Chromosomal Changes Research Articles

Characterization of Razi Bovine Kidney (RBK) Cell Line as a Sensitive Cell to Bovine Herpesvirus-1 (BoHV-1)

Viruses are obligate parasites and are completely dependent on host cells for survival and replication. RBK cell line developed and introduced by Razi Vaccine and Serum Research Institute, has been successfully established as a continuous cell line over successive passages.Viruses are obligate parasites that completely rely on host cells for survival and replication. Razi Bovine Kidney (RBK) cell line was introduced and developed by the Razi Vaccine and Serum Research Institute. It has been successfully established as a continuous cell line over successive passages. As demonstrated in this experimental study, the RBK cells have shown suitable sensitivity to certain viruses, including Bovine Herpesvirus-1 (BoHV-1) virus. In the present research, the RBK cell line characteristics were analyzed using molecular and karyotype methods and growth specifications. Cloning of the RBK cell line was performed using the limited dilution method, and each cell clone was quantitatively and qualitatively characterized. Four cell clones were compared based on their sensitivity to the BoHV-1 virus. Then, the RBK-D5 clone was selected as the most appropriate cell line for further studies. The RBK-D5 was subjected to tests for identity, chromosomal analysis, and doubling time. In the end, the origin of this cell line was confirmed by the PCR method. It was observed that the cell line exhibited karyotype diversity due to aneuploidy, which can be responsible for the procreation of chromosomal instability. This diversity represents chromosomal changes in the continuous cell line that carries the characteristic of an immortalized cell line. The RBK-D5 was found to be more sensitive to the BOHV-1 virus. Surprisingly, its titer was evaluated at 108.5 CCID50/ml. The obtained results suggested that the RBK cell line is suitable for the BoHV-1 virus and can be useful for virus detection, propagation, and quality control or viral titration.

Primary Cutaneous Epithelioid Mesenchymal Tumor With a Novel ATP2B4::GLI1 Gene Fusion.

GLI1 gene alterations (rearrangement or amplification) have been found in several bone and soft tissue tumors including pericytic tumors, gastric plexiform fibromyxoma, gastroblastoma, and a various group of epithelioid tumors with regional recurrence or distant metastasis. In this article, we describe a case of primary cutaneous epithelioid mesenchymal tumor harboring hitherto not reported ATP2B4::GLI1 gene fusion. A 42-year-old man presented with a growing firm lesion on the left postauricular scalp. Microscopically, the shave biopsy specimen revealed a dermal-based nodular proliferation of relatively monotonous epithelioid cells with round to ovoid nuclei and pale eosinophilic cytoplasm, accompanied by prominent stromal vasculature. Significant cytologic atypia, necrosis, and mitotic activity were absent. The tumor cells were partially positive for CD34 and S-100 protein, but were negative for other markers, including SOX-10, keratins, and myogenic markers. An ATP2B4::GLI1 gene fusion was identified by next-generation sequencing. Array CGH was also performed, but it did not show relevant chromosomal copy number changes. Awareness of this rare cutaneous tumor, and thus, reporting of additional cases is necessary for further delineating its full clinicopathologic spectrum.

CRISPR/Cas9 based manipulating oncogenic chromosomal changes in vivo

Chromosomal changes are important factors in the development of human cancers, leading to the creation of gene fusions that can be targeted by therapeutic treatments. One such gene fusion is EML4-ALK, which results from an inversion on chromosome 1 and is found in a subset of non-small cell lung cancers. This gene fusion is clinically significant because it makes the cancer cells sensitive to ALK inhibitors. However, modeling these genetic events in mice has been difficult and requires complex manipulation of the germ line. This study presents an efficient method of inducing specific chromosomal changes in vivo using viral-mediated delivery of the CRISPR/Cas9 system to somatic cells of adult animals. The method was used to create a mouse model of EML4-ALK-driven lung cancer. The resulting tumors consistently exhibited EML4-ALK inversion, expressed the EML4-ALK fusion gene and had molecular features of human NSCLCs and react to handling with ALK inhibitors. The capacity to simulate human malignancies in mice is substantially improved by this method.

