Male-Offspring-Specific, Haplotype-Dependent, Nonrandom Cosegregation of Alleles at Loci on Two Mouse Chromosomes

Corresponding author: Carmen Sapienza, Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, 3307 N. Broad St., Philadelphia, PA 19140., sapienza{at}unix.temple.edu (E-mail)

Communicating editor: C.-I WU

	ABSTRACT

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

F₁ backcrosses involving the DDK and C57BL/6 inbred mouse strains show transmission ratio distortion at loci on two different chromosomes, 11 and X. Transmission ratio distortion on chromosome X is restricted to female offspring while that on chromosome 11 is present in offspring of both sexes. In this article we investigate whether the inheritance of alleles at loci on one chromosome is independent of inheritance of alleles on the other. A strong nonrandom association between the inheritance of alleles at loci on both chromosomes is found among male offspring, while independent assortment occurs among female offspring. We also provide evidence that the mechanism by which this phenomenon occurs involves preferential cosegregation of nonparental chromatids of both chromosomes at the second meiotic divison, after the ova has been fertilized by a C57BL/6 sperm bearing a Y chromosome. These observations confirm the influence of the sperm in the segregation of chromatids during female meiosis, and indicate that a locus or loci on the Y chromosome are involved in this instance of meiotic drive.

IN our genetic analysis of the the DDK syndrome (BABINET et al. 1990 ), we have focused our efforts on two chromosomes, X and 11. The central portion of chromosome 11 has been the subject of continuing investigation because it is the location of the Om locus, at which both a maternal DDK allele and a paternal non-DDK allele are required for elaboration of the DDK syndrome (BALDACCI et al. 1992 , BALDACCI et al. 1996 ; SAPIENZA et al. 1992 ; COHEN-TANNOUDJI et al. 1996 ; PARDO-MANUEL DE VILLENA et al. 1997 , PARDO-MANUEL DE VILLENA et al. 1999 ).

We have shown previously that surviving offspring from semilethal crosses between both types of reciprocal F₁ hybrid females and C57BL/6 (B6) males show preferential inheritance of DDK alleles in the Om region of chromosome 11 (PARDO-MANUEL DE VILLENA et al. 1996 ). This result has been replicated in six additional independent backcrosses (PARDO-MANUEL DE VILLENA et al. 1997 , PARDO-MANUEL DE VILLENA et al. 2000 ). We have also provided evidence that this phenomenon is caused by unequal segregation of alleles to the polar body during the second meiotic division (MII) of the ovum (PARDO-MANUEL DE VILLENA et al. 2000 ), i.e., meiotic drive (SANDLER and NOVITSKI 1957 ).

We have also examined the transmission of alleles at chromosome X-linked loci among the offspring of F₁ females and noted transmission ratio distortion in favor of DDK alleles in the central portion of the X chromosome among female offspring (DE LA CASA-ESPERON et al. 2000 ). Because we observed reproducible transmission ratio distortion (TRD) at loci on two different chromosomes (X and 11) in the same backcrosses, we examined whether the inheritance of maternal alleles at loci on these chromosomes was independent.

We find that independent assortment occurs in female offspring but that a strong nonrandom association between the inheritance of alleles at loci on these two chromosomes occurs in male offspring. Furthermore, the nonrandom association of maternal alleles at loci on chromosomes X and 11 observed among male offspring occurs when they are sired by males of the B6 inbred strain but not when sired by males of the DDK inbred strain. The mechanism by which this phenomenon is achieved involves preferential cosegregation of nonparental chromatids of both chromosomes at MII, after the ova has been fertilized by a B6 sperm bearing a Y chromosome. These observations demonstrate that not only can the genotype of the sperm influence female meiosis but that a locus or loci on the Y chromosome are involved in this instance of meiotic drive.

	MATERIALS AND METHODS

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

Mouse crosses:
The two backcrosses used in this study have been described previously (PARDO-MANUEL DE VILLENA et al. 1996 , PARDO-MANUEL DE VILLENA et al. 1997 , PARDO-MANUEL DE VILLENA et al. 2000 ; DE LA CASA-ESPERON et al. 2000 ).

