Copyright 0 1992 by the Genetics Society of America
Letter to the Editor Does Sex of the Offspring Influence Transmission Ratio? TABLE 1 Transmission ratio distortion (TRD) is an interesting exception to mendelism that has been most conTransmission ratio distortion infour sets of intraspecific backcrosses of reciprocal F1 hybrids to C57BId/6Jinbred mice vincingly demonstrated in the mouse in studies of thaplotypes (BENNETT1975; BENNETT,ALTONand Cross F, parent N a a/N X2 ARTZT 1983; LYON1984,1986; SILVER1985). Recently, JENKINS, COPELAND and colleagues have re105 66 0.629 6.943 ( p = 0.008) Male STX/Le 85 39 0.459 0.576 Female ported evidence of TRD in interspecific backcross MWT/Le 109 67 0.615 5.734 ( p = 0.017) ROP/GnLe Male mice (SIRACUSA et al. 1989, 1991; CECIet al. 1989; 73 46 0.630 4.945 (p = 0.026) ROP/GnLe Female JUSTICE et al. 1990). I am most interested in their Total 218 372 0.586 11.01 1 ( p = 0.0009) reports of TRD involving chromosome 2 because we Note: Data from D. B. LIND and P. E. NEUMANN(unpublished). have seen TRD of thischromosome in crosses of Cross = the linkage stock crossed with C57BL/6J mice to prolaboratory mice (D. B. LINDand P. E. NEUMANN, duce the heterozygous parent; F1 parent = sex of the heterozygous unpublished results) and because they have reported parent; N = sample size; a = number of nonagouti ( a l a ) offspring; differences in TRD associated with the sex of the P = proportion of nonagouti offspring; ‘x values have one degree of freedom. offspring (SIRACUSA et al. 1991). In a set of four backcrosses in our laboratory in2a in the interspecific backcross. Therefore, transmisvolving C57BL/6J mice and F1 hybrids from crosses sion ratio (t) associated with a marker locus is linearly with linkage stocks obtained from The Jackson Labrelated to the recombination frequency (T) between oratory (Bar Harbor, Maine), more than half of the that marker locus and the TRD andBmp-2a loci; offspring were nonagouti ( a l a )(see Table 1). In three t = 0.658 - 0.316~. of the four backcrosses, 62.4% (weighted mean) of the offspring were nonagouti. One of the backcrosses The TRD associated with each of the marker loci in was not significantly different from the expected1:1, males, females and combined samples does not differ but it is significantly different from the TRD seen in significantly from that predicted by this model (see the other backcrosses (x2= 9.8, 1 d.f.). These results Table 2). The sex differences found by Siracusa et al. support the conclusion of Siracusa et al. (1 991) that a are partially accounted for by differences in recomlocus (or loci) on chromosome 2 is involved in TRD bination frequency in male and female offspring that of a region of that chromosome. It is reasonable to probably represent a statistical fluctuation, If the sex speculate that the same locus (or loci) may be responof offspring influences transmission ratio, analysis of sible for the TRD in the interspecific backcross and a larger sample is required to demonstrate it. the three intraspecific backcrosses because the transmission ratios associated with the tightly linked a and PAULE. NEUMANN, M.D. Emu-15 loci were virtually identical. However, it is Department of Neurology interesting to note thatwhile the proportion of alleles Children’s Hospital and derived from B6 is reduced in the interspecific backHarvard Medical School cross, we found an excess in backcrosses with other Boston, Massachusetts 02 1 15 laboratory mice. This is reminiscent of