Epistatic Control of Non-Mendelian Inheritance in Mouse ... - Genetics

Copyright 8 1996 by the Genetics Society of America

Epistatic Control of Non-Mendelian Inheritancein Mouse Interspecific Crosses Xavier Montagutelli,*9t Rowena Turnert andJoseph H. Nadeaut *Unit6 de Gnitique des Mammvires, Znstitut Pasteur, 75724 Paris cedex 15, France, and tTheJackson Laboratory, Bar Harbor, Maine 04609-1500 Manuscript received August 17, 1995 Accepted for publication May 15, 1996 ABSTRACT Strong deviationof allele frequencies from Mendelian inheritance favoring Mus spretusderived alleles has been described previously for X-linked loci in four mouse interspecific crosses. We reanalyzed data for three of these crosses focusingon the locationof the gene(s) controlling deviation on the Xchromosome and the genetic basisfor incompletedeviation. At least twoloci control deviationon the X chromosome, one near Xzst (the candidate gene controlling Xinactivation)and the other more centromerically located. In all three crosses, strong epistasis was found between loci near Xzst and marker loci on the central portionof chromosome 2. The mechanism for this deviation from Mendelian expectations is not yet known but it is probably based on lethality of embryos carrying particular combinations of alleles rather than true segregation distortion during oogenesis in F, hybrid females.

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HE few examples of transmission ratio distortion (TRD) are genetically complex and involve chromosome rearrangements that preserve particular combinations of distortioncontrolling alleles at closely linked loci(CROW1991). TRD is defined as a statistically significant departure from Mendeliantransmission, regardless of its basis. When due to meiotic drive, as in SD in Drosophila (SANDLER and NOVITSKI 1956; SANDLER and GOLIC 1985; LYITLE 1991) and the HSR inverted duplication in wild populations of Mus musculus musculus (AGULNIK et al. 1993a; RUVINSKY 1995), it is appropriate to refer to the phenomenon as segregation distortion. By contrast, TRD associated with t haplotypes is not a consequence of meiotic drive but rather of the differential ability of sperm to fertilize eggs (LYON1984; SILVER 1985). In a third situation, deviation from Mendelian inheritance (DMI) probably results from lethality of embryos carrying particular combinations of alleles at unlinked loci (ZECHNERet al. 1996). Modest but significant DM1 is occasionally found in linkage testing crosses, e.g., chromosome 2 (SIRACUSA et al. 1989), chromosome 4 (CECIet al. 1989) and chromosome 10 (JUSTICE et al. 1990). Except for chromosome 2 (SIRACUSA et al. 1991), these phenomena have not been studied further. It is likely that all three DMIs result simply from sampling fluctuations that are expected when relatively small numbers of mice are typed for many loci. This interpretation is supported by the fact that none of these DMIs has been replicated in independent crosses. By contrast,strong DM1 (70-90%) favoring M. spetuderived alleles at chromosome X-linked loci has Corresponding authur: Joseph H. Nadeau, Department of Human Genetics, RoomL3-109, Montreal General Hospital, 1650 Cedar Ave., Montreal, Quebec H3G 1A4, Canada. Genetics 1 4 3 1739-1752 (August, 1996)

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all four linkage crosses in which (C57BL/6J [or C3H] X M.spretus) F1 hybrid females were backcrossed to M. spetus males (BIDDLE 1987; EU-

MOUSE BACKCROSS COLLABORATIVE GROUP 1994; JOHNSONet al. 1994; ROW et al. 1994). Because

