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A G Searle

Publications and source records attributed to A G Searle.

At least 37 records · Page 2Linked to original sources
PubMed1986

The role of dominant visibles in mutagenicity testing.

Our results suggest that inclusion of growth retardation as one of the components of the dominant visible category will make this a useful end-point for mutational studies in which it is important to gauge the extent to which transmissible genetic damage of a particularly relevant kind is induced in mammals. These visibles are easily scored and the use of an automated weighing device would lessen subjectivity. In the present experiment with 5Gy + 5Gy spermatogonial X-irradiation (24h interval) 7309 offspring have been examined at weaning age and 23 heritable dominant visibles identified. These included 12 with growth retardation, one of which was mutant at the steel (S1) locus, as were 3-4 others of normal size. However, only 46 out of 112 offspring recorded as small were actually kept for genetic tests, while only 30 (65%) of these could be fully tested because of death or infertility in the others. Thus this experiment throws some light on the induction of presumptive dominant sub-lethals which survive until weaning age, a little-studied category. Twelve out of the 30 fully tested small mice (40%) proved to carry dominant visible mutations. If this proportion is applied to the total recorded as small then we can derive an overall total of about 45 mutations for growth retardation. It is hoped to determine the actual rate of induction of these by further work.

Animals↗
PubMed1985

Noncomplementation phenomena and their bearing on nondisjunctional effects.

In the mouse, unbalanced gametes with major gains and/or losses of chromosomal material seem just as capable of forming a zygote as normal, fully balanced gametes. This is shown by the results of intercrossing genetically marked translocation heterozygotes, in which complementary unbalanced gametes usually fuse to form fully viable zygotes. However, there are some notable exceptions to this. Studies on a number of reciprocal translocations have shown that gametes with maternal duplication of particular chromosome regions may fail to complement those with a corresponding paternal deficiency, but produce lethal zygotes instead, whereas the reciprocal combination of a paternal duplication with a maternal deficiency produces fully viable offspring. For a particular distal region on chromosome 7 the reverse situation holds. More recent studies on genetic methods of detecting nondisjunction with Robertsonian translocations have revealed the same phenomenon. Mouse chromosomes affected include numbers 2, 6, 7, and 8. There is also defective complementation on chromosome 11 and related phenomena on chromosome 17. These findings help to explain why diploid embryos with 2 male or 2 female pronuclei fail to come to term and may be connected with genetic imprinting of gametes. It seems probable that the same phenomenon occurs in homologous regions of human chromosomes and may mean that the severity of a trisomic effect will depend sometimes on the parental source of the extra chromosome. The phenomenon also affects the efficiency of certain genetic tests for nondisjunction which depend on full complementation.

Animals↗
PubMed1985

The influence of mating status and age on the induction of chromosome aberrations and dominant lethals in irradiated female mice.

Young and old hybrid female mice were given 0.5 Gy or 2 Gy acute x-irradiation, followed by (i) in utero examination for dominant lethal mutations, or (ii) examination of metaphase I oocytes for chromosome aberrations 2-3 weeks after the irradiation. Some of the old females had been mated when young to males of a specific locus stock. Others were left unmated until after the irradiation when they, and the young females, were mated to the same specific locus stock and allowed to have 1 (if given 2 Gy) or 2 (if given 0.5 Gy) litters before the dominant lethal test. In both the 0.5-Gy and 2-Gy series, mean sizes of first litters in the old late-mated group were markedly lower than in the old early-mated or young groups, the differences being significant at the 2-Gy level. The intrauterine examinations showed that this difference was largely the result of a reduced ovulation rate in the old late-mated females. Preimplantation loss tended to be higher in all the old females than in the young ones, but differences between the groups in postimplantation lethality were less pronounced. In the chromosome studies, only about half as many oocytes were recovered from the ovaries of old females than from young ones. At both the 0.5-Gy and 2-Gy dose levels interchange frequencies were non-significantly higher in old than in young females (with no clear-cut effect of mating status), while the overall frequency of aberrations (interchanges + fragments) was significantly higher in oocytes of old than young females after 2 Gy X-rays (35.5% against 12.5%). No specific locus mutations were found in 5616 offspring of unirradiated females.

Age Factors↗
PubMed1984

Chromosome maps of man and mouse II.

Chromosome displays and listings are presented showing loci whose position is known in both man and mouse, in similar manner to our previous report (Dalton et al. 1981). There is now evidence for at least 27 conserved autosomal segments with two or more loci in the two species. The human and mouse chromosome maps show the location of homologous genes. The mouse map also shows the positions of translocations used in gene location and of some other genes used in linkage studies on them.

Animals↗
PubMed1983

Two new X-autosome translocations in the mouse.

