Journal of Heredity Advance Access published online on June 24, 2007
Journal of Heredity, doi:10.1093/jhered/esm028
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Linkage to CFA29 Detected in a Genome-Wide Linkage Screen of a Canine Pedigree Segregating Sry-Negative XX Sex Reversal
From the J.A. Baker Institute for Animal Health, Cornell University, Ithaca, NY 14853 (Pujar, Kothapalli, Meyers-Wallen); and Department of Genetics, Southwest Foundation for Biomedical Research, San Antonio, TX (Göring)
Address correspondence to V. N. Meyers-Wallen at the address above, or e-mail: vnm1{at}cornell.edu.
Canine Sry-negative XX sex reversal is a disorder of gonadal development wherein individuals having a female karyotype develop testes or ovotestes. In this study, linkage mapping was undertaken in a pedigree derived from one proven carrier American cocker spaniel founder male and beagle females. All affected dogs in the analysis were XX true hermaphrodites and confirmed to be Sry negative by polymerase chain reaction. A genome-wide linkage screen conducted using 245 microsatellite markers revealed highest LOD score of 3.4 (marker CPH9) on CFA29. Fine mapping with additional microsatellites in the region containing CPH9 localized the Sry-negative XX sex reversal locus to a 5.4-Mb candidate region between markers CPH9 and FH3003 (LOD score 3.15). Insignificant LOD scores were found at genome-wide screen or fine mapping markers that were within 10 Mb of 45 potential candidate genes reported to have a role in mammalian sex determination or differentiation. Together, these results suggest that a novel locus on CFA29 may be responsible for sex reversal in this pedigree.
In mammalian sexual development, either an XX or XY sex chromosome complement is established at the time of fertilization. These zygotes develop similarly until differential gene expression determines whether the bipotential gonad becomes a testis or ovary. In the presence of testis secretions the genitalia are masculinized, and in their absence, female phenotypic features develop. Thus, testis induction is the pivotal point at which the male and female developmental pathways diverge. Sry (sex-determining region Y) is the only Y-linked gene known to initiate testis formation in mammals (Koopman et al. 1991). Its gonadal expression is the first molecular evidence of testis induction, followed immediately by Sox9 expression. Transgenic Sox9 expression in the absence of only Sry can induce a functional testis (Qin and Bishop 2005), indicating that this autosomal gene is also testis determining.
In XX sex reversal, individuals having a female karyotype develop testicular tissue in one or both gonads. The most common human etiology is translocation of SRY to another chromosome (SRY-positive XX sex reversal). However, in SRY-negative XX sex reversal, SRY and the entire Y chromosome are absent in individuals having a female karyotype (46,XX), yet testes or ovotestes develop. Such individuals are either XX males or XX true hermaphrodites, respectively. XX males occur in 1 in 20 000 male births, and approximately 10% of such patients are SRY negative (Sarafoglou and Ostrer 2000; Ergun-Longmire et al. 2005). XX males and XX true hermaphrodites occur as siblings in some families, suggesting a common genetic etiology (Skordis et al. 1987; Kuhnle et al. 1993; Ramos et al. 1996; Slaney et al. 1998; Jarrah et al. 2000; Sarafoglou and Ostrer 2000). In humans, abnormalities in only one chromosome (HSA22) have been associated with this condition (Aleck et al. 1999; Seeherunvong et al. 2004; Macville et al. 2006). Upregulation of SOX9 in the absence of SRY is associated with human XX males, but there is only one such report (Huang et al. 1999). A recent linkage study of a human family segregating XX males (Radi et al. 2005; Parma et al. 2006) revealed mutations in a gene RSPO1 (R-spondin 1). Interestingly, RSPO1, which probably interacts with Wnt proteins, is not required for testis differentiation and function (Parma et al. 2006).
