THE INFLUENCE OF GENETIC BACKGROUND AND THE HOMOLOGOUS CHROMOSOME 27 ON /!-HAPLOTYPE TRANSMISSION RATIO DISTORTION IN MICE

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1 opyright by the Genetics Society of America TH INLUN O GNTI AKGROUN AN TH HOMOLOGOUS HROMOSOM 27 ON /!-HAPLOTYP TRANSMISSION RATIO ISTORTION IN MI GRGORY R. GUMMR, PAULTT J. McORMIK AN OROTHA NNTT Memorial Sloan-Kettering ancer enter and Sloan-Kettering ivision, Graduate School of Medical Sciences, ornell University, New York, New York Manuscript received October 12, 1985 Revised copy accepted May 3, 1986 ASTRAT Transmission ratio distortion is a characteristic of complete t-haplotypes, such that heterozygous males preferentially transmit the t-haplotype bearing chromosome 17 to the majority of their progeny. At least two genes contained within the t-haplotype have been identified as being required for such high transmission ratios. In this study we examine the effects of the genetic background and the chromosome homologous to the t-haplotype on transmission ratio distortion. We use two different congenic lines: (1) TRT/Nev.Ttf/t, in which the tl2 haplotype has a transmission ratio of 52%, and (2) 3H/iSn.Ttf/tlP, in which the t haplotype has a transmission ratio of 99%. y intercrossing these two strains to produce reciprocal 1 and 2 generations, we have isolated the effects of the homologous chromosome 17 from the effects of the genetic background. We demonstrate that both the homologous chromosome and the genetic background have profound effects on t-haplotype transmission ratio distortion. urthermore, it is evident that the t-haplotype transmission ratio behaves as a quantitative character rather than an intrinsic property of t-haplotypes. H t-haplotypes are naturally occurring polymorphisms of mouse chro- T mosome 17 that are found in high frequencies in mouse populations around the world (UNN and SUKLING 1956; UNN 1957a; NNTT 1978; KLIN, SIPOS and IUROA 1984), and they carry genes that, when homozygous, are lethal at very early stages of embryonic development (NNTT 1975). The presence of such lethal genes on chromosomes that are very frequent and widely distributed throughout wild mice populations presents a paradox as to how t-haplotypes survive their apparent selective disadvantage. The paradox is resolved by consideration of two features of t-haplotype genetics; together they account for the unusual persistence of t-haplotypes in the mouse gene pool. irst, t-haplotypes suppress recombination approximately 1000-fold between themselves and normal chromosomes for a region of approximately 20 cm (UNN and GLUKSOHN-SHONHIMR 1943; UNN, N- Present address: epartment of iological Sciences, SUNY-Albany, Albany, New York Genetics 114: September, 1986.

2 236 G. R. GUMMR, P. J. MORMIK AN. NNTT NTT and ASLY 1962; ARTZT, MORMIK and NNTT 1982). Second, and most importantly, t-haplotypes promote their own transmission through males, so that more than 95% of the progeny from heterozygotes will contain the t-haplotype (UNN 1957b; NNTT 1975). The combination of these two properties causes an entire block of genes, some of which are lethals, to be transmitted as a unit at high frequencies throughout mouse populations. Many laboratories have attempted to identify and characterize the gene(s) of the t-haplotype and/or its homologue that is responsible for transmission ratio distortion (LYON and MRITH 1964a,b,c; LYON and MASON 1977; STYRNA and KLIN 1981; SILVR 1981; HAMMRRG 1981; LYON 1982; NNTT, ALTON and ARTZT 1983; LYON 1985). These studies utilized partial haplotypes,, either proximal or distal in origin, that were derivatives of complete t- haplotypes. Such partial haplotypes were generated by the isolation of recombinants between t and + chromosomes, or the isolation of recombinants between two different partial t-haplotypes. The study of the transmission ratio distortion of such partial haplotypes has suggested that more than one gene is responsible and that they are separable by recombination not only from each other but also from the tail interaction factor and the lethal genes (LYON and MASON 1977; STYRNA and KLIN 1981; SILVR 1981; HAMMRR 1981; NNTT, ALTON and ARTZT 1983; LYON, 1984). A consensus is that genes located proximally and distally within the t-haplotype act synergistically to produce the high transmission ratios characteristic of complete haplotypes. The effect of the individual genes or combinations of them in trans has yet to be agreed on because of the complexity of their interactions. An additional centrally located gene, low, A or Tcr, has also been postulated to exist and to affect t-haplotype transmission ratios (UNN and NNTT 1968; LYON and MASON 1977; SILVR 1981 ; HAMMRR 1981 ; NNTT, ALTON and ARTZT 1983; LYON 1984). The situation has been further complicated by the discovery that t-haplotypes maintained in the laboratory did not always retain the extraordinarily high ratios characteristic of males in the wild. uring the 1950s and 1960s there were reports in the literature of ratios ranging from 60 to 75% for a variety of haplotypes. In 1978, it was reported that over a 20-yr period, from the late 1950s to the late 1970s, the high transmission ratios of to and t'"" decreased steadily to 36 and 40%, respectively. However, when males of the to stock were outcrossed to random bred 1 females, the transmission ratios of the resultant l/to progeny were raised to an average of 94% (NNTT, ALTON and ARTZT 1983). Apparently, as they suggested, the t-haplotypes had not lost the intrinsic ability to be transmitted at high frequencies, but rather, the genetic backgrounds of some laboratory stocks were influencing t-haplotype transmission. urthermore, controlling for genetic background and using deletion mutations, they presented evidence suggesting that the chromosome 17 homologue of the t-haplotype had a strong effect on transmission ratio distortion. Other studies demonstrated that genetic background influenced both motility and the in vitro fertilization capability of sperm from t/+ males (OLS-LARK and MA 1982; OLS-LARK 1983).

