Pericentric Inversion Research Articles

Epigenetic state and gene expression remain stable after CRISPR/Cas-mediated chromosomal inversions.

The epigenetic state of chromatin, gene activity and chromosomal positions are interrelated in plants. In Arabidopsis thaliana, chromosome arms are DNA-hypomethylated and enriched with the euchromatin-specific histone mark H3K4me3, while pericentromeric regions are DNA-hypermethylated and enriched with the heterochromatin-specific mark H3K9me2. We aimed to investigate how the chromosomal location affects epigenetic stability and gene expression by chromosome engineering. Two chromosomal inversions of different sizes were induced using CRISPR/Cas9 to move heterochromatic, pericentric sequences into euchromatic regions. The epigenetic status of these lines was investigated using whole-genome bisulfite sequencing and chromatin immunoprecipitation. Gene expression changes following the induction of the chromosomal inversions were studied via transcriptome analysis. Both inversions had a minimal impact on the global distribution of histone marks and DNA methylation patterns, although minor epigenetic changes were observed across the genome. Notably, the inverted chromosomal regions and their borders retained their original epigenetic profiles. Gene expression analysis showed that only 0.5-1% of genes were differentially expressed genome-wide following the induction of the inversions. CRISPR/Cas-induced chromosomal inversions minimally affect epigenetic landscape and gene expression, preserving their profiles in subsequent generations.

Fertility problems in men carrying chromosome 7 inversion: A retrospective, observational study.

Infertility is a worldwide public health issue. Fifty percent of infertile couples are male-only. A number of male infertility etiologies are significantly influenced by chromosomal abnormalities. Clinical manifestations, however, differ according to the presence of aberrant chromosomes and distinct breakpoints. The reproductive effects of inversion are evident in those who carry it. The influence of inverted carriers on male infertility may be explained by the interchromosomal effect, although further research is still needed to determine the precise mechanism. Furthermore, selecting clinical reproductive technology presents difficulties for both physician and patients. The aim of this study is to determine the clinical characteristics of 4 males who have an inversion of chromosome 7, and to investigate the connection between the breakpoints of this chromosome and male infertility. For each patient, cytogenetic and semen analyses were carried out. Using PubMed or Online Mendelian Inheritance in Man, relevant research and genes on breakpoints on chromosome 7 were found. This study includes 4 male infertile patients, all of whom had chromosome 7 inversions. 46,XY,inv(7)(p22q22), 46,XY,inv(7)(p21q11.2), 46,XY,inv(7)(p21q21), and 46,XY,inv(7)(p15q36) were the results of the cytogenetic analysis. Three cases of aberrant semen parameters were detected by semen detection. After a literature search, 21 cases of chromosome 7 inversion carriers were found. These carrier couples have varying reproductive histories. Among the 5 cases where semen parameters are available, 1 is azoospermia and 1 is oligoasthenozoospermia. Five significant genes on chromosome 7 have been linked to male infertility. Changes in semen parameters may be connected to the breakpoints 7q11, 7q21, 7q22, and 7q36. Physicians should take into account the relevant breakpoints when offering genetic counseling to patients who have chromosome 7 inversion.

Maternal X chromosome pericentric inversion resulting in the genetic analysis of offspring pedigrees with deletions at Xp22.33 and Xp22.33p11.3, and duplications at Xq27.3q28: Case report.

This study investigates the genetic cause of primary infertility and short stature in a woman, focusing on maternal X chromosome pericentric inversion and its impact on offspring genetic outcomes, including deletions at Xp22.33 and Xp22.33p11.3, and duplications spanning Xq27.3 to the distal end of the X chromosome's long arm. The proband presented with primary infertility, menstrual irregularities, and ultrasound findings indicating a small uterus. Peripheral blood G-banded karyotype analysis and single nucleotide polymorphism array analysis revealed a 46,X,rec(X)dup(Xq)inv(X)(p11.3q27)dmat karyotype in the proband, inherited from her mother. Genetic testing identified pathogenic deletions at Xp22.33 and Xp22.33p11.3, and a pathogenic duplication at Xq27.3q28. Genetic counseling and pedigree analysis were conducted to trace the maternal origin of the pericentric inversion and assess recurrence risks. The study confirmed the maternal X chromosome pericentric inversion caused the observed genetic abnormalities, with a 50% recurrence risk for X-linked inheritance. Maternal X chromosome pericentric inversion significantly affects offspring genetic outcomes. Assisted reproductive technologies, including in vitro fertilization with preimplantation genetic testing, are recommended to reduce recurrence risks in future pregnancies. Prenatal genetic testing is advised for natural conception to ensure fetal genetic health.