Transgenic models for sex reversal disorders have been created through alteration of X-linked and autosomal genes, including Sox9 (Bishop et al. 2000; Vidal et al. 2001; Qin and Bishop 2005). However, Sry-negative XX sex reversal has not been reported as a naturally occurring disorder in the mouse. Sry-negative sex reversal occurs naturally in at least 18 canine breeds (Meyers-Wallen 2006a) and in goats (Pailhoux, Vigier, et al. 2001), pigs (Pailhoux et al. 1994; Pailhoux, Mandon-Pepin, Cotinot 2001), and horses (Meyers-Wallen et al. 1997; Buoen et al. 2000). Sex reversal in polled (hornless) goats is caused by a deletion that affects gonadal Pisrt1 and FoxL2 expression (Pailhoux, Vigier, et al. 2001). Mutations in human homologs are associated with premature ovarian failure but not with sex reversal (De Baere et al. 2003). Previous studies in the canine model indicated that the Pisrt1 homologous region and 8 other candidates were unlikely to contain the causative genetic defect (Kothapalli et al. 2003, 2004, 2005, 2006; Pujar et al. 2005).
The purpose of this study was to identify a chromosomal region linked to the canine disorder through a genome-wide linkage screen.
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Materials and Methods |
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Pedigree
The pedigree was previously generated from one proven carrier male American cocker spaniel from a family segregating Sry-negative XX sex reversal (Selden et al. 1978). In experimental matings, this male was bred to normal beagles to produce F1, F2, and F1 backcross (F1BC) generations and autosomal recessive inheritance of the trait was proposed (Meyers-Wallen and Patterson 1988), but DNA from those generations is not available. Inbreeding of subsequent generations, with introduction of beagle females to reduce inbreeding depression, gave rise to the pedigree under study, such that the genetic origin of sex reversal is presumed to be derived from the founder male American cocker spaniel (205, Figure 1). An informative subset of this pedigree (75 dogs) was subjected to genome-wide screen disequilibrium analysis: 6 XY males, 44 phenotypic females, including 1 beagle, and 25 Sry-negative XX true hermaphrodites.
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Diagnosis of affected dogs was obtained by 2 criteria: absence of the Sry gene in genomic DNA and presence of testicular tissue in gonadal histology. Sry-negative status of some affected animals in the pedigree subset under study was determined by Southern blot analysis (795, 796, 797, 798, Meyers-Wallen et al. 1999) or polymerase chain reaction (PCR) (795, 796, 798, Meyers-Wallen et al. 1995). For the remainder of the pedigree subset subjected to genome-wide linkage analysis, genomic DNA from affected animals was assayed for Sry by PCR or real-time PCR, with amplification from Sf1 or Sox9 primers serving as positive controls, as described previously (Meyers-Wallen et al. 1995; Meyers-Wallen 2003, 2005). Presence of testicular tissue in gonads was identified by examination of serial histologic sections of the gonads, using methods previously described (Meyers-Wallen and Patterson 1988). Affected gonads were classified as either ovotestis in which the testis comprised at least half of the gonad, ovotestis in which testis comprised less than half of the gonad, ovary containing Leydig cells but not seminiferous tubules (gonadal dysgenesis), or ovary. One gonad was lost to analysis (Table 1). Phenotypes of affected dogs in the pedigree subset chosen for linkage analysis, in terms of the proportion of testis in the ovotestis and percentage of animals affected, were similar to those in the previous report (Table 2) in which simple autosomal recessive inheritance of the trait was proposed in the American cocker spaniel (Meyers-Wallen and Patterson 1988).
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1/2 t), ovotestis in which less than half was composed of testis (ovt < 1/2 t), gonadal dysgenesis (GD), or ovary (ov).
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Marker Genotypes
Genomic DNA was extracted from blood or tissue samples by a commercial method (PureGene DNA purification kit, Gentra Systems, Minneapolis, MN). Genotyping at 241 microsatellite markers located at an average marker density of 8 cM throughout the canine genome (Marshfield Marker Set, Supplementary Table 1) was conducted by the NHLBI Mammalian Genotyping Service (Marshfield, WI), according to the method of Ghebranious et al. (2003).