3 TRANSMISSION RATIO O t-haplotyps 237 A. select 'nt select ~i select 6ot moles. 2d 3H.Ttf/ti2 x T. +ff/+ff f seleci nt 1 \ select r I 5U+tffkT)/tJ2 X Ttf(3H)/+tf I select 6 ot males 30 d Ttf (T)/ti2 x cl 30 d Tt f (3#)/t I2 X IGUR 1.-Mating schemes used to generate the I and P males. Tail phenotype abbreviations are as follows: nt = normal-tailed; r = rachyury; and ot = tailless. It should be noted that due to the high transmission ratios of the 3H.Ttf/t" males, it was not feasible to make the Ttf(3H)l +tf females from the parental generation of cross. Genetically equivalent females were produced by the following mating: d T.+tf/+tf X 0 JH.Ttf/t". The question of how the genetic background, including genes on other chromosomes as well as those on the homologous chromosome, affects t-haplotype transmission ratio, is an important one to resolve. Many of the studies conducted to date have been done on widely divergent inbred backgrounds (as well as some mixed backgrounds); therefore, comparisons of data for the purposes of constructing models or theories to account for transmission ratio distortion are suspect. In the research presented here, we take advantage of having within our mouse colony two different inbred lines of mice bearing the same t-haplotype, but with vastly different transmission ratios. The TRT/Nev.Ttf/t" line had an average transmission ratio of 52% (N = 751 gametes) over the last 2 yr, whereas the 3H/iSn.Ttf/t" line had an average ratio of 99% (N = 500 gametes) over the same period. We have made reciprocal I and 2 generations by intercrossing these two strains, and thus, have been able to isolate the effects of the chromosome homologous to the t-haplotype from the effects of the rest of the genetic background. We describe these effects and report unequivocal evidence that both the chromosome homologous to the t" haplotype and the genetic background play major roles in the transmission ratio distortion of t- haplotypes. MATRIALS AN MTHOS Mice of both strains, TRT/Nev (T) TtJHZ6/tJ2 and 3H/iSn (3H) TtjH-2'/ t", were maintained by brother-sister matings in the balanced lethal configuration of T/t" X T/t". The mating scheme to generate the reciprocal, and P generations is shown in igure 1. or the parental generations, two tailless males were used to generate the five matings of the I generation. The 1 generation consisted of five normaltailed +tflt'' males mated to their short-tailed Ttj/+tf sisters. ue to the high trans-

