Biomedical subjects
N A Johnson
Publications and source records attributed to N A Johnson.
Evolutionary biology. Endless forms, several powers.
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Conditions for soft selection favoring the evolution of hybrid inviability.
Hybrid inviability per se is not generally considered adaptive; it is believed to evolve as a pleiotropic consequence of other genetic changes, either adaptive or neutral, between diverging populations. However, given the pre-existence of hybrid sterility, there are circumstances under which hybrid inviability may be directly selected. In this report, we model the evolution of hybrid inviability in the context of within-family density-dependent selection (soft selection). This paper shows that under certain conditions, an allele causing hybrid inviability can increase when rare, despite also decreasing viability in conspecifics. These conditions depend upon the strength of density effects within families and upon the frequency of matings with heterospecifics. It is found that, under the most favorable conditions (strong soft selection and frequent hybridization), the inviability allele can invade when its deleterious effect on the hybrid viability exceeds four times its deleterious effects on conspecific heterozygotes. The conditions for fixation of the allele are also investigated and the circumstances under which this process might operate in natural populations are discussed. The conclusion is that the most restrictive condition is that for this process to evolve, there must be little opportunity for postzygotic reproductive isolation to evolve.
Beta 2-microglobulin with an endoplasmic reticulum retention signal increases the surface expression of folded class I major histocompatibility complex molecules.
With beta 2-microglobulin- (beta 2m-) cell lines such as R1E/Db, the surface expression of class I major histocompatibility complex molecules is greatly impaired, and class I molecules that are on the surface are generally misfolded. To determine whether beta 2m must be continually present with the class I heavy chain for the class I molecule to reach the surface in a folded conformation, a sequence encoding an endoplasmic reticulum (ER) retention signal (KDEL) was attached onto the 3' end of a beta 2m cDNA. After this chimeric cDNA was transfected into R1E/Db cells, beta 2m-KDEL protein was detectable by an anti-beta 2m serum within the cells but not at the cell surface. Interestingly, R1E/Db cells transfected with beta 2m-KDEL were found to express a high level of conformationally correct Db molecules at the cell surface. This observation implies that beta 2m has a critical and temporal role in the de novo folding of the class I heavy chain. We propose that the critical time for beta 2m association is when the class I molecule is docked with the transporter associated with antigen processing (TAP) and first interacts with peptide.
Leisure-time physical activity and other health behaviours: are they related?
Data on the associations between leisure-time physical activity and other health behaviours are conflicting. The National Heart Foundation 1989 Risk Factor Prevalence Survey data were analysed to examine the associations between leisure-time physical activity and other life-style health behaviours in a national representative sample with adjustment for potential confounders. Multivariate stepwise logistic regression analysis using data from 9054 respondents aged 20 to 69 years showed that participation in leisure-time physical activity, even when it was not vigorous, was weakly associated with not smoking, following a special diet and moderate consumption of alcohol; it was inversely associated with obesity. These weak associations could influence health practices at a population level if, as has been hypothesised, the adoption of leisure activity promotes the adoption of other good health practices. Confirmation of earlier findings of cross-sectional associations between activity and other positive health practices justifies future prospective or experimental studies to determine the behavioural response to adoption of leisure-time physical activity.
Wildervanck's syndrome presenting as hemiparesthesia.
A 41-year-old male presented with recent-onset left hemiparesthesia, described as a "tingling numbness" of the upper extremity, torso, and face. History revealed a lifelong horizontal diplopia, neck stiffness, and left-sided hearing loss for 5 months. Examination revealed an ocular exam consistent with Duane's retraction syndrome, clinical and radiographic evidence of congenital fusion of C2 and C3 demonstrative of the Klippel-Feil anomaly, and a sensorineural hearing loss confirmed by audiometry. The diagnosis of Wildervanck's syndrome was made based on this classic triad of findings. A thorough evaluation has not yielded an objective explanation for the episodic hemiparesthesia. We present a patient exhibiting the classic triad of Wildervanck's syndrome, whose presentation is unique because hemiparesthesia has not previously been reported in association with this rare syndrome.
Concern about use of narcotics for pain in sickle cell anemia.