Haplotype determination:
Parental and nonparental haplotypes on chromosomes X and 11 were determined as described previously (DE LA CASA-ESPERON et al. 2000 ; PARDO-MANUEL DE VILLENA et al. 2000 ).

	RESULTS

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

Inheritance of alleles at Om and DXMit210 is not independent in male offspring:
To determine whether the observed TRDs at loci on chromosomes X and 11 (DE LA CASA-ESPERON et al. 2000 ; PARDO-MANUEL DE VILLENA et al. 2000 ) were related, we tested for independence of inheritance of alleles at D11Mit66 and at DXMit210. These loci were selected because they mapped to the region of maximum TRD localized on each chromosome in the relevant backcrosses (DE LA CASA-ESPERON et al. 2000 ; PARDO-MANUEL DE VILLENA et al. 2000 ).

When all offspring from crosses in which we observed TRD on the X chromosome as well as on chromosome 11 are pooled, the combination of alleles inherited at DXMit210 and D11Mit66 does not appear to be random in a chi-square test of independence (total of all offspring in Table 1; ² = 6.51; 1 d.f., P < 0.05, corrected for performing three tests, see the following). We then divided the pooled data by sex of offspring (Table 1) because TRD on the X chromosome occurs only among female offspring in these crosses (DE LA CASA-ESPERON et al. 2000 ). When the chi-square test of independence is performed for male and female offspring separately, a somewhat unexpected result is obtained. The inheritance of alleles at D11Mit66 and DXMit210 is independent among female offspring (² = 0.05; 1 d.f., corrected for performing three tests, not significant), despite the fact that we observe significant and reproducible TRD at both loci. The nonindependence of inheritance of alleles observed in the total data set is the result of nonindependence only among male offspring, in which we observe TRD at D11Mit66 but not at DXMit210. Among male offspring, the inheritance of alleles at D11Mit66 and DXMit210 is not independent (² = 11.04; 1 d.f., P < 0.005, corrected for performing three tests; Table 1).

Even though we observe no TRD at loci on the X chromosome among male offspring (DE LA CASA-ESPERON et al. 2000 ), the overall TRD in favor of DDK alleles at Om [very near D11Mit66 (PARDO-MANUEL DE VILLENA et al. 1996 , PARDO-MANUEL DE VILLENA et al. 1997 , PARDO-MANUEL DE VILLENA et al. 2000 )] on chromosome 11 is found predominately among male offspring that inherit a B6 [or C57BL/6-Pgk1^a (PG)] allele at DXMit210. These individuals inherit 154 DDK alleles at Om vs. 72 B6 alleles (Table 1). Among those offspring that inherit DDK alleles at DXMit210, there is no apparent TRD at Om (120 DDK alleles vs. 107 B6 alleles). This effect of X chromosome genotype is specific to male offspring because similar levels of TRD at Om are found among female offspring regardless of whether they inherit a DDK allele at DXMit210 (60.2% Om DDK alleles) or a B6 or PG allele (61.4% Om DDK alleles).

This unexpected result does not appear to be due to chance. TRD at D11Mit66 is much greater among males that inherit a B6 or a PG allele at DXMit210 than among males that inherit a DDK allele at DXMit210. This is observed in each cross, individually, as well as in the combined data. The high level of significance of the combined observation (P < 0.005), even after correcting for multiple tests, also causes us to give less credence to the possibility that this observation is due to chance.

We note that DXMit210 was chosen as the chromosome X locus to examine in this study on the basis of its position in the region of maximum TRD among female offspring. Because we unexpectedly found an interaction between this locus and D11Mit66 among male offspring, in which no TRD is observed at any X-linked locus (DE LA CASA-ESPERON et al. 2000 ), we examined additional loci on chromosome X because we were concerned that some other locus on the X chromosome might show a higher level of cosegregation. The maximum deviation from random assortment was observed at DXMit144 (data not shown), ~4 cM proximal to DXMit210 (DE LA CASA-ESPERON et al. 2000 ). However, we have chosen to use the data obtained at DXMit210 in the remainder of the analysis because it is the closest locus at which all offspring have been scored, and the few recombinants observed between these loci do not affect the significance of the overall results.

