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The ovine callipyge locus: a paradigm illustrating the importance of non-Mendelian genetics in livestock M Georges, N Cockett To cite this version: M Georges, N Cockett. The ovine callipyge locus: a paradigm illustrating the importance of non-Mendelian genetics in livestock. Reproduction Nutrition Development, EDP Sciences, 1996, 36 (6), pp.651-657. HAL Id: hal-00899932 https://hal.archives-ouvertes.fr/hal-00899932 Submitted on 1 Jan 1996 HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L’archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d’enseignement et de recherche français ou étrangers, des laboratoires publics ou privés. Review article The ovine callipyge locus: a paradigm illustrating the importance of non-Mendelian genetics in livestock M 1 Georges N Cockett 2 Department of Genetics, Faculty of Veterinary Medicine, University of Liege (843), 20, boulevard de Colonster, 4000 Li6ge, Belgium; 2 Department of Animal, Dairy and Veterinary Sciences, College of Agriculture, Utah State University, Logan, UT 84322-4700, USA (Received 15 October 1996; accepted 17 October 1996) inheritable muscular hypertrophy was recently described in sheep and shown to be determined by the callipyge (CLPG) gene mapped to ovine chromosome 18. We demonstrate in this work that the callipyge phenotype is characterized by a non-Mendelian inheritance pattern, referred to as polar overdominance, in which only heterozygous individuals having inherited the CLPG mutation from their sire express the phenotype. The possible role of parental imprinting in the determinism of polar overdominance is envisaged. Summary ― An imprinting I domestic animals I callipyge Résumé ― Le locus ovin Callipyge: un paradigme illustrant l’importance de la génétique non mendélienne chez les animaux d’élevage. Une hypertrophie musculaire héritable a été décrite récemment chez le mouton ; elle est déterminée par le gène Callipyge localisé sur le chromosome 18. Nous montrons ici que le phénotype callipyge est caractérisé par un type d’hérédité non-mendélienne, nommée surdominance polaire dans laquelle les individus hétérozygotes qui ont hérité la mutation CLPG de leur père expriment le phénotype. Le rôle possible d’une empreinte parentale dans le déterminisme de la surdominance est envisagé. empreinte parentale lanimaux domestiques /Callipyge INTRODUCTION By selecting the individuals exhibiting properties as parents for next generations, animal breeders have been manipulating genes, albeit unwittingly, for centuries. During the latter half of this century, the quantitative genetics theory allowed for spectacular increases in genetic response by modelling an individual’s phenotype as the sum of an environmental and genetic component. For most continuously distributed production traits, the genetic comdesired was assumed to reflect the action of a large number of polygenes or quantitative trait loci (QTL), each contributing modestly to the overall genetic variance in an independent, additive and Mendelian way. ponent The emergence of genomics as a very powerful discipline for genome analysis has opened the possibility to dissect production traits at the molecular level, that is, identify the actual genes (both major genes and QTL) underlying the observed genetic variation for the traits of interest. Not only should the resulting information allow for the design of more efficient marker-assisted selection schemes, but it should lead to a better fundamental understanding of the so-called black box, ie, the functioning of the network of involved polygenes. The first whole genome scans performed during the last 5 years have already led to the mapping of a number of production genes (reviewed in Georges and Anderson, 1996), including major genes (such as the polled and mh loci causing hornlessness and double-muscling in cattle, the CRC and RN genes affecting meat quality in pigs, the FecB and callipyge loci underlying the Booroola fecundity and a muscular hypertrophy in sheep), and QTL (including a QTL affecting fatness in pigs and a QTL affecting milk production in cattle). Unexpectedly, detailed analysis of one of these mapped production genes - the ovine callipyge locus - revealed a nonMendelian inheritance mode, conflicting with the traditional view of the Mendelian action of the genes composing the ’black box’. Likewise, preliminary evidence suggested parent-of-origin effects for a QTL underlying trypanotolerance in a rodent model, suggesting that such a non-Mendelian mechanism might. not be that uncommon. The