Evolutionary adaptation under climate change: Aedes sp. demonstrates potential to adapt to warming

Climate warming is expected to shift the distributions of mosquitoes and mosquito-borne diseases, promoting expansions at cool range edges and contractions at warm range edges. However, whether mosquito populations could maintain their warm edges through evolutionary adaptation remains unknown. Here, we investigate the potential for thermal adaptation in Aedes sierrensis, a congener of the major disease vector species that experiences large thermal gradients in its native range, by assaying tolerance to prolonged and acute heat exposure, and its genetic basis in a diverse, field-derived population. We found pervasive evidence of heritable genetic variation in mosquito heat tolerance, and phenotypic trade-offs in tolerance to prolonged versus acute heat exposure. Further, we found genomic variation associated with prolonged heat tolerance was clustered in several regions of the genome, suggesting the presence of larger structural variants such as chromosomal inversions. A simple evolutionary model based on our data estimates that the maximum rate of evolutionary adaptation in mosquito heat tolerance will exceed the projected rate of climate warming, implying the potential for mosquitoes to track warming via genetic adaptation.

A variant W chromosome in Centromochlus heckelii (Siluriformes, Auchenipteridae) and the role of repeated DNA in its heteromorphism.

Centromochlus heckelii has the lowest diploid chromosome number (2n = 46) and the only described heteromorphic sex chromosome system in Auchenipteridae. This study presents a population of C. heckelii from the Central Amazon basin with subtle variations in the karyotype composition and a variant W chromosome with distinct morphology and increased C-positive heterochromatin content. In this population, the W chromosome is subtelocentric, whereas the only previous study on C. heckelii reported a metacentric W chromosome. Constitutive heterochromatin (CH) and accumulation of microsatellite motifs have significantly contributed to this W chromosome enlargement. Notably, this population exhibits numerous interstitial telomeric sites (ITSs). Some of these ITSs might represent genuine chromosomal fusion points due to the reduced 2n; however, additional mechanisms, such as chromosomal inversions, translocations, transpositions, or association with satellite DNA, are likely responsible for this unusual pattern. The 18S rDNA sites were found in both the Z and W chromosomes of all individuals. However, two individuals exhibited an additional 18S rDNA site in a single homologous of the chromosome pair 20, characterizing an intrapopulation polymorphism. The 5S rDNA sites were found in two chromosome pairs, distinguishing this population from other Centromochlinae species and further supporting it as one of the most efficient cytotaxonomic markers within the subfamily.

Connections Across Open Water: A Bi-Organelle, Genomics-Scale Assessment of Atlantic-Wide Population Dynamics in a Pelagic, Endangered Apex Predator Shark (Isurus oxyrinchus).

Large-bodied pelagic sharks are key regulators of oceanic ecosystem stability, but highly impacted by severe overfishing. One such species, the shortfin mako shark (Isurus oxyrinchus), a globally widespread, highly migratory predator, has undergone dramatic population reductions and is now Endangered (IUCN Red List), with Atlantic Ocean mako sharks in particular assessed by fishery managers as overfished and in need of urgent, improved management attention. Genomic-scale population assessments for this apex predator species have not been previously available to inform management planning; thus, we investigated the population genetics of mako sharks across the Atlantic using a bi-organelle genomics approach. Complete mitochondrial genome (mitogenome) sequences and genome-wide SNPs from sharks distributed across the Atlantic revealed contrasting patterns of population structure across marker types. Consistent with this species' long-distance migratory capabilities, SNPs showed high connectivity and Atlantic panmixia overall. In contrast, there was matrilineal population genetic structure across Northern and Southern Hemispheres, suggesting at least large regional-scale female philopatry. Linkage disequilibrium network analysis indicated that makos possess a chromosomal inversion that occurs Atlantic wide, a genome feature that may be informative for evolutionary investigations concerning adaptations and the global history of this iconic species. Mitogenome diversity in Atlantic makos was high compared to other elasmobranchs assessed at the mitogenome level, and nuclear diversity was high compared to the two other, highly migratory pelagic shark species assessed with SNPs. These results support management efforts for shortfin makos on at least Northern versus Southern Hemisphere scales to preserve their matrilineal genetic distinctiveness. The overall comparative genetic diversity findings provide a baseline for future comparative assessments and monitoring of genetic diversity, as called for by the United Nations Convention on Biological Diversity, and cautious optimism regarding the health and recovery potential of Atlantic shortfin makos if further population declines can be halted.

