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PubMed1995

Factor VIII gene inversions in severe hemophilia A patients.

The mutations causing hemophilia A are very heterogeneous with the exception of a large inversion involving intron 22 in the factor VIII (FVIII) gene which appears to be the underlying defect in approximately 45% of all severely affected patients (FVIII < or = 1%). In these patients it is thought that the factor VIII gene is disrupted within intron 22 due to inappropriate recombination of FVIIIA with one of 2 homologous regions upstream of the factor VIII gene resulting in a large (approximately 500 kb) inversion. The inversion can be detected by Southern blot analysis and greatly enhances the accuracy of genetic counselling services available to families with severe hemophilia A. We report here the presence of this mutation in a study of 27 unrelated families with severe hemophilia. The factor VIII inversion was identified in 12 of 27 (44%) severe hemophilia A patients and has been successfully used for direct carrier analysis and prenatal diagnosis.

Blotting, Southern↗
PubMed1997

A rapid method for measuring pericentric inversions using fluorescence in situ hybridization (FISH).

We used three common fluorescent probes to measure pericentric inversion frequencies in 2.9 Gy 60Co gamma-irradiated human lymphocytes. For a given chromosome, the first probe is specific to one telomeric region, the second probe is specific to one subcentromeric region and the third probe is specific to the centromere. A pericentric inversion is made observable by the change in position (switching) of the fluorescent signals relative to the chromosome centromere. Our data showed equality between pericentric inversions and centric rings. The calculated whole-genome F-ratio of apparently simple translocations to pericentric inversions was 5.6.

Animals↗
PubMed2002

Heterozygous submicroscopic inversions involving olfactory receptor-gene clusters mediate the recurrent t(4;8)(p16;p23) translocation.

The t(4;8)(p16;p23) translocation, in either the balanced form or the unbalanced form, has been reported several times. Taking into consideration the fact that this translocation may be undetected in routine cytogenetics, we find that it may be the most frequent translocation after t(11q;22q), which is the most common reciprocal translocation in humans. Case subjects with der(4) have the Wolf-Hirschhorn syndrome, whereas case subjects with der(8) show a milder spectrum of dysmorphic features. Two pairs of the many olfactory receptor (OR)-gene clusters are located close to each other, on both 4p16 and 8p23. Previously, we demonstrated that an inversion polymorphism of the OR region at 8p23 plays a crucial role in the generation of chromosomal imbalances through unusual meiotic exchanges. These findings prompted us to investigate whether OR-related inversion polymorphisms at 4p16 and 8p23 might also be involved in the origin of the t(4;8)(p16;p23) translocation. In seven case subjects (five of whom both represented de novo cases and were of maternal origin), including individuals with unbalanced and balanced translocations, we demonstrated that the breakpoints fell within the 4p and 8p OR-gene clusters. FISH experiments with appropriate bacterial-artificial-chromosome probes detected heterozygous submicroscopic inversions of both 4p and 8p regions in all the five mothers of the de novo case subjects. Heterozygous inversions on 4p16 and 8p23 were detected in 12.5% and 26% of control subjects, respectively, whereas 2.5% of them were scored as doubly heterozygous. These novel data emphasize the importance of segmental duplications and large-scale genomic polymorphisms in the evolution and pathology of the human genome.

Abnormalities, Multiple↗
PubMed2002

Molecular characterization of the pericentric inversion that causes differences between chimpanzee chromosome 19 and human chromosome 17.

A comparison of the human genome with that of the chimpanzee is an attractive approach to attempts to understand the specificity of a certain phenotype's development. The two karyotypes differ by one chromosome fusion, nine pericentric inversions, and various additions of heterochromatin to chromosomal telomeres. Only the fusion, which gave rise to human chromosome 2, has been characterized at the sequence level. During the present study, we investigated the pericentric inversion by which chimpanzee chromosome 19 differs from human chromosome 17. Fluorescence in situ hybridization was used to identify breakpoint-spanning bacterial artificial chromosomes (BACs) and plasmid artificial chromosomes (PACs). By sequencing the junction fragments, we localized breakpoints in intergenic regions rich in repetitive elements. Our findings suggest that repeat-mediated nonhomologous recombination has facilitated inversion formation. No addition or deletion of any sequence element was detected at the breakpoints or in the surrounding sequences. Next to the break, at a distance of 10.2-39.1 kb, the following genes were found: NGFR and NXPH3 (on human chromosome 17q21.3) and GUC2D and ALOX15B (on human chromosome 17p13). The inversion affects neither the genomic structure nor the gene-activity state with regard to replication timing of these genes.

