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PubMed1993

Transient terminal U wave inversion as a more specific marker for myocardial ischemia.

Transient U wave inversion can be caused either by regional myocardial ischemia or by an elevation of systemic blood pressure. The characteristics of U wave inversion during chest pain attacks in 21 patients with variant angina were compared with those observed in 38 patients with hypertension without apparent ischemic heart disease. Differentiation was possible according to the ECG phase in which U wave inversion appeared. U wave inversion was considered to be significant if there was a discrete negative deflection of more than 0.05 mV within the TP segment. U wave inversion proceeded to positive deflection of U wave in patients with hypertension without ischemic heart disease (initial U wave inversion). In contrast, inverted U wave occurred after positive U wave deflection during attacks in patients with variant angina (terminal U wave inversion). When cold pressor test was performed in patients with variant angina during treatment with calcium entry blockers, no patient had either anginal attacks or ischemic ST-segment deviation, but 9 of 21 patients (43%) had transient initial U wave inversion, which was followed by positive U wave deflection. U wave inversion can be classified as initial U wave inversion and terminal U wave inversion according to the phasic relationship to positive U wave deflection; the latter is observed in association with regional myocardial ischemia. The former seems to be related to elevated blood pressure rather than to myocardial ischemia.

Adult↗
PubMed1996

Agonist-induced modulation of inverse agonist efficacy at the beta 2-adrenergic receptor.

Sustained stimulation of several G protein-coupled receptors is known to lead to a reduction in the signaling efficacy. This phenomenon, named agonist-induced desensitization, has been best studied for the beta 2-adrenergic receptor (AR) and is characterized by a decreased efficacy of beta-adrenergic agonists to stimulate the adenylyl cyclase activity. Recently, several beta-adrenergic ligands were found to inhibit the spontaneous agonist-independent activity of the beta 2AR. These compounds, termed inverse agonists, have different inhibitory efficacies, ranging from almost neutral antagonists to full inverse agonists. The current study was undertaken to determine whether, as is the case for agonists, desensitization can affect the efficacies of inverse agonists. Agonist-promoted desensitization of the human beta 2AR expressed in Sf9 cells potentiated the inhibitory actions of the inverse agonists, with the extent of the potentiation being inversely proportional to their intrinsic activity. For example, desensitization increased the inhibitory action of the weak inverse agonist labetalol by 29%, whereas inhibition of the spontaneous activity by the strong inverse agonist timolol was not enhanced by the desensitizing stimuli. Interestingly, dichloroisoproterenol acted stochastically as either a weak partial agonist or a weak inverse agonist in control conditions but always behaved as an inverse agonist after desensitization. These data demonstrate that like for agonists, the efficacies of inverse agonists can be modulated by a desensitizing treatment. Also, the data show that the initial state of the receptor can determine whether a ligand behaves as a partial agonist or an inverse agonist.

Adenylyl Cyclases↗
PubMed1993

The fertility effects of pericentric inversions in Drosophila melanogaster.

Heterozygotes for pericentric inversions are expected to be semisterile because recombination in the inverted region produces aneuploid gametes. Newly arising pericentric inversions should therefore be quickly eliminated from populations by natural selection. The occasional polymorphism for such inversions and their fixation among closely related species have supported the idea that genetic drift in very small populations can overcome natural selection in the wild. We studied the effect of 7 second-chromosome and 30 third-chromosome pericentric inversions on the fertility of heterokaryotypic Drosophila melanogaster females. Surprisingly, fertility was not significantly reduced in many cases, even when the inversion was quite large. This lack of underdominance is almost certainly due to suppressed recombination in inversion heterozygotes, a phenomenon previously observed in Drosophila. In the large sample of third-chromosome inversions, the degree of underdominance depends far more on the position of breakpoints than on the inversion's length. Analysis of these positions shows that this chromosome has a pair of "sensitive sites" near cytological divisions 68 and 92: these sites appear to reduce recombination in a heterozygous inversion whose breakpoints are nearby. There may also be "sensitive sites" near divisions 31 and 49 on the second chromosome. Such sites may be important in initiating synapsis. Because many pericentric inversions do not reduce the fertility of heterozygotes, we conclude that the observed fixation or polymorphism of such rearrangements in nature does not imply genetic drift in very small populations.