Four additional markers were genotyped at Cornell: XP2 and REN230I20 on CFAX and KcnjCtgB and FH1014 on CFA9 (Supplementary Table 1). The XP2 and KcnjCtgB marker primers were designed with Primer 3 software (Broad Institute, Cambridge, MA). The XP2 primers flank a (gaaa)n nucleotide repeat within the 15-Mb pseudoautosomal region (Meyers-Wallen 2006b), and the KcnjCtgB primers flank a (gaaaa)n nucleotide repeat. The forward primer was 5'-end labeled with a 6-FAM fluorescent tag (IDT, Coralville, IA). Amplification of REN230I20 and FH1014 by PCR was performed according to published conditions (Clark et al. 2004; Guyon et al. 2003, respectively). Amplification of the XP2 and KcnjCtgB markers was performed from genomic DNA templates (50 ng) in a 30-µl reaction containing 1 µM of each primer, 0.25 mM dNTPs, 3 µl of 10x PCR buffer (Promega, Madison, WI), 2 mM MgCl2 and 1.5 U Taq polymerase (Ampli Taq II, Applied Biosystems, Foster City, CA). Annealing temperatures were 57.7 °C (XP2) and 62 °C (KcnjCtgB). A 1-µl portion of each product was pooled with 0.2 µl of size standard (GeneScan 500 Liz, Applied Biosystems) and 8 µl of formamide (HiDi, Applied Biosystems). Denatured samples (95 °C, 5 min) were analyzed by capillary electrophoresis (ABI 3730 Genetic Analyzer, Applied Biosystems). Reaction product sizes, relative to the internal Liz 500 standard, were determined by software (GENEMAPPER v 4.0, Applied Biosystems).
Linkage Analysis
Genome-wide screen and fine mapping data were analyzed by penetrance model–based, single-marker linkage analysis with the FASTLINK computer program (Cottingham et al. 1993). Previous segregation analysis suggested a recessive mode of inheritance, with founder XY male (205, Figure 1) being a homozygous carrier (Meyers-Wallen and Patterson 1988). However, linkage analysis was conducted under several different modes of inheritance to allow for the possibility that the previous inheritance model might be incorrect considering that the genetic background of the pedigree had changed to a predominantly beagle background over 20 years. We thus included an autosomal dominant, an autosomal recessive, and an X-linked model, all under the assumptions of a very rare disease allele, high penetrance (95%), and absence of phenocopies. All XY males were coded as phenotype unknown, and Sry-negative animals were coded as either affected (XX true hermaphrodite phenotype) or unaffected (female phenotype). The pedigree subset was analyzed as a whole (Figure 1). In addition, this multigenerational pedigree subset was broken into the nuclear families of which it was composed. Nuclear families are defined as a sire, a dam, and their offspring. Linkage analysis was performed on all possible nuclear families in the pedigree subset (Supplementary Figure 1), as results obtained by this method are much more robust to errors in an assumed mode of inheritance. These analyses were facilitated by use of ANALYZE software by Joseph D. Terwilliger. Multipoint penetrance model–based linkage analysis was performed on the nuclear families using GENEHUNTER (Kruglyak et al. 1996).
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Results |
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Genome-Wide Linkage Screen
Two hundred forty-five markers were genotyped across all 38 autosomes and the sex chromosomes (Supplementary Table 1). As most founder individuals and all affected animals were genotyped, the pedigree likelihood is relatively insensitive to marker allele frequency estimates, which were obtained by the conservative approach of simple allele counting.
Using single marker, penetrance model–based analysis, significant linkage was identified only on CFA29, with an LOD score of 3.4 for marker CPH9 under a dominant inheritance model, analyzing the nuclear families that jointly comprise the multigenerational pedigree. Other suggestive LOD scores were 1.5–2.4 (on CFA12 and 15) and 1.0–1.5 (on CFA1, 6, 8, 9, 13, 21, 24, and 27). Except for CFA29, further significant LOD scores were not obtained upon genotyping with additional microsatellite markers. No significant LOD scores were found on CFAX, including the pseudoautosomal region.