The interplay of the translocase activity and protein recruitment function of PICH in ultrafine anaphase bridge resolution and genomic stability.

Incomplete sister centromere decatenation results in centromeric ultrafine anaphase bridges (UFBs). PICH (PLK1-interacting checkpoint helicase), a DNA translocase, plays a crucial role in UFB resolution by recruiting UFB-binding proteins and stimulating topoisomerase IIα. However, the involvement of distinct PICH functions in UFB resolution remains ambiguous. Here, we demonstrate that PICH depletion in non-transformed diploid cells induces DNA damage, micronuclei formation, p53 activation, G1-phase delay and cell death. Whole-genome sequencing reveals that segregation defects induced by PICH depletion cause chromosomal rearrangements, including translocations and inversions, emphasizing its significance in preserving genomic integrity. Furthermore, a PICH mutant that impairs UFB recruitment of BLM and RIF1 partially inhibits UFB resolution while a translocase-inactive mutant (PICHK128A) fails to resolve UFBs. Notably, expression of PICHK128A inhibits single-stranded UFB formation and induces hypocondensed chromosomes. We propose that PICH's translocase activity plays a dual role in promoting UFB resolution by facilitating the generation of single-stranded UFBs and stimulating topoisomerase IIα.

Genome-wide association studies unveil major genetic loci driving insecticide resistance in Anopheles funestus in four eco-geographical settings across Cameroon

BackgroundInsecticide resistance is jeopardising malaria control efforts in Africa. Deciphering the evolutionary dynamics of mosquito populations country-wide is essential for designing effective and sustainable national and subnational tailored strategies to accelerate malaria elimination efforts. Here, we employed genome-wide association studies through pooled template sequencing to compare four eco-geographically different populations of the major vector, Anopheles funestus, across a South North transect in Cameroon, aiming to identify genomic signatures of adaptive responses to insecticides.ResultsOur analysis revealed limited population structure within Northern and Central regions (FST<0.02), suggesting extensive gene flow, while populations from the Littoral/Coastal region exhibited more distinct genetic patterns (FST>0.049). Greater genetic differentiation was observed at known resistance-associated loci, resistance-to-pyrethroids 1 (rp1) (2R chromosome) and CYP9 (X chromosome), with varying signatures of positive selection across populations. Allelic variation between variants underscores the pervasive impact of selection pressures, with rp1 variants more prevalent in Central and Northern populations (FST>0.3), and the CYP9 associated variants more pronounced in the Littoral/Coastal region (FST =0.29). Evidence of selective sweeps was supported by negative Tajima’s D and reduced genetic diversity in all populations, particularly in Central (Elende) and Northern (Tibati) regions. Genomic variant analysis identified novel missense mutations and signatures of complex genomic alterations such as duplications, deletions, transposable element (TE) insertions, and chromosomal inversions, all associated with selective sweeps. A 4.3 kb TE insertion was fixed in all populations with Njombe Littoral/Coastal population, showing higher frequency of CYP9K1 (G454A), a known resistance allele and TE upstream compared to elsewhere.ConclusionOur study uncovered regional variations in insecticide resistance candidate variants, emphasizing the need for a streamlined DNA-based diagnostic assay for genomic surveillance across Africa. These findings will contribute to the development of tailored resistance management strategies crucial for addressing the dynamic challenges of malaria control in Cameroon.

Genomic Islands of Divergence Between Drosophila yakuba Subspecies are Predominantly Driven by Chromosomal Inversions and the Recombination Landscape.

