Genetic mapping and developmental timing of transmission ratio distortion in a mouse interspecific backcross

Chevonne D Eversley 0 Tavia Clark 0 Yuying Xie 0 Jill Steigerwalt 0 1 Timothy A Bell 0 Fernando PM de Villena 0 David W Threadgill 0 1 0 Department of Genetics, Curriculum in Genetics and Molecular Biology, and Carolina Center for Genome Sciences, University of North Carolina , Chapel Hill, NC 27599 , USA 1 Department of Genetics, North Carolina State University , Raleigh, NC 27695 , USA Background: Transmission ratio distortion (TRD), defined as statistically significant deviation from expected 1:1 Mendelian ratios of allele inheritance, results in a reduction of the expected progeny of a given genotype. Since TRD is a common occurrence within interspecific crosses, a mouse interspecific backcross was used to genetically map regions showing TRD, and a developmental analysis was performed to identify the timing of allele loss. Results: Three independent events of statistically significant deviation from the expected 50:50 Mendelian inheritance ratios were observed in an interspecific backcross between the Mus musculus A/J and the Mus spretus SPRET/EiJ inbred strains. At weaning M. musculus alleles are preferentially inherited on Chromosome (Chr) 7, while M. spretus alleles are preferentially inherited on Chrs 10 and 11. Furthermore, alleles on Chr 3 modify the TRD on Chr 11. All TRD loci detected at weaning were present in Mendelian ratios at mid-gestation and at birth. Conclusions: Given that Mendelian ratios of inheritance are observed for Chr 7, 10 and 11 during development and at birth, the underlying causes for the interspecific TRD events are the differential post-natal survival of pups with specific genotypes. These results are consistent with the TRD mechanism being deviation from Mendelian inheritance rather than meiotic drive or segregation distortion. - Background Commonly used inbred mouse strains, which trace their genetic ancestry primarily to the Mus musculus domesticus subspecies [1], have extensive interspecific polymorphic differences when compared to Mus spretus. Because of the large number of polymorphisms that are distributed across the genome, interspecific crosses are frequently used to map genes responsible for variation in a variety of phenotypic traits [2]. In crosses between M. musculus and M. spretus only interspecific backcrosses using hybrid females are possible since hybrid males are sterile. However, interspecific backcrosses often result in skewed distributions in the inheritance of polymorphic alleles from the hybrid females, a phenomenon called transmission ratio distortion (TRD) [3-8]. Transmission ratio distortion is defined as statistically significant deviation from the expected 1:1 Mendelian ratios of allele inheritance, resulting in a reduction of the expected progeny of a given genotype. Transmission ratio distortion involving M. spretus crosses was first identified during linkage testing on Chromosomes (Chrs) 2, 4 and 10 [8-11]. Subsequent efforts attempted to map the causative loci influencing TRD in four backcrosses involving M. spretus [6]. Transmission ratio distortion has also been observed in wild M. musculus populations involving Chr 1 and in commonly derived inbred strains on Chr 11 [12-15]. Among the causes of TRD are meiotic drive, segregation distortion (SD), and deviation from Mendelian inheritance (DMI) [6]. The defining characteristic of meiotic drive is that TRD occurs during female meiosis [16]. Consequently, the resulting gametes are not lost and fertility is unaffected, but the inheritance of adjacent neutral polymorphisms is affected [17,18]. Meitoic drive is one of the more common examples in which a selfish gene drives the preferential selection and fertilization of an oocyte [6,17]. An example of meiotic drive at the second meiotic division can be seen in the DDK syndrome at the Om locus on mouse Chr 11 [19,20]. Segregation distortion is due to a chromosomal transmission imbalance that typically occurs after meiosis but prior to fertilization. This mechanism is responsible for the SD system in Droshophila melanogaster and the mouse t-haplotype [21-25]. Finally, DMI occurs as a result of post-fertilization lethality of embryos or neonates with a particular genotype. Therefore, DMI can be used to map loci at which specific alleles have detrimental effect on survival. This is particularly interesting in crosses between closely related species because DMI may provide an important tool to study the genetics of speciation. In this study we report three independent occurrences of TRD caused by post-meiotic lethality in a single interspecific backcross population between A/J (M. musculus) and SPRET/EiJ (M. spretus) mouse inbred strains. Preferential transmission of M. musculus alleles is observed on Chr 7 and of M. spretus alleles on Chrs 10 and 11. In addition, the Chr 11 TRD is modified by a locus on Chr 3. All three loci showing TRD are consistent with a DMI cause since allele-specific losses are not observed until after birth. Results The number of progeny inheriting S or A alleles from an ASF1 female backcrossed to an A male was used to measure transmission frequencies across the mouse genome and to detect TRD. Three genomic intervals were detected that showed non-Mendelian inheritance (Table 1). Transmission ratio distortion favoring A alleles was observed on Chr 7 (c2 = 7.87; p = 0.005), while elevated frequencies of S alleles were observed on Chr 10 (c2 = 30.68; p = 3.0 10-8) and Chr 11 (c2 = 19.93; p = 8.0 10-6). There was no difference in TRD presence and level between female and male progeny (data not shown). An approach developed to map TRD to a single locus or multiple linked loci was used to identify the location of the distorted loci with the minimum goodness-of-fit (GF) for each TRD region [6,19]. The distribution of allele frequencies along Chr 7 can be explained by TRD at a single locus located within a 6 cM interval centered at 27.8 cM (Figure 1A). The best GF location was Table 1 SNP markers displaying TRD determined by incrementally shifting 0.2 cM away from rs8260829 at 28 cM (GF = 10.003, 31 d.f., not significant p = 0.99). Among 19 SNPs on Chr 10, a single peak was evident at rs4228380 (Figure 1B). The model posits that a single distorted locus is located at 48.5 cM with an expected distortion of 71%. This is in good agreement with the predictions of the GF model (GF = 12.08, 19 d.f., not significant p = 0.88). Incremental adjustments of the location and TRD had no affect on the minimum GF. Chromosome 11 shows broad distortion spanning 16 SNPs incrementally spaced with a maximum peak of 67% TRD (Figure 1C). After adjusting the location of GF and TRD, the best GF was found to be near rs13481119 at 45 cM distal to the centromere (GF = 3.631, 16 d.f., not significant p = 0.99). In addition to reduced fitness of gametes inheriting the A allele on Chr 11, transmission of alleles on Chr 11 was strongly modified by co-segregating alleles on Chr 3 (Table 2). Gametes inheriting A (...truncated)