The association between alleles at Om and DXMit210 among male offspring is the result of meiotic drive:
We have provided evidence that TRD at Om is caused by unequal segregation of alleles to the polar body at MII (meiotic drive; PARDO-MANUEL DE VILLENA et al. 2000 ). If the nonrandom association of alleles at Om and DXMit210 observed among male offspring (Table 1) is related to the meiotic drive observed at Om, then this association should be observed most strongly among male offspring that inherit nonparental haplotypes on chromosome 11 (see DISCUSSION and PARDO-MANUEL DE VILLENA et al. 2000 ). As shown in Table 2, the nonrandom association of alleles at Om and DXMit210 is much stronger among male offspring that inherit nonparental haplotypes on chromosome 11 than in male offpring that inherit parental haplotypes, supporting the contention that this effect is related to meiotic drive at Om.

If the observed association between these two chromosomes is truly related through the common mechanism of meiotic drive, then the association should be apparent regardless of whether the data are stratified on the basis of parental or nonparental chromosome 11 haplotypes or parental or nonparental chromosome X haplotypes. Because the meiotic drive at Om takes place at MII, it must also exert its strongest effect on nonparental X chromosomes if this mechanism is also affecting chromosome X segregation. The bottom portion of Table 2 shows that male offspring that inherit nonparental chromosome X haplotypes also show a strong nonrandom association between alleles at loci on the two chromosomes, while those males inheriting parental haplotypes do not show a significant relationship between the two loci. Note, further, that there is no obvious relationship between the combination of alleles inherited at DXMit210 and Om and chromosome X or chromosome 11 haplotype among female offspring (Table 2), supporting the sex-of-offspring specificity of the effect and providing additional evidence that independent assortment of chromosomes X and 11 does occur among female offspring.

If MII meiotic drive is affecting the segregation of both chromosomes coordinately, one should be able to obtain an idea of the magnitude of this effect by comparing the frequency with which nonparental haplotypes of both chromosomes segregate together, compared with the frequency with which either segregates with a parental haplotype of the other, regardless of the alleles inherited. Table 3 shows such an analysis for chromosomes X and 11 among male and female offspring. Male offspring inherit nonparental haplotypes on both chromosomes 83 times, while inheriting a nonparental haplotype on only one of the two chromosomes 186 times (80 + 106, Table 3). Female offspring, which show no evidence of preferential cosegregation of these chromosomes, inherit nonparental haplotypes on both chromosomes 63 times, while inheriting a nonparental haplotype on only one of the two chromosomes 209 times (76 + 133, Table 3). Note that a similar number of offspring occurs in each comparison group above (269 males in these three categories vs. 272 females in the same three categories). However, in male offspring there has been a relative increase in the number of individuals inheriting both parental haplotypes and a relative decrease in the number of individuals inheriting one parental and one nonparental haplotype. These observations are consistent with the predictions that the nonrandom inheritance of alleles at loci on both chromosomes occurs as the result of meiotic drive at MII, in which nonparental chromosomal haplotypes nonrandomly cosegregate among male offspring.

	DISCUSSION

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

We have examined whether there was a relationship between the inheritance of maternal alleles on chromosomes X and 11 because we observed TRD at loci on both chromosomes (PARDO-MANUEL DE VILLENA et al. 1996 , PARDO-MANUEL DE VILLENA et al. 1997 , PARDO-MANUEL DE VILLENA et al. 2000 ; DE LA CASA-ESPERON et al. 2000 ). In contrast to the expectations of Mendel's law of independent assortment, we found that the inheritance of maternal alleles at D11Mit66 and at DXMit210 among the offspring of these backcrosses is not independent. This result does not arise from the preferential inheritance of DDK alleles at both loci among female offspring (in which TRD in favor of DDK alleles is observed at loci on both chromosomes), but from a more complex relationship between these two chromosomes among male offspring. Although the result of independent assortment among female offspring might be unexpected at first glance, given TRD on both chromosomes, we note that the failure to find any relationship between the inheritance of alleles on chromosomes X and 11 is consistent with our observation of different mechanisms leading to TRD in each case. TRD at Om on chromosome 11 is the result of meiotic drive (PARDO-MANUEL DE VILLENA et al. 2000 ), while the female-specifc TRD on chromosome X is most likely due to postfertilization death (DE LA CASA-ESPERON et al. 2000 ).

