Paracentric Inversion Of Chromosome Research Articles

Chromosomal plasticity and evolutionary potential in the malaria vector Anopheles gambiae sensu stricto: insights from three decades of rare paracentric inversions

BackgroundIn the Anopheles gambiae complex, paracentric chromosomal inversions are non-randomly distributed along the complement: 18/31 (58%) of common polymorphic inversions are on chromosome arm 2R, which represents only ~30% of the complement. Moreover, in An. gambiae sensu stricto, 6/7 common polymorphic inversions occur on 2R. Most of these inversions are considered markers of ecological adaptation that increase the fitness of the carriers of alternative karyotypes in contrasting habitats. However, little is known about the evolutionary forces responsible for their origin and subsequent establishment in field populations.ResultsHere, we present data on 82 previously undescribed rare chromosomal inversions (RCIs) recorded during extensive field sampling in 16 African countries over a 30 year period, which may shed light on the dynamics of chromosomal plasticity in An. gambiae. We analyzed breakpoint distribution, length, and geographic distribution of RCIs, and compared these measures to those of the common inversions. We found that RCIs, like common inversions, are disproportionately clustered on 2R, which may indicate that this arm is especially prone to breakages. However, contrasting patterns were observed between the geographic distribution of common inversions and RCIs. RCIs were equally frequent across biomes and on both sides of the Great Rift Valley (GRV), whereas common inversions predominated in arid ecological settings and west of the GRV. Moreover, the distribution of RCI lengths followed a random pattern while common inversions were significantly less frequent at shorter lengths.ConclusionBecause 17/82 (21%) RCIs were found repeatedly at very low frequencies – at the same sampling location in different years and/or in different sampling locations – we suggest that RCIs are subject mainly to drift under unperturbed ecological conditions. Nevertheless, RCIs may represent an important reservoir of genetic variation for An. gambiae in response to environmental changes, further testifying to the considerable evolutionary potential hidden within this pan-African malaria vector.

AID-deficient Bcl-xL transgenic mice develop delayed atypical plasma cell tumors with unusual Ig/Myc chromosomal rearrangements

Activation-induced cytidine deaminase (AID) is required for immunoglobulin (Ig) class switch recombination and somatic hypermutation, and has also been implicated in translocations between Ig switch regions and c-Myc in plasma cell tumors in mice. We asked if AID is required for accelerated tumor development in pristane-treated Bcl-xL transgenic BALB/c mice deficient in AID (pBxAicda−/−). pBxAicda −/− mice developed tumors with a lower frequency (24 vs. 62%) and a longer mean latency (108 vs. 36 d) than AID-sufficient mice. The tumors appeared in oil granuloma tissue and did not form ascites. By interphase fluorescence in situ hybridization, six out of nine pBxAicda −/− primary tumors had T(12;15) and one had T(6;15) chromosomal translocations. Two tumors were transplantable and established as stable cell lines. Molecular and cytogenetic analyses showed that one had an unusual unbalanced T(12;15) translocation, with IgH Cμ and Pvt-1 oriented head to tail at the breakpoint, resulting in an elevated expression of c-Myc. In contrast, the second was T(12;15) negative, but had an elevated N-Myc expression caused by a paracentric inversion of chromosome 12. Thus, novel mechanisms juxtapose Ig and Myc-family genes in AID-deficient plasma cell tumors.

RET oncogene amplification in thyroid cancer: Correlations with radiation-associated, high-grade malignancy, and genomic instability

Abstract. RET oncogene rearrangement is a well-known molecular alteration observed in papillary thyroid cancer (PTC). RET rearrangement is the commonest oncogenic alterations in Chernobyl-related PTC; nearly all to RET/PTC1 or RET/PTC3, resulting from paracentric inversion of chromosome 10. Other less common variants, usually forming as a result of interchromosomal translocation, occur in an extremely limited number of cases. Most often such translocations have been found in radiation-induced PTC. Here, we report the presence of RET oncogene amplification, a new type of RET cytogenetic alteration, in human thyroid cancers. RET amplification was correlated with radiation-associated, high-grade malignant potency, and p53 overexpression, suggesting genomic instability. We also examined p53-binding protein 1 (53BP1) expressions with immunostaining to clarify the presence of genomic instability in thyroid cancers. In thyroid tumors, the level of 53BP1-focus formation was associated with malignant transformation and high-grade malignant potency as well as RET amplification. RET amplification might be induced by a high level of genomic instability with progression of thyroid carcinogenesis and, subsequently, be associated with radiation-induced and/or high-grade malignant cases.