The reciprocal translocations T(X;4)37H and T(X;11)38H were induced by acute X-irradiation of spermatozoa. Male heterozygotes are completely aspermic with a spermatogenic block at pachytene and testis masses about one third of normal, though metaphase I is very occasionally reached in T37H. For both translocations the X chromosome breakpoints are in band XA2, and the autosomal breakpoints are in 4D3 for T37H and 11E1 for T38H, leading to long and short marker chromosomes. Chain quadrivalents predominated in oocytes at MI, with no rings; there were 32% trivalent + univalent configurations in T37H and 40% in T38H. These generated (1) XO mice, (2) tertiary trisomics carrying 20 bivalents and the small X4 (T37H) or X11 (T38H) markers. These trisomics were apparently lethal in T37H but sub-viable in T38H and sometimes fertile as XX11 and trisomic XXX11 females, though sterile as XX11Y males. However, many developed exencephaly in utero, probably because of the distal duplication on chromosome 11. No tertiary monosomics were found in 12 to 14 day embryos. Seven percent of all female progeny were XO, with a higher than expected frequency in T37H and a lower than expected one in T38H. T37H is about two units and T38H about five units from the spf locus on the X chromosome with evidence for some crossover suppression between the T38H breakpoint and Ta. Autosomal linkages found were T37H-m-b (R.F. of 16 +/- 4% between T37H and m) and T38H-Rewc (R.F. of 5 +/- 3%). T37H/+ females weighed about 10% less than normal females at birth and about 30% less at weaning; there was little if any effect in T38H/+ females or in males carrying either translocation. Neither translocation had any marked effect on viability. T37H/+ females showed variegation when heterozygous for b with the wild type allele in the long 4X marker. On average, about 20% of the coat was brown rather than black. However, no clear evidence for m variegation was found.

Animals↗
PubMed1983

A male-sterile insertion in the mouse.

Is(7;1)40H was found in the daughter of a male mouse given spermatozoal X-irradiation. It is a non-inverted insertion of about half of chromosome 7 into chromosome 1, generating a long somatic marker chromosome. Breakpoints are in bands 1B, 7B1, and 7F1; linkage tests show that these breakpoints are about midway between fz and In on the 1, and 0.2 units distal to ru-2 and 12 units proximal to fr on the 7. Female carriers had litters of about one-third normal size and showed some decline in length of reproductive life. Males were sterile, with testis weights only 30% of normal and with abrupt cessation of spermatogenesis in pachytene at stage IV of the seminiferous epithelial cycle. Positive sex-vesicle contact with the insertional configuration was found in only 40% of pachytene spermatocytes, which suggested that other factors may be involved in the spermatogonial breakdown. In oocytes at metaphase I 76% of insertion configurations were multivalent, because of one or more chiasmata in the inserted segment, as were 79% of synaptonemal complex configurations in male pachytenes. Karyotyping at 12.5 to 14.5 days of gestation showed that all embryos with duplications of the inserted segment were exencephalic, and the only example of a corresponding deficiency was retarded. Analysis of the consequences of heterozygosity for the insertion shows that the insertion length should be correlated with the frequency of unbalanced offspring and thus with the amount of F1 lethality. The genetic length of 36 cM estimated in this way from data on liveborn offspring is in reasonable agreement with estimates from cytological measurements and meiotic configurations but rather higher than that from linkage tests.

Animals↗
PubMed1982

An in vivo method for the detection of somatic mutations at the cellular level in mice.

This new method for detection of somatic mutations is based on the fact that recessive mutations at the dilute (d) and leaden (ln) loci change the shape of pigment-cells in the hair follicles from their normal highly dendritic appearance (nucleofugal) to a rounded-up almost non-dendritic form (nucleopetal). Gene action is autonomous and individual mutant melanocytes can be recognised in whole mounts of dorsal skin made after the post-natal onset of melanogenesis. Foetal heterozygotes for d and ln were treated with X-rays (0-200 rad) or procarbazine (0-300 mg/kg body mass by maternal i.p. injection) 17 days after detection of a vaginal plug; whole mounts of dorsal skin (fixed 3 days after birth) were microscopically scanned for mutant melanocytes in the hair follicles.About half a million follicular melanocytes were present in the 2 mounts made per mouse. Mutant cells were mainly in the form of small intrafollicular clones; the few mount containing large interfollicular clones were excluded from the analysis. For both treatments, dose-response relationships showed good fits to both a quadratic and a power-law curve. Equations for the latter were: For X-rays, y = 3.2 x 10(-5) + 3.12 x 10(-9) D2.07; for procarbazine, y = 3.6 x 10(-5) + 0.4 x 10(-10) D2.60. However, neither of these differed significantly from a square-law relationship. The estimated mutation rate at the 100 rad X-ray level of 4.7 x 10(-7)/rad/locus was in good agreement with that obtained by Russell and Major's (1957) pioneer studies of somatic mutation in mice, by looking for mutant patches in the coat ("spot test"). Possible ways in which the present method might be improved and extended are discussed.

