Meiotic drive of t-haplotypes: segregation of chromosomes in mice with partial trisomy

The properties of the t haplotypes, specific mutant states of the proximal region of chromosome 17 in the house mouse keep renewing interest. One such property is increased transmission of the t haplotype from heterozygous t/+ males to their offspring. By means of reciprocal translocation T (16; 17)43H, we have constructed males with tertiary trisomy 17 (+T43/++/RB7+) carrying Robertsonian translocation Rb(16.17)7Bnr. The offspring of these males was viable when sperm of +T43/++ and Rb7+ was used. The segregation patterns in the offspring of t-bearing trisomics were analysed on days 16-18 of embryonic development. It was found that in the case when the t haplotype is on the normal acrocentric (male male ++T43/+t12+/Rb7++), its presence in the gamete +t12+/++T43 does not produce meiotic drive. However, when t6 is on Rb7, meiotic drive was equal to 80%. It is concluded that the presence of a normal homolog and a t-bearing chromosome in sperm does not result in meiotic drive. Possible mechanisms of meiotic drive of the t haplotypes are discussed.     

Synapsis and chiasma distribution in mice heterozygous for translocations in chromosomes 16 and 17

Electron microscopic analysis of synaptonemal complexes and analysis of chiasmata distribution in male mice heterozygous for Robertsonian translocation T(16; 17)7Bnr - (Rb7), for synaptonemal reciprocal translocation T(16;17)43H - (T43), in double heterozygotes for these translocations and in males with partial trisomy of the proximal region of chromosome 17 was carried out. Synaptic disturbances around the breakpoints of the translocations, such as asynapsis of homologous regions of partners and non-homologous synapsis of centromeric regions of acrocentric chromosomes, were revealed. Synaptic regularity in the proximal part of the chromosome 17 appeared to be affected by no t12 haplotype. Good coincidence between sizes of mitotic chromosomes and corresponding lateral elements of synaptonemal complexes was found for all chromosomes, with the exception of Rb7 in trisomics. In the latter karyotype, the proximal part of chromosome 17 involved in Robertsonian fusion seems to be shortened in the course of zygotene and never synapted with homologous segment of neither the acrocentric chromosome 17 nor large product of reciprocal translocation. Drastic increase in chiasmata frequency in the proximal part of chromosome 17 was revealed in heterozygotes for T43H and in trisomics, as compared with the double heterozygotes Rb7/T43. The latter finding was explained by the existence of two independent pairing segments in the former karyotypes.     

Two new X-autosome Robertsonian translocations in the mouse. I. Meiotic chromosome segregation in male hemizygotes and female heterozygotes.

Two new X-autosome Robertsonian (Rb) translocations, Rb(X.9)6H and Rb(X.12)7H, were found during the course of breeding the Rb(X.2)2Ad rearrangement at Harwell. The influence of these new Rbs on meiotic chromosome segregation was investigated in hemizygous males and heterozygous females and compared to that of Rb(X.2)2Ad. Screening of metaphase II spermatocytes gave incidences of sex chromosome aneuploidy of 9.2% in Rb(X.2)6H/Y and 9.6% in Rb(X.9)2Ad/Y males; no metaphase II cells were present in the testes of the Rb(X.12)7H/Y males examined and no males with this karyotype have so far proved fertile. In breeding tests, 5% of the progeny of Rb(X.2)2Ad/Y males were sex chromosome aneuploids compared to 10% of the Rb(X.9)6H/Y offspring. The difference was not significant, however. Cytogenetic analyses of metaphase II stage oocytes showed elevated rates of hyperhaploidy (n + 1) in Rb heterozygous females over chromosomally normal mice: 4.2% for Rb(X.2)2Ad/+; 2.1% for Rb(X.9)6H/+; 2.2% for Rb(X.12)7H/+ and 1.1% for normal females. There was, however, no statistically significant difference in the rates of hyperhaploidy between the three different Rb types, nor overall between Rb/+ and normal females. Karyotypic analyses of liveborn offspring of Rb heterozygous females revealed low incidences of X0 animals but no other type of sex chromosome aneuploidy. Intercrosses of heterozygous females and hemizygous males yielded 5.5% aneuploidy for Rb(X.2)2Ad and 5.4% for Rb(X.9)6H. In heterozygous females, there was evidence from the metaphase II and breeding test data for all three rearrangements, of preferential segregation of the Rb metacentric to the polar body resulting in a deficiency of cells and progeny carrying a translocation chromosome.     