Breakpoint structure reveals the unique origin of an interspecific chromosomal inversion ( 2La ) in the Anopheles gambiae complex

Paracentric chromosomal inversions are major architects of organismal evolution and have been associated with adaptations relevant to malaria transmission in anopheline mosquitoes. The processes responsible for their origin and maintenance, still poorly understood, can be illuminated by analysis of inversion breakpoint sequences. Here, we report the breakpoint structure of chromosomal inversion 2La from the principal malaria vector Anopheles gambiae and its relatives in the A. gambiae complex. The distal and proximal breakpoints of the standard (2L+a) arrangement contain gene duplications: full-length genes and their truncated copies at opposite ends. Intact genes without pseudogene copies in the alternative arrangement (2La) imply that 2L+a is derived and was viable despite damage to genes, because duplication preserved gene function. A unique origin for the interspecific 2La inversion was challenged previously by indirect genetic evidence, but breakpoint sequences determined from members of the A. gambiae complex strongly suggest their descent from a single event. The derived position of 2L+a, long considered ancestral in this medically important group, has significant implications for the phylogenetic history and the evolution of vectorial capacity in the A. gambiae complex.

Delineation of a 2.2 Mb microdeletion at 5q35 associated with microcephaly and congenital heart disease

Fine mapping of chromosomal deletions and genotype-phenotype comparisons of clinically well-defined patients can be used to confirm or reveal loci and genes associated with human disorders. Eleven patients with cytogenetically visible deletions involving the terminal region of chromosome 5q have been described, but the extent of the deletion was determined only in one case. In this study we describe a 15-year-old boy with Ebstein anomaly, atrial septal defect (ASD), atrioventricular (AV) conduction defect, and microcephaly. He had an apparently balanced paracentric inversion of chromosome 5, with the karyotype 46, XY,inv(5)(q13q35) de novo. Further mapping of the chromosome breakpoints using fluorescence in situ hybridization (FISH) revealed a 2.2 Mb microdeletion at the 5q35 breakpoint, which spans 16 genes, including the cardiac homeobox transcription factor gene NKX2-5. The current data suggest that haploinsufficiency of NKX2-5 cause Ebstein anomaly and support previous results showing that NKX2-5 mutations cause ASD and AV conduction defect. Furthermore, we suggest presence of a new microcephaly locus within a 2.2 Mb region at 5q35.1-q35.2.

Peters Anomaly in Association with Multiple Midline Anomalies and a Familial Chromosome 4 Inversion

We describe the clinical presentation of a boy with Peters anomaly and a cataract of the left eye in association with multiple midline defects. His extraocular developmental abnormalities include cleft lip and palate, cardiac anomalies, an atretic cranial meningocele, as well as malformation of the left ear with chronic otitis media. Genetic analysis revealed a balanced paracentric inversion of chromosome 4, inv(4)(q12q13.3), also present in his asymptomatic father and siblings. His normal stature and cognitive development distinguish this case from the Peters Plus syndrome. The presence of a cranial meningocele represents a new association with Peters anomaly.

A Report of Paracentric Inversion of Chromosome 8 in Moebius Syndrome

An eight-year-old girl with bilateral facial paresis and restricted eye movements was diagnosed with Moebius syndrome. A chromosomal analysis showed a paracentric inversion on the long arm of chromosome 8 (46, XX, inv(8) (q21.3q24.13)). Candidate genes have been found on chromosomes 3q21, 10q21, and 13q12. We discuss the genes which are known to have associated ocular movement dysfunction in the 8q21-24 region. We hope this case will add to the current body of knowledge regarding Moebius syndrome and its genetics.

Is chromosome analysis mandatory in the initial investigation of normovulatory women seeking infertility treatment?

There is no agreement about the frequency of chromosomal abnormalities (CAs) in the female partner of an infertile couple and therefore there is no evidence base for determining whether karyotype analysis is mandatory before the initiation of infertility treatment. The aim of this prospective study was to estimate the prevalence of karyotype abnormalities in normovulatory women attending an infertility clinic and compare it to that known to be present in the newborn female population. Cytogenetic testing was performed in 1206 women with normal ovulatory cycle seeking infertility treatment. At least 15 GTG-banded metaphases were analysed in each case. In the case of a structural abnormality, fluorescent in situ hybridization (FISH) analysis and high resolution banding (HRB) were performed on a new blood sample to elucidate the aberration. When mosaicism was suspected, the number of analysed metaphases was increased to a total of 115 and an additional analysis of 200 metaphases was done on a second blood sample. A chromosomal abnormality was demonstrated in 0.58% (95% CI: 0.28-1.19) of cases which did not differ significantly from that reported in female newborns (0.79%; 95% CI: 0.68-0.94). Balanced reciprocal translocation was observed in 0.4% of patients (n = 5), paracentric inversion of chromosome X in 0.08% (n = 1) and gonosomal mosaicism in 0.08% (n = 1). However, chromosomal aberrations were less common among females with primary infertility compared to those with secondary infertility (0.25 versus 1.25%, P = 0.04). The present study suggests that routine cytogenetic analysis cannot be advocated in normovulatory infertile women. Nevertheless, the relatively higher frequency of abnormal karyotypes in women with secondary infertility indicates that this subgroup of patients might benefit from a routine karyotype analysis.