During the early stages of local adaptation and speciation, genetic differences tend to accumulate at certain regions of the genome leading to the formation of genomic islands of divergence (GIDs). This pattern may be due to selection and/or difference in the rate of recombination. Here, we investigate the possible causes of GIDs in Drosophila yakuba mayottensis, and reconfirm using field collection its association with toxic noni (Morinda citrifolia) fruits on the Mayotte island. Population genomics revealed lack of genetic structure on the island and identified 23 GIDs distinguishing D. y. mayottensis from generalist mainland populations of D. y. yakuba. The GIDs were enriched with gene families involved in the metabolism of lipids, sugars, peptides and xenobiotics, suggesting a role in host shift. We assembled a new genome for D. y. mayottensis and identified five novel chromosomal inversions. Twenty one GIDs (~99% of outlier windows) fell in low recombining regions or subspecies-specific inversions. However, only two GIDs were in collinear, normally recombining regions suggesting a signal of hard selective sweeps. Unlike D. y. mayottensis, D. sechellia, the only other noni-specialist, is known to be homosequential with its generalist relatives. Thus, whereas structural variation may disproportionally shape GIDs in some species, striking parallel adaptations can occur between species despite distinct genomic architectures.

Progressive chromatin rewiring by ETO2::GLIS2 revealed in a human iPSC model of pediatric leukemia initiation.

Pediatric acute myeloid leukemia frequently harbor fusion oncogenes associated with poor prognosis, including KMT2A, NUP98 and GLIS2 rearrangements. While murine models have demonstrated their leukemogenic activities, the steps from a normal human cell to leukemic blasts remain unclear. Here, we precisely reproduced the inversion of chromosome 16 resulting in ETO2::GLIS2 fusion in human induced pluripotent stem cells (iPSC). IPSC-derived ETO2::GLIS2-expressing hematopoietic cells showed differentiation alterations in vitro and efficiently induced in vivo development of leukemia that closely phenocopied human acute megakaryoblastic leukemia (AMKL) reflected by flow cytometry and single cell transcriptomes. Comparison of iPS-derived cells with patient-derived cells revealed altered chromatin accessibility at early and later bona fide leukemia stages with aberrantly higher accessibility and expression of the osteogenic homeobox factor DLX3 that preceded increased accessibility to ETS factors. DLX3 overexpression in normal CD34+ cells increased accessibility to ETS motifs and reduced accessibility to GATA motifs. A DLX3 transcriptional module was globally enriched in both ETO2::GLIS2 AMKL and some aggressive pediatric osteosarcoma. Importantly, DLX3 knock-out abrogated leukemia initiation in this ETO2::GLIS2 iPSC model. Collectively, characterization of a novel human iPSC-derived AMKL model revealed hijacking of the osteogenic homeobox transcription factor DLX3 as an essential early step in chromatin changes and leukemogenesis driven by the ETO2::GLIS2 fusion oncogene.

Craniofrontonasal syndrome in a patient with an inv(X)(p22.2q13.1), separating EFNB1 from its enhancer.

Craniofrontonasal syndrome (CFNS) is an X-linked developmental disorder caused by loss of function variants (LOFVs) in the ephrin B1 (EFNB1) gene located on Xq13.1. In CFNS, unlike in other X-linked disorders, females with heterozygous EFNB1 pathogenic variants (PVs) have a severe phenotype, whereas males carrying hemizygous EFNB1 PVs have a mild phenotype. Here we report a female CFNS patient who was diagnosed with the typical features of CFNS as a new-born. Chromosomal analysis revealed a de novo pericentric inversion of one X chromosome; inv(X)(p22q13). Molecular testing for EFNB1 mutations and a SNP-array test for genomic imbalances returned negative results. We identified the inversion breakpoints using whole genome sequencing (WGS). One of the breakpoints was about 97 kbp downstream of the 3' end of the EFNB1 gene, separating a potential EFNB1 enhancer region from the EFNB1 gene. To our knowledge, this is the first case of CFNS caused by a large structural variant, altering the genomic and regulatory context of EFNB1.

Comparison of chromosomal microarray and karyotyping in prenatal diagnosis using 491 amniotic fluid samples.