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the magnitudeof DM1 and the map location of affected loci were similar in all four backcrosses to M. spretus, it was unlikely that this deviation was due to sampling fluctuations alone. Threeof these crosses afford an exceptional opportunity to study the genetic basis of the deviation because, as mapping panels available to the community, they have been typed for numerous loci spanning the entire genome (EUROPEANMOUSE BACKCROSS COLLABORATIVE GROUP1994; JOHNSONet al. 1994; ROW et al. 1994). The aim ofwork presented here was to localize the gene(s) controlling DM1 on chromosome X and investigate the genetic basis for incomplete deviation. MATERIALS AND METHODS Interspecificcrosses: The backcrosses that we analyzed were either the BSStype [(C57BL/6J X M. spretus)F1X M. spretus] or the BSB type [ (C57BL/6J X M. spretus)F1 X C57BL/6J]. The following crosses were analyzed: (1) the Jackson Laboratory (C57BL/6J X M. spetus)F1 X C57BL/6J and (C57BL/6JEi X SPRET/Ei)F, X SPRET/Ei crosses ( R o w et al. 1994),referred to here as “JAX1 BSB” and “JAXI BSS,” respectively; (2) the (C57BL/6J X SPR)F1 X C57BL/6J and (C57BL/6J X SPR)F1X SPREuropean Collaborative Interspecific Backcross (EUCIB) crosses (EUROPEAN BACKCROSS COL LABORATIVEGROUP1994), referred to here as “EUCIB BSB” and “EUCIB BSS,” respectively; and (3) (C57BL/6J X SPRET/Ei)FI X SPRET/Ei and (C57BL/6JEi X SPRET/Ei)Fl X SPRET/Ei crosses (JOHNSON el al. 1994) made at the Jackson Laboratoryand referred to here as ‘JAXZ.” The M. spretus strain that was used (SPR) was not fully inbred although the mice are kept in a closed colony (EUROPEAN BACKCROSS COI, LABORATnTE GROUP 1994).Results for a second EUCIB inter-

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X. Montagutelli, R. Turner and J. H. Nadeau

specific backcross were not included in the present analysis because of small sample size and partial genotyping. Source of published genotypes: Genotypes for the JAXl BSS and BSB crosses were obtained from the WWW Jackson Laboratoryserver(URL: http://wwwjax.org). Thesedata were posted on Feb. 21, 1995. Genotypes for the EUCIB BSS and BSB crosseswere obtained from the MBx database as posted on Dec. 19, 1994 (BROWN1995). On the X chromosome, only anchor loci DXMZt8, DXWas70, G p r , Plp and Xist were considered because they were typed for most animals. Genotypes fromthe JAX2 cross were providedby K. JOHNSON (personal communication). The analysiswas restricted to a subset ofloci (Figure 1); some loci were excluded because they did not recombine with others, some because more than six genotypes were missing for a given locus, and some because certain genotypes were unlikely (double recombinants in a short genetic interval). Where possible, we retained loci that were typed in all three panels, thereby facilitating map comparison. Rules used to infer genotype: To increase the sample size for subsequent analyses, genotypes wereinferred for animals that did not have a crossover between anchor loci. The rules for inferring a genotype were as follows: genotypes were not inferred for anchor loci; the map position of the locus for which a genotype was inferred relative to the two flanking loci wasfirmly established before the inference, i e . , alternative inferences did not affect the gene order; and distances between this locus and each of the flanking loci was

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results for three large and independent crosses based on closely related strains. Similar resultsin independent crosses increases the chance that the results are real rather than sampling artifacts. TwoX-linked loci are proposed, one located near DXMit87 at -20.0 cM and the other located more telomerically near Xist at -42.0 cM. For the JAXl and EUCIB crosses, which involved different substrains of both C57BL/6 and M. spetus, DCSX loci were mapped to -21.3 and -20.5 cM (Table 1, Figures 1-3). Analysis of DM1 in mice with recombinant chromosomes mapped a DCSX to the same region in both crosses, namely the interval between -18.0 and -28.0 cM (Figure 4). Thefailure to find similar evidence in the JAX2/ J cross is perplexing, but may simply result from DM1 and statistical fluctuations. The most parsimonious explanation for these results is that a single DCSX near DXMit87 contributes to DMI. No evidence was found in any crossfor epistasis involvingthis DCSX locus (Figure 5 ) . Recently a locus affecting placental mass (Ihpd) was mapped near DXMit8 in interspecific backcrosses (ZECHNERet al. 1996). In backcrosses to M. spretus, placental mass wassignificantly decreased among heterozygous BS progeny as compared with their homozygous SS sibs. By contrast, placental hypertrophy was found in reciprocal backcrosses to inbred strains of laboratory mice with placental weight being significantly higher among heterozygous BS segregants than among homozygous BB sibs. Differences in placental mass could lead to biased embryonic lethality and to non-Mendelian inheritance. The similar map locations for the centromeric DCSX and loci controlling placental weight and non-Mendelian inheritance is striking.addition, In epistasis must be involved to account for these differences between segregating crosses and the parental strains (ZECHNERet al. 1996), but the chromosomal location and genetic identity of the autosomal locus remain to be determined. All three crosses provided evidence for a more telomerically locus DCSX locus within 13 cMof each other and near Xist at -42.0 cM. Modeling placed a DCSX at 47.3 cM in the EUCIB cross and at -36.6 in the JAX2/J cross. Analysis of mice with recombinant chromosomes in the EUCIB cross supported this localization with a DCSX in the interval between -42.0 and -56.0 cM. Because relatively few X-linked loci have been typed in the JAXP/J cross (JOHNSON et al. 1994; Table 1) , insufficient recombinant chromosomes were available for a meaningful analysis. No evidence was found for a telomeric DCSX in the JAXl cross, perhaps because C57BL/6Ei (JAX1) has a weaker allele at this locus than does C57BL/6J (EUCIB and JAX2/J). In all three crosses, remarkably strong epistasis involved the same X-linked locus: near DXBir5 at -46.8 cM in the JAXl cross, near Xist at -2.0 cM in the EUCIB cross, and near Hmgl7-rs3 at -34.5 cM in the JAX2/J cross.