Vecteurs de paludisme : du terrain à la génétique moléculaire Recherches en Afrique

Only about 60 Anopheline species transmit malaria among more than 3,000 mosquito species recorded in the world. In Africa, the major vectors are Anopheles gambiae,An. arabiensis, An. funestus, An. nili and An. moucheti. They all belong to species complexes or groups of closely related species that are very difficult to set apart on morphological grounds, but which may have highly variable behaviours and vectorial capacities. Understanding this complexity is of major importance in vector control programs or for implementing any public health intervention program such as drugs or vaccine trials. Among the seven species of the complex,Anopheles gambiaes.s. shows a huge chromosomal polymorphism related to adaptation to specific natural or anthropic environments, from equatorial forested Africa to dry sahelian areas. Recent studies conducted in West and Central Africa suggest an incipient speciation into 2 molecular forms provisionally called M and S. A similar evolutionary phenomenon is observed in An. funestus, in which sympatric populations carrying specific chromosomal paracentric inversions showed restricted gene flow. Distribution of species from An. nili group and An. moucheti complex is restricted to more humid regions of Africa. However in some areas these species play the major role in malaria transmission. Comprehensive knowledge of transmission cycles and of behavioural and underlying genetic heterogeneities that exist within and among natural vector populations will thus benefit the whole area of malaria control and epidemiology. Molecular and genetic studies, as well as in depth monitoring of vector biology, have been recently facilitated by advances in functional and comparative genomics, including recent publication of the nearly complete genome sequence of An. gambiae. Challenge for the next years is to answer to the very simple question: why is an insect a vector?

Paracentric inversion of chromosome 12 in myelodysplasia

Paracentric inversion of chromosome 12 in myelodysplasia

Renal Metanephric Adenoma with Previously Unreported Cytogenetic Abnormalities: Case Report and Review of the Literature

We report a case of a renal metanephric adenoma in a 10-year-old boy, in which cytogenetic analysis showed a balanced translocation, t(9;15)(p24;q24) and a balanced paracentric inversion of chromosome 12, inv(12)(q13q15). Immunohistochemically, the tumor showed diffuse reactivity for cytokeratin AE1/AE3, CAM5.2, CD57, and WT1; patchy reactivity for CD56; and focal reactivity for cytokeratin 7, epithelial membrane antigen, and CD10. Tumor cells were entirely nonreactive for alpha-methyl acyl coenzyme A racemase. Published cytogenetic data for metanephric adenomas are limited, and this is the first report of these cytogenetic abnormalities. The involvement of the chromosome region 9p24 is particularly interesting because of the recent identification of a tumor suppressor gene, KANK (kidney ankyrin repeat-containing protein), at this locus.

Paracentric inversion of chromosome 7(q22–31) associated with nonobstructive azoospermia

To examine an unusual paracentric inversion of chromosome 7 found in an azoospermic man. Case report. Infertility clinic at a private hospital. An azoospermic but otherwise apparently healthy man. Karyotyping with peripheral blood lymphocytes, microdissection testicular sperm extraction (TESE), and intracytoplasmic sperm injection (ICSI). Sperm count and GBG banding. A karyogram revealed paracentric inversion of chromosome 7 with breakpoints at 7q22 and 7q31. Testicular histopathology confirmed the Sertoli cell-only syndrome. Successful pregnancy and delivery were achieved with microdissection TESE and ICSI. Paracentric inversion of chromosome 7(q22-31) associated with nonobstructive azoospermia is rare. Chromosome 7q22-31 may be responsible for impaired spermatogenesis.