This study was aimed to investigate the performance of chromosomal microarray analysis (CMA) in prenatal diagnosis compared with traditional karyotyping analysis. Both CMA and karyotyping analyses were performed to detect the karyotypes in the amniotic fluid of 491 pregnant women who got prenatal diagnosis at the Center of Prenatal Diagnosis of Shangrao (China) during January 2019 to April 2021. After excluding 2 samples in the CMA analysis and 2 samples in the karyotyping analysis which were failed in detection, the remaining 487 amniotic fluid samples were detected. Both CMA and karyotyping analyses identified 22 cases of aneuploidy chromosome abnormalities, including trisomy 21 (10 cases), trisomy 18 (4 cases), sex chromosome abnormality (5 cases), and other chromosome abnormalities (3 cases). In addition, CMA and karyotyping analyses found 8 cases of fetal chromosomal imbalance. Interestingly, abnormal results were detected by CMA analysis in 10 cases whose results were normal by karyotype analysis. Furthermore, 23 cases of copy number variation (CNVs) with variation of unknown clinical significance (VOUS) were detected by CMA, which accounted for 4.68% (23/491) in all cases. However, CMA was not able to accurately identify some complex karyotypes and mixed chimeras, including 2 cases of chimeras, 4 cases of balanced translocations, 4 cases of pericentric inversions, and 8 cases of other chromosome polymorphisms, indicating karyotyping analysis was superior to detect these chromosome abnormalities compared with CMA analysis. CMA was better in detecting the fracture sites, microduplication and microdeletion with definite pathogenicity, and CNVs with VOUS compared with karyotype analysis.

Multi-omics analysis detail a submicroscopic inv(15)(q14q15) generating fusion transcripts and MEIS2 and NUSAP1 haploinsufficiency

Inversions are balanced structural variants that often remain undetected in genetic diagnostics. We present a female proband with a de novo Chromosome 15 paracentric inversion, disrupting MEIS2 and NUSAP1. The inversion was detected by short-read genome sequencing and confirmed with adaptive long-read sequencing. The breakpoint junction analysis revealed a 96 bp (bp) deletion and an 18 bp insertion in the two junctions, suggesting that the rearrangement arose through a replicative error. Transcriptome sequencing of cultured fibroblasts revealed normal MEIS2 levels and 0.61-fold decreased expression of NUSAP1. Furthermore, three fusion transcripts were detected and confirmed by Sanger sequencing. Heterozygous loss of MEIS2 (MIM# 600987) is associated with a cleft palate, heart malformations, and intellectual impairment, which overlap with the clinical symptoms observed in the proband. The observed fusion transcripts are likely non-functional, and MEIS2 haploinsufficiency is the likely disease causative mechanism. Altogether, this study’s findings illustrate the importance of including inversions in rare disease diagnostic testing and highlight the value of long read sequencing for the validation and characterization of such variants.

The haplotype-phased genome assembly facilitated the deciphering of the bud dormancy-related QTLs in Prunus mume.

Bud dormancy is a vital physiological process in woody perennials, facilitating their adaptation to seasonal environmental changes. Satisfying genotype-specific chilling requirements (CR) and heat requirements (HR) through exposure to specific chilling and warm temperatures is essential for dormancy release and the subsequent resumption of growth. The genetic mechanisms regulating bud dormancy traits in Prunus mume remain unclear. In this study, we first assembled the genome of 'Nanko', the leading P. mume cultivar in Japan, in a haplotype-resolved manner. Using an F1 segregating population from a cross between 'Nanko' (high-chill) and 'SC' (low-chill), a cultivar adapted to subtropical conditions, we identified quantitative trait loci (QTLs) for vegetative bud dormancy traits on chromosome 4 (LG4 QTLs) in the 'Nanko' genome and for CR and HR on chromosome 7 (LG7 QTL) in the 'SC' genome. A notable 5.6Mb chromosome inversion was overlapped with LG4 QTL interval in one of the 'Nanko' haplotypes. We also identified candidate genes based on haplotyping, differential expression between the parents or the presence of trait-correlated variants in coding regions. Notably, genes such as PmuMAIN, PmuNAC2, PmuDOG1, PmuSUI1, PmuATG8CL, PmubZIP44, and PmuSAUR50 were identified. This study provides valuable insights into the genetic regulation of vegetative bud dormancy in Prunus species.