4 238 G. R. GUMMR, P. J. MORMIK AN. NNTT mission ratio of the t haplotype (98%) from our 3H Ttf/t * males used in the parental generation of cross, it was impractical to generate the short-tailed, Ttf(3H)/+tf, 1 females. Genetically identical mice were produced by mating T.+tf/+tf males with 3H.Ttflt females and using the short-tailed female offspring as mates for the I males in cross. rom each of the five 1 matings, six tailless males, Ttf/t *, were selected and tested for their transmission ratios by mating with three random-bred normal-tailed I females (supplied by harles River). or each of the three matings the offspring were classified at birth for tail phenotype: normal-tailed (+/+ or +/t *); short-tailed or rachyury (T/+); and tailless ( T/t *). Transmission ratios were measured for each of the three generations as follows: parental generation, normal-tailed born/short-tailed + normal-tailed born; I generation, tailless born/short-tailed + tailless born; and 2 generation, normal-tailed born/short-tailed + normal-tailed born. Only nontufted males were used in the I and 2 generations, ensuring that rare recombinants involving the t-haplotype were not tested for transmission ratios. Recombination was expected to occur freely in the 1 Ttf/+tf females; such recombination would generate 2 males for which the normal chromosome 17 was not identical to that of their parental males. Therefore, after transmission ratio testing, all 2 males were typed for H-2 to determine whether or not they contained a recombinant chromosome. H-2 typing was performed using the complement mediated cytotoxocity assay on lymphocytes obtained from the mesenteric lymph node (ARTZT, SHIN and NNTT 1982). or statistical analyses, the transmission ratio data were transformed via the arcsine transformation. The transformed data were analyzed using a one-way analysis of variance (ANOVA) (OSTL and MNSIN 1975). Values for transmission ratios reported in the tables and text are untransformed. RSULTS The matings that produced the males for which transmission ratios were measured are diagrammed in igure 1. oth the T and 3H stocks are maintained as inbred lines in our laboratory by brother-sister matings. The two tailless males of the T parental generation had transmission ratios of 55 and 66%. The 3H parental males had ratios of 97 and 100%. Mating these males to normal-tailed tufted (+tfl+tj females of the opposite strain-namely, T males to 3H females and vice versa-produced the males of the 1 generation. The results presented in Table 1 show the transmission ratios of the 1 males. omparison of the 1 ratios presented in Table 1 with the ratios of the parental males shows a marked increase in the transmission of the t chromosome derived from the T stock, and a decrease of lesser magnitude in the ratio of the t chromosome derived from the 3H/iSn stock. ur- thermore, it can be seen that the A males, +tf(3h)/tj2, have higher ratios than the males, +tft)/t. Although no genetically meaningful comparisons could be made between the 1 males and the parental males because of their different genetic constitution, it was possible to directly compare and analyze the differences between the two groups of 1 males. In particular, we wanted to determine if the difference between the 1 ratios of the males (carrying the T-derived + chromosome) and the A males (carrying the 3H-derived + chromosome) was statistically significant. We performed a one-way ANOVA on the transmission ratio data of the 1 males. The results of the analysis, shown at the bottom of Table 1, indicated that the between groups variation

5 ~ TRANSMISSION RATIO O &HAPLOTYPS 239 TAL 1 Transmission ratios and ANOVA table for the 1 males +tf(3h)/t'z X Ttf(T)/+tf +tf(t)/t'z x Ttf(3H)/+tf Male 1 + %t Male t + %t A A A A A Significance Source of variation Sum of squares d.f. Mean square ratio Probability etween groups p(1.8) < 0.05 rror was indeed significant. This difference in transmission ratios between the A and 1 males must be attributable to their genetic differences. Since the A and males are reciprocal l's, their genetic background is identical except for the chromosome 17 homologous to t". ased on this finding and previous work from our laboratory (NNTT, ALTON and ARTZT 1983), we conclude that the homologous chromosome 17 is responsible for the observed variations in transmission ratio distortion between the A and 1 males. It seems likely that the lower ratios of the males are due either to the presence of negative modifiers of transmission ratio distortion on the T +tfchromosome or to the absence of positive modifiers of transmission ratio distortion on the 3H +tf chromosome. The converse would, of course, account for the higher ratios of the A males. The tailless 2 males, for which the chromosome 17 pair was identical to that of their respective parental generations, were mated with I females to analyze their transmission ratios. The results from these experiments are shown in Table 2 and depicted graphically in igure 2. Since the chromosome 17 pair in both sets of 2 males was identical to their parental generations, the differences in transmission ratio distortion between the 2 and parental generation males resulted from the inheritance of different non-chromosome 17 modifiers. omparisons between the A cross 2 males, for which the transmission ratios range from 44 to 98%, and males from the original T stock, for which the transmission ratios range from 34 to 67%, show enormous differences between the two groups. Many 2 males have extraordinarily high transmission ratios uncharacteristic of the T stock. We attribute these differences either to the presence of positive transmission ratio modifiers from 3H or to the lack of T negative modifiers. onversely, comparing the cross 2 males (range %) with the 3H stock (range %) shows many 2 males much lower than expected for the 3H chromosome 17; these differences are also attributable to varying amounts of 3H or T modifiers in their back-