Chromosomal Evolution of the Talpinae.

In recent years, the number of mole species with species status confirmed by genetic methods has been continuously increasing. Unfortunately, cytogenetic data are not yet available for all species. Here, for the first time, a GTG-banded karyotype of the small-toothed mole from Vietnam, Euroscaptor parvidens, a representative of the Eastern clade of the genus Euroscaptor, has been described. Through comparative analysis of available Euroscaptor (Euroscaptor parvidens, Euroscaptor klossi, and Euroscaptor malayana) and Oreoscaptor (Oreoscaptor mizura) karyotypes, we found cytogenetic signatures for each of the studied species. Zoo-FISH with sorted chromosomes of the Siberian mole (Talpa altaica) on chromosome sets of the small-toothed mole (E. parvidens), the small Japanese mole (Mogera imaizumii) from the closely related genus, and the Japanese shrew mole (Urotrichus talpoides) from the tribe Urotrichini made it possible to identify syntenic regions between these species. We propose a possible ancestral karyotype of the tribe and, based on it, traced the features of chromosomal rearrangements accompanying the divergence of moles. The low rates of chromosomal evolution within the species of the genus Talpa-T. altaica and T. europaea-and the high rates of karyotypic reshuffling within the Asian genera of the tribe were confirmed. The karyotype of the Japanese mountain mole O. mizura seems to be the most conserved among the Asian moles. The most frequently occurring types of chromosomal rearrangements in moles are the pericentric inversions and amplification of heterochromatin. The pericentric inversions on four pairs of autosomes are shared between the closely related genera Euroscaptor, Oreoscaptor, and Mogera, while many more apomorphic rearrangements have occurred in each lineage additionally. The highest rate of chromosomal changes, with five rearrangements occurring over approximately 7 million years, was recorded in the lineage of the small-toothed mole.

Microchromosome fusions underpin convergent evolution of chameleon karyotypes.

Evolutionary shifts in chromosome compositions (karyotypes) are major drivers of lineage and genomic diversification. Fusion of ancestral chromosomes is one hypothesized mechanism for the evolutionary reduction of the total chromosome number, a frequently implied karyotypic shift. Empirical tests of this hypothesis require model systems with variable karyotypes, known chromosome features, and a robust phylogeny. Here we used chameleons, diverse lizards with exceptionally variable karyotypes ($2n=20\text{-}62$), to test whether chromosomal fusions explain the repeated evolution of karyotypes with fewer chromosomes than ancestral karyotypes. Using a multidisciplinary approach including cytogenetic analyses and phylogenetic comparative methods, we found that a model of constant loss through time best explained chromosome evolution across the chameleon phylogeny. Next, we tested whether fusions of microchromosomes into macrochromosomes explained these evolutionary losses using generalized linear models. Multiple comparisons supported microchromosome fusions as the predominant agent of evolutionary loss. We further compared our results to various natural history traits and found no correlations. As such, we infer that the tendency of microchromosomes to fuse was a quality of the ancestral chameleon genome and that the genomic predisposition of ancestors is a more substantive predictor of chromosome change than the ecological, physiological, and biogeographical factors involved in their diversification.

Clastogenic, aneugenic, and tubulin polymerization properties of di-(2-ethylhexyl) phthalate and dibutyl phthalate.

Phthalate compounds were found to disrupt the endocrine system and alter transcriptomes during human embryonic development. In our previous work, we have isolated and reported two such phthalates di-(2-ethylhexyl) phthalate (DEHP) and dibutyl phthalate (DBP) from Brevibacterium mcbrellneri bacteria and evaluated their bioactive properties. Naturally derived phthalates might be less toxic compared with synthesized molecules. We have investigated biologically isolated phthalates to understand the possible genotoxic effects in mice and further investigated in silico binding and polymerization of β-tubulin. Three sub-lethal concentrations of DEHP (150μM, 175μM, and 200μM) and DBP (10μM, 15μM, and 30μM) were studied. The results showed that the phthalates were found to be highly genotoxic in nature. However, the pattern of genotoxic effects was not found to be dose-dependent in the induction of chromosome aberrations (CA), micronuclei (MN), and changes in the mitotic index (MI) in cells. In silico studies of phthalates on polymerization of β-tubulin suggested that both DBP and DEHP were able to interact with the hydrogen bonds and make strong van der Waals interactions with β-tubulin thereby possibly causing destabilization of microtubule network. Our study suggests that these phthalates might be playing an important role in normal cell division thereby showing highly genotoxic effects.