objective of the present article is to summarize the present knowledge about the unusual inheritance pattern characterizing the callipyge locus, referred to as polar overdominance (Cockett et al, 1996), as a paradigm of non-Mendelian genetics that is likely to be increasingly uncovered through future genomic analysis of complex production traits in livestock and other organisms. &dquo;CALLIPYGE&dquo;: A MONOGENIC MUSCULAR HYPERTROPHY MAPPING TO OVINE CHROMOSOME 18 8 In 1983, a sheep breeder in Oklahoma (USA) described a ram, premonitorily called Solid Gold, exhibiting an unusual muscularity transmitted to part of its descendants. Systematic crosses performed between male descendants of Solid Gold and normal ewes subsequently allowed for a rigorous characterization of this unusual phenotype (Jackson and Green, 1993; Jackson et al 1993a,b), showing that the callipygous animals were characterized by a generalized muscular hypertrophy (although manifesting itself primarily around the hind quarters; hence, its name) resulting in a 30% increase in muscle mass when compared to controls. Histological examination of skeletal muscle tissue revealed an hypertrophy of all but the slow twitch oxidative fibres. Interestingly, the callipyge phenotype manifested itself only after approximately 3 weeks of age. It should be noted that some concerns have been raised about the palatability of callipyge meat. The same callipyge d x normal !9 revealed a sex-independent 1:11 segregation of the callipyge versus normal phenotype, allowing Cockett et al (1994) to postulate an underlying autosomal dominant mutation, referred to as callipyge (CLPG). Linkage analysis performed in the same pedigree material quickly positioned the corresponding callipyge locus to the subtelomeric region of ovine chromosome 18, at approximately 3 cM for the nearest microsatellite markers: CSSM18 and IDVGA30 (Cockett et al 1994, 1996). Linkage analysis in these matings were performed assuming full penetrance of the dominant CLPG mutation, ie, the corresponding chromosome 18 locus accounted for all the trait variance in these crosses. Lod score values superior to 80 are presently obtained from such crosses, proving the chromosomal location of the callipyge locus beyond crosses any doubt. mal. The 51 offspring initially obtained from such matings yielded a x i value of 56.5 with 2 an associated P value of P < 0.0001. Since then, these ratios have been confirmed in a new crop of approximately 50 sheep. The results obtained in both these clearly pointed towards a non-conventional inheritance pattern of the callipyge crosses phenotype. MARKER-ASSISTED SEGREGATION ANALYSIS REVEALS POLAR OVERDOMINANCE AT THE OVINE CALLIPYGE LOCUS To gain better understanding of the observed inheritance pattern, all corresponding individuals were genotyped for the genetic markers known to flank the callipyge locus. This marker-assisted segregation analysis revealed a clear pattern. lCLPG d CLPG First, although + THE CALLIPYGE LOCUS EXHIBITS A NON-MENDELIAN INHERITANCE PATTERN regate types of matings yielded results conflicting with the simple model of an autosomal dominant mutation. Indeed, matings between callipygous female descendants of Solid Gold (assumed CLPG/CLPG’ genotype) and conventional Subsequently, however, two (CLPGICLPG genotype) yielded noroffspring exclusively, pointing towards non-equivalence of reciprocal crosses. At present, more than 35 such offspring have been generated, all of them being of conventional phenotype. Furthermore, matings between callipygous male and female descendants of the founder ram (assumed + genotype) resulted in 29% CLPGICLPG callipygous versus 71 % normal offspring rams mal where a dominant mutation in such cross would have yielded closer to the opposite ratios, ie, 75% callipyge versus 25% nor- x CLPG/CLPGmatings generated only conventional offspring, the maternal 18 homologues were shown from marker data to segas expected. However, offspring inherited the CLPG mutation from their dam (or CLPG+!Par)CLPG!Mar)) were unexpectedly not expressing the phenotype, contrary to individuals having inherited the same mutation from their sire (or having CLPG!Par)lCLPG+!