PubMed Health⌕ Search

Biomedical subjects

A G Searle

Publications and source records attributed to A G Searle.

At least 19 recordsLinked to original sources
PubMed1991

Spermatogenic effects of male-fertile translocations in the mouse.

Four male-fertile translocations, T(2;4)13H, T(2.8)26H, T(7;18)50H and T(1;13)70H were crossed to the inbred strains CBA/H and C57BL/6J. F1 heterozygotes were compared with wild-type litter-mates for signs of spermatogenic impairment, in view of previous reports that the C57BL strain had this effect in the T(14;15)6Ca translocation. There was a general tendency for body-weights to be slightly reduced in translocation carriers vs. wild-type. Mean testis weights were significantly reduced on the C57BL background with all four translocations as compared to wild-type, but also significantly increased in T26H on CBA. Sperm counts were also reduced on the C57BL background in T13H, T50H and T70H (significantly so in the last two) but were significantly increased in T13H on a CBA background. Only in T50H did the frequency of sperm-head abnormalities show any marked change in the translocation heterozygotes, being approximately doubled with both CBA and C57BL backgrounds although still remaining at a low level. It was concluded that the deleterious effects of C57BL strains on spermatogenesis in translocation heterozygotes were not confined to T6Ca but were probably widespread. Some inconclusive evidence suggested that this might be because some genetic factors associated with C57BL tended to reduce chiasma frequencies in translocation heterozygotes.

Animals↗
PubMed1991

Cytogenetic characterization of radiosensitive mouse mutants.

In order to develop mouse models for human mutagen-sensitive syndromes, we carried out cytogenetic characterization of several mouse mutants and MS/Ae mice showing enhanced radiosensitivities. The applied cytogenetic techniques include chromosomal analysis of in vitro cell cultures and lymphocyte cultures as well as in vivo UDS in hepatocytes, induction of micronuclei in polychromatic erythrocytes and translocation induction in spermatogonial stem cells. Among the mutations studied, namely the contrasted allele of steel (Slcon), viable dominant spotting (Wc), wasted (wst), varitint-waddler (Va) and dystonia musculorum (dt) as well as MS/Ae mice, various iso-, hyper- or hypo-sensitive conditions were recorded. Only Va and dt appear to be associated with some deficiency in DNA repair.

Animals↗
PubMed1991

Aneuploidy induction in mice: construction and use of a tester stock with 100% nondisjunction.

A new murine tester stock for primary nondisjunction incorporates three genetically marked Robertsonian translocations with tribrachial homology (TBH): Rb(6.15)1Ald, Rb(4.6)2Bnr, and Rb(4.15)4Rma. The resultant tricentromeric meiotic configuration leads to 100% aneuploid gametes, but the TBH stock can be maintained by intercrossing, through the complementation of nullisomic and disomic gametes. The only neonatal survivors from tescrosses to wild type come from complementation of aneuploid gametes and genetic tests allow wild type gains or losses of Chromosomes 4, 6, and 15 to be distinguished. Alternatively, cytogenetic examination allows products of wild type chromosome gain, with one metacentric, to be separated from chromosome loss with two metacentrics. A pilot study, with 0-2 Gy X-irradiation of oocytes at diakinesis, revealed twelve examples of chromosome loss in wild type gametes but none of chromosome gain and thus provided no evidence for the induction of nondisjunction.

Aneuploidy↗
PubMed1990

Comparative genetics of albinism.

Albinism in laboratory mammals is equivalent to human tyrosinase-negative oculocutaneous albinism, and thus the result of recessive mutation in the structural locus for tyrosinase (TYR), which prevents melanin biosynthesis. In the mouse, eight mutant alleles are now known at this locus, with differing effects on eye colour and on the degree of reduction in eumelanin and phaeomelanin pigmentation. Three of these alleles, namely chinchilla, himalayan (acromelanistic) and albino (c) itself, have also been recognized in a number of other species but only albino has been identified in man so far. The himalayan allele (equivalent to Siamese in the cat) is of particular interest because it converts tyrosinase into a thermolabile form, with greater production of melanin in colder areas of the body. The optic track misrouting found in human albinos also occurs in albino alleles in other mammals, which may also show reduced activity and stress responses. The TYR locus is on human chromosome 11, which now has at least 11 loci with homologues on mouse 7. However, their order is markedly different in the two species. For instance, c and Hbb (beta-globin), which are closely linked in mouse, rabbit, cat etc., are far apart on human 11q and 11p respectively. Moreover, some loci (e.g., Fes and Mod-2) which are close to c in the mouse appear to be on human chromosomes other than 11. This extensive chromosomal restructuring in mammalian evolution means that the effects of human albino deletions may differ greatly from those studied in the mouse, which are associated with defects of kidney, liver and thymus. Tyrosinase-positive albinos or near-albinos are known at a number of loci in mice and other mammals. They are the result of the absence or inhibition of melanocytes in the affected areas, so that no melanin is produced. In general they are associated with pathological pleiotropisms which may lead to anaemia, inner ear defects, megacolon, neurological effects, skeletal defects, microphthalmia, osteopetrosis, spina bifida, sterility and so on. Homologies between these and human loci affecting pigmentation are now being discovered.