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Postcopulatory, prezygotic isolation: intraspecific and interspecific sperm precedence in Tribolium spp., flour beetles.
We investigated intraspecific and interspecific patterns of paternity in Tribolium castaneum, the flour beetle, by mating females either to pairs of conspecific males or to one conspecific and one heterospecific male of the closely related species, T. freemani. Females of both species store sperm in the spermatheca after copulation and postcopulatory, prezygotic reproductive isolation has been reported between this pair of species. When conspecific males of contrasting genotype are mated simultaneously to T. castaneum females, we observed extremely high levels of variation among females in the pattern of sperm precedence as shown by the offspring genotypes. In contrast, T. castaneum females mated simultaneously to a conspecific and a heterospecific male produced over 99 per cent conspecific progeny. When conspecific males were mated sequentially to T. castaneum females, within 3-7 days, all offspring were sired by the second male. In contrast, when a conspecific male was replaced with a T. freemani male, most females continued to produce only first-male, conspecific offspring for the next 10 days. When a heterospecific male was replaced with a conspecific male, T. castaneum females changed from producing hybrid to conspecific offspring within 3 days. We discuss the evolutionary implications of these findings.
Reproductive isolation between two species of flour beetles, Tribolium castaneum and T. freemani: variation within and among geographical populations of T. castaneum.
Tribolium castaneum and T. freemani produce sterile hybrid progeny in reciprocal crosses. The reciprocal crosses differ significantly in the mean numbers of progeny, progeny sex ratios, hybrid male body size and male antennal and leg morphologies. These results suggest an effect of either the X chromosome or the cytoplasm on characteristics of F1 hybrids. In contrast, large X chromosome effects on morphological traits are not usually observed in interspecific crosses among drosophilid flies. We also report large, significant differences in progeny numbers, body mass and degree of female bias in sex ratio between different geographic strains of T. castaneum when mated in reciprocal crosses with T. freemani. Sex ratio bias also varies significantly among matings within geographic strains of T. castaneum. When T. castaneum males are mated with T. freemani females, but not in the reciprocal cross, the F1 sex ratio is female biased, uncorrelated with family size and ranges from 57.14 per cent to 72.23 per cent female, depending on the geographic strain of the T. castaneum male.
Postcopulatory, prezygotic isolation in flour beetles.
We report the existence of postmating but prezygotic reproductive isolation within flour beetles of the genus Tribolium. Specifically, when a female of either T. castaneum or T. freemani is paired simultaneously with both a conspecific and a heterospecific male, virtually all of the offspring are sired by the conspecific male. In contrast, when a female of either species is paired only with a heterospecific male, she produces near normal numbers of offspring. Mate choice experiments rule out the possibility that premating reproductive isolation accounts for this phenomenon. A number of different mechanisms could explain this phenomenon of postmating but prezygotic reproductive isolation.
Genetics of reproductive isolation in the Drosophila simulans clade: complex epistasis underlying hybrid male sterility.
We have analyzed the sterility associated with introgressions of the distal one-fourth of the X chromosome from either Drosophila mauritiana or Drosophila sechellia into the genome of Drosophila simulans using a series of visible and DNA markers. Because in Drosophila hybrids, male sterility is usually complete and is often tightly linked with each of several markers used in crosses, a simple genetic basis has generally been assumed. In our low resolution mapping experiment, we were not able to reject the null hypothesis that a single gene, introgressed from either D. mauritiana or D. sechellia, is the cause of male sterility. High resolution mapping, however, reveals a much more complex picture. At least three distinct factors from D. mauritiana, or two from D. sechellia, were identified that need to be jointly present to confer full sterility. Each individual factor by itself is relatively ineffective in causing sterility, or even a partial spermatogenic defect. Moreover, there appear to be more sterility factors on comparable introgressions from D. mauritiana than from D. sechellia. On the basis of these observations, we propose a model which suggests that multilocus weak allele interactions are a very common cause of reproductive incompatibility between closely related species. We also present theoretical argument and empirical evidence against extrapolating the results of within-species analysis to interpret the genetic basis of species differences. The implications of this model on the theories of evolution of species differences and the attempt to understand the mechanisms of hybrid sterility/inviability at the molecular level are discussed.
