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PubMed1978

Size and pericentric inversion heteromorphisms of secondary constriction regions (h) of chromosomes 1, 9, and 16 as detected by CBG technique in Caucasians: classification, frequencies, and incidence.

Eighty normal Caucasians were studied by CBG technique for estimation of size and inversion heteromorphisms of chromosomes 1, 9, and 16. Size heteromorphisms were classified into one of five sizes using 16p as a reference standard: very small, small, intermediate, large, and very large. Inversion heteromorphisms were also classified into 5 categories - eg, no inversion; partial inversion - minor; half inversion; partial inversion - major; and complete inversion. The frequencies of size heteromorphisms for chromosomes 1, 9, and 16 were 11.3%, 47.5%, and 7.5%, respectively. Thirty-four chromosomes were found to have inversions. Of these, 16 were in chromosome 1, and 18 were in chromosome 9. No inversions were found in chromosome 16. An increase in the size of the h region was more frequently associated with inversion, suggesting that there is a possible relationship between size and inversion. For example, there were 118 chromosomes that were classified as "intermediate" by size; 23 (19.5%) had inversions. In contrast, there were 225 that were "small" in size, and only 10 (4.4%) had inversions. There was no significant difference between males and females for size and position heteromorphisms.

Adult↗
PubMed1994

Construction of chromosomal rearrangements in Salmonella by transduction: inversions of non-permissive segments are not lethal.

Homologous sequences placed in inverse order at particular separated sites in the bacterial chromosome (termed "permissive") can recombine to form an inversion of the intervening chromosome segment. When the same repeated sequences flank other chromosome segments ("non-permissive"), recombination occurs but the expected inversion rearrangement is not found among the products. The failure to recover inversions of non-permissive chromosomal segments could be due to lethal effects of the final rearrangement. Alternatively, local chromosomal features might pose barriers to reciprocal exchanges between sequences at particular sites and could thereby prevent formation of inversions of the region between such sites. To distinguish between these two possibilities, we have constructed inversions of two non-permissive intervals by means of phage P22-mediated transduction crosses. These crosses generate inversions by simultaneous incorporation of two transduced fragments, each with a sequence that forms one join-point of the final inversion. We constructed inversions of the non-permissive intervals trp ('34) to his ('42) and his ('42) to cysA ('50). Strains with the constructed inversions are viable and grow normally. These results show that our previous failure to detect formation of these inversions by recombination between chromosomal sequences was not due to lethal effects of the final rearrangement. We infer that the "non-permissive" character of some chromosomal segments reflects the inability of the recombination system to perform the needed exchanges between inverse order sequences at particular sites. Apparently these mechanistic problems were circumvented by the transductional method used here to direct inversion formation.

Chromosome Inversion↗
PubMed2026

Lineage-associated small inversions disrupt dosT, dnaE2, and a promoter-adjacent region in some Mycobacterium tuberculosis isolates.

UNLABELLED: Large molecular inversions in the genome of Mycobacterium tuberculosis (Mtb) due to factors like the presence of insertion sequences and transposases are widely known. However, smaller inversions within coding sequences and non-coding control elements are rarely reported. The present study aims to identify inversions and their potential impact on Mtb biology in a lineage-specific manner. Structural variants (SVs) could only be detected by long reads. For this, we simulated long reads by de novo assembling the short-read sequencing data sets and subsequently aligned representative strains from each lineage using the Progressive Mauve algorithm. Independently, long-read sequencing from the Pacific Biosciences platform was acquired and analyzed using the structural variant identification method. Variants were merged, and Fisher's exact test was carried out to identify the inversion association with lineages. To visualize deoxyribonucleic acid (DNA) features, the DNA-features-viewer tool was used. Simulated reads from short-read sequencing gave indications of lineage (L)-specific inversions. The long-read sequencing approach led to the identification of seven unique inversions: two positively associated with L1, one positively associated with L3, two negatively associated with L4, and two positively associated with L3 but negatively associated with L4 (P < 0.05). The inversions encompassed primarily non-essential genes like sdaA, dosT, Rv2026c, dnaE2, Rv1341, Rv1342, and lprD. An interesting inversion was observed in the upstream control element of purB and Rv0776c. The study sheds light on small inversions that may be causing alterations in expression, formation of fusion genes, and nonsense mutations that may have a role in lineage-specific phenotypic changes. IMPORTANCE: The role of mutations like SNPs and INDELs and their association with drug resistance is well known in Mycobacterium tuberculosis (Mtb). However, structural variations, especially inversions, are largely overlooked and unreported. In this paper, publicly available whole-genome sequencing datasets from Illumina and Pacific Biosciences-Oxford Nanopore Technologies platform have been used to detect inversions and report seven unreported Mtb lineage-specific small inversions.