Albinism↗
PubMed1989

Chromosome maps of man and mouse. IV.

Current knowledge of man-mouse genetic homology is presented in the form of chromosomal displays, tables and a grid, which show locations of the 322 loci now assigned to chromosomes in both species, as well as 12 DNA segments not yet associated with gene loci. At least 50 conserved autosomal segments with two or more loci have been identified, twelve of which are over 20 cM long in the mouse, as well as five conserved segments on the X chromosome. All human and mouse chromosomes now have conserved regions; human 17 still shows the least evidence of rearrangement, with a single long conserved segment which apparently spans the centromere. The loci include 102 which are known to be associated with human hereditary disease; these are listed separately. Human parental effects which may well be the result of genomic imprinting are reviewed and the location of the factors concerned displayed in relation to mouse chromosomal regions which have been implicated in imprinting phenomena.

Animals↗
PubMed1988

Effects of X-irradiation at different times during development on the yield of somatic mutations in melanocytes of the mouse.

The effect of 2.0 Gy X-irradiation at different times during foetal and early post-natal development on the resultant somatic mutation frequency was investigated by scoring for changes in follicular melanocyte morphology (nucleofugal vs. nucleopetal) in mice heterozygous for the recessive coat colour mutations dilute (d) and leaden (ln). Two peaks were observed following X-irradiation on days 12.5 and 17.5 post coitus (p.c.). The biomodal character of the mutation frequency with time of X-irradiation may be related to changes in the dynamics of the melanocyte population with foetal age. Nonetheless, the results validate the treatment time used in the pilot study (Searle and Stephenson, 1982) as the most sensitive to the induction of somatic mutations within the follicular melanocyte population.

Aging↗
PubMed1988

Effects of zero to four copies of chromosome 15 on mouse embryonic development.

Intercrosses of mice doubly heterozygous for Rb(6.15)1A1d and Rb(4.15)4Rma (thus are characterized by monobrachial homology for chromosome 15) produced embryos with zero to four copies of chromosome 15 in their expected frequencies at the first cleavage division. By 3 1/2 days' gestation, nullisomy 15 embryos were missing. At 8 1/2 to 9 1/2 days, no monosomy 15 embryos were found, although trisomy 15 and tetrasomy 15 embryos were still present in their expected numbers. Tetrasomics were more severely affected than trisomics at this gestational age; the former were severely retarded "streak" embryos, while the latter had open neural tubes and were 2/3 the size of euploid embryos. The functional activity of chromosomes during the embryonic development of autosomal aneuploids is discussed in light of these findings.

Animals↗
PubMed1987

Chromosome maps of man and mouse, III.

Data on loci whose positions are known in both man and mouse are presented in the form of chromosomal displays, a table, and autosomal and X-chromosomal grids. At least 40 conserved autosomal segments with two or more loci, as well as 17 homologous X-linked loci, are now known in the two species, in which mitochondrial DNA is also highly conserved. Apart from the Y, the only chromosome now lacking a conserved group is human 13. Human 17 has a single conserved group which includes both short and long arms, and so may have remained largely intact in mammalian evolution. Human and mouse chromosomal maps show the approximate locations of homologous genes while the mouse map also shows the positions of translocations used in gene location.

Animals↗
PubMed1986

Male pachytene pairing in single and double translocation heterozygotes and spermatogenic impairment in the mouse.

