Department of Ecology and Evolutionary Biology, and Museum of Zoology, University of Michigan, Ann Arbor
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Abstract |
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Key Words: Mus sex chromosomes retrosequences zinc finger genes Zfx Zfy Zfa
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Introduction |
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Typically in eutherians there are two copies present, one on the X chromosome (Zfx) and one on the nonrecombining portion of the Y chromosome (Zfy) (Page et al. 1987). However, multiple Y-chromosomelinked copies have been detected in a diverse group of rodents in the family Muridae. These include wood lemmings (subfamily Arvicolinae: Lau et al. 1992), South American oryzomyne-akodontine mice (subfamily Cricitinae: Bianchi et al. 1992) and mice belonging to the genus Mus (subfamily Murinae). In several species of Mus there are two copies on the Y chromosome (Zfy-1 and Zfy-2) resulting from a recent intrachromosomal duplication, as well as an autosomal copy (Zfa) on chromosome 10, resulting from a recent retroposition of a processed Zfx transcript (Page et al. 1987; Ashworth, Swift, and Affara 1989; Mardon and Page 1989; Mardon et al. 1989; Mitchell et al. 1989; Nagamine et al. 1989; Mardon et al. 1990; Page et al. 1990).
Expression studies in laboratory mice demonstrate that these putatively functional genes have different patterns of expression. Zfx is ubiquitously expressed (Mardon et al. 1990). Zfa is expressed only in adult testes (Ashworth et al. 1990). Both Zfy-1 and Zfy-2 are expressed in the germ cells of adult testes. Zfy-1 and possibly Zfy-2 are expressed in somatic cells of the genital ridge and possibly at low levels in other tissues during development. Zfy-1, alone, is expressed in mouse embryonic stem cells and blastocysts (Koopman et al. 1989; Nagamine et al. 1989, 1990; Su and Lau 1992; Zwingman et al. 1993; Zambrowicz et al. 1994).
The presence of related and putatively functional genes located on the X and Y chromosomes as well as on an autosome in the genus Mus provides an opportunity to explore whether the evolution of specific genes is influenced by chromosomal location. Of particular interest is whether linkage to the Y chromosome can affect the pattern of gene evolution. Because the Y chromosome in mammals does not recombine with the X chromosome and is, thus, clonally inherited from father to son, Y-linked genes are potentially subject to a variety of phenomena that may result in higher rates of amino acid change relative to related genes elsewhere in the genome (reviewed in Tucker and Lundrigan 1995; Charlesworth and Charlesworth 2000).
Amino acid changes on the Y chromosome can reflect chromosome-specific effects such as an increased fixation of deleterious mutations caused by processes associated with the degeneration of the Y chromosome (Charlesworth and Charlesworth 2000). Specifically, an increase in the fixation of slightly deleterious mutations can result from the following phenomena: (1) genetic drift (Nei 1970) as a result of the Y chromosome having a smaller effective population size relative to the X chromosome and to the autosomes; e.g., when the male-to-female breeding sex ratio is one, Y-linked genes are only one-quarter as numerous as autosomes and one-third as numerous as X chromosomes; (2) Muller's ratchet (Muller 1964; Felsenstein 1974), a strictly stochastic process whereby the class of nonrecombining chromosomes with the fewest number of mutations is lost from the population; (3) background selection (Charlesworth, Morgan, and Charlesworth 1993; Charlesworth 1994), a process whereby nonrecombining chromosomes carrying strongly selected deleterious mutations are eliminated from the population, resulting in a reduced effective population of nonrecombining chromosomes, an increase in the fixation of slightly deleterious mutations, and a decrease in the fixation of mildly advantageous mutations (Charlesworth and Charlesworth 2000); (4) hitchhiking effects (Maynard Smith and Haigh 1974) in a nonrecombining genome where slightly deleterious alleles linked to a favorable mutation can become fixed; and (5) the Hill-Robertson effect (Hill and Robertson 1966; Felsenstein 1974, 1988; Birky and Walsh 1988) where alleles under selection interfere with selection at linked sites. All of these phenomena can have the effect of increasing the fixation of amino-acid changes at weakly constrained sites (see table 1 in Charlesworth and Charlesworth 2000).
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Finally, differences in functional constraint between related genes, also a gene-specific effect, may result in different evolutionary patterns. For example, expression patterns have been correlated with degree of functional constraint where ubiquitously expressed genes are under greater functional constraint than genes with restricted tissue expression (Hastings 1996; Duret and Mouchiroud 2000).