Animals↗
PubMed1987

Genetic functions promoting homologous recombination in Escherichia coli: a study of inversions in phage lambda.

We have studied homologous recombination in a derivative of phage lambda containing two 1.4-kb repeats in inverted orientation. Inversion of the intervening 2.5-kb segment occurred efficiently by the Escherichia coli RecBC pathway but markedly less efficiently by the lambda Red pathway or the E. coli RecE or RecF pathways. Inversion by the RecBCD pathway was stimulated by Chi sites located to the right of the invertible segment; this stimulation decreased exponentially by a factor of about 2 for each 2.2 kb between the invertible segment and the Chi site. In addition to RecA protein and RecBCD enzyme, inversion by the RecBC pathway required single-stranded DNA binding protein, DNA gyrase, DNA polymerase I and DNA ligase. Inversion appeared to occur either intra- or intermolecularly. These results are discussed in the framework of a current molecular model for the RecBC pathway of homologous recombination.

Bacteriophage lambda↗
PubMed1991

Lack of underdominance in a naturally occurring pericentric inversion in Drosophila melanogaster and its implications for chromosome evolution.

In(2LR)PL is a large pericentric inversion polymorphic in populations of Drosophila melanogaster on two Indian Ocean islands. This polymorphism is puzzling: because crossing over in female heterokaryotypes produces inviable zygotes, such inversions are thought to be underdominant and should be quickly eliminated from populations. The observed fixation for such inversions among related species has led to the idea that genetic drift can cause chromosome evolution in opposition to natural selection. We found, however, that In(2LR)PL is not underdominant for fertility, as heterokaryotypic females produce perfectly viable eggs. Genetic analysis shows that the lack of underdominance results from the nearly complete absence of crossing over in the inverted region. This phenomenon is probably caused by mechanical and not genetic factors, because crossing over is not suppressed in In(2LR)PL homokaryotypes. Our observations do not support the idea that the fixation of pericentric inversions among closely related species implies the action of genetic drift overcoming strong natural selection in very small populations. If chromosome arrangements vary in their underdominance, it is those with the least disadvantage as heterozygotes, like In(2LR)PL, that will be polymorphic or fixed in natural populations.

Alcohol Dehydrogenase↗
PubMed1994

Transposable element numbers in cosmopolitan inversions from a natural population of Drosophila melanogaster.

Population studies of the distribution of transposable elements (TEs) on the chromosomes of Drosophila melanogaster have suggested that their copy number increase due to transposition is balanced by some form of natural selection. Theory suggests that, as a consequence of deleterious ectopic meiotic exchange between TEs, selection can favor genomes with lower TE copy numbers. This predicts that TEs should be less deleterious, and hence more abundant, in chromosomal regions in which recombination is reduced. To test this, we surveyed the abundance and locations of 10 families of TEs in recombination-suppressing chromosomal inversions from a natural population. The sample of 49 chromosomes included multiple independent isolates of seven different inversions and a corresponding set of standard chromosomes. For all 10 TE families pooled, copy numbers were significantly higher overall within low frequency inversions than within corresponding regions of standard chromosomes. TEs occupied chromosomal sites at significantly higher frequencies within the In(3R)Mo and In(3R)K inversions than within the corresponding regions of standard 3R chromosomes. These results are consistent with the predictions of the ectopic exchange model.

Animals↗
PubMed1997

Selective introgression of paracentric inversions between two sibling species of the Anopheles gambiae complex.