Chromosome pairing and recombination in mice heterozygous for different translocations in chromosomes 16 and 17

In order to clarify the relationship between meiotic pairing and recombination, and electron microscopic (EM) study of synaptonemal complexes (SC) and an analysis of chiasma frequency and distribution were made in male mice singly and doubly heterozygous for Robertsonian [Rb(16.17)7Bnr] and reciprocal [T(16:17)43H] translocations and also in tertiary trisomics for the proximal region of chromosome 17. In all these genotypes an extensive zone of asynapsis/desynapsis around the breakpoints was revealed. At the same time a high frequency of non-homologous pairing was observed in precentromeric regions of acrocentric chromosomes. The presence in the proximal region of chromosome 17 of the t haplotype did not affect the synaptic behaviour of this region. Chiasma frequency in the proximal region of chromosome 17 in the T(16:17)43H heterozygotes and trisomics was increased when compared with that in Robertsonian heterozygotes.by H.C. Macgregor     

Characteristics of the expression of t12 mutation in mouse embryos with structural aberrations of chromosome 17

Developmental profiles of mouse embryos with deletions, duplications of nullisomy for the proximal part AB of chromosome 17, including genes of the T-t complex, were studied in mice with marker translocations Rb (16.17)7Bnr or T(16;17)43H and heterozygous for lethal t12 mutation. The embryos t12t12 and t12t12-(Dp17CDE; Dl16) were shown to be eliminated at the morula stage; embryos t12+, t12+ + or t12t12+ survive during preimplantation and early postimplantation stages: t12 embryos (hemizygous for all genes of the 17AB region, including all t-alleles) have quite normal cleavage, blastulation and implantation, but die soon thereafter. The embryos with nullisomy 17AB combined with deletion 17CDE survive up to the morula stage. These data are in line with previously proposed hypothetical mechanism for mutual activation of homologous chromosomes and their segments during initial stages of embryogenesis in mice. The system of marker chromosomes Rb7Bnr and T43H in combination with various alleles of the T complex might be recommended as a useful tool in analysis of primary developmental effects of different t-alleles in mice.     

Transmission of gametes with normal or translocation chromosomes in male and female single-sex mouse chimeras.

Three male and four female mouse single-sex chimeras derived from fusions of Rb(11.13)4Bnr T(1;13)70H homozygous embryos with +/+ embryos were caged with T(1;13)70H homozygotes of the opposite sex and followed through their reproductive lifespans. Six animals (three males and three females) were germline chimeras. The fz gene was used as a marker for the T70H reciprocal translocation. The ratio of fz/fz to fz/+ offspring did not change with increasing age in males, but decreased in two of the three female chimeras. Within males, there was generally good agreement between the proportions of translocation and nontranslocation germ cells from spermatogonial mitosis through the first and second meiotic division. In one male, this ratio was also reflected in the offspring. In the other two males, there was significant selection during haplophase, from which both types of spermatozoa could benefit.     

Two new X-autosome Robertsonian translocations in the mouse

The influence of X-autosome Robertsonian (Rb) translocation hemizygosity on meiotic chromosome behaviour was investigated in male mice. Two male fertile translocations [Rb(X.2)2Ad and Rb(X.9)6H] and a male sterile translocation [Rb(X.12)7H] were used. In males of all three Rb translocation types, the acrocentric homologue of the autosome involved in the rearrangement regularly failed at pachytene to pair completely with its partner in the Rb metacentric. The centric end of the acrocentric autosome was found regularly to associate either with the proximal end of the Y chromosome or with the ends of nonhomologous autosomal bivalents; the proportions of cells with such configurations varied between pachytene substages and genotypes. Various other categories of synaptic anomaly, such as nonhomologous synapsis, foldback pairing and interlocks, affected the sex chromosome multivalent in a substantial proportion of cells. In one of the Rb(X.12)7H males screened, an unusual, highly aneuploid spermatocyte that contained trivalent and bivalent configurations was found. Rb translocation hemizygosity did not appear to increase to a significant extent the incidence of X-Y pairing failure at pachytene, although the incidence was elevated at metaphase I in Rb(X.12)7H animals. Overall, a comparison of the frequencies and types of chromosome pairing anomalies did not suggest that these were important factors in the aetiology of infertility in males carrying the Rb(X.12)7H translocation.     