Here we compare the last zinc fingerencoding exon of Zfx, Zfy-1, Zfy-2, and Zfa, among species in the mouse genus Mus to determine whether these genes display different patterns of evolution and, if so, whether the patterns are consistent with chromosome-specific and/or gene-specific effects as described above. We provide evidence for distinctly elevated rates of amino acid change for the Zfa and Zfy genes in comparison to Zfx, and for slightly higher rates of amino acid change for the Zfy genes in comparison to the Zfa genes. We suggest that both gene-specific and chromosome-specific effects play a role in the differential evolution of the zinc finger genes.
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Materials and Methods |
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PCR Amplification of Targeted Sequences
The targeted region was amplified from genomic DNA by polymerase chain reaction (PCR) using gene-specific primers and sequenced directly in both directions by the dideoxynucleotide chain termination method in a thermocycling reaction (GIBCO BRL), using single primers kinased with 32P ATP. The last exon of Zfy-1 differs from that of Zfy-2 by the deletion of the fifth codon preceding the termination codon. This difference was used to design a primer specific for Zfy-1 (5'-TTAGGGCAGGCCAACTTT-3'). Other loci were amplified specifically by using unique primers at their 5' end (Zfa: 5'-GCTTATGGTAATAATTCTGATGGA-3'; Zfy: 5'-GGCCCTGATGGACATCCTTTGAC-3'; Zfx: 5'-ACTAAATCAGCATGTTTTGATCAC-3') and a common primer at the 3' end (5'-TTAGGGCAGGCCAACTTCTTT-3'). Zfy sequences were verified as being male-specific by the failure to produce a product in PCR reactions from female M. musculus and M. domesticus in the same PCR experiment. To guarantee that only one copy of Zfx was sequenced per individual, Zfx sequences were obtained from males. Zfa sequences were from the same males and are present in two copies. There was no evidence of heterozygosity at this locus. GenBank accession numbers for original data compared in this study include AY159976 through AY160025.
Alignment
The conceptually translated amino acid sequences for all genes were aligned in ClustalX (Thompson et al. 1997) and forced back onto the nucleotide sequence. Identical sequences were combined in the data matrix, leaving a total of 29 sequences for subsequent analyses.
Phylogeny Reconstruction
A parsimony analysis was performed using the parsimony ratchet as implemented in WinClada 1.00.08 (Nixon 2002) with 500 iterations per replication, 10 trees held per iteration, and 10 sequential ratchet runs. To assess support for the topology in the data set, a parsimony bootstrap (Felsenstein 1985) was performed using NONA (Goloboff 1999) with 1,000 replications, 10 search replicates, and one starting tree per replication.
For all parsimony searches, nucleotide characters were unordered and equally weighted, and gaps were treated as missing data. The alligator Azf-1 sequence was used as an outgroup.
A Bayesian phylogenetic analysis was conducted with MrBayes 2.1 (Huelsenbeck and Ronquist 2001). A general time reversible (GTR) model with a gamma rate distribution and a proportion of invariable sites was used (Yang 1994). The analysis was initiated with random starting trees and was run for 1 x 106 generations, sampling every 100th generation. Four continuous chains were run with the initial 50,000 generations discarded as burn-in. To check that stationarity had been reached, the fluctuating value of the likelihood was checked graphically. The simulation was conducted twice.
Codon Based Likelihood Analyses
Codon based maximum likelihood analyses were conducted using PAML 3.12 (Yang 1999) to assess evolutionary patterns within and among genes. Two methods were used. The first method allows for analysis of lineage-specific dN/dS ratios within a phylogeny (Goldman and Yang 1994) where dN is the number of nonsynonymous changes per nonsynonymous site and dS is the number of synonymous changes per synonymous site. Five models of nucleotide sequence evolution were applied to the data set. They include (1) a "one ratio" model where the dN/dS ratio is assumed to hold for all lineages; (2) a "two ratio" model where the dN/dS ratios are allowed to vary between Zfx, Zfa, and Azf-1 lineages (the X and autosomal genes) and Zfy lineages (the Y-linked genes); (3) a "three ratio" model where the dN/dS ratios are allowed to vary among Azf-1 (a gene whose expression pattern is not fully determined [Valleley et al. 1992]), the Zfy/Zfa lineages (genes with putatively restricted expression), and the Zfx lineages (putative ubiquitously expressed genes); (4) a "four ratio" model where the dN/dS ratios are allowed to vary among the Zfx, Zfy, Zfa, and Azf-1 gene lineages; and (5) a "free ratio" model where the dN/dS ratios are allowed to vary across all lineages. Given the data set and the inferred phylogeny, the fit of these four different models to the data was statistically compared using the likelihood ratio test. The test statistic compares twice the difference in log likelihood values with a 2 distribution with degrees of freedom equal to the difference in free parameters between the models.