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Heterogeneity between these map localizations, between-34.5 and -47.3 cM,is greater than for the centromeric DCSX. But heterogeneity is not surprising given the genetic and statistical variability for results with different crosses. In fact, the consistent map localizations despite heterogeneity is striking. The most parsimonious explanation forthese results is therefore that a second DCSX near Xist contributes to DM1 and shows strong epistasis with a locus on chromosome 2. SIRACUSA et al. (1991) foundstrong DM1 favoring "spetus"derived alleles and mapping to the central portion of chromosome 2 for female progeny; DM1 in male progeny mapped near the telomere.No evidence for epistasis was detected. Although DM1 did not occur on chromosome 2 in the BSS crosses, strong epistasis involving genes on the similar portion of the chromosome was detected (Table 2, Figure 5). It is possible that these two effects, namely, DM1 in BSB crosses and epistasis in BSS crosses, are different manifestations of the same chromosome 2 gene. A curious and perhaps informative feature of these crosses is similar litter sizesin the reciprocal backcrosses. If DM1 results from lethality of particular embryos, then litter sizes could be smaller in backcrosses to M. spetus than in crosses to C57BL/6J.However, review of the breeding records provided little evidence for a difference in litter size (results not shown; CJ: EUROPEAN MOUSE BACKCROSS COLLABORATIVE GROUP 1994;JOHNSON et al. 1994; ROWEet al. 1994). A possible explanation is that DM1 occurs early in development before litter size is determined. If gametogenesis is biased, or if more embryos are conceived than implant and loss of some embryos allows others to survive, then DM1 without litter size reduction could occur. For t haplotypes, the effects of distortion are revealed at conception and litter sizes are not substantially reduced, despite a transmission ratio of 90% (CHESLEYand DUNN 1936; SILVER1985). This hypothesis predicts that DM1 in interspecific crosses results from biased oogenesis in eggs fertilized by sperm from M. spetus but not from C57BL/6J (CJ: AGULNIK et al. 1993a; RUVINSKY 1995) or that DM1 arises from lossof certain embryos before implantation. Studies addressing this question are underway. The mechanism responsible for the non-Mendelian inheritance remains unclear. Because DM1is not o b served when F1 females are mated with B6 males, the simplest hypothesis is that deviation originates from early death of embryos with specific combinations of alleles. However, an additional hypothesis is required to explain the empirical data. In the EUCIB cross, only 10 (13%) p p males are PI", whereas 68 (87%) are pp.Under the differential embryonic viability model, this deviation from equalfrequency is explained by partial lethality of the 22 p p males. However, F1 males, which are also p p pp,should also be affected and a reduced number of males per F1 litter should result.