Oncogenic AKAP9-BRAF fusion is a novel mechanism of MAPK pathway activation in thyroid cancer

Genes crucial for cancer development can be mutated via various mechanisms, which may reflect the nature of the mutagen. In thyroid papillary carcinomas, mutations of genes coding for effectors along the MAPK pathway are central for transformation. BRAF point mutation is most common in sporadic tumors. By contrast, radiation-induced tumors are associated with paracentric inversions activating the receptor tyrosine kinases RET and NTRK1. We report here a rearrangement of BRAF via paracentric inversion of chromosome 7q resulting in an in-frame fusion between exons 1-8 of the AKAP9 gene and exons 9-18 of BRAF. The fusion protein contains the protein kinase domain and lacks the autoinhibitory N-terminal portion of BRAF. It has elevated kinase activity and transforms NIH3T3 cells, which provides evidence, for the first time to our knowledge, of in vivo activation of an intracellular effector along the MAPK pathway by recombination. The AKAP9-BRAF fusion was preferentially found in radiation-induced papillary carcinomas developing after a short latency, whereas BRAF point mutations were absent in this group. These data indicate that in thyroid cancer, radiation activates components of the MAPK pathway primarily through chromosomal paracentric inversions, whereas in sporadic forms of the disease, effectors along the same pathway are activated predominantly by point mutations.

Maternal paracentric inversion of chromosome 9 and recurrent pregnancy loss: Identification by Preimplantation Genetic Diagnosis (PGD) of a putative dicentric chromosome 9 in blastomeres from 6–8 cell cleaving embryos

Paracentric chromosome inversions occur when a single chromosome undergoes two breaks and recombines with the segment between the two breaks inverted. Paracentric inversions do not include the centromere. Inversion carriers are most often phenotypically normal, however they are at risk of producing genetically unbalanced gametes due to recombination within inverted segments. The traditional model for the meiotic behavior of a pair of chromosomes heterozygous for a paracentric inversion assumes occasional crossing over within the inverted region. When this occurs, a dicentric and an acentric are formed. When the dicentric’s two centromeres subsequently separate toward opposite poles, it breaks into two monocentrics. Resulting cells will have deficiencies, and may have duplications, of genetic material. Crossing over need not occur within the inversion; therefore chromosomally balanced gametes predominate. As unbalanced gametes are relatively rare and most of these would result in early pregnancy loss, paracentric inversions are rarely found to be involved in reproductive failure. Two recent cases of unbalanced live-born progeny with intact dicentrics have been described. It appears that, in these cases, one of the two centromeres inactivated immediately after dicentric formation with subsequent migration of an intact dicentric into the secondary oocyte or ootid. Therefore, we will determine the cytogenetic status of embryos from a female paracentric inversion carrier. Analysis of embryonic cells apparently with a derived dicentric chromosome. Case report. In vitro fertilization (IVF) and PGD was performed on a couple due to three pregnancy losses. The husband has normal semen parameters. The 36 year old female is a carrier of a paracentric inversion of chromosome 9[46, XX, inv(9)(q21.2q22.3)]. PGD-aneuploidy was first performed for chromosomes 9, 14, 15, 22, X and Y. We next performed PGD for teleomeric sequences of chromosome 9. Routine protocols were followed. Microscopy was performed using an epi-fluorescent microscope and multiple fluorescent signal detection was accomplished using a Spectral Cube imaging system. Eleven of 13 embryos were aneuploid. Seven of the 11 showed three chromosome 9 centromeres. As the standard model of paracentric behavior does not predict trisomic progeny, 9p and 9q telomere sequences were analyzed to determine whether entire chromosome 9s were present within the blastomeres. Five of 7 trisomy 9 blastomeres showed three 9p and one 9q sequence. The other two showed two 9p and two 9q sequences. Each of the remaining (n = 6) diploid chromosome 9 embryos tested showed the correct number of 9 telomeric sequences expected from two entire chromosome 9s. Dicentrics whose centromeres are joined by their q arms will have two p-arm and no q-arm telomeric sequences. Cells with a dicentric and a normal chromosome will therefore have a total of 3 p-arm and one q-arm telomeres. This was found in 5 of 7 embryos with three chromosome 9 centromeres. The apparent presence of a dicentric chromosome in a high percentage of embryos suggests the possibility that the recombinational event took place during a mitotic division in the maternal germ line. To our knowledge, this is the first report of a dicentic chromosome in embryos from couples undergoing IVF-PGD and the first suggesting mitotic recombination as a mechanism for the generation of a dicentric chromosome.