Aneuploidy↗
PubMed2025

Genome-wide diversity of chromosomal inversions and their disease relationships.

Chromosomal inversions shape evolution and are implicated in human disease, yet their effects on genomic variation and health outcomes remain poorly understood. We analyze genome-wide human inversion polymorphisms, contrasting single-event and recurrent loci. Inversion recurrence is validated using structured-coalescent simulations. We show that single-event inversions evolve in near-complete isolation: inverted haplotypes show ~16-fold lower diversity and strong differentiation from direct haplotypes (median FST = 0.33). By contrast, recurrent inversions maintain gene flow, resulting in similar diversity across orientations and ~4-fold lower differentiation. We further find marked differences in coding sequence conservation between single-event and recurrent inversions. Using the NIH All of Us biobank, we impute inversions and identify four inversions with significant disease associations. Notably, the 17q21 inversion is associated with reduced risk of cognitive decline (OR=0.919) and breast cancer (OR=0.910) but with increased obesity risk (OR=1.097), consistent with pleiotropic selection. These findings establish inversions as major drivers of human genetic diversity and disease, with evolutionary outcomes critically dependent on recurrence.

Evolution↗
PubMed1995

Factor VIII gene inversions in severe hemophilia A: results of an international consortium study.

Twenty-two molecular diagnostic laboratories from 14 countries participated in a consortium study to estimate the impact of Factor VIII gene inversions in severe hemophilia A. A total of 2,093 patients with severe hemophilia A were studied; of those, 740 (35%) had a type 1 (distal) factor VIII inversion, and 140 (7%) showed a type 2 (proximal) inversion. In 25 cases, the molecular analysis showed additional abnormal or polymorphic patterns. Ninety-eight percent of 532 mothers of patients with inversions were carriers of the abnormal factor VIII gene; when only mothers of nonfamilial cases were studied, 9 de novo inversions in maternal germ cells were observed among 225 cases (approximately 1 de novo maternal origin of the inversion in 25 mothers of sporadic cases). When the maternal grandparental origin was examined, the inversions occurred de novo in male germ cells in 69 cases and female germ cells in 1 case. The presence of factor VIII inversions is not a major predisposing factor for the development of factor VIII inhibitors; however, slightly more patients with severe hemophilia A and factor VIII inversions develop inhibitors (130 of 642 [20%]) than patients with severe hemophilia A without inversions (131 of 821 [16%]).

Blotting, Southern↗
PubMed1983

Genetic methods for analysis and manipulation of inversion mutations in bacteria.

A number of genetic methods for the isolation, characterization and manipulation of large chromosomal inversions in Salmonella typhimurium are described. One inversion-carrying mutant is characterized in detail and used to demonstrate a number of unique genetic properties of bacterial inversions. --Contrary to expectation, it was found that large inversion mutations can be repaired by generalized transduction. The repair results from the simultaneous introduction of two wild-type transduced fragments into a single recipient cell. Homologous recombination between the two transduced fragments and the two inversion breakpoints causes the inverted segment to be reinverted. This results in regeneration of the wild-type orientation of this chromosome segment. Similar recombination events allow a large inversion mutation to be introduced into a wild-type strain; two transduced fragments from an inversion strain cause recombination events resulting in inversion of a large chromosome segment. --Genetic methods for mapping the extent of a large inversion mutation by generalized transduction are described and tested. The methods are operationally simple and allow good resolution of the two inversion breakpoints.

Chromosome Mapping↗
PubMed1988

Effects of two gravity inversion methods on heart rate, systolic brachial pressure, and ophthalmic artery pressure.