Histological and molecular glioblastoma, IDH-wildtype: a real-world landscape using the 2021 WHO classification of central nervous system tumors.

Glioblastoma (GBM), the most lethal primary brain malignancy, is divided into histological (hist-GBM) and molecular (mol-GBM) subtypes according to the 2021 World Health Organization classification of central nervous system tumors. This study aimed to characterize the clinical, radiological, molecular, and survival features of GBM under the current classification scheme and explore survival determinants. We re-examined the genetic alterations of IDH-wildtype diffuse gliomas at our institute from 2011 to 2022, and enrolled GBMs for analysis after re-classification. Univariable and multivariable analyses were used to identify survival determinants. Among 209 IDH-wildtype gliomas, 191 were GBMs, including 146 hist-GBMs (76%) and 45 mol-GBMs (24%). Patients with mol-GBMs were younger, less likely to develop preoperative motor dysfunction, and more likely to develop epilepsy than hist-GBMs. Mol-GBMs exhibited lower radiographic incidences of contrast enhancement and intratumoral necrosis. Common molecular features included copy-number changes in chromosomes 1, 7, 9, 10, and 19, as well as alterations in EGFR, TERT, CDKN2A/B, and PTEN, with distinct patterns observed between the two subtypes. The median overall survival (mOS) of GMB was 12.6 months. Mol-GBMs had a higher mOS than hist-GBMs, although not statistically significant (15.6 vs. 11.4 months, p=0.17). Older age, male sex, tumor involvement of deep brain structure or functional area, and genetic alterations in CDK4, CDK6, CIC, FGFR3, KMT5B, and MYB were predictors for a worse prognosis, while MGMT promoter methylation, maximal tumor resection, and treatment based on the Stupp protocol were predictive for better survival. The definition of GBM and its clinical, radiological, molecular, and prognostic characteristics have been altered under the current classification.

Associations between birth defects and childhood and adolescent germ cell tumors according to sex, histologic subtype, and site.

Studies have reported increased rates of birth defects among children with germ cell tumors (GCTs). However, few studies have evaluated associations by sex, type of defect, or tumor characteristics. Birth defect-GCT associations were evaluated among pediatric patients (N = 552) with GCTs enrolled in the Germ Cell Tumor Epidemiology Study and population-based controls (N = 6380) without cancer from the Genetic Overlap Between Anomalies and Cancer in Kids Study. The odds ratio (OR) and 95% confidence interval (CI) of GCTs according to birth defects status were estimated by using unconditional logistic regression. All defects were considered collectively and by genetic and chromosomal syndromes and nonsyndromic defects. Stratification was by sex, tumor histology (yolk sac tumor, teratoma, germinoma, and mixed/other), and location (gonadal, extragonadal, and intracranial). Birth defects and syndromic defects were more common among GCT cases than controls (6.9% vs. 4.0% and 2.7% vs. 0.2%, respectively; both p < .001). In multivariable models, GCT risk was increased among children with birth defects (OR, 1.7; 95% CI, 1.3-2.4) and syndromic defects (OR, 10.4; 95% CI, 4.9-22.1). When stratified by tumor characteristics, birth defects were associated with yolk sac tumors (OR, 2.7; 95% CI, 1.3-5.0) and mixed/other histologies (OR, 2.1; 95% CI, 1.2-3.5) and both gonadal tumors (OR, 1.7; 95% CI, 1.0-2.7) and extragonadal tumors (OR, 3.8; 95% CI, 2.1-6.5). Nonsyndromic defects specifically were not associated with GCTs. In sex-stratified analyses, associations were observed among males but not females. These data suggest that males with syndromic birth defects are at an increased risk of pediatric GCTs, whereasmales with nonsyndromic defects and females are not at an increased risk. We investigated whether birth defects (such as congenital heart disease or Down syndrome) are linked to childhood germ cell tumors (GCTs), cancers that mainly develop in the ovaries or testes. We studied different types of birth defects (defects that were caused by chromosome changes such as Down syndrome or Klinefelter syndrome and defects that were not) and different types of GCTs. Only chromosome changes such as Down syndrome or Klinefelter syndrome were linked to GCTs. Our study suggests that most children with birth defects are not at an increased risk of GCTs because most birth defects are not caused by chromosome changes.

