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Functional Analysis of Mutations of Murine Chromosome 17 with the Use of Tertiary Trisomy

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Functional Analysis of Mutations of Murine Chromosome 17 with the Use of Tertiary Trisomy Copyright 0 1991 by the Genetics Society of America Functional Analysis of Mutations of Murine Chromosome 17 With the Use of Tertiary Trisomy Anatoly Ruvinsky, Alexander Agulnik, Sergei Agulnik and Margarita Rogachova Institute of Cytology and Genetics, Academy of Sciences of the USSR, Siberian Division, Novosibirsk 630090, USSR Manuscript receivedJune 5, 1990 Accepted January 7, 1991 ABSTRACT Analysis of the functional nature of mutations can be based on comparisons of their manifestation in organisms with a deletion or duplication of a particular chromosome segment. With the use of reciprocal translocation T(16;17)43H, it is feasible to produce mice with tertiary trisomy of the proximal region of chromosome 17. The mutations on chromosome17 we tested included brachyury (T),hairpin tail (T*P),kinky (Fu'"),quaking (qk), tufted (tf),as well as tct (t complex tail interaction), and tcl (t complex lethal) that are specific to t haplotypes. The set of dominant and recessive mutations was assigned to two groups: one obligatory, manifesting itselfin the phenotype independently of the number of normal alleles in di- and trisomics, and the other facultative, phenotypically manifesting itself depending upon the dosage of mutant alleles. A model was derived from analysisof the interaction of the T and ThP mutations with t haplotypes. It seeks to explain the morphogenetic effects of the mutations observed in mice of different genotypes. The tir gene is postulated to reside on chromosome 17 within its framework. It is suggested that the gene dosage ratio at the tir and tct loci " determines tail length. UTATIONS can be analyzed by nontraditional tfmutation), T tf/t6 +, T tf/tj2 +, ThP/+,+ qk/t12 +, homo- methods. One such method is comparison of zygotes for Robertsoniantranslocations Rb( 16.17)7Bnr M (Rb7Bnr/Rb7Bnr), Rb(8.17)lIem (RblIem/RblIem), for the manifestation of genesin the mono-, di-, and reciprocal translocationsT( 16; 17)43H (T43H/T43H). The trisomic condition. The method has been applied in mice bearing mutations in translocations T T43H/+ T43H, studies of mutations in Drosophila (MULLER 1932; Rb7Bnr t6 +/+ T tfhave been produced earlier (AGULNIK, ROBERTS1976). Its application in mammals, however, AGULNIKand RUVINSKY1985, 1986). The proximal partial has been limited because almost all the known forms haplotypes tN' and tN2,derived from tj2 and t6, respectively, have no lethal factors (AGULNIKand RUVINSKY1989). The of mono- and trisomy are lethal(DYBAN and BARANOV partial tN'" haplotype located in translocation T43H origi- 1987). The possibility of producing viable mice with nated from t6 haplotypes in T T43H/t6 + 0 X Rb7Bnr t6 +/ tertiary trisomy 17 (trisomyfor only part of the chro- + + T43H ~3cross. The tN" haplotypes retained the region mosome) by use of translocation T(16";17)43H has interacting with the T mutations of the original t6 haplotype been reported a few years ago (FOREJT,CAPKOVA and but lost its lethal factor. The mice with different sets of mutations and chromo- GREGOROVA1980). This possibility has not yet been some rearrangements involved in the crosses are listed in exploited in studies of the interaction between genes Table 1. They all have been derived from the above strains situated in the portion of the murine genome that is and stocks. "sprinkled over with different mutations" exhibiting Cytogenetic analysis: The phenotype of the offspring unusual properties(KLEIN 1986; Figure 1). The prox- resulting from the testcrosses was identified at the age of 1.5 months, thereafter bonemarrow biopsieswere per- imal region thechromosome 17 containsthe of t formed for karyotype analysis(UDALOVA 197 1). The mitotic complex with a set of dominant and recessive muta- chromosome preparations were obtained and C-banded ac- tions manifesting themselves morphologically in the cording to the standard techniques (DYBANand BARANOV most conspicuous fashion (SILVER1985). 1987). We have carried out and report here, functional analysis of a number of mutationssituated in the RESULTS proximal region of chromosome 17. The analysis in- Use of tertiarytrisomy in genedosage study: cludes comparisons of the functioning of mutant and Figure 2 is a scheme showing how tertiary trisomics normal alleles in organisms having them in different wereproduced by dintof reciprocal translocation dosage ratios and combinations. T43H. The localization of the breakpoints of this rearrangement is noteworthy: it is at about a third of MATERIALS AND METHODS the chromosome away from the centromere in chro- Mice: The following mouse stocksand strains were used mosome 17, and it is at the precentromeric hetero- BTBR - + Fu tf/+ + tf, TFN - tf/tf (homozygotes for the chromatin region in chromosome 16. As a result, a Genetics 127: 781-788 (April, 1991) 