In order to clarify the relationship between meiotic pairing and progress of spermatogenesis, an analysis of male meiotic pairing was carried out in four reciprocal translocation heterozygotes and two double heterozygotes for two semi-identical reciprocal translocations. The reciprocal translocations were chosen to range from fertility (T70H/+) through almost complete sterility (T31H/+) to complete sterility (T32H/+, T42/H+). If meiotic pairing in the translocation multivalent was incomplete, it concerned terminal or probably more often proximal chromosome segments (Chain IV). If both segments failed to pair the multivalent symbol is Chain III + I. Complete pairing is symbolized by Ring IV. To contrast and complement observations of this type, the double heterozygotes were introduced. Males of this type in theory possess two heteromorphic bivalents with a central area of incomplete meiotic pairing (loop formation). Of the T70H/T1Wa double heterozygotes, 36% of the males are capable of inducing at least one decidual reaction in two females whereas for T26H/T2Wa, 79% of the males can do so. For the reciprocal translocations, it was found that proximity of the multivalent to the sex bivalent during pachytene increased in the order Ring IV, Chain IV, Chain III + I. The degree of spermatogenic impairment as measured from cell counts in histological sections and tubular whole mounts, is positively related to the frequency of proximity between the sex chromosomes and the translocation multivalent and thus to lack of meiotic pairing within the multivalent. The meiotic pairing analysis of the double heterozygotes yielded the following findings. For the long heteromorphic bivalents a true loop was never seen in T70H/T1Wa and only rarely observed in T26H/T2Wa. Small marker bivalents of both types were usually recognizable by the following criteria: pairing confined to distal or proximal segments, both distal and proximal segments pairing and loop formation and pairing covering the entire length of both "homologues" but the longer one often with a "thickened" lateral element. The same positive correlation between the absence of pairing (proximal, distal or central) and the proximity of the small marker bivalent synaptonemal complex to the sex bivalent has been found as for unpaired segments within reciprocal translocation multivalents. One unexpected finding was the occurrence of diploid spermatids and spermatozoa especially in T32H/+ males (70-91%) but also in T31H/+ (3-39%).

Animals↗
PubMed1986

Deficiency of adenosine deaminase in the wasted mouse.

Wasted (wst) is a spontaneous mutation with autosomal recessive inheritance. Abnormally low levels of adenosine deaminase have been found in erythrocytes from the wasted mouse. Enzyme activity in wst/wst mice is reduced to 38% of that found in the erythrocytes from control mice, and the apparent Km for adenosine is reduced to 51% of control. These changes imply an alteration in the catalytic properties of the enzyme arising from a change in the primary structure of the protein. We postulate that wasted is a mutation in the structural gene for adenosine deaminase. In man, the autosomal recessive form of severe combined immunodeficiency is associated, in about one-third of cases, with a deficiency of adenosine deaminase. Wasted mice are immunodeficient, develop neurological abnormalities, and die soon after weaning. These features are shared with the human syndrome. We therefore further suggest that the wasted mouse is an animal model for this form of severe combined immunodeficiency that will have potential use in gene-therapy studies.

Adenosine Deaminase↗
PubMed1986

Cytogenetic effects of microwave irradiation on male germ cells of the mouse.

Hybrid male mice were exposed to 2.45 GHz microwaves for 30 min/day, 6 days a week for two consecutive weeks at power densities of 1.0, 100 or 400 W m-2, with sham-exposed controls. Rectal temperatures before and after exposure were measured on days 1, 6 and 12. Measurements made on day 1 were treated with caution because of heterogeneity in rectal temperatures taken before exposure between the groups of mice given different treatments. On days 6 and 12, rectal temperatures rose by approximately 1 degree C in mice sham exposed, or exposed to 1 W m-2 or 100 W m-2. Only in the group of mice exposed to 400 W m-2 was the mean rise in rectal temperature during exposure (about 3 degrees C) significantly increased above the sham value. In groups killed 2-3 days after treatment (mainly meiotic exposure) frequencies of chromosome aberrations in spermatocytes showed no significant heterogeneity although the highest frequency of 1.5 per cent was at the highest (400 W m-2) power density. Another group killed 30 days after 100 W m-2 exposures (spermatogonial sampling) showed no significant increase over controls in chromosome aberration frequency. There was a small but significant increase in sperm count with increasing power density in mice killed 12-13 days after exposure, but a non-significant one in those exposed as spermatogonia (killed 41 days later). Thus effects were markedly less severe than those reported previously by Manikowska-Czerska et al. (1985) with a very similar radiation regime and were probably caused by the temperature enhancement.

Animals↗
PubMed1986

Radiation and haematopoiesis in Harwell steel mice.