Prenatal Screening of Cytogenetic Anomalies -A Ten Year Retrospective Study on 1510 Cases

Introduction: Prenatal diagnostic is a diagnostic method which is used to prove the presence of chromosome changes, a large number of metabolic disorders and other morphological fetus abnormalities. Prenatal genetic testing mostly refers to the molecular genetic and cytogenetic methods used during pregnancy to diagnose genetic fetal conditions. Aim: To investigate the existence and incidence of cytogenetics abnormalities in fetuses. Material and Methods: The retrospective research is based on cytogenetic analysis of the 1510 amniotic fluid samples collected from pregnant women sent to the cytogenetic laboratory from January, 2012 to December, 2022. Results: The karyotype without visible structural and numerical changes was detected in 96.8% (1462/1510) cases. The fetal karyotype was abnormal in 3.2 % (48/1510) of the cases. Trisomy 21 was the most frequent chromosome aberration detected in 1.12% (17/1510) cases followed by pericentric inversion 9 (10/1510; 0.66%) and trisomy 18 (4/1510; 0.26%). Mosaics were detected in five cases (5/1510; 0.33%). Comparing the prevalence of chromosome abnormalities according to maternal age, we come to know the prevalence of chromosome aberrations in the group of females above age 35 (26/790; 17.2/1000) is higher than in the group of females under age 25 (7/95; 4.63/1000), but not significantly different (P= 0.09). Conclusion: Conventional cytogenetics maintains its role as a powerful diagnostic tool in detecting chromosomal changes during prenatal screening.

Arsenic induced chromosomal aberrations, biochemical and morphological changes in Vigna radiata L. (Mung bean) seedlings and its amelioration by Curcumin

Arsenic induced chromosomal aberrations, biochemical and morphological changes in Vigna radiata L. (Mung bean) seedlings and its amelioration by Curcumin

Bone Marrow Karyotype, Flow Cytometry, and FISH Analysis: Essential Tests to Improve the Initial Diagnosis of Patients with Myeloid Malignancies

Background and Aims: Diagnosing hematologic malignancies requires implementing several tests. This study aims to evaluate the chromosomal changes in patients with myeloid disorders and compare the results of flow cytometry and cytogenetics with the initial diagnosis performed by the oncologist.&#x0D; Materials and Methods: 115 patients with myeloid disorders, 57.2% males and 42.8% females with a mean age of 50.3 years, previously diagnosed by an oncologist based on the clinical features, complete blood count, and peripheral blood smear interpretations, were considered. Moreover, flow cytometry and cytogenetic analysis were implemented on the bone marrow samples.&#x0D; Results: Cytogenetic results showed that 30% of patients with myeloid disorders had abnormal karyotypes. 77% of patients with myelodysplastic syndromes, 65% of acute myeloid leukemia, and 30.7% of chronic myeloid leukaemia indices showed normal karyotypes, and the others resulted in common and uncommon abnormalities, including the translocation (13;17), 92, XXYY, and del (4q). Considering the flow cytometry and karyotype results, the improved diagnoses were made for 41 patients who had not been diagnosed initially.&#x0D; Conclusion: This study showed that, in some cases, an initial diagnosis is inconsistent with the flow cytometry and karyotype analysis results. Also, the flow cytometry results may differ from the karyotype depending on the case. Therefore, combining the results obtained by the cytogenetic investigation, flow cytometry, fluorescence in situ hybridization, and molecular testing is preferable to provide a comprehensive report for the appropriate disease diagnosis and prognosis.

