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Low frequency of t haplotypes in natural populations of house mice (Mus musculus domesticus).

The t haplotypes of the house mouse were first discovered in 1927 (Dobrovolskaia-Zavadskaia and Kobozieff 1927), and remain one of the best studied mammalian examples of meiotic drive, or ultraselfish DNA (Wu and Hammer 1991). They are a variant of the proximal third of chromosome 17 that can distort Mendelian segregation in their favor from +/t heterozygous males. Segregation in +/t heterozygous females is normal and produces offspring that inherit the two chromosomes with equal probability. However, in males heterozygous for a wild type (+) and t haplotype (t) form of chromosome 17, the t-bearing form is transmitted to [greater than or equal to] 90% of the offspring in a phenomenon known as transmission ratio distortion (TRD; Chesley and Dunn 1936; Dunn 1957; Silver 1985; Ardlie and Silver 1996a). This effect occurs postmeiotically, as both sperm types are produced in Mendelian ratios. However, t-haplotype-carrying sperm effectively "disable" their wild-type-carrying meiotic partners and thus gain a relative advantage at fertilization (Olds-Clarke and Peitz 1985; Brown et al. 1989; Cebra-Thomas et al. 1991).

t haplotypes span approximately a 20cM (30Mb) region of chromosome 17 (Silver 1985; Mancoll et al. 1992). Within this region a number of independent loci that cause the TRD effect have been defined genetically. These include a single responder locus, Tcr (Lyon 1984), and at least three (Tcd-1, Tcd-2, Tcd-3; Lyon 1984; Silver and Buck 1993), and possibly as many as five (Silver and Remis 1987; Silver 1989) distorter loci that have a cumulative effect on the level of transmission distortion. These loci are distributed throughout the t haplotype, but remain tightly linked through the suppression of recombination between t-haplotype and wild-type chromosomes, due to the presence of four major nonoverlapping inversions (Artzt et al. 1982a; Herrmann et al. 1986; Sarvetnick et al. 1986; Hammer et al. 1989).

Despite their high transmission advantage, t haplotypes have not become fixed in natural populations. This is because the selective advantage of drive at the gamete level is counterbalanced by two strong negative fitness effects acting on the individual. One is the complete sterility of t/t homozygous males, which appears to be a consequence of homozygosity for the same Tcd distorter genes involved in TRD (Lyon 1986, 1991). Additionally, most t haplotypes carry recessive lethal alleles. A total of 16 lethal complementation groups have been identified so far (Dunn 1957; Bennett 1975; Klein et al. 1984). Homozygotes for lethals in the same complementation group ([t.sup.x]/[t.sup.x]) all die early in embryogenesis, while individuals carrying t haplotypes from different complementation groups ([t.sup.x]/[t.sup.y]) are viable, but male-sterile (Silver and Artzt 1981; Artzt et al. 1982b). The nonlethal t haplotypes typically show a reduction in the viability of homozygous t/t embryos ranging between 10% and 90%, and are thus known as the "semilethal" t haplotypes.

Bruck (1957) formulated the first theoretical model of this polymorphism and showed that, under random mating, a lethal t haplotype with a high level of drive ([approximately] 95%) should reach a stable, high frequency equilibrium of 0.385 t alleles: roughly 77% of wild mice should be +/t heterozygotes. However, the frequency of t haplotypes observed empirically is typically much lower, averaging [approximately]20-25% +/t mice ([approximately]0.13 t allele frequency). Thus, much subsequent research has been focused on the question of why t haplotype frequencies are so low in natural populations, and what is the nature of selection opposing their spread.

[TABULAR DATA FOR TABLE 1 OMITTED]

Among the well-known drive systems, including segregation distorter (SD) and sex ratio (SR), that are maintained as polymorphisms in natural populations, all are found at low frequencies (Beckenbach 1991; Temin et al. 1991; Lyttle 1993), suggesting that there may be strong selection against the spread of drive chromosomes in general. However, the forces affecting the frequencies of driving chromosomes in natural populations remain little studied, are often elusive (Beckenbach 1996), and may well differ among the different systems. There are a large number of theoretical studies that have investigated several forces that might account for the low frequency of t haplotypes (Lewontin and Dunn 1960; Lewontin 1962; Petras 1967; Young 1967; Levin et al. 1969; Gummere et al. 1986; Erhart et al. 1989; Nunney and Baker 1993; Durand et al. 1997). These include selection in demestructured populations; systematic inbreeding; a reduction in transmission ratio distortion in wild populations; lowered fitness of +/t heterozygotes relative to +/+ wild type mice; and mate choice. However, these studies have typically failed to identify any single factor of sufficient strength that can produce the observed low frequency of t haplotypes, concluding that additional, or multiple, factors must be involved (Levin et al. 1969; Nunhey and Baker 1993); that the low t frequency may not be a single stable value (Durand et al. 1997); and that more accurate surveys of the frequency of t haplotypes in natural populations are needed (Nunney and Baker 1993).

