Pericentric inversions

Summary A review is given of the incidence, cytogenetics, and biologic relevance of pericentric inversions (pii). In 251 cases in the literature and our patients, 96 different inversion forms with different breakpoints are found. Eighteen of these cases have been observed several times in unrelated families; they are classified as types. The problem of pii in the heterochromatic regions of chromosomes 1 and 9 is especially emphasized and the investigations required are pointed out.The significance of the individual pii is checked with regard to their behavior in meiosis and their phenotypical relevance. An approximately 1:1 segregation is found. Fertility, stillbirth, and rates of abortion are not statistically altered. The gonadal findings available at present in man are reported and commented on. The occurrence of aneusomic recombinants among the live offspring of carriers shows a marked dependence on the length of the relative inversion segments. Since these are distinctly below average in inversion types, they only result in recombinants in exceptional cases.Certain pointers to an above-random common occurrence of other chromosomal aberrations are not found in families with pii. A correlation between pii and clinical symptoms like-wise cannot be detected. However, in this connection it is pointed out that trisomic mosaics were observed jointly with pii (9) and pii (22). The review is completed by a brief examination of the literature concerning the significance of pii in evolution.     

Paracentric inversions in man

Summary The Leuven cytogenetic center experience on paracentric inversions in man is discussed. From a total of 51,000 patients, referred for constitutional chromosome analysis during the period 1970–1985, paracentric inversions were found in 18 index patients. A puzzling finding is the high incidence (26%) of mental retardation and/or congenital malformation in the inversion carrier offspring of phenotypically normal parents with identical chromosomal rearrangements. There was also a high incidence of early fetal loss in the inversion carrier parents. This finding may be explained by an increase of chromosomally unbalanced gametes which result from crossing-over in the meiotic inversion loop. Finally, the possibility of an increased tendency to non-disjunction in paracentric inversion carrier parents is discussed. The most frequent paracentric inversion was inv(3)(p13p25); it was detected in seven unrelated index patients. According to the present experience and the literature data, the breakpoints in paracentric inversions seem to occur preferentially at 1p22, 1p36, 3p13, 3p25, 7q11, and 7q22 regions.     

Paracentric inversions: a review

This review of paracentric inversions in man includes what we know of the behaviour and reproductive consequences of paracentric inversions from other species. Observations of naturally occurring inversions in several species of plants and animals and results of experiments with mutagenically induced inversions in the mouse are discussed. From a review of 184 cases, it is concluded that most of the paracentric inversions in man are harmless and that the risk of heterozygotes having a child with an unbalanced karyotype is low. However, in some cases, it is difficult, if not impossible, to distinguish between a paracentric inversion and a paracentric insertion, the risk in the latter case being about 15%. Caution is also necessary in interpreting the results of prenatal diagnosis for heterozygotes of paracentric inversions, because of the possibility of a variety of unpredictable unbalanced chromosome products.     

Acquired inversions in human leucocytes

Peri- and paracentric inversions are observed in human leukocytes at various rates. Four categories are proposed, in relation to the frequency of occurrence, although it may vary with time for a same inversion. Category 1 corresponds to isolated, thus non recurrent inversions. Category 2 (f congruent to .001) corresponds to inv(14)(q12qter) and inv(7)(p14q35) in individuals with presumably normal genetic constitution. Category 3 (f congruent to .01) corresponds to inv(7)(p14q35) in patients affected by ataxia telangiectasia (AT). This inversion, when it is frequent, indicates an abnormal genetic constitution, radiation sensitive and predisposing to cancers. Finally, category 4 (f greater than or equal to .1) corresponds to inversions existing in precancer or in cancer clonal cells: inv(14)(q11.2q32.2) in AT patients affected by a T-cell hemopathy, inv(14)(q12qter) in chronic T-cell lymphocytic leukaemia, and inv(16)(p13q22) in acute myelomonocytic leukaemia with abnormal eosinophils. The prognostic and diagnostic interests of these inversions is discussed.     

