A telomere-to-telomere assembly of Oscheius tipulae and the evolution of rhabditid nematode chromosomes

Eukaryotic chromosomes have phylogenetic persistence. In many taxa, each chromosome has a single functional centromere with essential roles in spindle attachment and segregation. Fusion and fission can generate chromosomes with no or multiple centromeres, leading to genome instability. Groups with holocentric chromosomes (where centromeric function is distributed along each chromosome) might be expected to show karyotypic instability. This is generally not the case, and in Caenorhabditis elegans, it has been proposed that the role of maintenance of a stable karyotype has been transferred to the meiotic pairing centers, which are found at one end of each chromosome. Here, we explore the phylogenetic stability of nematode chromosomes using a new telomere-to-telomere assembly of the rhabditine nematode Oscheius tipulae generated from nanopore long reads. The 60-Mb O. tipulae genome is resolved into six chromosomal molecules. We find the evidence of specific chromatin diminution at all telomeres. Comparing this chromosomal O. tipulae assembly with chromosomal assemblies of diverse rhabditid nematodes, we identify seven ancestral chromosomal elements (Nigon elements) and present a model for the evolution of nematode chromosomes through rearrangement and fusion of these elements. We identify frequent fusion events involving NigonX, the element associated with the rhabditid X chromosome, and thus sex chromosome-associated gene sets differ markedly between species. Despite the karyotypic stability, gene order within chromosomes defined by Nigon elements is not conserved. Our model for nematode chromosome evolution provides a platform for investigation of the tensions between local genome rearrangement and karyotypic evolution in generating extant genome architectures.

Karyotype mosaicism in early generation synthetic hexaploid wheats

It is known that both the number and the structure of somatic chromosomes can vary in early generation hexaploid wheats. The phenomenon is generally assumed to arise as a result of the meiotic instability characteristic of freshly created allopolyploids. Here, an analysis of the somatic karyotype of a set of 33 early generation synthetic hexaploid wheats has revealed that variation, taking the form of sub-chromosomal fragments and inter-chromosomal translocations, can also arise in somatic tissue. A possible explanation for the observations was that karyotypic instability in early generation hexaploid wheat probably occurs not just during sporogenesis, but also in somatic tissue. However, other factors such as the use of nitrous oxide during the experiments could also cause the chromosome variations, and additional experimentation would be required to determine the most likely.

Donkey genome and insight into the imprinting of fast karyotype evolution

The donkey, like the horse, is a promising model for exploring karyotypic instability. We report the de novo whole-genome assemblies of the donkey and the Asiatic wild ass. Our results reflect the distinct characteristics of donkeys, including more effective energy metabolism and better immunity than horses. The donkey shows a steady demographic trajectory. We detected abundant satellite sequences in some inactive centromere regions but not in neocentromere regions, while ribosomal RNAs frequently emerged in neocentromere regions but not in the obsolete centromere regions. Expanded miRNA families and five newly discovered miRNA target genes involved in meiosis may be associated with fast karyotype evolution. APC/C, controlling sister chromatid segregation, cytokinesis and the establishment of the G1 cell cycle phase were identified by analysis of miRNA targets and rapidly evolving genes.

Evaluation of the cytogenetic aberration pattern in amyloid light chain amyloidosis as compared with monoclonal gammopathy of undetermined significance reveals common pathways of karyotypic instability

Chromosomal aberrations (CAs) have emerged as important pathogenetic and prognostic factors in plasma cell disorders. Using interphase fluorescence in situ hybridization (FISH) analysis, we evaluated CAs in a series of 75 patients with amyloid light chain amyloidosis (AL) as compared with 127 patients with monoclonal gammopathy of unknown significance (MGUS). We investigated IgH translocations t(11;14), t(4;14), and t(14;16) as well as gains of 1q21, 11q23, and 19q13 and deletions of 8p21, 13q14, and 17p13, detecting at least one CA in 89% of the patients. Translocation t(11;14) was the most frequent aberration in AL, with 47% versus 26% in MGUS (P = .03), and was strongly associated with the lack of an intact immunoglobulin (P < .001), thus contributing to the frequent light chain subtype in AL. Other frequent aberrations in AL included deletion of 13q14 and gain of 1q21, which were shared by MGUS at comparable frequencies. The progression to multiple myeloma (MM) stage I was paralleled by an increased frequency of gain of 1q21 (P = .001) in both groups. Similar branching patterns were observed in an oncogenetic tree model, indicating a common mechanism of underlying karyotypic instability in these plasma cell disorders.

Karyotypic Instability Is Common in t(8;21) AML at Relapse.

The t(8;21) is one of the most frequent chromosomal translocation in acute myeloid leukemia (AML). The t(8;21) AML is commonly associated with a favorable prognosis in regard to overall survival (OS) as well as high complete remission (CR) rate. However, approximately 35–45% of patients in first CR will relapse within 5 years. In t(8;21) AML, a worse outcome has been reported in patients with a high presenting white blood cell count, expression of CD56, and activating mutation of c-Kit (D816V). The clinical outcome of t(8;21) AML in first relapse have not been clarified. Further, factors predicting the outcome of patients in first relapse have not been defined. In this study, we evaluated the clinical features, the prognostic significance of c-Kit (D816V) mutation and karyotype instability in 14 relapsed patients among 32 de novo t(8;21) AML patients treated in our institution during the period 1987 to 2006. These 32 patients’ ages ranged from 15 to 73 years (median, 46 years) and they were classified as RAEB-T (n=2), M1 (n=2) and M2 (n=28) according to the FAB classification. Another additional cytogenetic aberrations at diagnosis were loss of Y (n=5), del(9q) (n=3), del(7q) (n=1), and trisomy 4 and 6 (n=1). Of the 32 patients, 14 (44%) were treated with BHAC-DMP (behenoylcytosine arabinoside, daunorubicin, 6-mercaptopurine, and prednisolone) induction therapy and 18 (56%) were treated with induction therapy consisted of an idarubicin or daunorubicin in combination with cytarabine (200mg/m2 for 7 days). For post remission therapy, 26 (82%) were received sequential multiagent chemotherapy and 6 (18%) were received high dose cytarabine alone. All patients achieved first CR (100%), median OS and disease-free survival (DFS) was 5.1 years and 2.4 years, respectively. 14 (44%) had a relapsed and the median duration from initial diagnosis to relapse amounted to 10.5 months (range, 3.8 months to 2.4 years). Among the 14 relapsed patients treated with salvage therapy, 9 (64%) of patients achieved second CR and median OS and DFS after first relapse was 2.0 years and 1.0 year. 4 patients (12%) with c-Kit (D816V) mutation at first diagnosis relapsed within 12 months with the same mutation and died within 2.2 years. Karyotype examination at first relapse were performed in 12 patients and additional karyotypic abnormalities were found in 6 patients. Three or more complex aberrations involving del(5q), del(6q), del(7q) or del(9q) were found in all of 6 patients. Among 6 patients showing karyotypic evolution (KE), 5 achieved second CR and relapsed again shortly. Two patients with KE had c-Kit D816 mutation at diagnosis, however, c-Kit mutations of exon 17 and 8 were not detected in 4 patients with KE at diagnosis and during the course of disease. In conclusion, karyotypic instability is common in t(8;21) AML at relapse and is not associated with c-Kit mutation. Karyotypic instability may contribute to the development of refractoriness of AML to chemotherapy.