In contrast with the numerous theoretical studies, there are very little empirical data on t haplotypes in wild populations. A summary of all previously published data on t-haplotype frequencies shows that while the overall frequency in wild mice is low (0.15-0.25 +/t heterozygotes, see Table 1), individual localities may range in frequency from 0.0 to 1.0 (Bennett 1978; Klein et al. 1984; Lenington et al. 1988; Ruvinsky et al. 1991). Despite their ubiquity on the mainland, lethal t haplotypes have been reported to be absent from the few islands examined (Dunn et al. 1960; Myers 1973; Dooher et al. 1981). Additionally, the different lethal complementation groups also show restricted and often localized distributions among European Mus musculus domesticus (Klein et al. 1984), as well as among M. m. musculus populations, to which the [t.sup.w73] lethal is restricted (Forejt et al. 1988). Lethal t haplotypes may occur more frequently than semilethal t haplotypes (Klein et al. 1984; Lenington et al. 1988), although in populations where the latter predominate, their mean frequency has been reported to be higher (Lenington et al. 1988). Sex differences in the relative frequencies of t haplotypes have also been reported (Lenington et al. 1988).

How general these findings are remains unknown, as there have been relatively few surveys of t haplotypes in wild mice. Moreover, sample sizes have typically been small (from 2 to [approximately] 50 individuals), and populations have generally been sampled on a broad geographic basis, without regard to aspects of population structure or ecology. t-haplotype-bearing mice display no overtly observable phenotype, and neither +/t nor t/t mice are discernable from their wild type (+/+) counterparts. Thus they have historically been identified, and frequencies estimated, by breeding wild caught mice to Brachyury-bearing (T) laboratory mice (Dunn et al. 1960; Bennett 1978; Lenington et al. 1988). Brachyury (+/T) heterozygotes have a shortened tail, whereas Brachyury and t-haplotype heterozygotes (T/t) are tailless. These breeding studies were often uninformative, because wild mice frequently will not breed in captivity or do not produce enough offspring to reliably determine the parental genotype (Dunn et al. 1960; Sage 1981). Only with the recent availability of molecular probes that identify polymorphisms between t-haplotype and wild-type DNA has it become possible to definitively genotype larger numbers of wild mice.

In this study we report the findings of a survey of the frequency and distribution of t haplotypes in natural populations of mice. The large scale of this study was facilitated by the use of molecular markers, rather than progeny testing, to identify the presence of t haplotypes. Here we present the overall and mean frequencies of mice heterozygous and homozygous for t haplotypes and examine the distribution of t haplotypes principally with respect to sex and population size and structure.

MATERIALS AND METHODS

Trapping and Mice

Mice were obtained from 63 independent populations (80 independent samples), primarily from the United States. Additional population samples were obtained from other countries, including Australia, the United Kingdom, and Italy, through collaborative studies (see footnote to Table 2). At each U.S. location, traps were set within and around farm buildings, in agricultural and in old fallow fields, on islands, and in buildings where animal feed was being produced and/or stored. Only the sites where mice were actually caught are reported, and these were predominantly commensal settings such as farm buildings housing livestock or feed and occasionally adjacent fields with mature crops. While the majority of populations were sampled only once, a subset were trapped on more than one occasion to examine temporal variation in t haplotype frequencies. Mice were generally considered as members of the same population if they were trapped in close location on the same farm. One exception was the Thompson Farm, Tennessee, where the indoor barn site and the outdoor cornfield site were within 0.5 km of one another, but the two habitats were quite distinct. All other sites represent distinct locations, typically different farms, and were separated by more than 5 km.