Identification of polymorphic inversions from genotypes

Background  

Polymorphic inversions are a source of genetic variability with a direct impact on recombination frequencies. Given the difficulty of their experimental study, computational methods have been developed to infer their existence in a large number of individuals using genome-wide data of nucleotide variation. Methods based on haplotype tagging of known inversions attempt to classify individuals as having a normal or inverted allele. Other methods that measure differences between linkage disequilibrium attempt to identify regions with inversions but unable to classify subjects accurately, an essential requirement for association studies.     

Genetic counseling in balanced chromosomal inversions

The genetic counseling given at carriers of equilibrated chromosomal inversions is in relation with the type of the inversion. The risk for carriers of pericentric inversions concerning euchromatic regions depends on many factors, i.e. the length of the inserted segment in relation with the total length of the chromosome involved, the sex of the carrier and the way of assortment. In contrast, the carriers of pericentric inversions concerning the heterochromatic regions, as well as of paracentric inversions, have not a particular risk for their descendance.     

Paracentric inversions in human chromosome 7

Summary A paracentric inversion (7)(q11q22) and mosaicism 46,XX/45,X was detected in a female with minor malformations. The same inversion was observed in the mother of the patient. The analysis of high resolution banded chromosmes revealed no visible imbalance in the inverted long arm of the chromosome 7. All published cases of paracentric inversions in the human chromosome 7 are reviewed and the relationship between this inversion and the occurrence of an aneuploidy of the sex chromosomes is discussed.     

Accommodating chromosome inversions in linkage analysis

This work develops a population-genetics model for polymorphic chromosome inversions. The model precisely describes how an inversion changes the nature of and approach to linkage equilibrium. The work also describes algorithms and software for allele-frequency estimation and linkage analysis in the presence of an inversion. The linkage algorithms implemented in the software package Mendel estimate recombination parameters and calculate the posterior probability that each pedigree member carries the inversion. Application of Mendel to eight Centre d'Etude du Polymorphisme Humain pedigrees in a region containing a common inversion on 8p23 illustrates its potential for providing more-precise estimates of the location of an unmapped marker or trait gene. Our expanded cytogenetic analysis of these families further identifies inversion carriers and increases the evidence of linkage.     

Assaying chromosomal inversions by single-molecule haplotyping

Inversions are an important form of structural variation, but they are difficult to characterize, as their breakpoints often fall within inverted repeats. We have developed a method called 'haplotype fusion' in which an inversion breakpoint is genotyped by performing fusion PCR on single molecules of human genomic DNA. Fusing single-copy sequences bracketing an inversion breakpoint generates orientation-specific PCR products, exemplified by a genotyping assay for the int22 hemophilia A inversion on Xq28. Furthermore, we demonstrated that inversion events with breakpoints embedded within long (>100 kb) inverted repeats can be genotyped by haplotype-fusion PCR followed by bead-based single-molecule haplotyping on repeat-specific markers bracketing the inversion breakpoint. We illustrate this method by genotyping a Yp paracentric inversion sponsored by >300-kb-long inverted repeats. The generality of our methods to survey for, and genotype chromosomal inversions should help our understanding of the contribution of inversions to genomic variation, inherited diseases and cancer.     

Chromosome inversions in Indian Drosophila melanogaster

Ten laboratory stocks of Drosophila melanogaster initiated from females collected in different localities in India were analysed for chromosome inversions. Six inversions were found to be present, three in 2L, one in 2R, one in 3L and one in 3R. Out of these six inversions, three are new and are being reported for the first time. Furthermore, this is the first report of inversion polymorphism in Indian D. melanogaster. The persistence of inversion polymorphism in our laboratory stocks of D. melanogaster which were maintained for more than one year under laboratory conditions, suggests some heterotic advantage of inversion heterozygotes.     

Short inversions and conserved gene cluster

MOTIVATION: Two independent sets of recent observations on newly sequenced microbial genomes pertain to the prevalence of short inversion as a gene order rearrangement process and to the lack of conservation of gene order within conserved gene clusters. We propose a model of inversion where the key parameter is the length of the inverted fragment. RESULTS: We show that there is a qualitative difference in the pattern of evolution when the inversion length is small with respect to the cluster size and when it is large. This suggests an explanation of the lack of parallel gene order in conserved clusters and raises questions about the statistical validity of putative functionally selected gene clusters if these have only been tested against inappropriate null hypotheses.     