The purpose of this study was to investigate the effects of two static gravity inversion methods with either ankle or thigh suspension on heart rate (HR), systolic brachial pressure (SBP), and ophthalmic artery pressure (OAP). Twenty healthy subjects were assigned randomly to one of two treatment groups of 10 subjects each. Each group completed a 25-minute protocol with two 5-minute inversion periods. The research attempted to control for treatment anxiety and for the effects of ocular plethysmography (the procedure used to measure OAP). A 2 X 2 multivariate analysis of variance for repeated measures was used to analyze the differences of cardiovascular change between the two inversion methods. The hypothesis that the subjects' HRs, SBPs, and OAPs would not differ between ankle and thigh suspension methods for five minutes of inversion was not rejected. Leg position did not affect the HR or arterial responses during full static inversion. Gravity inversion produced no significant changes in HR and SBP between 2.5 and 5 minutes of inversion. Arterial pressures measured at 5 minutes of static inversion did not differ from arterial pressures measured between 2.5 and 5 minutes, but because of increases in OAP during inversion, ocular safeguards are recommended for subjects during inversion.

Adult↗
PubMed1988

The inverse problem in electrocardiography: solutions in terms of epicardial potentials.

The objective of the inverse problem in electrocardiography is to recover noninvasively regional information about intracardiac electrical events from electrical measurements on the body surface. The choice of epicardial potentials as the solution to the inverse problem is motivated by the availability of a unique epicardial potential solution for each body surface potential distribution, by the ability to verify experimentally the inverse-recovered epicardial potentials, by the proven relationship between epicardial potentials and the details of intracardiac regional events, and by the possibility of using the inverse solution as a supplement or possible replacement to clinical epicardial potential mapping prior to surgical intervention. Although, in principle, the epicardial potential distribution can be recovered from the body surface potential distribution, the inverse problem in terms of potentials is ill-posed, and naive attempts to reconstruct the epicardial potentials result in incorrect solutions which are highly oscillatory. Large deviations from the actual solution may result from inaccuracy of the data measurement, incomplete knowledge of the potential data over the entire torso, and inaccurate description of the inhomogeneous torso volume conductor. This review begins with a mathematical and qualitative description of the inverse problem in terms of epicardial potentials. The ill-posed nature of the problem is demonstrated using a theoretical boundary value problem. Effects of inaccuracies in the body surface potential data (stability estimates) are introduced, and a sensitivity analysis of geometrical and inhomogeneity parameters is presented using an analytical eccentric spheres model. Various computational methods for relating epicardial to body surface potentials, i.e., the computation of the forward transfer matrix, are described and compared. The need for regularization of the inverse recovery of epicardial potentials, resulting from the need to invert the ill-conditioned transfer matrix, is demonstrated. Several regularization techniques are compared in terms of their performance regarding noise in the data and inaccuracies in geometry and inhomogeneities. Finally, several existing, regularized inverse procedures that compute epicardial potentials from measured body surface potential data are introduced and compared. The review concludes with a section that points toward future directions for improving the quality of the inverse-reconstructed epicardial potentials. Future directions for the use of the inverse problem to obtain epicardial potential distributions noninvasively in both experimental animals and patients in a clinical se

Animals↗
PubMed1987

Pericentric inversions in man: personal experience and review of the literature.

The Leuven cytogenetic centre experience on pericentric inversion in man is discussed with exclusion of the pericentric inversions of the heterochromatic blocks of chromosomes 1 and 9. In a total of 51,500 patients, referred for constitutional chromosome analysis during the period 1970-1985, pericentric inversions were found in 24 index patients. The breakpoints detected in these different pericentric inversions are summarized and compared to those found in previous reports. Bands 2p13, 2q21, 5q31, 6q21, 10q22, and 12q13 were shown to be repeatedly involved in the different studies and, furthermore, breakpoints at bands 2q11, 5p13, 5p15, 5q13, 7q11, 11q25, and 14p11 were present in this study as well as in our previous review on reciprocal autosomal translocations. In 13 familial pericentric inversions, even after exclusion of all inversion carrier probands, a 1.6:1 excess of pericentric inversion carriers versus karyotypically normal progeny was observed. While chromosomally unbalanced offspring represent 3.5% of all chromosomally investigated liveborns of the present study, 7.1% of all liveborn inversion carrier offspring presented with a mental retardation and/or multiple congenital anomalies (MR/MCA) problem. Additional chromosomal abnormalities, i.e. a 21 trisomy and an accessory small ring chromosome were observed in two pericentric inversion carriers. These data and results are discussed and compared to the data available in the literature.