Longworth and Sherman live-capture traps were used to catch mice. Trapping intensity was similar among sites. All populations were trapped for five consecutive nights each, unless it was impossible to do so, and sites were saturated with traps. The density of traps per unit area was similar among sites: traps were placed roughly 1-2 m apart. The number of traps set at each site always greatly exceeded the number of mice caught. The maximum number of traps filled on a single night of trapping was 65% (in the Kerr and Houghton populations), but trapping success otherwise was typically less than 30%.

Wherever possible, mice were marked when caught and released for recapture on subsequent nights (Table 3). In some locations, however, property owners demanded that trapped mice be permanently removed from the population. Trapping was not otherwise different in these populations, which were trapped for an equivalent number of nights and with the same intensity as the mark-release populations. Population sizes of the marked populations were estimated from mark-release-recapture data using the Jolly-Seber open population model (Pollock et al. 1990). In most cases, population sizes were estimated using the unpooled data from each consecutive day of trapping (usually five days). Mean population size is calculated for the middle three days, although estimates of population size on each separate day were generally very similar. For the Kerr Farm population, which was trapped repeatedly over several months, population sizes were additionally estimated by pooling over the consecutive days of trapping within each monthly period and using the information on whether an animal was captured at least once during the period.

All new mice caught were weighed, sexed, and individually marked using a combination of toe and ear clipping. A tail biopsy of [approximately] 1 cm was taken from each trapped mouse and preserved in 95% ethanol for subsequent DNA analysis. In addition, samples of live mice were retained from 18 of the populations to estimate TRD by breeding studies (Ardlie and Silver 1996a).

DNA Analysis

The presence or absence of t haplotypes in each wild animal was determined by analysis of DNA samples with multiple molecular markers. DNA was isolated from tail biopsies as follows. Ethanol was removed from all tail samples by drying under vacuum for 30 min. Samples were then left to digest overnight in tail buffer (50 mM TRIS pH 8.0, 100 mM EDTA, 100 mM NaCl, 1% SDS) and Proteinase K. High molecular weight DNA was prepared according to standard protocols (Hogan et al. 1994).

Approximately 10 [[micro]gram] of DNA was cut to completion with TaqI restriction endonuclease (New England Biolabs). The digested DNA samples were electrophoresed on 0.9% (w/v) agarose gels, and blotted onto nylon membranes (Genescreen, NEN Research) following the manufacturer's specifications. DNA was bound to the membranes by UV cross-linking, and hybridized following the procedure of Church and Gilbert (1984). Blots were washed twice at room temperature with 2X SSC, and twice at 65 [degrees] C in 0.1X SSC. Membranes were exposed to film at -80 [degrees] C for 24 to 48 h (Pilder et al. 1991). All probes (described below) were radio-labeled using random oligonucleotides on templates of denatured DNA (Feinberg and Vogelstein 1984). Membranes were stripped for reprobing following the manufacturer's instructions.

To assay for the presence of t haplotypes in each sample, membranes were probed with a number of cloned chromosome 17 markers derived from different regions of the t haplotype. A cosmid subclone, Bb40, was the principle marker used. It defines the locus D17Leh66b and detects four TaqI restriction fragments in complete t haplotypes that are not found in wild-type chromosome 17 DNA (Schimenti et al. 1987). All mice were typed with Bb40. Mice were additionally typed with Tu119 and/or Tu89, which are genomic clones derived by microdissection that define the loci D17Leh119 and D17Leh89 respectively (Rohme et al. 1984). Both detect t-specific and wild-type alleles (Herrmann et al. 1986; Bucan et al. 1987). Individuals were scored as homozygous wild type (+/+), heterozygous for a t haplotype (+/t), or homozygous t haplotype (t/t). Double heterozygotes ([t.sup.x]/[t.sup.y]) were distinguished from mice homozygous for the same t haplotype [TABULAR DATA FOR TABLE 2 OMITTED] ([t.sup.x]/[t.sup.x]) where possible, either by Bb40 (which detects two t-specific RFLP patterns due to the presence or absence of a Tcp 10 pseudogene, Tcp10ps; Schimenti et al. 1987), or by microsatellite analysis (Ardlie and Silver 1996b).

A subset of the samples that were positive for a t haplotype with Bb40, Tu119, or Tu89 have been screened with additional markers including Hba-ps4, Tu122, Tu54, Tcp1, and Tu80 (Fox et al. 1984, 1985; Willison et al. 1986; Bucan et al. 1987). This is part of a larger study of wild t haplotypes collected not only from the United States but also from European populations. In every case so far, the t haplotypes [TABULAR DATA FOR TABLE 3 OMITTED] defined by the first markers have been confirmed as complete with additional data (K. G. Ardlie, A. E. M. Baker, B. Dod, P. Boursot, F. Bonhomme, and L. M. Silver, unpubl. data).