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Because lethality of x"x" females is partially avoided by M. spetus-derived alleles on chromosome 2 (Table 2), F1 female embryos should be less affected than males, resulting in strong sex ratio distortion (one1 male per four females). Such distortion has not been reported in the literature or observed in our experience (data not shown). This model would require either thatadditional autosomal loci (undetected so far) are involved in the epistatic control ofDMI, or that the lethality associated with the p p or x"xs genotype depends on the genotype of the mother that transmitted the p chromosome (no lethality if p transmitted by a C57BL/6J female and partial lethality if transmitted by an F1 female). An alternative mechanism for DM1 is meiotic drive during female gametogenesis. Femalemeiosis is arrested at metaphase I1 until fertilization. When the sperm enters the oocyte, meiosis resumes, resulting in the productionof the second polar body, before pronuclei merge to constitute the zygote. AGULNIK et al. (1993a,b; RUFINSKY 1995) reported meiotic drive in mice that areheterozygous for an inversion on chromosome 1. Progeny from heterozygous females mated with inversion homozygous males showmodest deficiency of inversion heterozygotes among their progeny because of increased preweaning lethality. When inversion heterozygous females were mated withwild-typemales, wild-type progeny were found in large excess (85%).By comparing the number of resorbing and developing embryos in pregnant females, these authors showed that distortion was due to meiotic drive in females and that it was controlled by the genotype of the sperm fertilizing the oocyte (AGULNIK et al. 1993b). The DM1 observed in interspecific crosses shows many similarities and could have the same origin. However, the molecular mechanism would be complex being controlled by both chromosome X- and chromosome >linked genes. DM1 in interspecific crosses may be an example of genetic coadaptation (DOBZHANSKY1936; MULLER 1939,1940,1942;HURST and POMIANKOWSKI 1991b; COYNE 1992; W O T et al. 1994; w u and PALOPOL1 1994; ORR1995) rather than true meiotic drive (or segregation distortion) (SANDLER and NOVISTKI1957;CROW 1991). With genetic divergence, coadaptations arise that cause or reinforce reproductive isolation and speciation. Disrupted coadaptations are usually detected as reduced fitness in interspecific hybrids (DOBZHANSKY 1936; MULLER1942; WOT et al. 1994). These coadaptations could also be disrupted among progeny of interspecific crosses. If appropriate loci are typed among progeny of these crosses, these disruptions might be detected as DM1 where deficiency of progeny with the maladaptive allelic combination causes biased transmission ratios (GUENET 1985; COYNE 1986). Because coadaptations do not depend on linkage, epistasis would be a characteristic of coadapted genes in segregating interspecific crosses. DM1 in these interspecific crosses