Highlighting chromosomal rearrangements of five species of Galliformes (Domestic fowl, Common and Japanese quail, Barbary and Chukar partridge) and the Houbara bustard, an endangered Otidiformes: banding cytogenetic is a powerful tool.

Birds are one of the most diverse groups among terrestrial vertebrates. They evolved from theropod dinosaurs, are closely related to the sauropsid group and separated from crocodiles about 240 million years ago. According to the IUCN, 12% of bird populations are threatened with potential extinction. Classical cytogenetics remains a powerful tool for comparing bird genomes and plays a crucial role in the preservation populations of endangered species. It thus makes it possible to detect chromosomal abnormalities responsible for early embryonic mortalities. Thus, in this work, we have provided new information on part of the evolutionary history by analysing high-resolution GTG-banded chromosomes to detect inter- and intrachromosomal rearrangements in six species. Indeed, the first eight autosomal pairs and the sex chromosomes of the domestic fowl Gallusgallusdomesticus Linnaeus, 1758 were compared with five species, four of which represent the order Galliformes (Common and Japanese quail, Gambras and Chukar partridge) and one Otidiformes species (Houbara bustard). Our findings suggest a high degree of conservation of the analysed ancestral chromosomes of the four Galliformes species, with the exception of (double, terminal, para and pericentric) inversions, deletion and the formation of neocentromeres (1, 2, 4, 7, 8, Z and W chromosomes). In addition to the detected rearrangements, reorganisation of the Houbara bustard chromosomes mainly included fusions and fissions involving both macro- and microchromosomes (especially on 2, 4 and Z chromosomes). We also found interchromosomal rearrangements involving shared microchromosomes (10, 11, 13, 14 and 19) between the two analysed avian orders. These rearrangements confirm that the structure of avian karyotypes will be more conserved at the interchromosomal but not at intrachromosomal scale. The appearance ofa small number of inter- and intrachromosomal rearrangements that occurred during evolution suggests a high degree of conservatism of genome organisation in these six species studied. A summary diagram of the rearrangements detected in this study is proposed to explain the chronology of the appearance of various evolutionary events starting from the ancestral karyotype.

A Detailed Karyological Investigation of three Endemic Cobitis Linnaeus, 1758 Species (Teleostei, Cobitidae) in Anatolia, Türkiye

Introduction: Comparative cytogenetics is a vital approach for diagnosing chromosome abnormalities and identifying species-specific patterns. In this study, chromosomal analysis of three Anatolian endemic Cobitis species was performed: Cobitis bilseli, C. fahireae, and C. turcica. Methods: Conventional cytogenetic techniques such as Giemsa staining, C-banding, and Ag-NOR staining were applied, followed by measurements of chromosome arm lengths including analysis of the measured data. Results: The diploid chromosome number, 2n = 50, was determined for all three species. The karyotype formulas were as follows: four pairs of metacentric, 5 pairs of submetacentric, and 16 pairs of subtelo-telocentric chromosomes in C. bilseli; 11 pairs of metacentric, 7 pairs of submetacentric, and 7 pairs of subtelo-telocentric chromosomes in C. fahireae; and 4 pairs of metacentric, 4 pairs of submetacentric, and 17 pairs of subtelo-telocentric chromosomes in C. turcica. Dark C-bands were observed on the pericentromeres of nearly all chromosomes in C. bilseli and C. turcica, whereas light C-bands appeared on the pericentromeres of some chromosomes in C. fahireae. Silver-stained metaphases revealed signals on the short arm of a submetacentric chromosome pair in C. fahireae (each homologous chromosome carries one signal), while in C. bilseli and C. turcica, Ag-NOR signals were detected on the long arm of a single metacentric chromosome (only one homologous chromosome carries the signal, and the signal-carrying chromosome is the largest chromosome in the karyotype). Conclusion: This study provides new cytogenetic data consistent with the phylogenetic distances between the studied species, indicating that pericentric inversions and/or translocations govern the formation of Cobitis karyotypes.