Chromosome segregation in mice heterozygous for Robertsonian translocations. II. Changes in the structure of homologs as a cause of abnormal disjunction in females

It was demonstrated that mutations T, Fu, Ki, t6 of chromosome 17 cause preferential transmission of the acrocentric homologues to the progeny from female Rb heterozygotes. The results indicate that the effects of these mutations on segregation are restricted to the Robertsonian translocations involving chromosome 17. Substitution of the parts of chromosome 17 distal or proximal to the T-locus did not alter the effect, of this chromosome on the transmission rate of the homologue. The transmissions effects of these mutations, whether cis or trans with Rb, were the same. It was observed that mothers Rb7/T43H transmitted the chromosome with the reciprocal translocation T43H to 70.9% of their progeny. Data were obtained supporting the idea that structural changes of the chromosomes caused by mutations affect segregation of the homologues in Rb heterozygous females. The possible mechanism of this influence is discussed.     

Meiotic studies of translocations causing male sterility in the mouse. II. Double heterozygotes for Robertsonian translocations.

Unusual meiotic behavior of the XY chromosome pair was observed in sterile male mice doubly heterozygous for two Robertsonian translocations, Rb(16.17)7Bnr and Rb(8.17)1Iem. Nonrandom association between the X chromosome and the translocation configuration, ascertained from the frequencies of relevant C-band contacts, was found in 9 of 10 sterile males. Besides the nonrandom association, the XY chromosomes showed signs of impaired condensation, as judged by measurement of their lengths at diakinesis/MI of the first meiotic division. In contrast, neither nonrandom contact nor decondensation of the XY chromosomes pair was found in fertile males heterozygous for a single Robertsonian translocation, Rb1Iem or Rb7Bnr. The present observations lend indirect support to the working hypothesis advanced previously, the assumption that interference with X-chromosome inactivation is a possible cause of spermatogenic breakdown in carriers of various male-sterile chromosomal transloations. Alternative explanations of the available data, which cannot be ruled out, are briefly discussed.     

No induction of interchromosomal effect in male meiosis of Chinese hamsters with reciprocal translocations

Chinese hamsters from five strains with reciprocal translocations, T(1;3)7Idr, T(1;3)8Idr, T(1;2)9Idr, T(7;9)16Idr, and T(1;5)17Idr, and a karyotypically normal strain, CHS/Idr, were used to look for an interchromosomal effect by chromosomal analysis of meiotic cells and one-cell embryos. The frequencies of nondisjunction at first meiosis in five normal (+/+) males, calculated by doubling the number of hyperhaploid cells, ranged from 0.43% to 1.33%, and there was no significant difference in frequency among individuals. On the other hand, the frequency of hyperhaploid cells in males heterozygous for each translocation ranged from 3.0% to 11.8%, and the frequency of hyperhaploid cells with an extra translocation-unrelated chromosome ranged from 0.2% to 0.4%, which is no different from that estimated from scoring of +/+ males at the second meiotic metaphase. In one-cell embryos from crosses between karyotypically normal females and male heterozygotes for T(1;2)9Idr and T(7;9)16Idr, 1.1% and 0.5% of embryos had an extra translocation-unrelated chromosome. Compared with the control, the frequency of meiotic nondisjunction showed no increase in male heterozygotes for the reciprocal translocations. Therefore, the results suggest that multivalents and rearranged chromosomes existing at first and second meiosis in male Chinese hamsters exert no influence on segregation of normal bivalents and chromosomes unrelated to the rearrangements.     

