistent with several studies of gene families in which positive Darwinian selection was shown to be at least partially responsible for a rate increase following gene duplication (Ohta 1993, 1994
; Zhang, Rosenberg, and Nei 1
998; Duda and Palumbi 1999
; Rooney and Zhang 1999
; Schmidt, Goodman, and Grossman 1999
). However, in the only other case in which the relative contribution of both models was investigated, the Dykhuizen-Hartl effect was ruled out (Zhang, Rosenberg, and Nei 1998
). Although in this respect our findings appear to differ, it is important to point out that the method we employed to accommodate variation in selective pressures among lineages calculated as an average across all sites. Because an episode of positive selection at a subset of sites could elevate at a specific branch without causing it to exceed 1, it is not possible to completely rule out the positive- selection model. More complex models which can simultaneously accommodate rate variation among sites and lineages are under development and might be useful in distinguishing between positive selection and the Dykhuizen-Hartl effect.
Darwinian selection appears to be a relatively common feature of mammalian reproductive proteins (Karn and Nachman 1999
; Rooney and Zhang 1999
; Wyckoff, Wang, and Wu 2000
). Our findings indicate the DAZ gene family represents another example of this pattern. However, not all lineages of the DAZ gene family are presently evolving by positive Darwinian selection; both DAZ and DAZL1 of M. fascicularis are evolving by purifying selection. With regard to the difference between humans and M. fascicularis, it is interesting to note that the mature DAZ protein of humans has only 1 processed copy of exon 8, whereas the mature DAZ protein of M. fascicularis has 10 processed copies of exon 8. The DNA sequence for DAZ in both species contains multiple copies of both exons 7 and 8. However, at some point in the human lineage, a mutation disabled the splice sites of exons 8A and 8D. Because all but one copy of exon 8 in present-day human DAZ are descended from the disabled copies of exons 8A and 8D, the mature DAZ protein of humans includes only one processed copy of exon 8 (Gromoll et al. 1999
). Because the open reading frame was preserved in M. fascicularis despite several duplication and rearrangement events, multiple copies of exons 7 and 8 must have evolved functional importance during divergence of this gene family (Gromoll et al. 1999
). It is tempting to speculate that in the human lineage a loss of processing of all but one copy of exon 8 initiated adaptive evolution at other sites in both DAZ and DAZL1 to maintain proper spermatogenesis. Additional sequences of DAZ and DAZL1 from a variety of primate species are needed to understand the role of positive selection in functional divergence of the DAZ gene family.
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Acknowledgements |
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TOPAbstract IntroductionMaterials and MethodsResultsDiscussionAcknowledgementsliterature cited |
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We thank Katherine A. Dunn for helpful comments and discussion. We also thank the associate editor and two anonymous reviewers for their constructive comments. This study was supported by a Biotechnology and Biological Sciences Research Council grant (31/ G10434) to Z.Y.
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Footnotes |
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Edward Holmes, Reviewing Editor
1 Keywords: DAZ
DAZL1
gene family
maximum likelihood
codon model
positive selection 
2 Address for correspondence and reprints: J. P. Bielawski, Department of Biology, University College London, 4 Stephenson Way, London NW1 2HE, United Kingdom. j.bielawski{at}ucl.ac.uk
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TOPAbstract IntroductionMaterials and MethodsResultsDiscussionAcknowledgementsliterature cited |
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Y. Lu and M. D. Rausher Evolutionary Rate Variation in Anthocyanin Pathway Genes Mol. Biol. Evol., November 1, 2003; 20(11): 1844 - 1853. [Abstract] [Full Text] [PDF]
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 S. S. Choi and B. T. Lahn Adaptive Evolution of MRG, a Neuron-Specific Gene Family Implicated in Nociception Genome Res., October 1, 2003; 13(10): 2252 - 2259. [Abstract] [Full Text] [PDF]
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X. Bailly, R. Leroy, S. Carney, O. Collin, F. Zal, A. Toulmond, and D. Jollivet The loss of the hemoglobin H2S-binding function in annelids from sulfide-free habitats reveals molecular adaptation driven by Darwinian positive selection PNAS, May 13, 2003; 100(10): 5885 - 5890. [Abstract] [Full Text] [PDF]
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L. C. Hileman and D. A. Baum Why Do Paralogs Persist? Molecular Evolution of CYCLOIDEA and Related Floral Symmetry Genes in Antirrhineae (Veronicaceae) Mol. Biol. Evol., April 1, 2003; 20(4): 591 - 600. [Abstract] [Full Text] [PDF]
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E. Y. Xu, D. F. Lee, A. Klebes, P. J. Turek, T. B. Kornberg, and R. A. Reijo Pera Human BOULE gene rescues meiotic defects in infertile flies Hum. Mol. Genet., January 15, 2003; 12(2): 169 - 175. [Abstract] [Full Text] [PDF]
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A. Civetta Positive Selection Within Sperm-Egg Adhesion Domains of Fertilin: An ADAM Gene with a Potential Role in Fertilization Mol. Biol. Evol., January 1, 2003; 20(1): 21 - 29. [Abstract] [Full Text] [PDF]
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J. Yang, J. Huang, H. Gu, Y. Zhong, and Z. Yang Duplication and Adaptive Evolution of the Chalcone Synthase Genes of Dendranthema (Asteraceae) Mol. Biol. Evol., October 1, 2002; 19(10): 1752 - 1759. [Abstract] [Full Text] [PDF]
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T. Dagan, Y. Talmor, and D. Graur Ratios of Radical to Conservative Amino Acid Replacement are Affected by Mutational and Compositional Factors and May Not Be Indicative of Positive Darwinian Selection Mol. Biol. Evol., July 1, 2002; 19(7): 1022 - 1025. [Abstract] [Full Text] [PDF]
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D. A. Filatov and D. Charlesworth Substitution Rates in the X- and Y-Linked Genes of the Plants, Silene latifolia and S. dioica Mol. Biol. Evol., June 1, 2002; 19(6): 898 - 907. [Abstract] [Full Text] [PDF]
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Z. Yang and W. J. Swanson Codon-Substitution Models to Detect Adaptive Evolution that Account for Heterogeneous Selective Pressures Among Site Classes Mol. Biol. Evol., January 1, 2002; 19(1): 49 - 57. [Abstract] [Full Text] [PDF]
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E. Y. Xu, F. L. Moore, and R. A. R. Pera A gene family required for human germ cell development evolved from an ancient meiotic gene conserved in metazoans PNAS, May 30, 2001; (2001) 131090498. [Abstract] [Full Text] [PDF]
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E. Y. Xu, F. L. Moore, and R. A. R. Pera From the Cover: A gene family required for human germ cell development evolved from an ancient meiotic gene conserved in metazoans PNAS, June 19, 2001; 98(13): 7414 - 7419. [Abstract] [Full Text] [PDF]
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