RESULTS

Overall Frequency of t Haplotypes

In total, the genotypes of 3263 mice from 63 separate populations, 80 independent samples, were determined (Table 2). Historically, t haplotype frequencies in natural populations have most commonly been reported as the overall frequency of +/t animals among all sampled individuals, or occasionally as the mean frequency of +/t heterozygotes across several sampled populations (see Table 1). In this study, the overall frequency of +/t heterozygous mice IN THE entire sample is 0.062 (0.004 SE). The overall allele frequency of t haplotype chromosomes in this sample, including homozygous t/t chromosomes, is 0.039 (Table 1). The mean population frequency of +/t mice over the 63 populations is 0.107 (0.023 SE; where only the first samples from repeatedly sampled populations are included).

t haplotypes were completely absent from many of the populations sampled here [ILLUSTRATION FOR FIGURE 1 OMITTED]. Only 46% of populations (29 of 63) had mice carrying t haplotypes. Previous estimates of t haplotype frequency often excluded the populations in which t haplotypes were absent (Dunn et al. 1960; Bennett 1978) or the samples with fewer than 10 animals (Lenington et al. 1988), as it was generally considered that these populations were not truly negative but that t haplotypes had simply been overlooked due to the difficulties of determining genotypes by breeding mice. If we consider only the 46% of our populations in which t haplotypes were present, the overall frequency of +/t heterozygotes in our sample is increased somewhat to 0.141 (Table 1). In contrast, however, the removal of small samples with less than 10 individuals does not alter the frequency substantially relative to the total overall frequency: the overall frequency of +/t mice becomes 0.061 (0.004 SE; with a mean population frequency of +/t mice of 0.095 (0.019 SE).

t Haplotype Frequencies in Relation to Population Size

Mark-release-recapture information from consecutive days of trapping was used to estimate population sizes for 19 of the populations sampled (Table 3). Estimates of population size are generally very similar to the sample sizes. However, only the very large samples ([greater than or equal to] 70 individuals) yield reliable estimates of population sizes with relatively small standard errors. Population size estimates for samples with less than 10 individuals are probably misleading because of the small number of individuals caught and the relatively large standard errors. Nevertheless, small sample sizes here do accurately represented small populations. That is, all small populations represented in Table 2 are not simply small samples taken from a much larger population, but represent the total number of mice caught from an extensively trapped population where there were few mice present. Increasing trap number or the number of nights trapped beyond five had no impact on increasing the numbers of mice caught in these populations. Although estimates of population size over short periods of several days are less accurate than repeated samples over longer time periods, such as months, where population sizes were determined in both ways for the Kerr Farm samples, there was generally a good correspondence between the two estimates of population size (Table 3).

Population sizes cannot be estimated for the samples where individuals were permanently removed from the population. However, these populations were trapped for an equivalent length of time and in an identical manner to all mark-release populations. Moreover, trapping intensity was similar at every site and was sufficient to catch a large proportion of all mice present. In general, the rate of capture of new mice in all populations was highest during the second and third nights of trapping and declined thereafter. This was true for both the mark-release and destructively sampled populations, and thus the sample sizes of the latter populations also represent, at least, reasonable estimates of relative population sizes. Of all the samples in Table 2, population sizes are absolutely unknown only for the Bronx Zoo and several of the early Australian samples, where tail samples were provided without information on trapping duration or intensity. Collectively, the mark-release and destructively sampled populations, for which trapping information is known, represent 75% of all samples. Thus most sample size differences reported here do at least reflect real differences in the sizes of the populations trapped.