Mycobacterium tuberculosis↗
PubMed1987

Characterization of nutrition-induced helix hand inversion of Bacillus subtilis macrofibers.

The kinetics of Bacillus subtilis macrofiber helix hand inversion was examined. Inversion was induced by transfer of structures produced in one medium to another medium. When cultured at 20 degrees C in either medium, the doubling time was approximately 100 min. To establish a baseline, the macrofiber twist state produced in one medium was measured over the same time course during which other macrofibers underwent inversion after transfer to a second medium. The baseline was used to identify the time of inversion initiation: the point at which curves representing changes of twist as a function of time after transfer to the new medium intersected the baseline. Right- and left-handed macrofibers of different twists were produced by growth in mixtures of TB and S1 media. These were used to determine the influence of initial twist on the time course of inversion initiation. In the right to left inversion, a positive correlation was found between initial twist and the time of inversion initiation. The left to right inversion differed, however, in that a constant time was required for inversion initiation regardless of the starting left-handed twist. When a nutritional pulse was administered by transferring fibers from TB to S1 to TB medium, the time to initiation of inversion was found to decrease with incubation of increasing duration in S1 medium. A similar pulse protocol was used in conjunction with inhibitors to examine the protein and peptidoglycan synthesis requirements for the establishment of nutrition-induced memory that leads to initiation of inversion. Nutritionally induced right to left inversion but not left to right inversion required protein synthesis. The addition of trypsin to left-handed macrofibers apparently required, as described previously for the temperature-regulated twist system (D. Favre, D. Karamata, and N. H. Mendelson, J. Bacteriol. 164:1141-1145, 1985), for the production of left-handed twist states in the nutrition system.

Bacillus subtilis↗
PubMed1983

Anatomic and prognostic significance of new T-wave inversion in unstable angina.

The significance of the development of new T-wave inversion was studied in 118 consecutive patients with unstable angina. The electrocardiograms during hospitalization in the coronary care unit were analyzed for occurrence of new T-wave inversion greater than or equal to 2 mm and correlated with findings at coronary angiography (73 patients) and at follow-up (112 patients). Twenty-nine patients had anterior T-wave inversion. Of these, 25 patients (86%) had greater than or equal to 70% diameter reduction of the left anterior descending (LAD) artery, compared with 11 (26%) of 42 patients without anterior T-wave inversion (p less than 0.001). The sensitivity of T-wave inversion for significant LAD stenosis was 69%, specificity 89%, and positive predictive value 86%. Two patients had T-wave inversion in the inferior leads. Both patients had significant right coronary artery disease, compared with 18 of 55 patients without inferior T-wave inversion (difference not significant [p = NS]. Seventy-one patients who were treated medically had 16 +/- 9 months' follow-up. Of 26 patients who had T-wave inversion, 10 (38%) had cardiac events, compared with 7 (16%) of the remaining 45 patients without T-wave inversion (p less than 0.05). Forty-one patients who had undergone coronary bypass surgery had 19 +/- 9 months' follow-up. Of 22 patients with T-wave inversion, 4 (18%) had cardiac events, compared with 2 (11%) of the remaining 19 patients without T-wave inversion (p = NS). Thus, development of new T-wave inversion greater than or equal to 2 mm in patients with unstable angina (1) is predictive of significant coronary artery stenosis, and (2) identifies a subgroup with poor prognosis when treated medically.

Angina Pectoris↗
PubMed1981

Peri- and paracentric inversions in chromosome 12: prenatal diagnosis and family study.

Three different types of chromosome 12 inversion were seen in 15 individuals out of 44 individuals examined in one 8 generation family. Type 1: a pericentric inversion inv(12) (p112; q131) was found in 7 individuals and twice at prenatal diagnosis. Type 2: a paracentric inversion inv(12) (p123; p131) was seen in two individuals. Two individuals carried both inversion chromosomes, namely type 1 and type 2. The two inversion chromosomes were transmitted from each of the parents. Type 3: a double pericentric and paracentric inversion (type 3) inv(12) (p123; p131) (p112; q131) was observed in the daughter of one of the carriers of type 1 and 2 inversions and again at prenatal diagnosis in her son. The double inversion most likely arose through crossing-over in between the two inversion loops. A balanced translocation t(7; 13) and the inversion type 1 was observed in one individual, who transmitted the translocation only to an offspring. The frequency of inversions in amniotic fluid cells observed in our laboratory was 1.9 per cent. The clinical implications of these findings are discussed.