Analysis of autosomal polygenic variation for the expression of Haldane's rule in flour beetles.
Haldane's rule states that, in interspecific crosses, when hybrid viability or fertility is diminished more in one sex of the hybrids than in the other, the heterogametic sex is more adversely affected. We used quantitative genetic methods to investigate the genetic basis of variation for the expression of the viability aspect of Haldane's rule when Tribolium castaneum males are crossed to Tribolium freemani females. Using a half-sib design, we found significant genetic variance for the expression of Haldane's rule, i.e., variation among T. castaneum sires in the hybrid sex ratios produced by their sons. We also derived 23 independent lineages from the same base population by 8 generations of brother-sister mating. From the same experiments, we also found heritable variation among surviving hybrid males in the incidence of antennal deformities. Upon inbreeding, the variance of both traits (hybrid sex ratio and proportion deformities) increased substantially but the means changed little. Because fitness within T. castaneum lineages declined substantially with inbreeding, we infer that hybrid male viability may have a different genetic basis than viability fitness within species. Deleterious recessive alleles held within species by mutation/selection balance appear not to be a major contributor to hybrid incompatibility.
Treatment of acute vascular rejection with immunoadsorption.
BACKGROUND: Acute vascular rejection (AVR) is characterized by vascular injury and systolic graft dysfunction and is often associated with elevated panel reactive antibodies (PRAs) to HLA antigens. Plasmapheresis has been shown to improve the otherwise poor prognosis of AVR, but its use is often complicated and limited by hypotension. METHODS AND RESULTS: In three cardiac transplant recipients with severe hemodynamic compromise during AVR, refractory to standard therapy, extracorporeal immunoadsorption was performed using a protein A column. Plasma was removed at 10 to 20 cm3/min, passed through the column, and reinfused. All three patients had negative pretransplant PRAs. PRA rose before or during AVR and became negative in all three patients following immunoadsorption. Time course and number of treatments required to decrease PRA to < 5% varied. Concomitant with a decrease in PRA, histological findings and ventricular function improved and normalized. Ejection fraction rose from 23 +/- 2 to 56 +/- 8% and shortening fraction from 14 +/- 7 to 36 +/- 7%, P < .05 (both). One patient died from infection 2 months after resolution of AVR; the other two patients are alive 25 and 31 months after AVR with normal left ventricular function and coronary arteries. In both, since initial immunoadsorption course, PRA has remained negative and no rejection has occurred. In two patients, a circulating donor-specific or donor-related anti-HLA class I antibody was identified and removed by protein A column. CONCLUSIONS: Our preliminary data suggest that (1) immunoadsorption is effective in removing circulating immunoglobulins and is well tolerated; (2) AVR is preceded by or associated with circulating antibodies against HLA class I antigens; (3) their removal is temporarily associated with recovery of graft function and normalization of biopsy; and (4) anti-HLA class I antibodies can mediate vascular injury if they appear in the post-transplant period.
Management of advanced juvenile granulosa cell tumor of the ovary.
Juvenile granulosa cell tumor of the ovary occurs most frequently in young women and children. Ten percent of cases present during pregnancy. The majority of tumors are in FIGO Stage I and have a favorable prognosis. The prognosis of higher stage tumors, however, is generally less favorable. We report the long-term, disease-free survival of a patient with FIGO Stage III juvenile granulosa cell tumor of the ovary. We believe this to be the first report of a successful pregnancy following "MAC" chemotherapy for this particular malignancy.
Genetics of reproductive isolation in the Drosophila simulans clade: DNA marker-assisted mapping and characterization of a hybrid-male sterility gene, Odysseus (Ods).