the ordering of a series of t-haplotypes with respect to TRD. The effect of the sex of the parent on TRD has LITERATURE CITED been well documented in the case of various t-haploBENNETT,D., 1975 The T-locus of the mouse. Cell 6 441-454. types, however, the recent report of differences in BENNETT,D., A. ALTONand K. ARTZT,1983 Genetic analysis of T R D associated with the sex of backcross offspring is transmission ratio distortion by t-haplotypes in the mouse. less compelling. A simpler model cannot be ruled out. Genet. Res. 41: 29-45. This model assumes a single locus (or a clusterof loci) CECI,J. D., L. D. SIRACUSA, N . A . JENKINSand N. G . COPELAND, 1989 A molecular genetic linkage map of mouse chromosome o n chromosome 2 is involved in the TRDeffect. This 4 including localization of several proto-oncogenes. Genomics locus probably maps close to Bmp-2a because this 5: 699-709. marker locus is associated with the greatest TRD. For JUSTICE,M. J., L. D. SIRACUSA, D. J. GILBERT,N. HEISTERKAMP, J. the purposes of this model, we will assume that there GROFFEN,K. CHADA, C.M. SILAN,N. G. COPELAND and N. A. is no recombination between the TRD locus and BmpJENKINS,1990 A genetic linkage map of mouse chromosome ~~
Genetics 130 685-686 (March, 1992)
P. E. Neurnann
686
TABLE 2 Chi-squared analysis of linear model of transmission ratio distortion as a function of recombination frequency Total (N = 117) Locus
Vim Spna Ab1 HC His- 1 Neb HOX-4.1 D2Hgul Fshb Actc-1 B2m Bmp-2a Pax-1 Hck-1 Emu- 15 Ada Pck-1
Females (N = 49)
Males (N = 68)
r
t
EXP
X*
r
t
EXP
X2
r
t
EXD
x=
0.419 0.393 0.368 0.342 0.291 0.273 0.188 0.137 0.111 0.085 0.043 0.00 0.06 0.128 0.128 0.154 0.231
0.479 0.487 0.530 0.521 0.590 0.607 0.624 0.607 0.615 0.624 0.632 0.658 0.632 0.632 0.632 0.641 0.581
0.526 0.534 0.542 0.550 0.566 0.572 0.599 0.61 5 0.623 0.631 0.644 0.658 0.639 0.618 0.618 0.609 0.585
1.04 1.02 0.07 0.38 0.27 0.59 0.32 0.03 0.03 0.02 0.07
0.286 0.245 0.245 0.224 0.224 0.224 0.163 0.143 0.122 0.102 0.061 0.00 0.02 0.143 0.143 0.163 0.286
0.592 0.592 0.633 0.612 0.653 0.653 0.673 0.653 0.673 0.653 0.653 0.673 0.653 0.6 12 0.612 0.592 0.469
0.568 0.581 0.581 0.587 0.587 0.587 0.606 0.613 0.6 19 0.626 0.639 0.658 0.651 0.613 0.613 0.606 0.568
0.12 0.03 0.54 0.12 0.51 0.51 0.93 0.34 0.38 0.13 0.04 0.06 0.00 0.00 0.00 0.04 1.92
0.515 0.50 0.456 0.426 0.338 0.309 0.206 0.132 0.103 0.074 0.029 0.00 0.088 0.1 18 0.1 18 0.147 0.191
0.397 0.412 0.456 0.456 0.544 0.574 0.588 0.574 0.574 0.603 0.618 0.647 0.618 0.647 0.647 0.676 0.662
0.495 0.50 0.514 0.523 0.551 0.560 0.593 0.616 0.625 0.635 0.649 0.658 0.630 0.621 0.621 0.6 12 0.598
2.64 2.12 0.90 1.25 0.01 0.05 0.01 0.52 0.77 0.31 0.28 0.03 0.04 0.20 0.20 1.20 1.18
0.02 0.12 0.12 0.49 0.0 1
Note: Data from SIRACUSA et al. (199 1). r = recombination frequency between marker locus and Bmp-2a; t = transmission ratio, the proportion of offspring with the allele derived from M. spretus; Exp = the expected value o f t based on the linear regression t = 0.658 - 0.316r; x' values have one degree of freedom. 10: localization of eighteen molecular markers using a single interspecific backcross. Genetics 125: 855-866. LYON, M. F., 1984 Transmission ratio distortion in mouse thaplotypes is due to multiple distorter genes acting on a responder locus. Cell 37: 621-628. LYON,M. F., 1986 Male sterility of the mouse t-complex locus is due to homozygosity of the distorter genes. Cell 44:357-363. SILVER, L. M., 1985 Mouse t-haplotypes. Annu. Rev. Genet. 1 9 179-208.