^’rar) individuals), clearly pointing towards a parent-of-origin effect. Genotyping the offspring of the second + d x type of matings, ie, CLPG/CLPG CLPG/CLPG! 9, revealed that CLPGIPar)) (Mat), CLPG+!Pat)/CLPG!n!at) + CLPG and at individuals generM ( )/CLPG P ( CLPG + at ) ally expressed the same phenotypes as observed in previous matings namely callipygous, normal and normal, respectively. )/ t a P Unexpectedly, however, CLPG( CLPG!!’rar) offspring did not express the callipygous phenotype (fig 1 a). The inactive CLPG!Mar) allele therefore seemed to dom- inate the active CLPG( ) allele. The resultPat ing segregation pattern, where only heterozygous individuals having inherited the mutation from their sire express the phenotype, has been referred to as polar overdominance (Cockett et al, 1996). To verify whether the inactivation of the CLPG!Mar! allele (ie, the CLPG allele transmitted by the ewe) was reversible, normal P ( + CLPG CLPG(Mat) at and looking )/ CLPG!Par!lCLPG!Mar! rams were mated to unrelated conventional CLPG /CLPG + Callipygous offspring were indeed generated from both types of matings, demonstrating the reversible nature of the maternal inactivation of the CLPG allele. Moreover, the proportions of callipygous versus conventional offspring as well as the correlation with the segregation of chromosome 18 markers were in agreement with the polar overdominance model. Indeed, CLPG+!Pat)/CLPG!Mat) produced 50% cal)/ t a P lipyge offspring (fig 1 b), while CLPG( CLPG!Mar! rams yielded close to 100% calewes. lipyge offspring (30/33, 91%). DOES POLAR OVERDOMINANCE INVOLVE PARENTAL IMPRINTING ? To the best of our knowledge, only two other phenotypes show polar overdominance: Pelement dependent hybrid dysgenesis in Drosophila (Bregliano and Kidwell, 1983), and an early embryonic lethality referred to as polar lethality in DDK mice (Wakasugi, 1974). Hybrid dysgenesis is well understood and due to P-element transposition in the germline of offspring from paternal (P) males x maternal (M) females crosses. This zygotic mechanism seems, however, difficult to reconcile with the muscle-specific expression of the callipyge phenotype. The molecular mechanisms underlying polar lethality are yet unknown, but imprinting has been invoked as a possible cause (Baldacci et al, 1992; Sapienza et al, 1992). The conventional phenotype of homozy- gous CLPGICLPG individuals, however, is difficult to reconcile with the allele-specific transcriptional silencing observed for all known imprinted genes (reviewed in Efstradiatis, 1994). A number of molecular models based on conventional parental imprinting can, however, be envisaged to account for the observed segregation pattern (Cockett et al 1996). It could be postulated that the callipyge mutation switches the expression pattern of the corresponding imprinted callipyge gene from paternal to maternal. )/CLPG individuals would then be t a P CLPG( + the only genotype with two transcriptionally silent copies of the gene, which would explain their unique phenotype (fig 2a). An alternative model considers two closely linked genes, one of which is paternally expressed and coded for a trans-acting suppressor of the other one. The CLPG muta- tion would be a deletion of both genes, resulting in the expression of the otherwise suppressed gene in CLPG!Par!lCLPG+ individuals only (fig 2b). Interestingly, the homologous chromosomal regions in humans (chromosome 14) and mice (chromosome 12) are known to harbour imprinted regions (Temple et al 1991; Wang et al 1991; Cattanach and Raspberry, 1993; Beechey and Cattanach, 1994). Moreover, the phenotypic manifestation of this gene seems to be in agreement with the predictions made from evolutionary considerations by Moore and Haig (1991namely that imprinting is expected at loci that influence how much an offspring receives at the expense of its mother (including genes that affect postnatal growth rate), with the paternal allele stimulating growth and the maternal one opposing it. It is noteworthy that, from the point of view of population genetics, dominant negative imprint- ing may generate balanced polymorphism at corresponding loci. the SHORTCOMINGS OF THE POLAR OVERDOMINANCE MODEL Whereas the polar overdominance model explains the majority of our observations, some of the inconsistencies between the phenotype and the callipyge genotype as inferred from marker data remain puzzling (see fig 1 and Cockett et al, 1996). While at this point we cannot exclude that this involves trivial phenotypic misclassifications, this hypothesis is hardly convincing as a recombination rate as low as 6% was found with the closest microsatellite marker for more than 600 offspring issued x from )ICLPG(mat) t a P CLPG( 6 CLPG(Pal)/CLPG(Mal) q mating, putting an upper limit of 6% misclassification in these crosses. Genotypic misclassification due to undetected recombinations could account for some of the observed discrepancies. This will be verified