Chromosome Banding↗
PubMed1976

Geographical variability in the pericentric inversion system of the grasshopper Trimerotropis pseudofasciata.

Island and mainland populations of Trimerotropis pseudofasciata from California were compared with respect to the nature and extent of their percentric inversion systems. Island populations generally have more chromosomes polymorphic for centromere position than mainland populations and a considerably higher percentage of the genome in these island populations is in a structurally heterozygous state. Thus, although geographically peripheral, the islands provide habitats capable of supporting denser and more chromosomally polymorphic populations than the mainland. Chiasmata are generally localized to terminal positions in all classes of chromosomes and do not occur in the inverted regions of inversion heterozygotes. Chiasma frequency is highest in inversion homozygotes. It is hypothesized that the inversion system in T. pseudofasciata serves the dual synergistic function of preserving allelic sequences in the inversion region intact through inversion heterozygosity and limiting the generation of variability in regions outside the inversion by increasing terminal chiasmata. Additionally, it is argued that it is the gene sequence on only the inversion chromosome that is important in Trimerotropis. This condition contrasts with the "co-adapted" pattern seen in Drosophila where the gene sequences on both chromosomes in the inversion heterozygote are simultaneously important.

Animals↗
PubMed1991

Limits of the distal inversion in the t complex of the house mouse: evidence from linkage disequilibria.

The suppression of crossing-over and the consequent linkage disequilibrium of genetic markers within the t complex of the house mouse is caused by two large and two short inversions. The inversions encompass a region that is some 15 centiMorgans (cM) long in the homologous wild-type chromosome. The limits of the proximal inversions are reasonably well-defined, those of the distal inversions much less so. We have recently obtained seven new DNA markers (D17Tu) which in wild-type chromosomes map into the region presumably involved in the distal inversions of the t chromosomes. To find out whether the corresponding loci do indeed reside within the inversions, we have determined their variability among 26 complete and 12 partial t haplotypes. In addition, we also tested the same collection of t haplotypes for their variability at five D17Leh, Hba-ps4, Pim-1, and Crya-1 loci. The results suggest that the distal end of the most distal inversion lies between the loci D17Leh467 and D17Tu26. The proximal end of the large distal inversion was mapped to the region between the D17Tu43 and Hba-ps4 loci, but this assignment is rather ambiguous. The loci Pim-1, Crya-1, and the H-2 complex, which have been mapped between the Hba-ps4 and Grr within the large distal inversion, behave as if they recombine from time to time with their wild-type homologs.

Animals↗
PubMed1980

Variation in activities of amylase allozymes associated with chromosome inversions in Drosophila pseudoobscura, D. persimilis and D. miranda.

Different electrophoretic alleles of amylase show associations with particular chromosome 3 inversions in D. pseudoobscura and D. persimilis. Relative adult amylase activities were compared in 37, 37 and 10 strains of D. pseudoobscura, D. persimilis and D. miranda, respectively. Strains carrying the same electrophoretic allele were compared by crossing these lines individually to a reference strain carrying a different electrophoretic mobility allele. This procedure allows comparisons among species, inversions, electromorphs and strains for genetic variation in amylase activity. F2 analysis established that the activity variation co-segregates with the structural amylase locus. This type of variation could be due to either structural gene differences or differences in closely linked, cis-acting regulatory regions. Variation has been detected among and within electrophoretic mobility classes. Moreover, this variation is clearly nonrandom and reveals more of the genetic structure associated with the chromosomal inversion phylogeny of D. pseudoobscura and D. persimilis. ----Some of the findings are: (1) Similar electromorphs in D. pseudoobscura and D. persimilis usually show different activities. These species show nearly complete differentiation of amylase alleles, based on activities. (2) D. persimilis has the broadest range of variation in amylase activity, about four-fold between the highest and lowest alleles. D. pseudoobscura and D. miranda are also polymorphic for activity, but have more constrained ranges of variation. D. miranda alleles show on the average about four times the activity of D. pseudoobscura alleles. (3) Some association of electrophoretic mobility and activity has been found. Alleles 1.09 of D. persimilis, as well as 1.43 and 1.55 of D. miranda, have relatively high activity. It may be that these high activity alleles are part of an adaptation to cooler habitats. (4) Within electrophoretic classes, associations of activities with inversions have been found. These are especially strong in D. persimilis. The 1.00 alleles in the ST, KL, MD and WT inversions, the 0.92 allele in the ST and MD inversions and the 1.09 allele in the WT and KL inversions have levels of activities that depend upon the arrangement in which they are located. These results demonstrate that suppression of recombination in inversion heterokaryotypes can result in extensive genic divergence between inversions.