The Anopheles gambiae complex includes the major vectors of malaria in sub-Saharan Africa where > 80% of all world-wide cases occur. These mosquitoes are characterized by chromosomal inversions associated to the speciation process and to intraspecific ecological and behavioral flexibility. It has been postulated that introgressive hybridization has selectively transferred inversions on the second chromosome between A. gambiae and A. arabiensis, the two most important vectors of malaria. Here we directly test this hypothesis with laboratory experiments in which hybrid populations were established and the fate of chromosomal inversions were followed. Consistent with the hypothesis, "foreign" X chromosomes were eliminated within two generations, while some "foreign" second chromosomes persisted for the duration of the experiments and, judging from the excess of heterozygotes established stable heterotic polymorphisms. Only those second chromosome inversions found naturally in the species could be introgressed.

Animals↗
PubMed1999

Molecular population genetics of the rp49 gene region in different chromosomal inversions of Drosophila subobscura.

Nucleotide variation at the ribosomal protein 49 (rp49) gene region has been studied in 75 lines of Drosophila subobscura belonging to four chromosomal arrangements (Ost, O3+4, O3+4+8, and O3+4+23). The location of the rp49 gene region within the inversion loop differs among heterokaryotypes: it is very close to one of the breakpoints in heterozygotes involving Ost chromosomes, while it is in a more central position in all other heterokaryotypes. The distribution of nucleotide polymorphism in the different arrangements is consistent with a monophyletic origin of the inversions. The data also provide evidence that gene conversion and possibly double crossover are involved in shuffling nucleotide variation among gene arrangements. The analyses reveal that the level of genetic exchange is higher when the region is located in a more central position of the inverted fragment than when it is close to the breakpoints. The pairwise difference distributions as well as the negative values of Tajima's and Fu and Li's statistics further support the hypothesis that nucleotide variation within chromosomal arrangements still reflects expansion after the origin of the inversions. Under the expansion model, we have estimated the time of origin of the studied inversions.

Animals↗
PubMed2000

Effect of inversion polymorphism on the neutral nucleotide variability of linked chromosomal regions in Drosophila.

Recombination is a main factor determining nucleotide variability in different regions of the genome. Chromosomal inversions, which are ubiquitous in the genus Drosophila, are known to reduce and redistribute recombination, and thus their specific effect on nucleotide variation may be of major importance as an explanatory factor for levels of DNA variation. Here, we use the coalescent approach to study this effect. First, we develop analytical expressions to predict nucleotide variability in old inversion polymorphisms that have reached mutation-drift-flux equilibrium. The effects on nucleotide variability of a new arrangement appearing in the population and reaching a stable polymorphism are then studied by computer simulation. We show that inversions modulate nucleotide variability in a complex way. The establishment of an inversion polymorphism involves a partial selective sweep that eliminates part of the variability in the population. This is followed by a slow convergence to the equilibrium values. During this convergence, regions close to the breakpoints exhibit much lower variability than central regions. However, at equilibrium, regions close to the breakpoints have higher levels of variability and differentiation between arrangements than regions in the middle of the inverted segment. The implications of these findings for overall variability levels during the evolution of Drosophila species are discussed.

Animals↗
PubMed1976

Evidence for coadaptation: negative correlation between lethal genes and polymorphic inversions in Drosophila melanogaster.

Through examination of all available data on lethal and inversion frequencies on the second chromosome in natural populations of Drosophila melanogaster, we have discovered that there is a clear negative correlation between the two quantities. Lethal genes are located more densely on the regions of standard gene arrangement than the inverted regions, and this accounts for the negative correlation. To reveal the underlying mechanism of the phenomena, we have carried out an experiment and found that effect of EMS-induced mutations on the inversion-carrying chromosome is more severe than that on the standard chromosome. We interpret these results as evidence for coadaptation or position-effect within the inversion chromosomes. New mutations within the coadapted gene complex are quickly eliminated from the population and polymorphic inversions are kept free of mutants through selective elimination.

Animals↗
PubMed1980

Developmental variation in amylase allozyme activity associated with chromosome inversions in Drosophila persimilis.

