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• Large structural variations frequently occur in higher plants; however, the impact of such variations on plant diversification, adaptation and domestication remains elusive. • Here, we mapped and characterised a reciprocal chromosomal translocation in soybeans and assessed its effects on diversification and adaptation of wild (Glycine soja) and semiwild (Glycine gracilis) soybeans, and domestication of cultivated soybean (Glycine max), by tracing the distribution of the translocation in the USDA Soybean Germplasm Collection and population genetics analysis. • We demonstrate that the translocation occurred through CACTA transposon-mediated chromosomal breakage in wild soybean c. 0.34 Ma and is responsible for semisterility in translocation heterozygotes and reduces their reproductive fitness. The translocation has differentiated Continental (i.e. China and Russia) populations from Maritime (i.e. Korea and Japan) populations of G. soja and predominately adapted to cold and dry climates. Further analysis revealed that the divergence of G. max from G. soja predates the translocation event and that G. gracilis is an evolutionary intermediate between G. soja and G. max. • Our results highlight the effects of a chromosome rearrangement on the processes leading to plant divergence and adaptation, and provides evidence that suggests G. gracilis, rather than G. soja, as the ancestor of cultivated soybean.

Chromosomal rearrangements of the human MLL (mixed lineage leukemia) gene are associated with high-risk infant, pediatric, adult and therapy-induced acute leukemias. We used long-distance inverse-polymerase chain reaction to characterize the chromosomal rearrangement of individual acute leukemia patients. We present data of the molecular characterization of 1590 MLL -rearranged biopsy samples obtained from acute leukemia patients. The precise localization of genomic breakpoints within the MLL gene and the involved translocation partner genes (TPGs) were determined and novel TPGs identified. All patients were classified according to their gender (852 females and 745 males), age at diagnosis (558 infant, 416 pediatric and 616 adult leukemia patients) and other clinical criteria. Combined data of our study and recently published data revealed a total of 121 different MLL rearrangements, of which 79 TPGs are now characterized at the molecular level. However, only seven rearrangements seem to be predominantly associated with illegitimate recombinations of the MLL gene (∼90%): AFF1/AF4 , MLLT3/AF9 , MLLT1/ENL , MLLT10/AF10 , ELL , partial tandem duplications ( MLL PTDs) and MLLT4/AF6 , respectively. The MLL breakpoint distributions for all clinical relevant subtypes (gender, disease type, age at diagnosis, reciprocal, complex and therapy-induced translocations) are presented. Finally, we present the extending network of reciprocal MLL fusions deriving from complex rearrangements.

The identification of structural variant (SV) breakpoints plays a crucial role in understanding the genetic variants, mutagenic mechanisms, and functional consequences that drive various genetic diseases. While next-generation sequencing (NGS) has become a cornerstone in single nucleotide variant (SNP) discovery and characterization, short-read NGS technology faces significant challenges in resolving large genomic rearrangements such as duplications, deletions, inversions, and translocations. Nanopore sequencing offers a promising alternative by enabling precise mapping of chromosomal rearrangement breakpoints, and characterization of chromosomal alterations, thereby improving the genetic diagnosis of such conditions. Using long-read whole-genome sequencing, we examined the breakpoints of a cytogenetically balanced chromosomal translocation, t(8;22)(q13.3;q11.23), initially detected during prenatal diagnosis and later confirmed as de novo in a patient who developed NF2-associated schwannomatosis in late infancy. Nanopore sequencing revealed that the translocation disrupted the NF2 gene. This case highlights the power of nanopore long-read sequencing in detecting the exact consequences of de novo , apparently balanced translocations and in uncovering the genetic underpinnings of abnormal phenotypes. Given its ability to resolve complex SVs with high precision, nanopore sequencing might be considered a valuable complement to conventional genetic diagnostic methods, enhancing our understanding of genetic diseases and potentially improving diagnostic yield and risk assessment.

Reciprocal translocation and Robertsonian translocation are known to be causative factors of male infertility. However, the association between autosomal reciprocal translocation, Robertsonian translocation and semen parameters remains controversial. We performed a retrospective study and systematic review to investigate semen parameters in patients with autosomal reciprocal translocation or Robertsonian translocation. We recruited a total of 1,033 controls, 723 reciprocal translocation carriers and 326 Robertsonian translocation carriers. Men in the control, reciprocal translocation and Robertsonian translocation groups had a median age of 32.0 (95% CI, 32.0–33.0), 32.0 (95% CI, 32.0–33.0) and 33.0 (95% CI, 32.0–33.0) years respectively. Results showed that sperm concentration, total number per ejaculate, total motility, progressive motility of autosomal reciprocal translocation and Robertsonian translocation carriers were statistically lower than controls (p < .001). Eleven studies featuring 794 patients were enrolled in this systematic review. Compared with controls, autosomal reciprocal translocation and Robertsonian translocation carriers showed lower sperm concentration, total motility, progressive motility and normal morphology. Our results support the conclusion that sperm concentration, total number per ejaculate, total motility and progressive motility are significantly lower in autosomal reciprocal translocation and Robertsonian translocation carriers than in controls.