Amylases↗
PubMed2025

Cosmopolitan inversions have a major impact on trait variation and the power of different GWAS approaches to identify associations.

The ability of genomic inversions to reduce recombination and generate linkage can have a major impact on genetically based phenotypic variation in populations. However, the increase in linkage associated with inversions can create hurdles for identifying associations between loci within inversions and the traits they impact. As a consequence, the role of inversions in mediating genetic variation in complex traits remains to be fully understood. This study uses the fruit fly Drosophila melanogaster to investigate the impact of inversions on trait variation. We tested the effects of common inversions among a diverse assemblage of traits including aspects of behavior, morphology, and physiology, and identified that the cosmopolitan inversions In(2L)t and In(3R)Mo are associated with many traits. We compared the ability of different approaches of accounting for relatedness and inversion presence during genome-wide association to identify signals of association with SNPs. We report that commonly used association methods are underpowered within inverted regions, while alternative approaches such as leave-one-chromosome-out improve the ability to identify associations. In all, our research enhances our understanding of inversions as components of trait variation and provides insight into approaches for identifying genomic regions driving these associations.

Drosophila melanogaster↗
PubMed1994

[Variability of inversion polymorphism in populations of Drosophila lummei, Hackman].

Comparison of inversion polymorphism in Drosophila lummei populations from Finland (Kemi) and Russia (Rybnyi) revealed additional species-specific paracentric inversions in chromosomes 2-4. The newly found inversions, 2V, 3M, 4U, and V, were reported only for the Russian population. The 2U inversion had been earlier detected in D. lummei and in the second chromosome of a D. ezoana population from Kamchatka. Species-specific 5T inversion from the Finland population was not found in the Russian population. 4R, S, and 5S inversions were common for both populations but had different sample frequencies. 4R and 5S inversions were more frequent in the Finland, and 4S in the Russian population which may indicate their different adaptive values in these areas. All inversions except 3M were localized in subterminal chromosome regions. 3M inversion was localized in the submedian region.

Animals↗
PubMed1990

Physiological interpretations based on lumped element models fit to respiratory impedance data: use of forward-inverse modeling.

Respiratory impedance (Zrs) data at lower (less than 4 Hz) and higher (greater than 32 Hz) frequencies require more complicated inverse models than the standard series combination of a respiratory resistance, inertance, and compliance. In this paper, a forward-inverse modeling approach was used to provide insight on how the parameters in these more complicated inverse models reflect the true physiological system. Forward models are set up to incorporate explicit physiological and anatomical detail. Simulated forward data are then fit with identifiable inverse models and the parameter estimates related to the known detail in the forward model. It is shown that inverse fitting of low frequency data alone will not allow a distinction between frequency dependence due to airway inhomogeneities and frequency dependence due to tissue viscoelasticity. With higher frequency data, a forward model based on an asymmetric branching airways network was used to simulate Zrs from 0.1-128 Hz with increasing amounts of nonuniform peripheral airway obstruction. Here, inverse modeling is more amenable to sensibly separating estimates of airway and tissue properties. A key result, however, is that changes in the tissue parameters of an inverse model (which provides an excellent fit to Zrs data) will appropriately occur in response to inhomogeneous alterations in airway diameters only. The apparent altered tissue properties reflect the decreased communication of some tissue segments with the airway opening and not an explicit change at the tissue level. These phenomena present a substantial problem for the inverse modeler. Finally, inverse model fitting of low and high frequency Zrs data simultaneously with a single model is not helpful for extracting additional physiological detail. Instead, separate models should be applied to each frequency range.

Airway Obstruction↗
PubMed1984

Evidence for heterosynaptic pairing of the inverted segment in pericentric inversion heterozygotes of the deer mouse (Peromyscus maniculatus).