The second method allows for the detection of positively selected sites within genes. The NSsites models in PAML (Yang 1999) were used to evaluate whether positive selection has acted on particular sites in Zfy, Zfa, and Zfx (Nielsen and Yang 1998). Two types of models were applied to the data set, one that allows for only neutral and negatively selected sites and one that allows for positively selected sites in addition to neutral and negatively selected sites. The test was also performed with a model that allows for heterogeneity of the dN/dS rate ratio among sites. As described above, the fit of the data to each of the models was statistically compared using the likelihood ratio test where the test statistic compares twice the difference in log likelihood values with a 2 distribution with degrees of freedom equal to the difference in free parameters between the models.
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Results |
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Variation Within and Between Genes
Percent identity within the genus Mus among Zfx nucleotide sequences ranges from 99 to 100; among Zfa sequences, from 97.5 to 100; among Zfy-1 sequences, from 98.5 to 100; and among Zfy-2 sequences, from 95.8 to 100. Percent identity between all Zfy and all Zfa sequences ranges from 82.1 to 85.7; between all Zfy and Zfx sequences, from 82.8 to 85.8; and between all Zfx and Zfa sequences, from 96.9 and 98.7.
Phylogenetic Analyses
One-hundred and fifty-three equally most parsimonious trees were recovered from the heuristic search of 29 taxa. A strict consensus of these trees (not shown) is consistent with a 50% majority rule bootstrap consensus tree (fig. 1). Bayesian analyses yielded a compatible topology, the only differences being the resolution of two nodes that are collapsed in the parsimony analyses. Two distinct clades exist when the tree is rooted with the alligator zinc finger gene (Azf-1). One clade comprises the Zfx and Zfa sequences. The other clade comprises the Zfy sequences and one sequence from Tokudaia osimensis spp. labeled in GenBank as a Zfx gene (Xiao, Tsuchiya, and Sutou 1998). There is a lack of resolution among Zfx sequences after the MusRattus split but varying degrees of resolution among Zfa sequences and Zfy sequences.
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Likelihood analyses for detecting positively selected amino acid sites yielded varying results. For Zfx, the model allowing positive selection performs significantly better (P < 0.05) than the model allowing for only neutral or negatively selected sites, both when the dN/dS rate ratio is constant and when it is allowed to vary across sites according to a beta distribution (data not shown). According to these models, a single codon (position 185 in our alignment) is positively selected (dN/dS > 1). However, the meaning of positive selection at this site is difficult to interpret without more structural and/or functional information on the Zfx protein. For Zfy and Zfa, models that allow for positive selection do not perform significantly better than models that allow for only neutral or negatively selected sites.
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Discussion |
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The clade comprising the Zfy sequences includes a sequence from Tokudaia osimensis spp. labeled in GenBank as a Zfx gene (Xiao, Tsuchiya, and Sutou 1998). This taxon has a 2N = 45 XO karyotype with no distinguishable differences in karyotype between males and females (Honda et al., 1978). Because of the absence of the Y chromosome in this taxon, the gene was labeled Zfx. However, based on our phylogenetic analyses, this sequence is clearly related to Zfy. In all likelihood this gene is the result of a "recent" translocation of Zfy from the Y to the X chromosome associated with the loss of the Y chromosome from this taxon. A closely related taxon, T. osimensis muenninki, in addition to the closely related genus Rattus has the standard XX/XY sex-dermining system (Sutou, Mitsui, and Tsuchiya 2001), indicating that the lack of the Y chromosome is a recently derived condition. Although the translocation of Zfy to the X chromosome in populations of Tokudaia osimensis could in theory provide a test for the effects of chromosome location on gene evolution, the translocation event probably occurred too recently to detect changes in evolutionary pattern.
The clade comprising the Zfy-1 genes includes a sequence labeled Zfy-2 from M. spretus. This sequence is more closely related to Zfy-1 than to other Zfy-2 sequences and suggests either that the sequence is a recent intrachromosomal duplication of Zfy-1i.e., it is nonhomologus to other Zfy-2 genesor a Zfy-2 sequence has undergone gene conversion. An analysis of the 3' portion of the gene may shed light on these alternatives.