Testing the evolutionary theory of inversion polymorphisms in the yellow monkeyflower (Mimulus guttatus)

Chromosomal inversions have been implicated in a remarkable range of natural phenomena, but it remains unclear how much they contribute to standing genetic variation. Here, we evaluate 64 inversions that segregate within a single natural population of the yellow monkeyflower (Mimulus guttatus). Nucleotide diversity patterns confirm low internal variation for the derived orientation (predicted by recent origin), elevated diversity between orientations (predicted by natural selection), and localized fluctuations (predicted by gene flux). Sequence divergence between orientations varies idiosyncratically by position, not following the suspension bridge pattern predicted if the breakpoints are the targets of selection. Genetic variation in gene expression is not inflated close to inversion breakpoints but is clearly partitioned between orientations. Like sequence variation, the pattern of expression variation suggests that the capture of coadapted alleles is more important than the breakpoints for the fitness effects of inversions. This work confirms several evolutionary predictions for inversion polymorphisms, but clarity emerges only by synthesizing estimates across many loci.

CATG: Software for Collinearity-Based Genome Assembly Correction.

Genome assembly errors can have a profound effect on downstream analyses. Collinearity-based Assembly Correction Tool (CATG) is designed to rectify these errors by leveraging collinearity information between the assembled genome and a reference genome. CATG provides a user-friendly interface for visualizing and manually correcting assembly errors. It supports various operations such as insertion, deletion, inversion, and swapping of contigs and chromosomes. The software automatically re-clusters, re-labels, and re-draws the assembly after each modification, ensuring that users can easily track changes. CATG is a robust tool designed to efficiently correct large-scale assembly errors in polyploid genomes, featuring advanced collinearity detection capabilities.

The co-receptor Neuropilin-1 enhances proliferation in inv(16) acute myeloid leukemia via VEGF signaling.

Oncogenic programs regulate the proliferation and maintenance of cancer stem cells, and can define pharmacologic dependencies. In acute myeloid leukemia (AML) with the chromosome inversion 16 (inv(16)), the fusion oncoproteinCBFβ::MYH11 regulates pathways associated with leukemia stem cell activity. Here we demonstrate that expression of Neuropilin-1 (NRP1) is regulated by the fusion oncoprotein, and promotes AML expansion. Mechanistically, we show that the NRP1 locus has open chromatin in inv(16) AML, and that CBFβ::MYH11 modulates the local function of the transcription factors ERG, GATA2 and RUNX1 to sustain NRP1 levels. We found that ERG activates NRP1 expression, and that CBFβ::MYH11 knockdown represses ERG expression, thereby allowing the repressive activity of GATA2/RUNX1 at three NRP1 enhancers. Functionally, we demonstrate that NRP1 enhances the expansion of leukemic cells in vitro and in mice, and that this activity is dependent on its VEGFR-associated FV/FVIII domain. Finally, we show that treatment with VEGF inhibitor axitinib reduces AML cell growth and delays median leukemia latency in vivo. Our findings reveal that the NRP1/VEGF axis mediates proliferation in inv(16) AML blasts, and suggest that targeting NRP1 function could be promising in combination AML therapy.

Centromeres are hotspots for chromosomal inversions and breeding traits in mango.

Chromosomal inversions can preserve combinations of favorable alleles by suppressing recombination. Simultaneously, they reduce the effectiveness of purifying selection enabling deleterious alleles to accumulate. This study explores how areas of low recombination, including centromeric regions and chromosomal inversions, contribute to the accumulation of deleterious and favorable loci in 225 Mangifera indica genomes from the Australian Mango Breeding Program. Here, we identify 17 chromosomal inversions that cover 7.7% (29.7 Mb) of the M. indica genome: eight pericentric (inversion includes the centromere) and nine paracentric (inversion is on one arm of the chromosome). Our results show that these large pericentric inversions are accumulating deleterious loci, while the paracentric inversions show deleterious levels above and below the genome wide average. We find that despite their deleterious load, chromosomal inversions contain small effect loci linked to variation in crucial breeding traits. These results indicate that chromosomal inversions have likely facilitated the evolution of key mango breeding traits. Our study has important implications for selective breeding of favorable combinations of alleles in regions of low recombination.