The frequency of t-haplotype-carrying mice in individual populations ranged from 0.0 to 1.0 (Table 2) and was greater for the small to medium-sized populations ([less than or equal to] 60 individuals, range = 0.0-1.0, [s.sup.2] = 0.038, n = 54) than for the larger populations ([greater than] 60 individuals, range = 0.0-0.11, [s.sup.2] = 0.003, n = 9; [ILLUSTRATION FOR FIGURE 2A OMITTED]). Among the small populations, several have t haplotype frequencies that fall above the 95% confidence interval, calculated for a hypothetical true mean population frequency of 0.107 +/t heterozygotes (from the pooled data; see Table 1). In contrast, t haplotype frequencies in larger population samples are typically low or zero. Only three of the nine samples larger than 60 fall within the 95% confidence interval for a mean frequency of 0.107. This distinction could not have been made in previous studies where samples sizes were generally less than 50 animals (max. n = 71; [ILLUSTRATION FOR FIGURE 2B OMITTED]). Overall in this study, large mouse populations were uncommon and were found only in instances where there was a relatively permanent and large food supply. Small, often ephemeral, populations of mice were the most common, comprising 86% of all populations we sampled, but less than half the total number of mice ([approximately] 45%; [ILLUSTRATION FOR FIGURE 3 OMITTED]).

Homozygous t/t Mice

By using molecular markers to genotype mice, we were able to distinguish between heterozygous +It animals and homozygous t/t animals (although the DNA markers used could not always distinguish between [t.sup.x]/[t.sup.x] and [t.sup.x]/[t.sup.y] animals). Homozygotes for t haplotypes were present in four of the populations (Table 2), and the highest frequencies of t haplotypes we observed were in these populations where mice with complementing (and/or semilethal) t haplotypes were present (e.g., Mount View Rd., NJ, and Huntting Grain Elevator, IA). Such high frequencies of t/t mice were not described in previous studies that used breeding techniques to genotype mice. Although semilethal t/t mice are viable and may have been present in previous samples, the males are always sterile and could not have produced progeny for testing. The frequency of t/t homozygotes was similar among the sexes.

Temporal Fluctuations in t Haplotype Frequencies

t haplotype frequencies fluctuated over short periods of time in several of the populations sampled repeatedly (Table 2). In the Kerr Farm population, New Jersey, the frequency of a semilethal allele decreased over time and was lost from the population (August 1990 frequency to September 1992, [[Chi].sup.2] = [5.8.sub.[1],P] = 0.01). In another population, Walpeup, Australia, which contained two complementing t haplotypes, overall allele frequency increased over time (Walpeup 1 to 3, [[Chi].sup.2] = [9.8.sub.[1],P] = 0.002). Populations without t haplotypes tended to remain without them over the time periods examined here. The Darling Downs site in Australia had no t haplotypes in both 1988 and 1992; Jungle World, Bronx Zoo, New York, had no t haplotypes in 1991 and 1992; and the Rosedale Mills population, New Jersey, had no t haplotypes in both 1990 and 1991. This last population was also drastically reduced in size from the first trapping period to the next, due to heavy poisoning. In several small populations no mice were caught when trapping was conducted on a second occasion (e.g., Belle Mead, NJ, and Mercer Mall Farm, N J).

Sex Differences in t Haplotype Frequencies

There were no sex-specific differences in t haplotype frequency in the 32 samples that contained t haplotypes (Table 4). In 11 of these, the frequencies of heterozygotes were higher in males, whereas in 19 they were higher in females, and in two they were equal in both sexes. The sex ratio among all the mice was slightly female biased (0.45). The overall frequencies of +/t heterozygotes among the two sexes in [TABULAR DATA FOR TABLE 4 OMITTED] these samples is 0.13 for males (n = 544) and 0.13 for females (n = 673). In a two-by-three contingency test of the three genotypic categories (+/+, +/t, and t/t) and the two sexes, there was no difference between the sexes in the frequency of any genotype ([G.sub.adj[2]= 0.702], P = 0.704). A Mann Whitney U-test of t haplotype frequencies among males and females in all samples further confirmed that there was no difference in mean t haplotype frequency between the sexes (Mann Whitney [U.sub.[32,32]=458], P = 0.468).

DISCUSSION

Despite the growing number of genetic and molecular studies of drive systems, there are still relatively few studies that have investigated driving chromosomes in natural populations, principally because they are often phenotypically cryptic and difficult to survey. Using molecular markers to identify t haplotypes, we were able to survey roughly threefold the number of mice from all previous studies combined (Table 1). Our main finding is that the frequency of t haplotypes among wild mice is low, and less than has previously been reported, and that they are patchily distributed among mouse populations. We first discuss the differences between this study and earlier studies that might account for this discrepancy and then consider the role of population ecology and related factors in influencing the frequencies of t haplotypes in nature.