The amylase locus in Drosophila persimilis is polymorphic for allozymes, two of which show associations with naturally occurring chromosome 3 inversions. Amy1.09 occurs at high frequencies only in Whitney (WT), while the other common arrangements-Standard (ST), Klamath (KL) and Mendocino (MD)-are predominantly Amy 1.00. We have examined numerous strains, representing various electromorphs and inversions, for variation in cis-specific activity expression in both third-instar larvae and adults. Comparisons of these two life stages also allows the survey of developmental variation in amylase activities. The amount of activity variation exceeds electrophoretic variation at this locus. Moreover, this variation is largely nonrandom and reveals more genic divergence among inversions. The 1.00 allozyme of MD is more active than 1.00 KL in larvae and adults and shows a different developmental pattern. The activity of the 1.00 allozyme of KL is greater than 1.00 allozyme of ST in larvae and adults, but these two arrangements have similar developmental patterns. WT 1 with a 1.00 allele is dramatically different from the 1.00 allozymes of other arrangements in its developmental pattern. The 1.09 allozymes has high activity in WT and KL, but these arrangements differ in their developmental pattern of expression, WT being more active in adults. F2 segregational analyses are consistent with the variation being due to either structural enzyme variants or closely linked cis-acting regulatory elements. We argue that the suppression of recombination between arrangements has allowed the divergence in amylase activity among inversions.

Amylases↗
PubMedDate not supplied

Genomic distribution of P elements in Drosophila willistoni and a search for their relationship with chromosomal inversions.

According to the recent-invasion hypothesis, Drosophila melanogaster may have acquired its P elements in a fairly recent process of horizontal transmission between species. Drosophila willistoni has been identified as the potential donor species in that transfer process. A most remarkable feature of D. willistoni is its extensive chromosomal polymorphism due to inversions-the adaptiveness of which has been the subject of many classical studies on evolutionary genetics. In this article, we further extend the study of P elements in D. willistoni, focusing on the possible role they may play in the generation of chromosomal inversions. Our results may be summarized as follows. P-homologous sequences were detected in South American populations of D. willistoni. In two of them, a recently collected wild population and an old laboratory stock, the P insertion sites were located in the polytene chromosomes. Several hybridization sites were mapped in all major chromosome arms of the natural population, which was also chromosomally polymorphic; in the laboratory population, nearly devoid of inversions, hybridization sites were found to be confined to the chromocenter. In the wild population, 10 of the 24 P hybridized sites coincided with several inversions break points and another five sites located themselves very close to those points. The results are discussed within the context of evolutionary hypotheses.

Animals↗
PubMed2005

Candidate psychiatric illness genes identified in patients with pericentric inversions of chromosome 18.

Both the long and short arms of chromosome 18 have been consistently identified as potential locations for schizophrenia and bipolar affective disorder susceptibility genes. We previously described the identification of two independent pericentric inversions of chromosome 18 [inv(18)(p11.31;q21.2) and inv(18)(p11.31;q21.1)] occurring in two small families in which carriers have been diagnosed with schizophrenia and bipolar affective disorder, respectively. Using fluorescence in situ hybridization on patient metaphase chromosomes we have identified the locations of all four chromosome breakpoints in the inversion carriers. Neither pericentric inversion results in a direct gene disruption. However, each inversion breakpoint has the potential to perturb local gene expression by position effect or by the separation of important regulatory (enhancer) sequences from the core gene sequences. Five genes in the localities of the breakpoints have been identified as good candidates for the genetic basis of psychiatric illness in these families; TTMA, a novel membrane spanning protein; TCF4, a basic helix-loop-helix transcription factor; DLGAP1, an interactor of the PSD-95 synaptic protein; and ARKL1 and ARKL2, novel members of the ubiquitin ligase gene family.

Amino Acid Sequence↗
PubMed2002

Homologous recombination between the inverted terminal repeats of defective transposon TCp3.2 causes an inversion in the genome of Cydia pomonella granulovirus.