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J. H. Nadeau

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(and may therefore represent an opportunity to study the in males) are incompatible, but 2’;’ and ps evolution of coadapted genes that contribute to repro(and in males), 2B“ and p‘(and in males but to ductive isolation and speciation. a lesser extent),and 2’ and p’ (and in males) Epistasisinvolving unlinked loci is not a common are compatible. This asymmetry may simply reflect an feature of the classical examples of DMI. SD, t haplointermediate stage in the divergence of interacting proteins where one protein must lose its ability to interact types, the HSR inversion, and many other examples of DM1 involveclosely linked loci that act as“selfish first, e.g., a receptorloses its abilityto recognize a ligand DNA,” in violation of Mendel’s laws (SILVER 1993). Parbefore theligand loses its ability to activate the receptor. ticular combinations of alleles at these loci are called Reinforcing epistasis may also explain why DM1 does haplotypes. Preferential transmission of selfish haplonot occur in reciprocal backcrosses, but instead occurs types to the detriment of alternative haplotypes results only in backcrosses to M. spretus and not to C57BL/6J. in DMI. Distortion can occur in females, e.g., one chroIn backcrosses to C57BL/6J, all progeny have C57BL/ 6J-derived chromosome 2 alleles that seem to be remosome is preferentially included in the egg nucleus rather than the polar body (AGULNIK quired for transmission ofC57BL/GJ-derived the X et al. 199313; RUchromosome alleles (Table 2). Butincrosses to M. VINSKY 1995), orin males, e.g., sperm with a particular chromosome are preferentially transmitted (SANDLER spretus, progeny will be at a disadvantage if they inherit and GOLIC1985; SEITZand BENNETT1985; LYITLE the CFiyBL/GJ-derived the X chromosomewithout also inheriting the C57BL/GJ-derived chromosome 2. Rein1991). Chromosome rearrangementssuch as inversions protect these haplotypes from crossingover and recomforcing epistasis may represent a step in the process bination, thereby preserving the selfish alleles (LYON leading to reproductive isolation, The next step might be loss of the alternative allelic incompatibility, e.g., 2H“ 1984; SANDLER and GOLIC1985; SILVER1985; LWTLE 1991; ACULNIKet al. 1993a,b; CROW1991; RUVINSKY and p’, and speciation. 1995). Unlinked loci are rarely involved because indeThe parental strains used in these crosses cannot be pendent assortment disrupts the allelic combination restrictly compared with natural populations for at least quired for DM1 (HARTL1975; THOMSON and FELDMAN two reasons. First, C57BL/6J, like most laboratory in1974-1976; LIBERMAN 1976; ESHEL1985; CROW1991; bred strains, is an artificial hybrid whose genome is HAIC andGWEN 1991; HURSTand POMIANKOWSKI composed of DNA derived from at least two different subspecies, namely M. musculus domesticus and M. muscu1991a).Unlinked modifiers ofDM1 have been delus musculus. Second, C57BL/6J and SPRET/Ei are inscribed in these systems, but their effects are generally bred strains where genetic variation is rarely found. weak (BENNETTet al. 1983; SANDLER and GOLIC1985; However, these interspecific backcrosses provide a simCROW 1991). ple experimental system to investigate genetic coadapThe effect of the chromosome 2 locus is consistent tation because mice with various allelic combinations with theoretical expectations in that the C57BL/6J-decan be created and characterized. Allelic interactions rived allele decreases rather than increases DMI. As may not be similar to those acting in wild populations, CROW(1991) showed, selection favors unlinked modparticularly since M. musculus domesticus and M. spretus ifiers that reduce DMI. As shown in Table 2, DM1 for are sympatric in parts of their range but very rarely X-linkedloci in pooled data for the three crosses is interbreed or produce hybrids. However, these crosses 91.3% (221 of242 progeny) without the C57BL/6Jcan be used as a model to study coadapted genes that derived allele and only73.8% (234 of317 progeny) contribute to reproductive isolation and speciation. with the allele. Of course, DM1 in these interspecific Finally, it is tempting to speculate that an anomaly crosses would onlyoccur in hybrid zones between natuin Xinactivation (or reactivation) (CHAPMAN 1986; RAS ral populations. Presumably the combinationsof alleles TAN 1994) accounts for DMI. In the EUCIB and JAX2 that occur within each population or species are mutucrosses, an X-linked DCSX gene maps near Xist, the ally adapted and it is only in interspecific crosses that candidate gene for X inactivation (BROCKDORFF et nl. allelic incompatibilities are manifested. The effect of 1991, 1992). In addition, the X-linked locus showing the chromosome 2 gene as a modifier of DM1may the strongest association with loci on chromosome 2 is therefore be special a case because it would havelimited near Xist in all three crosses. If the timing or specificity opportunities to evolve as a response to X-linked DMI. of Xinactivation (or reactivation) differed between the MULLER(1942) showed that allelic incompatibilities species represented in these inbred strains, fertilization should be asymmetric: if one combination of alleles at or embryogenesis might be compromised (KAY et al. two loci is incompatible, the other combination must 1993). An autosomal locus is thought to be involved be compatible. This phenomena has been called “reinin controlling X inactivation (or reactivation), but its forcing” epistasis (CROWand KIMURA 1970, pp. 80location and identity are unknown (KAY et al. 1994). If 81), where a maladaptive effect at one locus depends it is on chromosome 2 near D2Mit254 and D2Mit304 on the genotype at other loci. The interspecific crosses (Table 2), these interspecific crosses may offer an opdescribed here represent an example of this phenomportunity to find this gene. ena. The allelic combinations 2”’and p‘in females

Non-Mendelian Inheritance in Mice We are grateful to KEN JOHNSON for sharing DNAs for additional marker typings and pedigrees for mice in his mapping panel, FRANCK BOURCARDE for technical assistance, and ARAVINDA CHAKRAVARTI, FRANKEL, KEN JOHNSON, KEN MORGAN, CARMEN SAPIENZA, LEE WAYNE SILVER,BENTAYLORand FERNANDO PARD0 MANUEL DE VILLENA for discussions of this problem and comments on a draft of’ this manuscript. This work was supported by National Institutesof Health Grant HG00330.

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