DNA inversions in phages and bacteria

In certain phages and bacteria, there is a recombination system that specifically promotes the inversion of a DNA fragment. These inversion events appear to act as genetic switches allowing the alternate expression of different sets of genes which in general code for surface proteins. The mechanism of inversion in one class of inversion systems (Gin/Hin) has been studied in detail. It involves the formation of a highly specific nucleoprotein complex in which not only the two recombination sites and the DNA invertase participate but also a recombinational enhancer to which the DNA-bending protein Fis is bound.     

Chromosomal inversions and genetic control revisited: the use of inversions in sexing systems for higher Diptera

Summary Genetic sexing systems based on sex-linked translocations and deleterious mutations are subject to breakdown from genetic recombination in males. Including inversions in these strains may provide a solution to this problem, by ensuring selective elimination of recombinant products. Inversions could be used either in coupling to or in repulsion to the translocation. The latter system, requiring homozygous-viable inversions, would be more difficult to construct, but would offer several advantages not available with coupled translocation/inversion systems. A system proposed for the blowfly Lucilia cuprina is outlined, which combines homozygous-viable pericentric inversions in repulsion to existing sex-linked translocations. This system should both stabilize the genetic sexing system and increase the suppressive potential of such strains.     

Unanticipated ankle inversions are significantly different from anticipated ankle inversions during drop landings: overcoming anticipation bias

Few ankle inversion studies have taken anticipation bias into account or collected data with an experimental design that mimics actual injury mechanisms. Twenty-three participants performed randomized single-leg vertical drop landings from 20 cm. Subjects were blinded to the landing surface (a flat force plate or 30° inversion wedge on the force plate). After each trial, participants reported whether they anticipated the landing surface. Participant responses were validated with EMG data. The protocol was repeated until four anticipated and four unanticipated landings onto the inversion wedge were recorded. Results revealed a significant main effect for landing condition. Normalized vertical ground reaction force (% body weights), maximum ankle inversion (degrees), inversion velocity (degrees/second), and time from contact to peak muscle activation (seconds) were significantly greater in unanticipated landings, and the time from peak muscle activation to maximum VGRF (second) was shorter. Unanticipated landings presented different muscle activation patterns than landings onto anticipated surfaces, which calls into question the usefulness of clinical studies that have not controlled for anticipation bias.     

Chromosome inversions, local adaptation and speciation

We study the evolution of inversions that capture locally adapted alleles when two populations are exchanging migrants or hybridizing. By suppressing recombination between the loci, a new inversion can spread. Neither drift nor coadaptation between the alleles (epistasis) is needed, so this local adaptation mechanism may apply to a broader range of genetic and demographic situations than alternative hypotheses that have been widely discussed. The mechanism can explain many features observed in inversion systems. It will drive an inversion to high frequency if there is no countervailing force, which could explain fixed differences observed between populations and species. An inversion can be stabilized at an intermediate frequency if it also happens to capture one or more deleterious recessive mutations, which could explain polymorphisms that are common in some species. This polymorphism can cycle in frequency with the changing selective advantage of the locally favored alleles. The mechanism can establish underdominant inversions that decrease heterokaryotype fitness by several percent if the cause of fitness loss is structural, while if the cause is genic there is no limit to the strength of underdominance that can result. The mechanism is expected to cause loci responsible for adaptive species-specific differences to map to inversions, as seen in recent QTL studies. We discuss data that support the hypothesis, review other mechanisms for inversion evolution, and suggest possible tests.     

The interchromosomal effect of inversions in maize

Summary The interchromosomal effect of inversions in maize along the short arm of chromosome 9 yields results which are distinctly different from those which are reported with Drosophila melanogaster. Recombination was increased in the c ₁-sh₁ region of chromosome 9 while the sh ₁-wx region was unaffected. This increased frequency of recombination appears to be due to an increase in single exchange events as multiple events were unchanged. Increases in recombination were accompanied by either an increase in chromosome interference or normal interference levels. The magnitude of increase in recombination was much smaller than that seen in interchromosomal effects in Drosophila and is consistent with other observations made in maize. When two inversions were present in the same nucleus simultaneously, the effect on recombination was of the same magnitude as the effect of a single inversion. All inversions tested, regardless of size or position with respect to the centromere showed the same magnitude of increase.