6 240 G. R. GUMMR, P. J. MORMIK AN. NNTT TAL 2 Transmission ratios and ANOVA table for the P males T@(T)/t * X, Gametes Ttf(jH)/t x, Gametes Male A5A A6A A7A A8A A9A t T %t Male A 6A 7A 8A 9A 1 T %t Significance Source of variation Sum of squares d.f. Mean square ratio Probability etween groups P(1.a.~) < rror etween groups (1.34) rror ground. One-way ANOVAs were performed to compare the differences between the transmission ratios of the Z males and their respective parental stocks. The results are shown at the bottom of Table 2 and clearly show that

7 A. TRANSMISSION RATIO O khaplotyps P P P P P p P P p P: T. Ttf/tJ2, : +tf (3H)A I2 04/ io 40 ;. * * * * a * **** *** **I* ***I* * * * I O so 70 sl~ sb Transmission Ratio ('10) * : 10 PP PP PP PP P: 3H. Ttf/tI2 ** I I * * I**** I+***** ****+***** I I I I I I * : IGUR 2.-istributions Transmission Ratio (YO) of the transmission ratios from all three generations of males. eno- types O each generation of males are shown at the right. Underlined parental generation males were used to produce the I males. Symbols are as follows: P = parental generation; + = I; * = 2. the difference is significant, thus demonstrating the strong influence of genetic background. ISUSSION In this report we demonstrate that genes on chromosomes other than 17 must affect t-haplotype transmission ratio distortion. Additionally, we have confirmed and extended previous work showing that the chromosome 17 homologous to the t-haplotype has a very powerful, although not exclusive, influence on the t-haplotype transmission ratio (HAMMRRG 1981 ; NNTT, AL- TON and ARTZT 1983). An explanation for the previously mentioned reports in the literature of t- haplotype transmission ratios of 60-75% may now be possible upon consideration of our results. Upon discovery of new t-haplotypes from wild mouse populations, it was common to maintain the haplotype in the balanced lethal configuration by breeding two tailless animals, frequently brother and sister. Such a mating scheme does not allow for continual monitoring of transmission ratios; therefore, selection for males with high transmission ratios did not occur, and as a result, many generations of such matings may have created

8 242 G. R. GUMMR, P. J. MORMIK AN. NNTT tailless lines of mice with lowered transmission ratios. The TRT/Nev strain (TqhtJ/+tA used by UNN and colleagues to establish many of the tailless lines within our laboratory is such an example. Nearly all complete t-haplotypes show reduced transmission ratios on this background relative to the 3H/iSn background (NNTT, ALTON and ARTZT 1983). ased on our results presented here, it appears that the T strain provided both the homologous chromosome 17 and genetic background that are responsible for the reduction in transmission ratios. Our results present strong evidence suggesting that the effects of the homologous chromosome 17 and the effect of genetic background must be controlled in order to obtain a reliable measure of transmission ratio. Our 2 males clearly demonstrate that a heterogeneous genetic background causes a high degree of intermale variability, which would lead to transmission ratios with a very large variance. Such variability is likely to be present in previous measurements of transmission ratio distortion that showed large standard deviations or a large range. Additionally, during our testing of 2 males we observed a considerable amount of intramale heterogeneity. or example, one male threw only two T- gametes in his first three litters (41 progeny) and then 15 in another three litters (49 progeny). Another male had six rachy progeny in his first litter (out of 17), but had only one rachy in his next eight litters (out of 77). Similar intramale variability can be found also in the 1 males. Obviously, this intramale heterogeneity suggests that, for an accurate measure of transmission ratios, large numbers of offspring must be generated from individual males. reeding for only informative offspring per male, as was done in the past (YANAGISAWA, UNN and NNTT 1961 ; LYON and MRITH 1964a,b,c; LYON and MASON 1977; STYRNA and KLIN 1981; NNTT, ALTON and ARTZT 1983; LYON 1984), may lead to a misrepresentation of transmission ratio. An extension of this is that, for comparative studies, males must also have similar breeding histories. Our I and 2 males were bred immediately at weaning, and their transmission ratio testing was not stopped until they had produced at least 150 offspring. Similar breeding histories for the males, testing large numbers of males and breeding for large numbers of offspring per male reduces the likelihood of intramale heterogeneity influencing the transmission ratio. LYON (1984) proposed a model for t-haplotype transmission ratio distortion involving three distortion loci (Tcd-1, Tcd-2 and Tcd-3) and a responder locus (Tcr) contained within complete t-haplotypes. Transmission ratio distortion occurs when there is heterozygosity at the Tcr locus with the distortion loci acting additively in cis or in trans to promote the transmission of the chromosome bearing the t-haplotype form of the Tcr gene. In the case of a complete t- haplotype, the three distortion loci are present and act to drive t-haplotype transmission ratio to its characteristically high level (90-100% transmission). An example of dramatic background effects is that the LYON model works perfectly well for measurements of transmission ratio distortion on the 3H background; however, the model is difficult to reconcile with our data regard-