by typing the corresponding families with additional genetic markers in the callipyge region when they become available in order to detect and characterize previously undetected recombinations. The observed inconsistencies, however, to fit two distinct patterns. First, we observe a number of CLPG!PAT!lcIpglMar! individuals issued from d clpg(Pat) / ) xCLPG/CLPG matings and l a M CLPG( d CLPGlCLPGx !CLPG/CLPG matings, which are normal in appearance contrary to what would be predicted under the polar overdominance hypothesis. Assuming that parental imprinting occurs at the callipyge locus, the four individuals with normal phenotype, although having inherited the CLPG mutation from their clpg( ) or l )/CLPG(Ma Pal ) sire, might be due to Mat )/CLPG( Pat CLPG( incomplete erasure of the grand-maternal seem imprint. The capacity to erase the maternal imprint could itself be under genetic control of modifier ’imprintor’ loci either in the sire (Sapienza, 1990; Forejt and Gregorova, 1992) or transmitted by the ewes (Sapienza et al 1989; Allen et al, 1990). It would be of interest to determine the grand-parental origin of the CLPG mutation for the three phenotypically normal offspring of the ) sires, predicted to be Mat )/CLPG( Pat CLPG( grand-maternal under the hypothesis of incomplete imprint erasure. As they become available, additional markers will be typed on the corresponding pedigrees in order to resolve this issue. Moreover, when mated to CLPG/CLPG ewes these normal looking CLPG!Pat)lclpg!Mar) rams should yield offspring segregating for the callipyge phenotype in linkage with chromosome 18. Offspring from such offspring will be generated in order to verify this prediction. Second and more intriguing, a few CLPG/CLPG individuals issued from d pgIPat) x CLPG/CLPG matI c IMat) /CLPG ings are callipygous in appearance while they are obviously expected to be of conventional phenotype. As the segregation of the callipyge locus accounted for virtually all the trait variance in the d )/CLPG(Mat) x t a P CLPG( CLPG(Pat)/CLPG(Mat)matings (Cockett et al, 1994), a two-locus model is difficult to fit to the data. It could be postulated either a transposition of the callipyge locus in some CLPG!Par)lCLPG!Mat) sires or the conversion of the paternal CLPG!Pat) allele by its CLPG!Mar) homologue, possibly by a transsensing effect (Tartof and Henikoff, 1991). The latter hypothesis will first be tested by producing offspring from such callipygous clpglclpg rams mated to normal clpglclpg ewes. Segregation of the callipygous phenotype in such pedigrees in linkage with the chromosome 18 callipyge locus would point towards a conversion event. Segregation of the callipygous phenotype in the absence of linkage with chromosome 18 would point towards the transposition hypothesis. A new would then have to be under- genome scan taken to identify the new locus. CONCLUSION unravelling of the polar overdominance characterizing the ovine callipyge locus clearly illustrates the importance of dissecting production traits into their ’Mendelian’ (or not-so-Mendelian) components using the new genomic techniques. Elucidating the molecular mechanisms underlying polar overdominance is of fundamental interest. It might help to explain complex inheritance patterns observed in other organisms, including humans. Already, linkage analysis performed under the polar overdominance model might uncover previously undetected causative loci. In addition, this work demonstrates how a genomic analysis of a production gene might have immediate implications for breeding pro- The grams. It is evident that conventional selection programs could not deal appropriately with genes exhibiting polar overdominance. For instance, it would be impossible to fix the callipyge phenotype by selecting hypertrophied parents in subsequent generations. From the point of view of population genetics, polar overdominance generates balanced polymorphism at the corresponding loci. Based on our model, however, we could predict that non-expressing CLPG!Par!! t) males mated to cIpg(Pat)/clpg(Mat) Ma CLPG( females might produce 100% callipyge offspring, which would be the breeding scheme of choice to optimally exploit the callipyge entity. REFERENCES Allen ND, Norris ML, Surani MA (1990) Epigenetic control of transgene expression and imprinting by genotype specific modifiers. Cell61, 853-861 Baldacci PA, Richoux V, Renard JP, Gu6net JL, Babinet C (1992) The locus Om, responsible for the DDK syndrome, maps close to Sigje on mouse chromosome 11. 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