In this study, we address the question of whether there exist major genes that cause complete male sterility in the interspecific hybrids of Drosophila and, if they do, how these genes may be characterized at the molecular level. Our approach is to introgress small segments of the X chromosome from Drosophila mauritiana (or Drosophila sechellia) into Drosophila simulans by repeated backcrosses for more than 20 generations. The introgressions are monitored by both visible mutations and a series of DNA markers. We compare the extent of introgressions that cause male sterility with those that do not. If a major sterility factor exists, there should be a sharp boundary between these two classes of introgressions and their breakpoints should demarcate such a gene. Furthermore, if male sterility is the only major fitness effect associated with the introgression, recombination analysis should yield a pattern predicted by the classical three-point cross. Both the genetic and molecular analyses suggest the presence of a major sterility factor from D. mauritiana, which we named Odysseus (Ods), in the cytological interval of 16D. We thus formalize three criteria for inferring the existence of a major gene within an introgression: (1) complete penetrance of sterility, (2) complementarity in recombination analysis, and (3) physical demarcation. Introgressions of Ods from D. sechellia do not cause sterility. Twenty-two introgressions in our collection have breakpoints in this interval of about 500 kb, making it possible to delineate Ods more precisely for molecular identification. The recombination analysis also reveals the complexity of the introgressed segments--even relatively short ones may contain a second male sterility factor and partial viability genes and may also interfere with crossovers. The spermatogenic defects associated with Ods and/or a second factor were characterized by phase-contrast microscopy.
The effects of interspecific Y chromosome replacements on hybrid sterility within the Drosophila simulans clade.
We attempted to introgress Y chromosomes between three sibling species of Drosophila: D. simulans, D. sechellia and D. mauritiana. Four D. sechellia Y chromosomes were introgressed into D. simulans without loss of fertility whereas the four reciprocal introgressions (D. simulans Y introgressed into D sechellia) all result in sterility. Both reciprocal Y introgressions of D. simulans and D. mauritiana (four of each) also result in sterility. Compared with D. simulans males, the males with the D. sechellia Y chromosome in D. simulans background had lower productivity but only after multiple matings with virgin females. These males also were inferior compared with pure species males in sperm displacement and/or remating ability. The two different Y genotype males, however, were comparable in viability, longevity and mating success in female choice tests. We also use our results to estimate the effective number of autosomal loci interacting with X-linked genes to produce hybrid male sterility.
A test of reciprocal X-Y interactions as a cause of hybrid sterility in Drosophila.
Elucidation of the nature of the gene interactions that underly the sterility of interspecific hybrids is important in evolutionary biology. The interactions between the heterospecific X and Y (or Z and W) chromosomes are often used as an explanation for two reasons. First, the fertility of the hybrids of the heterogametic sex is much more often affected than that of the homogametic sex (Haldane's rule) and X-Y interactions are specific to the heterogametic sex. Second, sex chromosomes, especially the X chromosome, are often considered to be of special importance in determining the fertility of hybrids. X-Y interactions have been addressed in studies of males with a heterospecific Y chromosome in a mixed genetic background. A more stringent test of the X-Y interaction model requires each X chromosome sterility factor to be tested separately for its interaction with the Y chromosome in a homogeneous background of the pure species. Here we report such a test of the X-Y interaction model and conclude that X-Y interactions should not be assumed to be the only or even the most common cause of hybrid sterility.
T cell receptor rearrangements in various S49 lymphoma sublines.
The S49 cell lines are a unique series of tumor sublines isolated from a single BALB/c thymoma. Several different sublines were previously isolated from non-mutagenized cells using pharmacologic agents that would select for different stages of thymic development. In this report we show that all seven of the sublines studied express TL class I Ag confirming their derivation from immature thymocytes. This uniform TL expression is in contrast to the previously characterized locus-specific shut off of Kd,Dd, and/or LdAg by various S49 sublines. Furthermore, S49 sublines were found to display disparate CD4/CD8 expression. Whereas the unselected subline is a CD4+/CD8+ double positive, each of the selected sublines is singly positive for either CD4 or CD8. All seven sublines were found to be CD3+ and express alpha beta TCR heterodimers. To establish whether the S49 sublines have a monoclonal or polyclonal origin, their TCR rearrangements were compared. Based on the detection of identical but unusual TCR gamma rearrangements and similarity of the alpha and beta rearrangements, we propose that the S49 sublines probably had a monoclonal origin. However, significant differences between the TCR alpha and beta gene rearrangement were observed, suggesting that these sublines have undergone further differentiation at TCR loci in addition to CD4/CD8 and MHC loci. Evidence is presented that much of this phenotypic diversity preceded their in vitro selection.