Silver-stained pachytene cells of male deer mice, Peromyscus maniculatus, which were heterozygous for a naturally occurring pericentric inversion of chromosome 6, were analyzed by light microscopy. The presence of the terminally positioned inversion, involving approximately 30% of the length of chromosome 6, was detected by G-banding. Within the inversion, C-band-positive heterochromatin was restricted to the centromeric region. Silver-staining of spermatocytes revealed the synaptonemal complexes (SCs) of the autosomal bivalents and the X-Y chromosome association. Pachytene cells were scored for the presence of inversion loops corresponding to the pericentric inversion of chromosome 6. Possible loop 6 configurations were detected in less than 1% of the cells examined, the vast majority of cells having regularly formed autosomal SCs similar to those reported for homomorphic chromosome pairs in other rodent species. It appears, therefore, that in these mice the inverted region of chromosome 6 was heterosynaptic throughout pachytene. Heterosynapsis is hypothesized as a mechanism which might obviate the production of duplication and deletion chromatids expected from crossing-over in pericentric inversion loops. The observation of heterosynaptic pairing in the inverted segment and the hypothesis of inversion heterosynapsis as a mechanism averting gametic loss are consistent with the widespread occurrence of pericentric inversion polymorphisms in P maniculatus and the apparent failure of pericentric inversions to genetically isolate populations of this species.

Animals↗
PubMed1996

Clinical correlates among 49 families with hemophilia A and factor VIII gene inversions.

Inversions between a gene A copy within intron 22 of the factor VIII gene and additional copies outside the factor VIII gene were found in 49 families with hemophilia A. Inversion patterns were that of recombination with a distal gene A copy in 34, a proximal copy in 14, and a third (variant) copy in one. Baseline factor VIII clotting levels were <1% of normal in 43 and 1% in 6. No inversion was detected in 61 other families whose affected members had < or = 1% activity levels nor in 42 families with moderately severe hemophilia A and 2-5% baseline levels. Both high titer and low level alloantibody inhibitors were found in patients with of without an inversion. Of 13 high titer inhibitors, 8 were persistent and 1 of these patients had an inversion. Of 5 that responded to daily factor VIII infusions, 4 were in patients with gene inversions. Of the 49 families with an inversion, the occurrence of hemophilia was isolated in 30 and the mother was a carrier in the 25 in which additional family members were informative. In three of these families with isolated occurrence, the maternal grandmother was a carrier whereas in three others a de novo mutation occurred in the maternal grandfather's factor VIII gene. Screening for gene inversions in patients with severe (or "borderline" severe) hemophilia A provides a direct marker of the mutation in 45% of families. It is useful even if there is no living affected member and in predicting the likely severity of an infant in which there are no reliable baseline clotting activities, including 70% of families with isolated occurrences of hemophilia A.

Blotting, Southern↗
PubMed1981

Human chromosome heteromorphisms in Americans Blacks: II. Higher incidence of pericentric inversions of secondary constriction regions (h).

Eighty normal American blacks were studied by the CBG technique (C-bands by barium hydroxide using Giemsa) for estimation of size and inversion heteromorphism of chromosomes 1, 9, and 16, and the data were compared to those of whites using subjectively defined criteria. Size and inversion heteromorphisms were classified into 5 levels. The frequencies of size hetromorphisms of chromosomes 1 and 16 were 10.63% and 6.88%, respectively, which are not significantly different from those of a normal population of whites. A higher incidence of size heteromorphisms for chromosome 9 was noted in whites (47.5% vs 30%). The frequencies of inversion heteromorphism of chromosomes 1, 9, and 16 were 17.5%, 21.9%, and 0.0%, respectively. Overall, 61 chromosomes were found to have an inversion. Of these, 28 were in chromosome 1, and 33 were in chromosome 9. A higher incidence of inversion heteromorphisms of chromosomes 1 and 9 was noted in American blacks, while no inversions were found in chromosome 16 in either population. A significant association of increased size of the h region with inversion (r = 0.99 P less than 0.01) is demonstrated, ie, enlarged h regions have a higher frequency of inversions.

Adult↗