Gene editing techniques have been extensively used to attempt to model recurrent genomic rearrangements found in tumor cells. These methods involve the induction of double-strand breaks at endogenous loci followed by the identification of breakpoint junctions within a population, which typically arise by nonhomologous end joining. The low frequency of these events, however, has hindered the cloning of cells with the desired rearrangement before oncogenic transformation. Here we present a strategy combining CRISPR-Cas9 technology and homology-directed repair to allow for the selection of human mesenchymal stem cells harboring the oncogenic translocation EWSR1–WT1 found in the aggressive desmoplastic small round cell tumor. The expression of the fusion transcript is under the control of the endogenous EWSR1 promoter and, importantly, can be conditionally expressed using Cre recombinase. This method is easily adapted to generate any cancer-relevant rearrangement.

Chromosomal translocations are products of the illegitimate repair of DNA double-strand breaks (DSBs). Their formation can bring about significant structural and molecular changes in the cell that can be physiologically and pathologically relevant. The induced changes may lead to serious and life-threatening diseases such as cancer. As a growing body of evidence suggests, the formation of chromosomal translocation is not only affected by the mere close spatial proximity of gene loci as potential translocation partners. Several factors may affect formation of chromosomal translocations, including chromatin motion to the potential sources of DSBs in the cell. While these can be apparently random events, certain chromosomal translocations appear to be cell-type-specific. In this review, we discuss how chromosomal translocations are formed and explore how different cellular factors contribute to their formation.

BCL6 translocation is one of the most common chromosomal translocations in cancer and results in its enhanced expression in germinal center B cells. It involves the fusion of BCL6 with any of its twenty-six Ig and non-Ig translocation partners associated with diffuse large B cell lymphoma (DLBCL). Despite being discovered long back, the mechanism of BCL6 fragility is largely unknown. Analysis of the translocation breakpoints in 5′ UTR of BCL6 reveals the clustering of most of the breakpoints around a region termed Cluster II. In silico analysis of the breakpoint cluster sequence identified sequence motifs that could potentially fold into non-B DNA. Results revealed that the Cluster II sequence folded into overlapping hairpin structures and identified sequences that undergo base pairing at the stem region. Further, the formation of cruciform DNA blocked DNA replication. The sodium bisulfite modification assay revealed the single-strandedness of the region corresponding to hairpin DNA in both strands of the genome. Further, we report the formation of intramolecular parallel G4 and triplex DNA, at Cluster II. Taken together, our studies reveal that multiple non-canonical DNA structures exist at the BCL6 cluster II breakpoint region and contribute to the fragility leading to BCL6 translocation in DLBCL patients.

Background As the inflorescence of wheat, spike architecture largely determines grain productivity. Dissecting the genetic basis for the spike morphology of wheat can contribute to the designation of ideal spike morphology to improve grain production. Results The present study characterizes a dense spike1 ( ds1 ) mutant, derived from Nongda3753, induced by EMS treatment, which exhibits a dense spike and reduced plant height. Through bulked segregant analysis sequencing (BSA-Seq) of two segregating populations, ds1 was mapped to the short arm of chromosome 7B. Further genotypic and phenotypic analyses of the residual heterozygous lines from F 3 to F 6 of Yong3002× ds1 revealed that there was a 0-135 Mb deletion in chromosome 7B associated with the dense spike phenotype. The reads count analysis of the two bulks in BSA-Seq, along with the cytological analysis of ds1 , ND3753, NIL- ds1 and NIL-Y3002, confirmed that the partial unidirectional translocation of 5AL (543–713 Mb) to 7BS (0-135 Mb) exists in ds1 . This translocation led to an increase in both copy number and expression of the Q gene, which is one of the reasons for the dense spike phenotype observed in ds1 . Conclusion Partial unidirectional translocation from 5AL to 7BS was identified in the EMS-induced mutant ds1 , which exhibits dense spike phenotype. This research illustrates the effect of one chromosome structure variation on wheat spike morphology, and provides new materials with several chromosome structure variations for future wheat breeding.

Fibroblast growth factors (FGFs) and their receptors (FGFRs) play critical roles in many biological processes and developmental functions. Chromosomal translocation of FGFRs result in the formation of chimeric FGFR fusion proteins, which often cause aberrant signaling leading to the development and progression of human cancer. Due to the high recurrence rate and carcinogenicity, oncogenic FGFR gene fusions have been identified as promising therapeutic targets. Erdafitinib and pemigatinib, two FGFR selective inhibitors targeting FGFR fusions, have been approved by the U.S. Food and Drug Administration (FDA) to treat patients with urothelial cancer and cholangiocarcinoma, respectively. Futibatinib, a third-generation FGFR inhibitor, is under phase III clinical trials in patients with FGFR gene rearrangements. Herein, we review the current understanding of the FGF/FGFRs system and the oncogenic effect of FGFR fusions, summarize promising inhibitors under clinical development for patients with FGFR fusions, and highlight the challenges in this field.

High mobility group AT-hook 2 (HMGA2) has been associated with increased cell proliferation and cell cycle dysregulation, leading to the ontogeny of varied tumor types and their metastatic potentials, a frequently used index of disease prognosis. In this review, we deepen our understanding of HMGA2 pathogenicity by exploring the mechanisms by which HMGA2 misexpression and ectopic expression induces mesenchymal and epithelial tumorigenesis respectively and distinguish the pathogenesis of benign from malignant mesenchymal tumors. Importantly, we highlight the regulatory role of let-7 microRNA family of tumor suppressors in determining HMGA2 misexpression events leading to tumor pathogenesis and focused on possible mechanisms by which HMGA2 could propagate lymphangioleiomyomatosis (LAM), benign mesenchymal tumors of the lungs. Lastly, we discuss potential therapeutic strategies for epithelial and mesenchymal tumorigenesis based on targeting the HMGA2 signaling pathway.