Surveys of t Haplotypes in Natural Populations

The overall frequency of mice carrying t haplotypes (+/t heterozygotes) reported from studies conducted prior to this one ranged from 0.14 to 0.30, averaging [approximately]0.23 (see Table 1; Anderson 1964; Petras 1967; Bennett 1978; Klein et al. 1984; Figueroa et al. 1988; Lenington et al. 1988; Ruvinsky et al. 1991). Most modeling of t haplotype frequency has assumed there is a low equilibrium frequency in natural populations of [approximately]0.20 to 0.25 +/t heterozygotes (Lewontin and Dunn 1960; Petras 1967; Nunney and Baker 1993). In this study we found that the overall frequency of +/t heterozygotes was only 0.062 (mean population frequency of 0.107), however, which is much less than all previous estimates. The difference between this finding and the higher frequencies of t haplotypes described in earlier studies has two likely causes: differences in the techniques used to assay for t haplotypes and sample size differences.

One possible cause of the difference in t haplotype frequencies may reflect the differing methods of assaying for them in wild mice. All previous studies but one (Figueroa et al. 1988), were conducted prior to the availability of DNA techniques to distinguish t haplotypes and were dependent upon traditional breeding methods to genotype mice (Chesley and Dunn 1936; Bennett 1978; Lenington et al. 1988; Ruvinsky et al. 1991). There are several inherent difficulties with the breeding assay, most notably that wild mice can be difficult to breed in captivity, and so the sample sizes of reliably tested mice tended to be small. Also, the frequency of t/t homozygous males could not be estimated because they are sterile.

The first surveys of t haplotypes in natural populations with molecular markers, reported unexpectedly high frequencies of seemingly partial (or mosaic) chromosomes, containing both t-specific and wild-type-specific DNA (Figueroa et al. 1988; Erhart et al. 1989). This was interpreted as either the persistence of ancestral polymorphisms or as evidence of recombination between t haplotypes and wild-type chromosomes. However, much of this mosaicism has been shown to be the result of restricted genetic exchange across the distal inversion, probably through gene conversion, at loci that do not play a role in the TRD phenotype (Hammer et al. 1991). All DNA markers we used here identify RFLP alleles that are associated exclusively with t haplotypes (Shin et al. 1982; Rohme et al. 1984; Fox et al. 1985; Silver et al. 1987; Herrmann and Lehrach 1988; Hammer et al. 1991; Pilder et al. 1991; Horiuchi et al. 1992). Additionally, several t-haplotype-carrying mice were retained from this study for breeding analyses. In all cases, we found full concordance between t haplotypes identified with DNA markers and the TRD phenotype determined from breeding studies (Ardlie and Silver 1996a), indicating that this is an accurate way of identifying t haplotypes in natural populations.

A second major difference between this study and earlier ones is that we sampled a much greater range of population sizes than have most previous studies, which were typically less than 50 individuals [ILLUSTRATION FOR FIGURE 2B OMITTED]. In contrast, many of the populations we sampled here were much larger than this. As the frequency of t haplotypes in the larger samples was uniformly low or zero [ILLUSTRATION FOR FIGURE 2A OMITTED], the inclusion of these samples contributed to the lower overall frequency of t haplotypes we found. Selander (1970) first suggested that there was a distinction between small and large populations of mice, finding that the variance in allozyme allele frequency was much higher for smaller populations than for large ones, with a greater deficiency of heterozygotes in the latter. In our study, sample sizes do accurately reflect population sizes, at least in order of magnitude, and the small and large populations differ in several key ways (see below). Although any absolute numerical distinction between small and large populations is somewhat arbitrary, if we consider the samples of [less than or equal to] 60 and [greater than] 60 mice separately (where there is a break in the data), then the overall frequency of +/t mice in the smaller samples is 0.12 (n = 54 populations, 1105 mice), which is closer to previously reported values (Table 1). In contrast, in the larger samples, the overall frequency is 0.036 (n = 9 populations, 1280 mice), which is much lower.

Several other results of this study differ in minor ways from previous findings. First, Lenington et al. (1988) reported that the frequency of +/t mice was twofold higher among males (0.44) than among females (0.22). However, we did not find such a sex-specific difference in t haplotype frequency among males and females in both a larger sample of mice and with the unambiguous determination of all genotypes. Thus the previous sex difference reported may have been a consequence of determining genotypes by breeding, as wild female house mice are considerably more difficult to breed in the laboratory than are wild male house mice and generally produce fewer young (Dunn et al. 1960; Sage 1981; this study). Additionally, because females do not exhibit transmission ratio distortion, it is easier to miss the presence of a t haplotype in females than in males.