In this study, a new mutant of the Cydia pomonella granulovirus (CpGV), which shows spontaneous inversion of a transposable element during in vivo replication, is described. CpGV-MCp4 is a natural mutant of CpGV-M, containing the transposable element TCp3.2, which originated from the genome of the host C. pomonella. During in vivo cloning studies of CpGV-MCp4, a mutant called CpGV-MCp4inv was isolated. CpGV-MCp4inv shows heterogeneity in the genome area of transposon insertion. Restriction mapping, PCR analysis and subsequent sequence analysis gave strong evidence that an inversion of TCp3.2 is caused by homologous recombination between the long inverted terminal repeats (ITRs) of the transposon. This finding demonstrated that extensive homologous repeat regions such as the ITRs of transposons cause inversions by homologous recombination during in vivo replication. The observed in vivo inversion between the ITRs can be considered as a model for the contribution of repeated sequences in the genome rearrangement of baculoviruses and a source for genetic heterogeneity among different baculoviruses and baculovirus genotypes.

Animals↗
PubMed1997

Physical map of the Bacillus subtilis 166 genome: evidence for the inversion of an approximately 1900 kb continuous DNA segment, the translocation of an approximately 100 kb segment and the duplication of a 5 kb segment.

An I-CeuI-NotI-SfiI endonuclease map of the Bacillus subtilis 166 genome was constructed. It was almost identical to that of B. subtilis 168 except for the inversion of an approximately 1900 kb DNA segment, the translocation of an approximately 100 kb segment and the duplication of a 5 kb segment. Continuity of the inverted segment was investigated by direct measurement of the distances between the two genomic loci where I-SceI recognition sites were created in the 168 and the 166 genomes. Size difference of the I-SceI fragments between the two strains fully demonstrated the inversion of an approximately 1900 kb long 'continuous' DNA segment and the 'location' of the two inversion junctions in the genome. The 100 kb DNA segment including the lysogenic SP beta prophage was translocated close to one of the inversion junctions and was probably associated with the duplication of a 5 kb segment. These rearrangements are consistent with those indicated by genetic analyses.

Bacillus subtilis↗
PubMed1987

Fis binding to the recombinational enhancer of the Hin DNA inversion system.

The recombinational enhancer of the Hin inversion system in Salmonella stimulates recombination in vitro 150-fold in the presence of the Escherichia coli host factor Fis. To gain an understanding of the roles of the enhancer and Fis in stimulating the Hin-mediated inversion reaction, we have used nuclease and chemical protection/interference studies and gel retardation assays to examine the interactions between Fis and the recombinational enhancer. These studies combined with mutational analysis defined the enhancer sequences required for Fis binding and function. Fis binds with different affinities to two domains within the enhancer sequence. The binding of Fis at each domain is independent of the occupancy of the other domain and appears to be to opposite faces of the DNA helix. These results support a model for the role of the recombinational enhancer in Hin-mediated inversion in which the interaction between Hin bound at recombination sites and Fis bound to each domain of the recombinational enhancer results in a structure with the proper alignment and topology to promote DNA inversion.

Base Sequence↗
PubMed2001

Twin priming: a proposed mechanism for the creation of inversions in L1 retrotransposition.

L1 retrotransposons are pervasive in the human genome. Approximately 25% of recent L1 insertions in the genome are inverted and truncated at the 5' end of the element, but the mechanism of L1 inversion has been a complete mystery. We analyzed recent L1 inversions from the genomic database and discovered several findings that suggested a mechanism for the creation of L1 inversions, which we call twin priming. Twin priming is a consequence of target primed reverse transcription (TPRT), a coupled reverse transcription/integration reaction that L1 elements are thought to use during their retrotransposition. In TPRT, the L1 endonuclease cleaves DNA at its target site to produce a double-strand break with two single-strand overhangs. During twin priming, one of the overhangs anneals to the poly(A) tail of the L1 RNA, and the other overhang anneals internally on the RNA. The overhangs then serve as primers for reverse transcription. The data further indicate that a process identical to microhomology-driven single-strand annealing resolves L1 inversion intermediates.

Chromosome Inversion↗