Because meiotic drive causes TRD at Om (PARDO-MANUEL DE VILLENA et al. 2000 ), we tested whether the observed nonrandom inheritance of alleles at loci on both chromosomes among male offspring had the same origin. We find that the inheritance of combinations of alleles at Om and DXMit210 is strongly dependent on the chromosome X and chromosome 11 haplotype inherited (Table 2), consistent with the predictions of a meiotic selection mechanism (PARDO-MANUEL DE VILLENA et al. 2000 ).

True meiotic drive through females causes preferential transmission of favored alleles without a net decrease in maternal reproductive fitness (SANDLER and NOVITSKI 1957 ). The preferential segregation of a particular chromatid to the polar body at the expense of the other chromatid results in a relative increase in the number of offspring from the favored genotypic category and a relative decrease in the number of offspring from the disfavored category. In this regard, we point out that the symmetries observed in the inheritance of alleles among male offspring in both Table 1 and Table 2 are characteristic of meiotic drive. For example, in Table 1 the overall bias in inheritance of the favored DDK allele at D11Mit66 results, predominately, from shifting offspring from one genotypic alternative to another among those offspring that have inherited B6 alleles at DXMit210. There is both a relative decrease in the number of individuals inheriting the X^b11^b combination (72 individuals) and a relative increase in the number of individuals inheriting the X^b11^k combination (154 individuals). Note, further, that the total number of males inheriting B6 alleles at DXMit210 (226) is the same as the total number of individuals inheriting DDK alleles at DXMit210 (227). Similar symmetric patterns are apparent among male offspring in Table 2; one category shows a relative decrease (the X^b11^b category), while the alternative category shows a corresponding relative increase (the X^b11^k category). This table shows, further, that the shift from one genotypic category to the other is most pronounced among the offspring inheriting nonparental haplotypes [that category expected to be most affected by MII meiotic drive (PARDO-MANUEL DE VILLENA et al. 2000 )], regardless of whether chromosome X or 11 is considered. Last, male offspring that inherit nonparental haplotypes on both chromosomes appear overrepresented in comparison to female offspring that inherit nonparental haplotypes on both chromosomes (Table 3), a point that suggests that the segregation of chromosomes X and 11 is coordinated when the ovum has been fertilized by a sperm bearing a B6 Y chromosome.

Because the conclusions we have drawn are based on comparisons in which our data set, though large, has been subdivided by both sex-of-offspring and chromosome haplotype, it is worthwhile to consider the number of corrections that must be applied to the levels of statistical significance that we have given throughout this article. In general, P values must be corrected for the number of tests performed. In our case, we have not corrected for testing whether significant TRD is present at Om because this result has been reported several times (PARDO-MANUEL DE VILLENA et al. 1996 , PARDO-MANUEL DE VILLENA et al. 1997 , PARDO-MANUEL DE VILLENA et al. 2000 ), demonstrating that TRD at Om is a constant feature of these crosses. The data in Table 1 that reject the hypothesis that inheritance of alleles at DXMit210 and D11Mit66 is independent must be corrected for performing three tests (independence of inheritance of alleles at D11Mit66 and DXMit210 in the total offspring, in male offspring, and in female offspring). Note that the nonrandom assortment is restricted to male offspring (P < 0.005 in males and nonsignificant in females). In addition, the significance level for whether there is an effect of chromosome haplotype on the nonrandom inheritance of alleles at both loci must be corrected for performing four additional tests (parental and nonparental haplotypes on chromosomes X and 11, Table 2). Note that this correction only applies to male offspring because we do not test for such an effect in females, as the data in Table 1 indicate that inheritance of alleles at both loci among females is random. Therefore, we have corrected the P values for an effect of chromosome haplotype on inheritance of alleles among male offspring for performing seven tests. The minimum chi-square value required to find significance at P < 0.05, when performing seven tests, is ~7.2. When male offspring are classified according to their haplotype, the chi-square values that we observe are 1.27 and 13.82 for the chromosome 11 haplotype effect, and 1.92 and 11.16 for the chromosome X haplotype effect (Table 2). In both cases the level of significance is high (P < 0.005) and is restricted to the nonparental class. We have not conducted any tests on the data in Table 3 because we regard them as corroborating evidence that the nonrandom association observed is due to preferential cosegregation of nonparental haplotypes of both chromosomes at meiosis II, a point that has been shown for each chromosome individually in Table 2.