Chromosome segregation in mice heterozygous for Robertsonian translocations. I. The effect of mutation in chromosome 17 on the disjunction of homologs in females

The effects of mutations on chromosome 17 upon the segregation of the metacentric and acrocentric homologues in the progeny of female mice heterozygous for Robertsonian translocations Rb(8.17) 1Iem and Rb(16.17) 7Bnr were studied. Genetic analysis indicated that the ratio of Rb to non-Rb (normal karyotype) progeny from mothers heterozygous for mutations tf, qk, t12 were not significantly different from 1:1 expected. Introduction of mutations T, Ki, Fu, t6 into the female genotype caused strong distortion of segregation and an increase in the proportion of progeny with normal karyotype (65-70%). From the data on embryonic mortality and cytogenetic observations, it is concluded that distortion of equal transmission arises before MII of meiosis. Consequently, preferential distribution of the metacentric chromosome into the polar body during the first meiotic division is relevant to the segregation distortion observed.     

Meiotic nondisjunction and translocation segregation in dwarf (dw/dw) and control T(1;13)70H heterozygous mice

The meiotic behavior of translocation heterozygous T70 (1;13)H/+ male mice with a Snell dwarf (dw/dw) genotype was compared with that of nondwarf T70H/+ controls. A four-fold increase in the nondisjunction frequency of the normal bivalents occurred as a consequence of the dwarf genotype. This increase is identical to that seen in karyologically normal dwarf males. No effect of the dwarf condition on the segregation of the translocation multivalent could be noted. Thus, translocation heterozygosity does not enhance the meiotic instability caused by the hypopituitary dwarf condition. From a small sample of oocytes from T70H/+ and chromosomally normal dwarf females it is concluded that nondisjunction in females is not increased by the dwarf condition. In general we conclude that animals with higher spontaneous nondisjunction levels are not necessarily more sensitive to factors increasing nondisjunction.     

XY pair associates with the synaptonemal complex of autosomal male-sterile translocations in pachytene spermatocytes of the mouse (Mus musculus)

Analysis of the chromosome behaviour at pachytene has been performed by means of the silver staining technique visualizing the synaptonemal complexes (SCs) in male mice heterozygous for the male-sterile translocations T(5;12)31H, T(16;17)43H and T(7;19)145H, respectively. The T(9;17)138Ca male heterozygotes and T43H/T43H homozygous males were used as fertile controls. The sterile mice displayed a high frequency (about 60%) of pachytene spermatocytes with autosomal translocation configuration located in close vicinity of the XY pair. The dense round body (XAB), normally located near the X-chromosome axis in fertile males, exhibited abnormal affinity to translocation configuration in the sterile translocation heterozygotes. The incomplete synapsis of autosomes involved in translocation configuration was observed in more than 70% of the pachytene spermatocytes with the male-sterile translocations but in less than 20% of the cells from T138Ca fertile male.s. A hypothesis relating the spermatogenic arrest of carriers of male-sterile rearrangements to the presumed interference with X chromosome inactivation in male meiosis is discussed.     

Transmission ratio distortion in offspring of mouse heterozygous carriers of a (7.18) Robertsonian translocation

Transmission ratio distortion (TRD) is defined as a significant departure from expected Mendelian ratios of inheritance of an allele or chromosome. TRD is observed among specific regions of the mouse and human genome and is frequently associated with chromosome rearrangements such as Robertsonian (Rb) chromosomes. We intercrossed mice heterozygous for a (7.18) Rb translocation and genotyped chromosomes 7 and 18 in 1812 individuals, 47% of which were informative for chromosome segregation. We substantiated previous findings that females were less likely than expected to transmit the Rb chromosome to their offspring. Surprisingly, however, we report that heterozygous males transmitted the Rb translocation chromosome significantly more frequently than the acrocentrics. The transmission of the Rb chromosome was not significantly influenced by either the sex of the Rb grandparent or the strain of the Rb.     