Eight additional markers from CFA29 were genotyped and analyzed (Table 3). A second marker with significant LOD score (FH3003, LOD score 3.15) identified a 5.4-Mb chromosomal region linked to the disease phenotype, defined by the markers CPH9 and FH3003.
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Candidate Genes
Insignificant LOD scores were found for genome-wide screen or fine mapping microsatellite markers that were located within 10 Mb of 45 genes reported to have a role in mammalian sex determination or differentiation (Supplementary Table 2). Ten candidate genes (Lhx9, Wt1, Dmrt1, Sox9, Gata4, Lhx1, Sf1, Fog2, Pisrt1, and FoxL2) were previously considered unlikely to be causative based on failure of an intragenic marker to segregate with the disease phenotype in a subset of affected animals, their parents, and grandparents (Kothapalli et al. 2003, 2004, 2005, 2006; Pujar et al. 2005). Those analyses assumed an autosomal recessive mode of inheritance. In the present study, linkage on CFA29 was obtained under an autosomal dominant inheritance model. Therefore, the previous candidate gene intragenic marker data were reanalyzed for segregation with the affected phenotype assuming autosomal dominant inheritance. Under that model, Gata4, Sf1, Lhx9, Fog2, Pisrt1, and FoxL2 would still be unlikely, but results would be inconclusive for Wt1, Sox9, Lhx1, and Dmrt1.
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Discussion |
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Genome-Wide Linkage Screen
Linkage analysis in the canine model has identified a critical region mapping to a different chromosome than any of the genes previously reported in association with XX males: Pisrt1 (goat) and RSPO1 and SOX9 (human). The results of the genome-wide screen suggest that a locus causing sex reversal (XX males and XX true hermaphrodites) is likely to be located in the linked region of CFA29. Significant LOD scores on CFA29 (Table 3) were obtained from linkage analysis on the nuclear families in the pedigree subset, based on a model of dominant inheritance. LOD scores obtained with 2-point and multipoint analyses were similar (data not shown).
A total of 45 candidate genes known to have a role in sex determination or differentiation in humans or mice had insignificant LOD scores at adjacent markers, obtained by linkage analysis as above (Supplementary Table 2). Although none of these LOD scores are sufficiently low for exclusion with statistical confidence (LOD < –2), they were too low (<3) to warrant priority in fine mapping. At present, there is no evidence to link any of these gene candidates with the affected phenotype.
Although recent studies have shown that Sox9 can substitute completely for Sry as a testis-determining factor in XX transgenic mice (Qin and Bishop 2005), a defect in the Sox9 coding region was not expected in the canine model. Rather, in the absence of Sry, a gain of function mutation that upregulates Sox9 expression in the XX gonad would be expected, as in mouse models (Bishop et al. 2000, Vidal et al. 2001). Such a defect now appears unlikely, as Sox9 is not located on CFA29 and an insignificant LOD score was obtained at a polymorphic marker within 5.1 Mb of the Sox9 coding region and within 7 Mb of the Sox9 regulatory regions (Supplementary Table 2), reported to range from 350 kb to 1.3 Mb upstream of the coding region (Wunderle et al. 1998; Bishop et al. 2000). Thus, there is no evidence to link Sox9 with the affected phenotype.
No significant linkage was observed with CFA15 in this study, including the region syntenic to RSPO1 (Supplementary Table 2) that was recently reported to be linked to human XX males (HSA1q34, Parma et al. 2006). Therefore, there is no evidence to link Rspo1 with the affected phenotype. No gene mutations are yet known for the type of SRY-negative XX sex reversal in which XX true hermaphrodites and XX males occur as siblings. Transgenic mouse models have been produced, but only by ectopic SOX9 expression. Thus, the canine model, a naturally occurring model of this type of sex reversal, is critical to identifying a novel mutation for this disorder.