Animals↗
PubMed1982

Cytogenetic effects of protracted gamma exposures from conception of male mice.

In order to gain an overall picture of the genetic effects of an increased level of background radiation it is necessary to study the results of protracted exposures to embryonic and immature germ-cell stages as well as to stages found in the mature organism. For this purpose, litters produced by female mice, kept in a 10 or 20 rad/day 60 Co gamma-irradiation field, were kept in the same fields from conception until about 60 days later, having absorbed doses of 526 and 1078 rad respectively. Tests on exposed female offspring showed them to be sterile. 8 weeks after removal from the gamma field, mean testis masses of males in the 20 rad/day series were only half normal but those receiving 10 rad/day were little affected. Frequencies of translocations in spermatocytes at diakinesis/metaphase I were only slightly increased in the exposed series, differences not being significant. Estimated rates of translocation induction were around 5 x 10(-6) per rad, about one-third of those found after protracted gamma-irradiation of stem-cell spermatogonia in the adult. Embryonic lethality in progeny of other similarly irradiated males(absorbed doses of 560 and 1040 rad), mated 2 months after removal from the radiation fields, was also increased slightly, but not significantly. Results are compared with others on the induction of chromosome aberrations and gene mutations, mainly by acute irradiation, in prenatal and neonatal male mice. It is concluded that early male germ-cell stages generally show a reduced genetic radiosensitivity after both acute and chronic exposures.

Animals↗
PubMed1982

Dominant lethal and ovarian effects of plutonium-239 in female mice.

In two separate experiments (C3H x 101)F1 female mice were injected intravenously with 239Pu in trisodium citrate, then mated in pairs to strain CBA males, to test for dominant lethality. In the first experiment 10 muCi kg-1 and in the second 20 muCi kg-1 body mass was injected. Matings were after 6 days in the first experiment (estimated ovarian absorbed dose of 0.1 Gy) and after 3, 6 or 12 weeks in the second (estimated ovarian doses of 1.11, 2.45 and 5.91 Gy respectively). No evidence of dominant lethal induction was found in the first experiment, but in the second there was a significant increase over controls in pre-implantation loss in all three series. Post-implantation lethality increased significantly (by 12 per cent) only after 12 weeks' exposure. With the 6- and 12-week exposures (especially the latter) luteal counts fell and fewer females became pregnant than in controls. This is attributed to oocyte killing by the alpha-particles. Histological and autoradiographic investigations showed a marked reduction in ovarian size and follicular numbers with fission-tracks clustered mainly over the medullary stroma. The pre-implantation loss may stem from lowered fertilization of oocytes because of their damage, so that the best measure of dominant lethality is that based on post-implantation death. Thus there is only slight evidence for the induction of genetic damage, which is in line with previous findings after chronic exposures of female mice.

Animals↗
PubMed1982

The use of Robertsonian translocations in the mouse for studies on non-disjunction.

In the mouse, gametes with gross chromosome duplications and deficiencies can complement each other to give viable zygotes (with some notable exceptions involving particular chromosomes). These complementation-type offspring can be recognised in intercrosses between translocation heterozygotes in which one parent is homozygous for a recessive genetic marker not carried by the other. This system has beeN used by Lyon and colleagues (1976) to study non-disjunction in heterozygotes for tobacco mouse and laboratory-derived Robertsonian translocations. Although non-disjunction is frequent in the former group, still higher frequencies are needed for a workable test system in which wild type mice are treated and mated to a tester stock generating many aneuploid gametes. Possible approaches include (1) use of semidominant markers, (2) marking both arms, (3) combining two or three independent Robertsonians in the tester stock, (4) use of compounds of Robertsonians wih monobrachial homology, since these give very high frequencies of non-disjunction, (5) generation of a compound of three Robertsonians with tribrachial homology, which should produce aneuploid gametes only. This last seems the most promising approach, if the compound proves fertile, and would be analogous to the isochromosome system of Drosophila.

Aneuploidy↗
PubMed1981

The effects of radiation dose-rate and quality on the induction of dominant lethals in mouse spermatids.