Wild-derived Robertsonian translocation in mice. Chromosome 17, Rb (16:17)7, shows novel interactions with t-alleles

We have studied the effects of wild-derived (Rb7) and laboratory-derived (Rb1) Robertsonian translocations involving chromosome 17 on t-complex determined transmission ratio distortion and crossing-over suppression in mice. The Rb7 chromosome is significantly unlike all other wild-type chromosome 17s tested, while Rb1 is not. t0/Rb7 males are uniformly extremely high distorters (greater than 96 percent) while th2/Rb7 males are uniformly extremely low distorters. t0/Rb7 animals allow genetic recombination in the centromere to t-lethal region interval. These observations could be explained if the Rb7 chromosome contains one or more t-like regions.     

Une triple translocation chez le Triton Pleurodeles waltlii

A cytogenetic study has lead us to a stock of fertile heterozygotes for a triple translocation. The chromosomal rearrangement has first been detected in a female resulting from a cross between a normal female and a male submitted to X ray-irradiation. The aberration consists of rearrangements between a chromosome 3, a chromosome 6 and a chromosome 7. Abnormal chromosomes have the following constitution: 7q?: the terminal portion of the long arm is lost and replaced by the end of the short arm of the chromosome 3. 6 q+: the terminal portion of the long arm is lost and replaced by the end of the long arm of the chromosome 7. 3p+: the terminal portion of the short arm is lost and replaced by the end of the long arm of the chromosome 6. On the analogy of the human chromosome standardization, the formula of heterozygotes is 24, t (3p+, 6q+, 7q?). The first meiotic division shows both in the female and in the male 9 bivalents and one hexavalent. The formulae of the gametes are the same in both sexes. When a heterozygote is bred with a normal individual the offspring is composed of phenotypically normal or abnormal animals, depending on their karyotypes. The unbalanced karyotypes are lethal or semilethal. The importance of the malformations depends on the temperature of the water where the animals grow. The study of the meiotic slides brings a cytological confirmation of the results obtained from the study of the phenotypes and karyotypes which appear in the offspring.     

Testicular functions in mice bearing an autosomal translocation (T 145H)

In the mouse, the autosomal reciprocal translocation T (7; 19) 145 H caused complete male sterility. The spermatogenesis was arrested at prophase or early metaphase I stages during the first meiotic division. The exocrine and endocrine testicular functions of azoospermic males (T 145 H/+) were compared with those of normal male littermates (+/+) at 63 days of age. Testis and epididymis weights in T 145 H/+ were significantly lower than those in +/+. By histological examination, the interstitial cells appeared preponderant but this was probably illusory due to the decrease in seminiferous tubular size and diminished testicular size. Moreover, androgen activity in T 145 H/+ seemed normal judging by weights of androgen target tissues (prostate, seminal vesicles), and plasma testosterone level.     

The influence of the Robertsonian translocation Rb(X.2)2Ad on anaphase I non-disjunction in male laboratory mice

A Robertsonian translocation in the mouse between the X chromosome and chromosome 2 is described. The male and female carriers of the Rb(X.2)2Ad were fertile. A homozygous/hemizygous line was maintained. The influence of the X-autosomal Robertsonian translocation on anaphase I non-disjunction in male mice was studied by chromosome counts in cells at metaphase II of meiosis and by assessment of aneuploid progeny. The results conclusively show that the inclusion of Rb2Ad in the male genome induces non-disjunction at the first meoitic division. In second metaphase cells the frequency of sex-chromosomal aneuploidy was 10.8%, and secondary spermatocytes containing two or no sex chromosome were equally frequent. The Rb2Ad males sired 3.9% sex-chromosome aneuploid progeny. The difference in aneuploidy frequencies in the germ cells and among the progeny suggests that the viability of XO and XXY individuals is reduced. The pairing configurations of chromosomes 2, Rb2Ad and Y were studied during meiotic prophase by light and electron microscopy. Trivalent pairing was seen in all well spread nuclei. Complete pairing of the acrocentric autosome 2 with the corresponding segment of the Rb2Ad chromosome was only seen in 3.2% of the cells analysed in the electron microscope. The pairing between the X and Y chromosome in the Rb2Ad males corresponded to that in males with normal karyotype. Reasons for sex-chromosomal non-disjunction despite the normal pairing pattern between the sex chromosomes may be seen in the terminal chiasma location coupled with the asynchronous separation of the sex chromosomes and the autosomes.(ABSTRACT TRUNCATED AT 250 WORDS)