We conclude that the association we observe is caused by nonrandom cosegregation of alleles on chromatids bearing nonparental haplotypes. Selection takes place on both chromosomes and occurs at meiosis II, after fertilization of the ovum by the sperm. In this regard, we (PARDO-MANUEL DE VILLENA et al. 1997 , PARDO-MANUEL DE VILLENA et al. 2000 ) and others (AGULNIK et al. 1993 ) have observed that meiotic drive through female meiosis is strongly affected by the type of sperm used to fertilize the ovum. The data presented in this article indicate a further effect of sperm genotype in that the segregation of two nonhomologous chromosomes to the polar body is affected and is, furthermore, specific to male offspring. This male-specific effect suggests that a locus or loci on the B6 Y chromosome (or the pseudoautosomal region) are involved. These data suggest that the F₁ ovum is able to distinguish between B6 sperm that carry different sex chromosomes and respond by meiotic drive only on chromosome 11 in one case and by nonrandom cosegregation of two different chromosomes to the polar body in the other case.

The influence of the sire in nonrandom cosegregation of alleles among male offspring is futher supported because alleles at DXMit210 and D11Mit66 segregate independently when the same F₁ females used in this study are mated to DDK males (data not shown). We also note that in crosses between (B6 x DDK)F₁ females and reciprocal (BALB/c-DBA/2)F₁ males that show meiotic drive at Om (PARDO-MANUEL DE VILLENA et al. 2000 ) the nonrandom cosegregation among male offspring appears to be present when the sire has a DBA/2 Y chromosome but absent when the Y chromosome of the sire is of BALB/c origin (data not shown). However, these latter observations should be treated with caution because the sample size in these experiments (PARDO-MANUEL DE VILLENA et al. 2000 ) does not allow us to reach definitive conclusions.

Although an effect of paternal sex chromosome constitution of the sperm on the transmission ratio of maternal alleles is an unexpected finding, data from a number of other studies are not inconsistent with this conclusion. SHENDURE et al. 1998 have also examined the transmission of alleles on mouse chromosome 11. In their experiment, the authors demonstrate female-offspring-specific TRD in favor of B6 alleles in the same region of chromosome 11 we have examined. Interestingly, the authors also report that male offspring from the same cross inherit preferentially DBA/2 alleles in this region. Although the latter result fell short of statistical significance (79 male offspring inherited the B6 allele, while 101 inherited the DBA/2 allele at D11Mit195), these observations also suggest that the transmission of maternal alleles at chromosome 11 loci may be affected by which sex chromosome is carried by the sperm. Sex-of-offspring-specific maternal TRD on mouse chromosome 2 (SIRACUSA et al. 1992 ) and on human chromosome X (NAUMOVA et al. 1998 ) has also been described, and is compatible with the hypothesis that sperm genotype may affect the second meiotic division of the ovum.

Maternal meiotic drive has also been described and characterized in maize (RHOADES 1942 , RHOADES 1952 ; RHOADES and VILKOMERSON 1942 ; RHOADES and DEMPSEY 1966 ; DAWE and CANDE 1996 ; YU et al. 1997 ; KASZAS and BIRCHLER 1998 ). In this system, one or more chromosomes may exhibit preferential segregation to the megagametophyte as a result of a neocentromeric activity. Although the precise mechanism by which MII meiotic drive is achieved at Om is unknown, a mechanism similar to that found in maize could explain the meiotic drive we have described (PARDO-MANUEL DE VILLENA et al. 2000 ). However, such a mechanism does not easily explain the effect of sperm genotype on the nonrandom cosegregation of alleles at both Om and DXMit210.

	ACKNOWLEDGMENTS

We are grateful to the National Institutes of Health (R01GM52332 and R01HD34508 to C.S.) for support. E.C.-E. is a recipient of a fellowship from the Ministerio de Educación y Cultura (Spain).

Manuscript received May 25, 1999; Accepted for publication September 13, 1999.

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