Genetic Interpretation of Phenotype Variation
All affected dogs in the model pedigree presumably have the same genetic defect leading to sex reversal, inherited from the proven carrier XY male American cocker spaniel founder (identical by descent). However, the genetic background of this pedigree has been changed over a period of 20 years to a predominantly beagle background. This was a concern in choosing an inheritance model for linkage analysis because change in genetic background has been shown to affect phenotypic expression and inheritance patterns in murine transgenic models of Sry-negative XX sex reversal (Eicher et al. 1996; Poirier et al. 2004). For example, in the Odsex model, a heterozygous transgene insertion in the FVB/N strain causes Sry-negative XX males by inducing ectopic Sox9 expression (Bishop et al. 2000). When the Odsex transgene was placed on a different strain (Poirier et al. 2004), the proportion of testis development in affected gonads changed, from only testis in the original mouse strain (FVB/N) to ovotestis or ovary in the new background (A/J). Furthermore, on the FVB/N background, the trait was inherited as a simple autosomal dominant, but in the A/J strain it was inherited as a complex trait with at least 2 modifier loci and imprinting effects. Thus, genetic background can have a profound effect on phenotypic expression and inheritance patterns in murine models of gonadal sex determination and could have similar effects in dogs.
To examine the genetic background effect in the study pedigree, we compared the proportion of affected phenotypes in the linkage analysis pedigree subset with the phenotypes observed in the F1BC and F2 generations in our previous report (Table 2). The phenotypes observed were similar, in terms of the proportion of testis in ovotestes and percentage of animals affected. Nevertheless, the most severe phenotype (testis) has been observed only in the F1BC generation, which has the highest probability (0.5) of having an ACS allele at any one locus. Conversely in those studies, the mildest phenotype (ovotestis composed of <1/2 testis paired with an ovary) was observed in 3 of the 5 affected dogs in the F2 generation, which has a lower probability (0.25) of an ACS allele at any locus. Phenotypes in the linkage analysis pedigree subset ranged between those of the F1BC and F2, but did not include the most severe phenotype (testes), as might be expected if there is an additive effect of ACS alleles upon phenotypic expression. This suggested that the predominantly beagle background may affect trait expression and that additional inheritance models should be considered.
To account for the likelihood that the original inheritance model could be inaccurate, considering the change in pedigree genetic background, linkage analysis was performed using several inheritance models and also with a method where results are only marginally affected by errors in an assumed inheritance model. Therefore, it is important to keep in mind that results obtained by the multipoint analysis allowing for heterogeneity, which was conducted on the nuclear families that jointly comprise the multigenerational pedigree subset rather than the pedigree subset as a whole, are valid because this method is robust to misspecification of the mode of inheritance.
In the canine genome, the 5.4-Mb linked region identified in this study, which is syntenic to human chromosome 8q21 and mouse chromosome 3, contains 30 known genes and 103 predicted genes (Ensembl). None of these has a known function in sex reversal. Thus, Sry-negative XX sex reversal may involve more than one mechanism in mammals. Our data indicate the involvement of a novel gene located in the linked region on CFA29. Fine mapping in this linked interval with additional microsatellite and SNP markers is underway to identify a disease haplotype shared among affected animals (Lindblad-Toh et al. 2005). Identification of the causative genetic defect in this canine model could provide additional clues to the genetic complexity of mammalian testis induction.
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Supplementary Material |
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Supplementary Tables 1 and 2 and Figure 1 can be found at http://www.jhered.oxfordjournals.org/.
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Acknowledgments |
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These studies were supported by the National Institutes of Health (RO1 HD40351). Genotyping was performed by the NHLBI Mammalian Genotyping Service, Marshfield Medical Research Foundation, Marshfield, WI, and through services of the Biotechnology Resource Center, Cornell University. Studies at the Southwest Foundation for Biomedical Research were supported by the National Institutes of Mental Health (RR013556) and a gift from the SBC Foundation. The authors thank Katelyn Romeo, Mari Waterman, and Roxanne Van Wormer for technical assistance; Anita Hesser for clerical assistance; and the Cornell Canine Genomics Group for provision of MSS2 markers.
This paper was delivered at the 3rd International Conference on the Advances in Canine and Feline Genomics, School of Veterinary Medicine, University of California, Davis, CA, August 3–5, 2006.
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Footnotes |
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Corresponding Editor: Urs Giger
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References |
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