782 A. Ruvinsky et al. Rb (8. f ?) IIem hyperploidgametes with two doses of the proximal portion of chromosome 17 in T43H/+ female heter- ozygotes. Fertilization of these eggs with haploid sperm produces a zygote with tertiary trisomy. Differentmutations introduced into aparental chromosome 17 can generate a large set of trisomics ]Thp consisting of mutant gene combinations designed for our particular purposes. Crossing over in this region in females does not affect the allelic constitution of t *-to the trisomics because gametes with partial disomy carry both homologs in the proximal region of chro- mosome 17. tCP Males heterozygous for T43H are sterile; hetero- zygosity for Robertsonian translocation Rb( 16.17)7- 1 Bnr restores their fertility. In T43H/Rb7Bnr males, crossing over in chromosome 17 is completely sup- pressed (FOREJT,CAPKOVA and GREGOROVA1980). To ensure unambiguous identification of offspring genotype, the chromosomes of theparents were marked with Robertsonian translocations. Table 1 shows data for the crosses involving female heterozy- FIGURE 1.-Genetic c map of chromosome 17 of the house mouse, gotes for T43H and different mutations. Although showing the loci and mutations usedin the experiments: Cen - the number of offspring and that of trisomics identi- centromere; Rb(8.17)l Iem, Rb( 16.17)lBnr-Robertsonian translo- fied varied, we recovered individuals of appropriate cations; T( 16;17)43H-reciprocal translocation, arrow indicates genotypes. The total number of identified trisomics breakpoint; to- t", t haplotypes; tct, t complex tail interaction; tcP, t complex lethal-6; T, brachyury; qk, quaking; Fu'", fused kinky; Fukb, was 116.Their occurrence frequency was 12.1 & knobbly; tJ tufted; H-2, major histocompatibility complex; ThP 1.3%, on the average, in those crosses in which no (hairpin tail) and thZo,chromosome 17 deletions. The numbers single class of offspring died. indicate distance (in cM) in structurally normal chromosomes. The phenotype of the trisomics is characterized by a retardation in the development, in altered propor- large productof the translocation comprises the prox- tions of the visceral and cranial portions of the skele- imal portion of chromosome 17 and the entire chro- ton, defective formation of the vertebral column (Fig- mosome 16. During the meiotic disjunction of the ures 3 and 4) and a sharp decrease in the fertility of chromosomes, there arises acertain percentage of both sexes. TABLE 1 Production of mice with tertiary trisomy 17 Trisornics progeny Total No. of Genotype Po Genotype 88 progeny trisornics Percent 1. Fu" If+/++ T43H Rb7Bnr + +/Rb7Bnr + + 165 16 10+2 2. Fu'" If+/++ T43H + Fu" tflRb7Bnr + + 144 10 7+2 3. Fu" tf+/+ + T43H tf/lf 36 8 22 f 7 4. If+/+T43H tfltf 13 2 15 + 10 5. tf+/+ T43H Rb7Bnr +/Rb7Bnr + 70 6 9+3 6. + T43H/tf+ Rb7Bnr t6/+ + 38 2 5+3 7. T + T43H/+ qk + Rb7Bnr + +/Rb7Bnr + + 26 6 3+8 8. T + T43H/+ qk + Rb7Bnr + +/+ + qk 107 8 7+3 9. ThP +/+ T43H Rb7Bnr +/Rb7Bnr + 27 8 30 + 9 10. ThP +/+ T43H + Thp/Rbl Iem + 35 7 20 f 7 11. T T43H/+ + Rb7Bnr +/Rb7Bnr + 61 9 15+7 12. T T43H/+ + + T T43H/Rb7Bnr + + 58 3 5+3 13. T T43H/t6''" + Rb7Bnr +/Rb7Bnr + 80 10 13+4 14. + T43H/t" + + T T43H/Rb7Bnr + + 54 10 19 f 5 15. T T43H/t"+ + Thp/RblIem+ 1 1 100 16. tNfoT43H/t6+ + Thp/RblIem + 9 4 44?18 17. T T43H/t6 + Rb7Bnr t6/+ + 8 1 13+13 18. T T43H/t6(") tNf(N2) tf/tNI(N2) f 24 5 21+8 MutationsChromosome of Murine 17 783 P N" 16 I/ 18" /6 I6 I/ i? 7-43/+ +/+ FIGURE2.-Experimental scheme for obtaining the mice with tertiary trisomy of chromosome 17 using the T(16;I 7)43H recip rocal translocation. To illustrate the portions of the translocation chromosomes derived from chromosome 16 and 17, the chromo- some I7 dark G-bands are shown as solid black and the chromosome 16 bands are shown as hatched. TABLE 2 Phenotypes of mice with Fu' mutation Penetrance Genotype" Phenotype Genotype" (W) ~~ +ID? Normal 100 Fu"/+ tail Kinky 90-95 Fu"/+/+ tail(25) Kinky a4 Fu'/Fu"/+ tail(5)' Kinky 100 Fuk'/Fub Embryonic lethal 100 Fu'"/Dfd Embryonic lethal 100 Number of trisomics scored is indicated in parentheses. Df- t"" deletion. ' Obtained in cross 2, Table 1. There may be a few Fu" tf +/+ + T43H/+ + + mice among thesetrisomics as a result of crossin FIGURE3.-Mouse with Fu" tf/Fu" tj/+ + genotype on the left, over in Rb7Bnr + +/+ Fu tfmales between centromere and Fu E Fu" tf/++ sib on the right. (less than 8%). The breeding data, considered together with the developmental stage (GLUECKSOHN-SHOENHEIMER cytogenetic and phenotypic descriptions, allowed us 1949; LYON and BECHTOL1977; GREENSPANand to carry out Mullerian gene dosage studies of the O'BRIEN 1986). Taking all this into consideration, it various mutations. becomes apparent that the phenotypic manifestation Functional analysis of the mutations kinky,tufted of Fukiis unrelated to a hyperfunction of the gene in and quaking:Kinky (Fuki)is a mutation that maps 10 question. If this were the case, mice of Fuki/Fu'/+ cM distal to the centromere of chromosome 17.
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