Hybrid male mice were given 3 Gy (300 rad) doses of X- or gamma-irradiation at dose-rates of either 0.6 or 0.002 Gy/min for each radiation. Germ-cells treated as spermatids were tested for dominant lethality. Effects on spermatogonia were evaluated by studying testis-weight, sperm-count and sperm abnormalities. The rate of induction of dominant lethal mutations was 2.1 times as high after acute X-irradiation as after protracted gamma-irradiation. Most of this difference resulted from the change in radiation quality, since the relative effectiveness of X- versus gamma-irradiation was 1.9 at low and 1.6 at high dose rates. For each radiation, however, fewer dominant lethals were induced at low dose-rates than at high (low/high ratios of 0.8 and 0.9 respectively) although differences did not reach a significant level. There were no statistically significant effects of dose rate on testis-weight or sperm-count in the X-ray series, but there were significantly less severe effects on both with protraction of the gamma-irradiation. Evidence for effects of radiation quality on these characters was conflicting. Frequencies of abnormal spermatozoa were markedly increased 7 weeks after irradiation but there were no consistent effects of radiation intensity or quality.

Animals↗
PubMed1980

Linkage analyses of murine immunoglobulin heavy chain and serum prealbumin genes establish their location on chromosome 12 proximal to the T (5;12) 31H breakpoint in band 12F1.

Analysis of backcross mice carrying the Harwell translocation T(5;12)31H has led to the definitive localization of the immunoglobulin heavy chain gene cluster. Both Igh-1 and Pre-1 loci were found to segregate in tight linkage with the chromosomal markers 5(12) and 12(5), which define the balanced translocation T(5;12)31H. Additional data establish the location of these genes at the telomeric end of chromosome 12. That both loci are proximal to the chromosomal breakpoint in band 12F1 is shown by the phenotypes of segregants aneuploid for the presence or absence of the small marker 5(12). The order of loci inferred from a single recovered recombinant is: centromere-Igh-1-Pre-1-T(5;12)31H.

Animals↗
PubMed1980

Comparative effects of protracted exposures to 60Co gamma-radiation and 239Pu alpha-radiation on breeding performance in female mice..

Breeding performances are compared of hybrid female mice given 239Pu (5 or 10 mu Cikg-1 body mass in 1% trisodium citrate via the tail-vein), or kept in a 10 rad/day or 20 rad/day 60Co gamma-irradiation field (but mated in the control area), or unirradiated. Ovarian dose-rates from the injected plutonium were initially 0.8 and 1.7 rad/day, changing little thereafter; actual gamma-ray dose-rates to breeding females averaged around 8 and 16 rad/day respectively. Both gamma-ray treatments affected reproductive performance more than the plutonium injections, with respet to duration of fertility and to offspring per litter in successive 4-weekly periods, though overall mean litter-sizes were not significantly less than controls. The r.b.e. for these effects on reproduction, attributed to germ-cell killing, is about 2.5 for the alpha-particles vs. gamma-rays, lower than for testis mass reduction in males. This low r.b.e. may be connected with inhomogeneity of alpha-particle dose within the ovary, but it is known that fission neutron versus gamma r.b.e.'s for impairment of female fertility are also lower than those for impairment of male fertility.

Alpha Particles↗
PubMed1980

An overall genetic risk assessment for radiological protection purposes.

Risks of serious hereditary damage in the first and second generations after low level radiation exposure and at equilibrium were calculated by using a doubling dose of 100 rem (based on experimental work with the mouse) and by considering separately the various categories of genic and chromosomal defect. Prenatal lethality has not been included. It is estimated that after the exposure of a population of future parents to a collective dose of 1 million man-rem, about 125 extra cases of serious genetic ill health would appear in children and grandchildren. In all future generations, a total of about 320 cases is expected, provided the population remains of constant size. It is emphasised, however, that a number of major assumptions have to be made in order to arrive at any overall genetic risk estimate, so that the confidence limits of these figures are bound to be wide.

Genes, Dominant↗
PubMed1979

A disruption of pachytene DNA metabolism in male mice with chromosomally-derived sterility.

DNA metabolism was analyzed in spermatocytes of mice that were sterile either because of X-autosome or autosome-autosome translocations, or because of trisomy. In the strains analyzed, spermatogenic development is arrested by metaphase I or soon thereafter. In all such strains a disruption of the normal pattern of pachytene DNA metabolism occurred. Prepachytene metabolism appeared normal. Disruption was manifest in both the level of endogenously generated nicks during pachytene and in the distribution of nicks among the different DNA sequence classes. Nicking was more intense in the steriles and tended to be randomized in distribution. Satellite DNA underwent pachytene nick-repair in the steriles but not in fertile controls. The repair capacity of spermatocytes from steriles was equal to that of the fertiles; the higher frequency of nicks in the steriles was due to a persistence of nicking activity.

Animals↗