Second, short-term stability in t haplotype frequencies has been reported (Lenington et al. 1988). In the few instances in our study where populations were repeatedly sampled, we found that t haplotype frequencies fluctuated over short periods of time, although populations without t haplotypes tended to remain without them. However, there are still only a few studies of temporal changes in t haplotype frequency and the time periods have generally been too short to determine any general patterns.

Finally, we found that t haplotype frequencies were often very high in populations where t/t mice were present. This might account for an earlier observation that the mean frequency of +/t mice was higher in populations containing primarily semilethal t haplotypes than in populations in which lethal t haplotypes predominated (Lenington et al. 1988). t-haplotype allele frequencies of greater than 0.5 can be achieved only in populations containing semilethal (or two independent, complementing lethal) t haplotypes, where t/t mice survive, and such females can contribute as breeders to the population. In contrast, allele frequencies greater than 0.5 are not possible in populations containing only a single lethal t haplotype. Unfortunately, we were unable to examine the general distribution of lethal and semilethal t haplotypes in more detail in this study, because a caveat of using DNA techniques with the current level of knowledge of t haplotypes is that it still remains largely impossible to distinguish the different t haplotypes from one another (Ardlie and Silver 1996b). Breeding analysis remains the only certain way to distinguish lethal from semilethal t haplotypes.

t Haplotype Frequency and Population Structure

The role that population structure might play in contributing to the low t haplotype frequency remains controversial. Several theoretical studies have demonstrated that the subdivision of mouse populations into demes, with restricted between-deme migration, will effectively lower the overall frequency of t haplotypes due to the fixation of the wild type (+) chromosome by drift (Lewontin and Dunn 1960; Lewontin 1962; Nunney and Baker 1993). However, the extent of deme-structure required to produce a t frequency of 0.13 in a population is generally so extreme that it is unlikely to occur in natural populations where migration rates are reported to be much higher and more variable (Levin et al. 1969; Nunney and Baker 1993; Durand et al. 1997).

Genetic studies suggest that population subdivision may occur at several levels. Continentwide patterns of genetic differentiation are the result of genetic drift (Britton-Davidian, 1990). On a smaller scale, significant genetic subdivision has also been found for mouse populations among different farms or villages, where gene flow is limited and occurs predominantly among neighboring subpopulations and occasionally among buildings within a farm as well (Blair 1953; Anders on 1964; Petras 1967; Selander 1970; Lidicker 1976; Pennycuik et al. 1978; Britton-Davidian 1990; Dallas et al. 1995). Further, in a few instances there is also evidence that some large commensal populations may be subdivided into social, territorial breeding units (Anderson 1964; Selander 1970; Ardlie 1995). However, short- and long-distance gene flow may be quite common (Berry and Jakobson 1974; Myers 1974; Stickel 1979; Baker 1981; Berry et al. 1991; Dallas et al. 1995), and both commensal and feral populations of mice can show a considerable amount of flexibility and fluctuation in their population structure.

The data presented here cannot address this relationship between population subdivision and t-haplotype frequency explicitly, however, they do suggest that there is a relationship between population size, and possible structure, and t-haplotype frequency. t haplotypes were at low or zero frequency in all of the large populations of mice trapped and at more variable frequencies in small to medium-sized populations.

With the exception of two populations trapped on islands (the Isle of May and Faray), all large populations we trapped were associated with relatively permanent human agricultural dwellings. These populations were characterized by the continuous availability of food and shelter (and a lack of predators on the islands). They supported persistent populations of mice, frequently at high densities, for relatively long periods of time because control measures such as poisoning could not be taken (property owners, pers. comm.).

t haplotypes might be at low frequency in these large populations for several reasons. They may have been absent among the original founders of the population. If it is difficult for mice to immigrate into established populations (Pennycuik et al. 1978; Gerlach 1990) or they are isolated on islands, this might prevent the subsequent establishment of t haplotypes. Another possibility is that these larger, persistent mouse populations may be characterized by relatively stable subdivision into social or territorial groups (Gerlach 1990; Sugg et al. 1996). This "demic" subdivision may well contribute to the loss of t haplotypes through drift, at least to some extent (Nunney and Baker 1993), although the magnitude of this effect will depend on how commonly individuals mate within versus outside their territories (Potts et al. 1991) and how temporally stable the territories and populations are.