9 TRANSMISSION RATIO O t-haplotyps 243 ing the T genetic background. We have previously reported the transmission ratios of three complete t-haplotypes t"', P5 and tw3' congenic on the TRT/ Nev background to be 70, 68 and 71%, respectively. ased on these ratios, the LYON model would predict that t"', tw5 and P3' are lacking one or more of the distorter loci; however, by all other criteria: (1) the length of recombination suppression (ARTZT 1984), (2) presence of the t-haplotype form of Tcp proteins (SILVR et al. 1983) and (3) the presence of t-haplotype specific restriction fragments (ox et al. 1985), these three haplotypes have been demonstrated to be complete. When transmission ratios of these three haplotypes are measured on the 3H/iSn background, they indeed behave as complete haplotypes, for their ratios are all 97% or greater (NNTT, ALTON and ARTZT 1983). Our results presented in this paper do not prove or disprove the results and models of others; rather, we wish to broaden the understanding that transmission ratio distortion is significantly influenced by genes other than those of t- haplotypes. Transmission ratio distortion has behaved as a quantitative character throughout our analyses; therefore, we believe that it can no longer be considered an absolute invariant characteristic of t-chromosomes whether they are partial or complete haplotypes. We have provided unequivocal evidence in this paper that transmission ratio distortion of t-haplotypes is quite sensitive to the influence of its genetic environment, both the genetic background and the homologous chromosome 17. urther analyses of such a character will require careful and thorough measurements of transmission ratios in order to deal with these influences. Our results do not directly address the mechanism used by t-haplotypes in distorting their own transmission; rather, we have provided evidence of the danger of analyzing t-haplotype transmission ratio as if it were an invariant character. inally, our evidence extends the parallels between the Segregation istortion system in rosophila and t-haplotype transmission ratio distortion. Our results demonstrating that the background genotype can influence transmission ratio distortion are similar to the findings that several loci, both autosomal and X-linked, can suppress the effect of Segregation istortion in rosophila (HIR- AIZUMI and THOMAS 1984). urthermore, such suppressors are present at high frequencies within natural populations of flies where no Segregation istortion chromosomes are found. It is tempting to speculate that suppressors of transmission ratio distortion exist in natural populations of mice. Perhaps, in the few populations studied that lack t-haplotypes, such suppressors prevent the introgression of t-haplotypes. The authors would like to express their gratitude to ANN KNNAR for her patience in typing numerous drafts of this manuscript. This work was supported in part by National Institutes of Health grants A (..) and H (P.Mc.) and by National ancer Institute core grant A LITRATUR IT ARTZT, K., 1984 Gene mapping within the T/t complex of the mouse t-lethal genes are arranged in three clusters on chromosome 17. ell 39:

10 244 G. R. GUMMR, P. J. MORMIK AN. NNTT ARTZT, K., P. MORMIK and. NNTT, 1982 Gene mapping within the T/t complex of the mouse. I. t-lethal genes are nonallelic. ell 28: ARTZT, K., H-S. SHIN and. NNTT, 1982 Gene mapping within the T/t complex of the mouse. 11. Anomalous position of the H-2 complex in t-haplotypes. ell 28: NNTT,., 1975 The T-locus of the mouse. ell NNTT,., 1978 Population genetics of T/t complex mutations. pp In: NIH Workshop on Origins of Inbred Mice, dited by H.. MORS. Academic Press, New York. NNTT,., A. K. ALTON, and K. ARTZT, 1983 Genetic analysis of transmission ratio distortion by t-haplotypes in the mouse. Genet. Res. 41: UNN, L.., 1957a Studies of the genetic variability in populations of wild house mice. 11. Analysis of additional alleles at locus T. Genetics 42: UNN, L.., 1957b vidence of evolutionary forces leading to the spread of lethal genes in wild populations of house mice. Proc. Natl. Acad. Sci. USA 43: UNN, L.. and. NNTT, 1968 A new case of transmission ratio distortion in the house mouse. Proc. Natl. Acad. Sci. USA 61: UNN, L..,. NNTT and A.. ASLY, 1962 Mutation and recombination in the vicinity of a complex gene. Genetics 47: UNN, L.. and S. GLUKSOHN-SHONHIMR, 1943 Tests for recombination amongst three lethal mutations in the house mouse. Genetics UNN, L.. and J. SUKLING, 1956 Studies of the genetic variability in wild populations of house mice. I. Analysis of seven alleles at locus T. Genetics 41: ox, H. S., G. R. MARTIN, M.. LYON,. HRRMANN, A-M. RISHAU, H. LHRAH and L. M. SILVR, 1985 Molecular probes define different regions of the mouse t-complex. ell 40: HAMMRRG,., : The influence of T"' upon male fertility in t-bearing mice. Genet. Res. HIRAIZUMI, Y. and A. M. THOMAS, 1984 Suppressor systems of segregation distorter (S) chromosomes in natural populations of rosophila melanoguster. Genetics KLIN, J,, P. SIPOS and. IGUROA, 1984 mice. Genet. Res. 44: Polymorphism of t-complex genes in uropean wild LYON, M.., 1982 Genetic basis of male sterility and segregation distortion due to t-haplotypes in the mouse. Genet. Res LYON, M.., 1984 Transmission ratio distortion in mouse t-haplotypes is due to multiple distorter genes acting on a responder locus. ell 37: LYON, M.. and I. MASON, 1977 Information on the nature of t-haplotypes from the interaction of mutant haplotypes in male fertility and segregation ratio. Genet. Res. 29: LYON, M.. and R. MRITH, 1964a Investigations of the nature of t-alleles in the mouse. I. Genetic analysis of a series of mutants derived from a lethal allele. Heredity LYON, M.. and R. MRITH, Investigations of the nature of t-alleles in the mouse. 11. Genetic analysis of an unusual mutant allele and its derivatives. Heredity 19: LYON, M.. and R. MRITH, 1964c Investigations of the nature of t-alleles in the mouse Short tests of some further mutant alleles. Heredity 19: OLS-LARK, P., 1983 Nonprogressive sperm motility is characteristic of most complete t-haplotypes in the mouse. Genet. Res. 42: OLS-LARK, P. and P. MA, 1982 Genetic background affects expression of t-haplotype in mouse sperm. Genet. Res. 40:

11 TRANSMISSION RATIO O i!-haplotyps 245 OSTL,. and R. W. MNSING, 1975 Statistics in Research, d. 3. Iowa State University Press, Ames. ROHM,., H. ox,. HRRMANN, A-M. RISHAU, J.. STROM, P. MAINS, L. M. SILVR and H. LHRAH, 1984 Molecular clones of the mouse t-complex derived from microdissected metaphase chromosomes. ell SILVR, L. M., 1981 A structural gene (Tcp-I) within the mouse t-complex is separable from effects on tail length and lethality, but may be associated with effects on spermatogenesis. Genet. Res SILVR, L. M., J. UMAN, J. ANSKA and J. I. ARRLS, 1983 A diversified set of testicular cell proteins specified by genes within the mouse t-complex. ell 35: STYRNA, J. and J. KLIN, 1981 vidence for two regions in the mouse t-complex controlling transmission ratios. Genet. Res YANAGISAWA, K., L.. UNN and. NNTT, 1961 On the mechanism of abnormal transmission ratios of T locus in the house mouse. Genetics 46: ommunicating editor: S. L. ALLN