L. D., A. M. BUCHBERG, N. G . COPELAND and N. A. 1989 Recombinant inbredstrain and interspecific backcross analysis of molecular markers flanking the murine agouti coat color locus. Genetics 122: 669-679. S*RAcusA9 L. D.9 w." ALVoRD9 w.A' BICKMoRE' N' A.JENKINS and N. G . COPELAND, 1991 Interspecific backcross mice show sex-specific differences inallelic inheritance. Genetics 128: 813-821. SIRACUSA,
JENKINS,
Letter to the Editor Does Sex of the Offspring Influence Transmission Ratio? TABLE 1 Transmission ratio distortion (TRD) is an interesting exception to mendelism that has been most conTransmission ratio distortion infour sets of intraspecific backcrosses of reciprocal F1 hybrids to C57BId/6Jinbred mice vincingly demonstrated in the mouse in studies of thaplotypes (BENNETT1975; BENNETT,ALTONand Cross F, parent N a a/N X2 ARTZT 1983; LYON1984,1986; SILVER1985). Recently, JENKINS, COPELAND and colleagues have re105 66 0.629 6.943 ( p = 0.008) Male STX/Le 85 39 0.459 0.576 Female ported evidence of TRD in interspecific backcross MWT/Le 109 67 0.615 5.734 ( p = 0.017) ROP/GnLe Male mice (SIRACUSA et al. 1989, 1991; CECIet al. 1989; 73 46 0.630 4.945 (p = 0.026) ROP/GnLe Female JUSTICE et al. 1990). I am most interested in their Total 218 372 0.586 11.01 1 ( p = 0.0009) reports of TRD involving chromosome 2 because we Note: Data from D. B. LIND and P. E. NEUMANN(unpublished). have seen TRD of thischromosome in crosses of Cross = the linkage stock crossed with C57BL/6J mice to prolaboratory mice (D. B. LINDand P. E. NEUMANN, duce the heterozygous parent; F1 parent = sex of the heterozygous unpublished results) and because they have reported parent; N = sample size; a = number of nonagouti ( a l a ) offspring; differences in TRD associated with the sex of the P = proportion of nonagouti offspring; ‘x values have one degree of freedom. offspring (SIRACUSA et al. 1991). In a set of four backcrosses in our laboratory in2a in the interspecific backcross. Therefore, transmisvolving C57BL/6J mice and F1 hybrids from crosses sion ratio (t) associated with a marker locus is linearly with linkage stocks obtained from The Jackson Labrelated to the recombination frequency (T) between oratory (Bar Harbor, Maine), more than half of the that marker locus and the TRD andBmp-2a loci; offspring were nonagouti ( a l a )(see Table 1). In three t = 0.658 - 0.316~. of the four backcrosses, 62.4% (weighted mean) of the offspring were nonagouti. One of the backcrosses The TRD associated with each of the marker loci in was not significantly different from the expected1:1, males, females and combined samples does not differ but it is significantly different from the TRD seen in significantly from that predicted by this model (see the other backcrosses (x2= 9.8, 1 d.f.). These results Table 2). The sex differences found by Siracusa et al. support the conclusion of Siracusa et al. (1 991) that a are partially accounted for by differences in recomlocus (or loci) on chromosome 2 is involved in TRD bination frequency in male and female offspring that of a region of that chromosome. It is reasonable to probably represent a statistical fluctuation, If the sex speculate that the same locus (or loci) may be responof offspring influences transmission ratio, analysis of sible for the TRD in the interspecific backcross and a larger sample is required to demonstrate it. the three intraspecific backcrosses because the transmission ratios associated with the tightly linked a and PAULE. NEUMANN, M.D. Emu-15 loci were virtually identical. However, it is Department of Neurology interesting to note thatwhile the proportion of alleles Children’s Hospital and derived from B6 is reduced in the interspecific backHarvard Medical School cross, we found an excess in backcrosses with other Boston, Massachusetts 02 1 15 laboratory mice. This is reminiscent of the ordering of a series of