Adult↗
PubMed1995

Distribution of genetic diversity in relation to chromosomal inversions in the malaria mosquito Anopheles gambiae.

The epidemiology of malaria in Africa is complicated by the fact that its principal vector, the mosquito Anopheles gambiae, constitutes a complex of six sibling species. Each species is characterized by a unique array of paracentric inversions, as deduced by karyotypic analysis. In addition, most of the species carry a number of polymorphic inversions. In order to develop an understanding of the evolutionary histories of different parts of the genome, we compared the genetic variation of areas inside and outside inversions in two distinct inversion karyotypes of A. gambiae. Thirty-five cDNA clones were mapped on the five arms of the A. gambiae chromosomes with divisional probes. Sixteen of these clones, localized both inside and outside inversions of chromosome 2, were used as probes in order to determine the nucleotide diversity of different parts of the genome in the two inversion karyotypes. We observed that the sequence diversity inside the inversion is more than three-fold lower than in areas outside the inversion and that the degree of divergence increases gradually at loci at increasing distance from the inversion. To interpret the data we present a selectionist and a stochastic model, both of which point to a relatively recent origin of the studied inversion and may suggest differences between the evolutionary history of inversions in Anopheles and Drosophila species.

Animals↗
PubMed1988

Familial pericentric and paracentric inversions of chromosome 1.

We investigated 33 individuals (21 carriers) from one family with a pericentric inversion involving a large part of chromosome 1 (1p36.1----1q32). In addition, we investigated 15 individuals (10 carriers) from another family with a paracentric inversion of a small part of chromosome 1 (1p32----1p36.1). In each family, the index patient was ascertained because three miscarriages had occurred. Each carrier of these inversions was phenotypically normal. If the miscarriages of the index patients are excluded, the frequency of recognized miscarriages among the carriers of childbearing age was 9% (4 of 46) for the family with pericentric inversion and 17% (4 of 23) for the family with paracentric inversion. One of the pericentric inv(1) carriers had had a stillborn daughter. The carriers of the pericentric inversion who were of childbearing age had 41 children; carriers of the paracentric inversion who were of childbearing age had 19 children. No live-born children with birth defects were observed in either family. This evidence, together with the low frequency of miscarriages, suggests that crossover within the inversion loop occurs much less frequently than might be expected from the large size of this inversion. Our investigation suggests that the risk of recognized miscarriages, stilbirths, and live-born children with recombinant chromosomes who have birth defects may be much lower for inv(1) carriers than previously reported. The risk of having a malformed child because of a recombinant chromosome is probably less than 3% for carriers of the pericentric inversion and less than 6% for the carriers of the paracentric inversion.

Chromosome Banding↗
PubMed1989

Evolution of mouse chromosome 17 and the origin of inversions associated with t haplotypes.

Mouse t haplotypes are variant forms of chromosome 17 that exist at high frequencies in worldwide populations of several species of house mouse. They are known to differ from wild-type chromosomes with respect to two relative inversions referred to as proximal and distal. An untested assumption has been that these two inversions originated in the chromosomal lineage leading to present-day t haplotypes. To investigate the evolutionary origins of these inversions and the possibility of additional inversions, interspecific crosses were performed between Mus spretus or Mus abbotti and laboratory strains of Mus domesticus that carried wild-type and t haplotypes forms of chromosome 17. The results provide evidence for the existence of two additional nonoverlapping inversions--one between the proximal and distal inversions and one between the centromere and the proximal inversion. These four inversions span nearly the entire region of t haplotype recombination suppression. Considering the distribution of these inversions among the species studied as well as the organization of the D17Leh66 family of DNA elements, we infer that the proximal inversion occurred on the lineage leading to the common ancestor of M. domesticus and M. abbotti, and that the other three inversions occurred on the separate lineage leading to present-day t haplotypes. Alternative models for the evolution of t haplotypes are discussed in light of these findings.

Animals↗
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↗
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↗