Several additional forces are now known to contribute to lowering t haplotype frequencies. Evidence of selection acting against +/t heterozygotes, in terms of a [approximately]20% reduction in litter size, has been observed in several studies (Johnson and Brown 1969; Lenington et al. 1994; Ardlie 1995). There is also evidence from a small number of litters that multiple mating might substantially reduce the effective TRD of +/t males (Ardlie and Silver 1996a; A. Baker, pers. comm.). Simulation studies show that t haplotypes are lost due to drift within 200 generations in demes of size 10, even with a TRD of 0.9 (Durand et al. 1997; D. Durand, pers. comm.). Thus a combination of some degree of demic structure, with reduced TRDs due to multiple matings, and a reduction in heterozygote fitness could well contribute to lowering t frequencies in these populations. The dynamics of t haplotype frequency in a large population of mice has been investigated further, and these findings are the topic of a separate paper (K. G. Ardlie and L. M. Silver, unpubl. data).

In contrast, many of the small to medium-sized populations we trapped were often ephemeral, or seasonal, and were frequently in places where food sources were present for only limited periods of time. These populations were characterized by short-term persistence, extinction, and recolonization, due to the use of poisons, fluctuating food supplies, and disruptions to temporary habitats. This pattern has been commonly observed in smaller populations of mice (Hauffe and Searle 1993; Dallas et al. 1995). It is also characteristic of other human commensal species, such as mosquitoes (Chevillon et al. 1995), or species that live in temporally unstable and spatially heterogeneous environments. Frequent extinctions and recolonizations can result in an increase in genetic variance among populations (Whitlock 1992) and this may contribute to the higher variance in t haplotype frequencies observed among the populations analyzed here.

t haplotypes could again be lacking from the smaller populations if they were not present among the founders, but they may be at an advantage when present as founders in populations. Because of their high transmission ratios, t haplotypes should reach high frequencies rapidly in expanding, unstructured populations (Bruck 1957). Although most populations trapped in this study were closely associated with humans (e.g., in farm buildings), a similar, variable range of t haplotype frequencies might also be seen in more feral populations inhabiting farm fields, where mice often show considerable fluctuations in population size and repeated colonizations of agricultural fields on a seasonal basis (Stickel 1979; Kaufman and Kaufman 1990). The variation in t-haplotype frequencies among the smaller populations will reflect their temporal stability and the composition and proximity of neighboring populations that are likely to be the predominant source of new colonists (Dallas et al. 1995).

Mice are ecological opportunists and can live in a heterogeneous range of environments and exhibit a variety of population structures. The distribution of t haplotypes in different populations has not generally been considered, but our findings suggest that it may be important in understanding t-haplotype frequency in the wild because the frequency of t haplotypes may vary among different mouse populations in relation to their size and temporal stability. A similar finding was obtained in a recent simulation study of population subdivision and interdemic migration rate (Durand et al. 1997), which concluded that there might not be a stable low-level t polymorphism: rather, there might be two stable states characterized by the extinction of t haplotypes and a high t-haplotype frequency, respectively. Populations were assumed to be in one or other stable state or in transition between them, and the overall t frequency is thus low but transient. Here we found that the frequency of t haplotypes among wild mice was lower than previous estimates, primarily due to the inclusion of the larger populations where t haplotypes were at low frequency or absent. Although there were few large populations of mice, they accounted for more than half the total number of mice and could thus have a large impact on lowering t frequency. If this pattern is typical of wild mice in general, then it might be that the smaller, ephemeral populations are important in acting as reservoirs for the maintenance of t haplotypes in natural populations. Further population sampling is needed across a range of habitats and countries in which house mice are found to determine how general this pattern might be.

ACKNOWLEDGMENTS

Thanks to D. Stratton, P. R. Grant, R. C. Lewontin, and J. Dolven for comments on the manuscript; to G. Singleton, L. Drickamer, A. Berry, H. Hauffe, and curators of the Bronx Zoo for providing samples; and to S. Pilder for probes. KGA gratefully thanks M. Magrath, H. Akashi, R. Mulder, and A. Berry for repeated help trapping mice and all the farm owners who gave permission to trap mice on their properties. This research was supported by a grant from the National Institutes of Health (HD20275) to LMS.

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