t-haplotypes with respect to TRD. The effect of the sex of the parent on TRD has LITERATURE CITED been well documented in the case of various t-haploBENNETT,D., 1975 The T-locus of the mouse. Cell 6 441-454. types, however, the recent report of differences in BENNETT,D., A. ALTONand K. ARTZT,1983 Genetic analysis of T R D associated with the sex of backcross offspring is transmission ratio distortion by t-haplotypes in the mouse. less compelling. A simpler model cannot be ruled out. Genet. Res. 41: 29-45. This model assumes a single locus (or a clusterof loci) CECI,J. D., L. D. SIRACUSA, N . A . JENKINSand N. G . COPELAND, 1989 A molecular genetic linkage map of mouse chromosome o n chromosome 2 is involved in the TRDeffect. This 4 including localization of several proto-oncogenes. Genomics locus probably maps close to Bmp-2a because this 5: 699-709. marker locus is associated with the greatest TRD. For JUSTICE,M. J., L. D. SIRACUSA, D. J. GILBERT,N. HEISTERKAMP, J. the purposes of this model, we will assume that there GROFFEN,K. CHADA, C.M. SILAN,N. G. COPELAND and N. A. is no recombination between the TRD locus and BmpJENKINS,1990 A genetic linkage map of mouse chromosome ~~
Genetics 130 685-686 (March, 1992)
P. E. Neurnann
686
TABLE 2 Chi-squared analysis of linear model of transmission ratio distortion as a function of recombination frequency Total (N = 117) Locus
Vim Spna Ab1 HC His- 1 Neb HOX-4.1 D2Hgul Fshb Actc-1 B2m Bmp-2a Pax-1 Hck-1 Emu- 15 Ada Pck-1
Females (N = 49)
Males (N = 68)
r
t
EXP
X*
r
t
EXP
X2
r
t
EXD
x=
0.419 0.393 0.368 0.342 0.291 0.273 0.188 0.137 0.111 0.085 0.043 0.00 0.06 0.128 0.128 0.154 0.231
0.479 0.487 0.530 0.521 0.590 0.607 0.624 0.607 0.615 0.624 0.632 0.658 0.632 0.632 0.632 0.641 0.581
0.526 0.534 0.542 0.550 0.566 0.572 0.599 0.61 5 0.623 0.631 0.644 0.658 0.639 0.618 0.618 0.609 0.585
1.04 1.02 0.07 0.38 0.27 0.59 0.32 0.03 0.03 0.02 0.07
0.286 0.245 0.245 0.224 0.224 0.224 0.163 0.143 0.122 0.102 0.061 0.00 0.02 0.143 0.143 0.163 0.286
0.592 0.592 0.633 0.612 0.653 0.653 0.673 0.653 0.673 0.653 0.653 0.673 0.653 0.6 12 0.612 0.592 0.469
0.568 0.581 0.581 0.587 0.587 0.587 0.606 0.613 0.6 19 0.626 0.639 0.658 0.651 0.613 0.613 0.606 0.568
0.12 0.03 0.54 0.12 0.51 0.51 0.93 0.34 0.38 0.13 0.04 0.06 0.00 0.00 0.00 0.04 1.92
0.515 0.50 0.456 0.426 0.338 0.309 0.206 0.132 0.103 0.074 0.029 0.00 0.088 0.1 18 0.1 18 0.147 0.191
0.397 0.412 0.456 0.456 0.544 0.574 0.588 0.574 0.574 0.603 0.618 0.647 0.618 0.647 0.647 0.676 0.662
0.495 0.50 0.514 0.523 0.551 0.560 0.593 0.616 0.625 0.635 0.649 0.658 0.630 0.621 0.621 0.6 12 0.598
2.64 2.12 0.90 1.25 0.01 0.05 0.01 0.52 0.77 0.31 0.28 0.03 0.04 0.20 0.20 1.20 1.18
0.02 0.12 0.12 0.49 0.0 1
Note: Data from SIRACUSA et al. (199 1). r = recombination frequency between marker locus and Bmp-2a; t = transmission ratio, the proportion of offspring with the allele derived from M. spretus; Exp = the expected value o f t based on the linear regression t = 0.658 - 0.316r; x' values have one degree of freedom. 10: localization of eighteen molecular markers using a single interspecific backcross. Genetics 125: 855-866. LYON, M. F., 1984 Transmission ratio distortion in mouse thaplotypes is due to multiple distorter genes acting on a responder locus. Cell 37: 621-628. LYON,M. F., 1986 Male sterility of the mouse t-complex locus is due to homozygosity of the distorter genes. Cell 44:357-363. SILVER, L. M., 1985 Mouse t-haplotypes. Annu. Rev. Genet. 1 9 179-208.
L. D., A. M. BUCHBERG, N. G . COPELAND and N. A. 1989 Recombinant inbredstrain and interspecific backcross analysis of molecular markers flanking the murine agouti coat color locus. Genetics 122: 669-679. S*RAcusA9 L. D.9 w." ALVoRD9 w.A' BICKMoRE' N' A.JENKINS and N. G . COPELAND, 1991 Interspecific backcross mice show sex-specific differences inallelic inheritance. Genetics 128: 813-821. SIRACUSA,
JENKINS,