Haematological information on steel (Sl) mice is limited largely to Sl/Sld mice of Bar Harbor stock (WC.B6 F1). Therefore, two Harwell alleles, SlgbH and Slcon, were investigated. In the steady state both heterozygotes were modestly anaemic, homozygous Slcon and compound Slcon/SlgbH more so. On perturbation by X-irradiation Slcon/SlgbH showed a decrease in median lethal dose (MLD)--6.5 Gy, Slcon/+ and Slcon/Slcon slightly less change (7.5 Gy) compared with +/+, 8 Gy. In recovery from sublethal doses single heterozygotes, double heterozygotes with Wv, and compounds showed no delay in restoration of the count of red blood corpuscles (RBC) such as that seen in typical W mice (e.g. Wv/+, W/Wv). Effects on Slcon/Slcon and Slcon/SlgbH differ from those reported for Sl/Sld in that they show normal growth of spleen colonies when used as lethally irradiated recipients of bone marrow, they support growth of implanted bone marrow to form radiation chimaeras. When Harwell steel mice are donors of bone marrow to lethally irradiated +/+ mice the chimaeras ultimately are not anaemic; when lethally irradiated Harwell steel mice are recipients of +/+ marrow they remain macrocytically anaemic. One deduces that, for normal development and production of normal RBC in the steady state, the erythron requires intrinsic factors determined by wild type alleles at the W locus and extrinsic factors determined by wild type alleles at the Sl locus. Mutant alleles at either locus may determine macrocytosis. Two mutant alleles at either locus are still more deleterious, often lethal. Whereas mutant W alleles may also influence the pluripotent haematopoietic stem cell (HSC) leading to reduced MLD on X-irradiation, a similarly reduced MLD for Sl mutants may represent an increased need for and consumption of products of the haematopoietic stem cells rather than truly increased radiosensitivity, since the Do for spleen colony-forming units is the same for Slcon/SlgbH as +/+ mice.

Animals↗
PubMed1986

Effects of X-rays on the induction of somatic mutations and growth in the retinal pigmented epithelium during development of the mouse eye.

The coat and eye colour mutant beige (bg) leads to the production of distinctive retinal melanocytes with abnormally large pigment granules. Heterozygotes for bg were given 2 Gy acute X-irradiation at various times between day 11.5 of fetal life and 3 days after birth, at which age whole mounts were prepared of the retinal pigmented epithelium (RPE). These were scanned for the presence of mutant retinal melanocytes with large granules, either as single cells or as clones. The earlier the fetal irradiation, the greater was the effect on RPE area at 3 days post-partum (p.p.), which fell to about half normal with the 11.5-day fetal exposures. However, the ultimate size of the retinal melanocytes seemed little affected by the irradiation, although their normal size increased approximately 3-fold between 12.5 days post-coitum (p.c.) and 3 days p.p. Mean numbers of mutant melanocytes per eye were markedly higher than in +/bg controls at all irradiation ages other than 3 days p.p.; when allowance was made for final sizes of irradiated RPE's mutation frequencies fell steadily from 30.0 x 10(-5) at 11.5 days p.c. to 1.0 x 10(-5) at 3 days p.p., with 0.8 x 10(-5) in +/bg and 0.1 x 10(-5) in +/+ controls. The doubling dose of 0.18 Gy at 16.5 days p.c. was similar to that found at 17.5 days p.c. in a previous somatic mutation experiment in which follicular melanocytes were scanned for mutations at different (d and ln) loci.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1986

The estimation of risks from the induction of recessive mutations after exposure to ionising radiation.

Since recent assessments of genetic risks from radiation have concentrated on harmful dominant effects, a quantitative assessment of risks from recessives is needed. Presumably, harmful recessives can arise at all loci coding for essential proteins (perhaps 10 000), but mutation to dominant alleles is likely to be a property of relatively few loci. While many recessives doubtless remain to be discovered, those known at present tend to have earlier and more severe effects than dominants. Induced recessive mutations can cause harm by partnership with a defective allele already established in the population; partnership with another recessive mutation induced at the same locus; the formation of homozygous descendants, that is, identity by descent; and heterozygous effects. Calculations based on a combination of data from observations on human populations and from mouse experiments suggest that an extra genetically significant dose of 1 cGy (centiGray, equivalent to 1 rad) X or gamma irradiation received by each parent in a stable population with a million liveborn offspring would induce up to 1200 extra recessive mutations. From partnership effects, about one extra case of recessive disease would be expected in the following 10 generations. Homozygosity resulting from identity by descent could not normally occur until the fourth generation after exposure but, on certain assumptions, about ten extra cases of recessive disease would be expected from this cause by the tenth generation. In the same period, about 250 recessive alleles would be eliminated in heterozygotes (that is, Muller's 'genetic deaths') given 2.5% heterozygous disadvantage. These deleterious heterozygous effects should not be combined with those of dominants, as has been done in some previous risk estimates. It is considered unlikely that many radiation induced recessives would show heterozygous advantage. Certain dominants (combined frequently at least 10(-3)) should be excluded from calculations of mutational risk because they are unlikely to be maintained by mutation.

Abnormalities, Radiation-Induced↗
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↗