Habitat-related genetic substructuring in a marine snail (Littorina fabalis) involving a tight link between an allozyme and a DNA locus

Metapopulation structure and genetic differentiation among subpopulations will be tightly related to patterns and processes of local adaptation and microevolution. Understanding the mechanisms behind genetic substructuring will aid in the interpretation of species’ ecological performances and strategies. The marine gastropod Littorina fabalis occurs in two size morphs – a small and a large – found in microhabitats of different wave exposure, but overlapping in distribution where wave exposure is intermediate. Earlier studies have found substantial genetic differentiation linked to morph in one allozyme locus (arginine kinase), while 29 other allozyme loci reveal no or minute differences between morphs. Here we add new results showing DNA variation in a RAPD marker being tightly linked to the allozyme variation. Indeed, 97% of the snails homozygotic for one of the Ark alleles had a unique DNA band, while 89% of the snails homozygotic for the other Ark allele lacked the marker. We discuss alternative hypotheses explaining the genetic substructure and suggest that the linkage of size, allozyme and DNA traits might be due to a paracentric chromosomal inversion involving loci coding for these traits. A genetic linkage of traits might promote microhabitat specialization of this species, and such a chromosomal transformation may therefore be adaptive. © 2004 The Linnean Society of London, Biological Journal of the Linnean Society, 2004, 81, 301–306.

Stable chromosomal inversion polymorphisms and insecticide resistance in the malaria vector mosquito Anopheles gambiae (Diptera: Culicidae).

Anopheles gambiae Giles has been implicated as a major vector of malaria in Africa. A number of paracentric chromosomal inversions have been observed as polymorphisms in wild and laboratory populations of this species. These polymorphisms have been used to demonstrate the existence of five reproductive units in West African populations that are currently described as incipient species. They have also been correlated with various behavioral characteristics such as adaptation to aridity and feeding preference and have been associated with insecticide resistance. Two paracentric inversions namely 2La and 2Rb are highly ubiquitous in the wild and laboratory populations sampled. Both inversions are easily conserved during laboratory colonization of wild material and one shows significant positive heterosis with respect to Hardy-Weinberg proportions. Inversion 2La has previously been associated with dieldrin resistance and inversion 2Rb shows an association with DDT resistance based on this study. The stability and maintenance of these inversions as polymorphisms provides an explanation for the transmission and continued presence of DDT and dieldrin resistance in a laboratory strain of An. gambiae in the absence of insecticide selection pressure. This effect may also be operational in wild populations. Stable inversion polymorphism also provides a possible mechanism for the continual inheritance of suitable genetic factors that otherwise compromise the fitness of genetically modified malaria vector mosquitoes.

Receptor tyrosine kinase mutations in myeloid neoplasms.

Receptor tyrosine kinase mutations in myeloid neoplasms.

Analysis of the Population Structure ofAnopheles funestus(Diptera: Culicidae) from Western and Coastal Kenya Using Paracentric Chromosomal Inversion Frequencies

In total, 324 Anopheles funestus Giles specimens collected from seven houses in western Kenya and seven in coastal Kenya were scored for their paracentric chromosomal inversions with the aim of determining the level of genetic differentiation based on these inversions. Houses in each area were within a 2-km radius. The two areas are approximately 700 km apart. Only inversions 2a, 3a, 3b, and 5a were found to be polymorphic. Levels of polymorphism varied greatly between inversions. There were no significant deviations from Hardy-Weinberg expectations for samples from individual houses at one site or when data for houses in each area were pooled. Overall, the level of differentiation between western and coastal Kenya was significant, suggesting that the two populations are genetically isolated. Results based on inversion 2a alone were, however, not consistent with this conclusion. Founder effects and selection against the 2a inversion are discussed as possible explanations for this discrepancy.

Chromosomal variability ofDrosophila polymorphapopulations from Atlantic Forest remnants of continental and insular environments in the State of Santa Catarina, Brazil

In the present study, we investigated chromosomal polymorphism for paracentric inversions found in Drosophila polymorpha populations common in five fly communities (one continental and four insular) collected in Atlantic For- est remnants in Santa Catarina, Brazil, during a one-year sampling. Our analyses showed that the more polymorphic the populations, the greater the abundance of flies. The insular populations were more polymorphic than the continental one, probably because the greater environmental heterogeneity found in the islands provided more niches for fly colonisation and was more suitable for supporting a community. Stochastic effects, however, need to be taken into account to under- stand the low polymorphism found at the continental site, since the D. polymor- pha sample collected there was small. We also present here the occurrence of six previously undescribed paracentric chromosomal inversions in heterozygosis, increasing to 7 the number of variants identified in the D. polymorpha polytene chromosomes.

Inv(12)(q15q24): A Nonrandom Change Associated with Myelodysplasia?

A patient with refractory anemia and a paracentric inversion of chromosome 12, inv(12)(q15q24), is described. This is the second reported case with this chromosome anomaly, suggesting that this rearrangement is a rare but nonrandom change associated with myelodysplastic syndromes.