Evolutionary Patterns
Variation in dN/dS ratios across genes over time is generally attributed to differential selective constraints. Typically, genes appear to be highly selectively constrained and dN/dS values are low. For example, Wolfe and Sharp (1993) estimated the average dN/dS for 363 genes compared between mouse and rat to be 0.14. The elevated rates for Zfy (0.38 under the four ratio model) and Zfa (0.27) may indicate such gene-specific effects as the action of positive Darwinian selection, reduced selective constraint, or, in the case of Zfy, its position in the nonrecombining region of the Y chromosome.
When dN/dS ratios are greater than one for a gene, positive selection is hypothesized to account for the rapid amino acid divergence. However, dN/dS ratios greater than one are a conservative estimate of positive selection, especially when made over long periods of time because positive selection can be episodic and followed by purifying selection (Zhang, Rosenberg, and Nei 1998). This can result in a muted signal for positive selection (Schaner et al. 2001), i.e., elevated dN/dS that are not greater than 1. While ratios of dN/dS for the Zfy genes are generally not greater than 1, the exception being the lineage giving rise to the M. spretus Zfy genes (fig. 1), they are relatively high for a functional gene, especially compared to the related gene, Zfx, which presumably shares a similar function (i.e., transcription activation).
This pattern is similar to what was found for another Y-chromosomelinked functional gene, the male sexdetermining locus, Sry (Whitfield, Lovell-Badge, and Goodfellow 1993; Tucker and Lundrigan 1993; Pamilo and O'Neill 1997; Wang, Zhang, and Zhang 2002; Jansa, Lundrigan, and Tucker in press). In comparative studies of primates and rodents dN/dS values for Sry ranged from 0.47 to 1.88 for primates and from 0.33 to 0.45 for rodents, with values being especially high in the C-terminal region of the gene (Tucker and Lundrigan 1993; Whitfield, Lovell-Badge, and Goodfellow 1993; Pamilo and O'Neill 1997). In addition, variation in the elevated dN/dS was observed among lineages (Wang, Zhang, and Zhang 2002). Both weak positive Darwinian selection and purifying selection have been offered as explanations for these patterns (reviewed in O'Neill and O'Neill 1999; Wang, Zhang, and Zhang 2002; Jansa, Lundrigan, and Tucker 2003). However, studies of 12 closely related species of rock wallaby (Petrogale) indicated that Sry evolution was not rapid over a short evolutionary time (O'Neill et al. 1997). In O'Neill et al. (1997), the dN/dS ratios were quite low with 71% being less than 0.03 (reviewed in O'Neill and O'Neill 1999). Furthermore, a population level study of M. domesticus (Nachman and Aquadro 1994), in which levels of polymorphism to divergence were compared for Sry flanking sequence, revealed no evidence for selection acting on the nonrecombining portion of the Y chromosome. Taken together, these data suggest that positive Darwinian selection may not account for the elevated dN/dS in Sry, at least not over short evolutionary time periods. This may also be the case for Zfy, as there is no other evidence for positive selection acting on this gene; e.g., no positively selected sites were detected in Zfy using the codon-based likelihood analysis.
Assuming that expression patterns are similar within gene lineages, the elevated dN/dS ratios for Zfy and Zfa genes in comparison to the Zfx genes is consistent with the prediction that ubiquitously expressed genes are under greater functional constraint than genes with limited tissue expression (Hastings 1996; Duret and Mouchiroud 2000). The more slowly evolving Zfx is ubiquitously expressed in inbred mouse strains (Mardon et al. 1990) that are of M. domesticus/M. musculus origin (Tucker et al. 1992) in contrast to Zfy and Zfa tissue expression, which is limited primarily to the adult testis in inbred mouse strains (Koopman et al. 1989; Nagamine et al. 1989, 1990; Ashworth et al. 1990; Su and Lau 1992; Zwingman et al. 1993; Zambrowicz et al., 1994).
The even higher dN/dS for Zfy genes in comparison to Zfa genes under the four and free ratios models, however, may reflect inefficient selection on weakly constrained sites, which is an outcome of several of the hypotheses proposed to explain the degeneration of the Y chromosome over evolutionary time (Charlesworth and Charlesworth 2000). Indeed, in a mouserat comparison of 834 genes the dN/dS for genes with the most restricted tissue expression is lower (avg. = 0.16; Duret and Mouchiroud 2000) than was found for Zfy. A study of the evolution of an X- and Y-linked gene pair exhibiting similar tissue expression would provide a more straightforward interpretation of the role of chromosome-specific effects on gene evolution.
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Acknowledgements |
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Footnotes |
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Adam Eyre-Walker, Associate Editor
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