Cytogenetic study for Iraqi patients with epilepsy

The current study was conducted with the aim of identifying the chromosomal changes that associated with epilepsy Iraqi patients. Chromosomal analysis was carried on for 37 of a number of epilepsy patients exclusively for cases of idiopathic epilepsy (unknown cause)after excluding the symptomatic epilepsy (known causes) range age from 2-51 years. Only five cases showed chromosomal changes associated with epilepsy cases, their ages ranged from 2-30 years, while the rest of the patients had normal karyotype. The chromosomes were prepared using the GTG band with average of 25-30 cells was examined for each person. The chromosomal changes that associated with epilepsy cases, ranged from the presence of a number of derivative chromosomes, inversion, additions, deletions, chromatid fractures, and the premature centromere division (PCD).Finally the recurrence of aberrations in some chromosomes (more than one defect associated with the same chromosome). Which may indicate that these chromosomes carry more than one fragile site sin same chromosome. During questionnaire there were other symptoms associated with epilepsy which has been mentioned to them in the study.

Abstract 102: Transient chromosomal instability as a driver of ovarian cancer genome evolution

Abstract Chromosomal instability (CIN) is a major driver of tumor progression and treatment resistance in many cancers. CIN is characterized by ongoing chromosome missegregation, generating copy number heterogeneity that provides a substrate for natural selection. Although CIN has been well studied in model systems, the evolutionary dynamics and genomic impact of CIN is underexplored in primary tumors and metastases. Newly developed single cell genomics assays allow for the measurement of the whole genomes of single cells obtained from patient tissues, thus providing a direct view into the evolution of tumor genomes undergoing CIN. To study the single-cell and spatial variation of chromosomally unstable tumors, we performed multi-region analysis of 128 tumor samples in a cohort of 45 patients with high-grade serous ovarian cancer (HGSOC), an archetype of high CIN cancers. We performed single-cell whole genome sequencing (scWGS) and profiled a total of 70,644 single cells from 63 pre-treatment samples obtained across 43 patients. For each patient, we computed total and allele specific copy number per cell, and inferred the evolutionary history of each tumor, including clonal and subclonal whole genome doubling (WGD) events and cell-specific whole chromosome or arm level copy number changes, indicative of missegregations. To determine whether missegregated chromosomes fail to become part of the primary nucleus (PN) upon mitotic exit and become enclosed in a micronucleus (MN), we used high-resolution cGAS immunofluorescence (IF) microscopy to profile site-matched FFPE tissues and quantify spatially-resolved rates of MN formation and rupture across 128 site-matched samples. A majority of tumors were characterized by early clonal WGD (61%, 22/36 cases). The remaining patients exhibited subclonal WGD subpopulations averaging 10% of the patient’s cells in total. To understand the interplay between recent WGD and CIN across the cohort, we subset all patients cells into non-WGD, subclonal WGD, and clonal WGD and computed missegregation rates for these subsets. Non-WGD cells showed the lowest levels of missegregation. Subclonal WGD exhibited the highest rates of missegregation indicative of CIN following a recent WGD event. Clonal WGD exhibited intermediate levels of missegregation indicative of stabilization following a historical WGD event. CIN following WGD often resulted in a reduction in ploidy relative to the ancestral WGD cell. Using IF, we quantified the frequent breakdown of the MN membrane, and estimated spatially-resolved CIN rates by tracking localization of cGAS to the MN, which revealed elevated rates of MN formation and rupture. Through multimodal single cell measurements of HGSOC tumors, we were able to characterize genomic complexity from individual cell division errors in HGSOC, and shed light into how the transient processes governing ovarian cancer cell evolution impact the genomes of cell populations. Citation Format: Ignacio Vazquez-Garcia, Florian Uhlitz, Marc J. Williams, Jun Li, Hongyu Shi, Samuel Freeman, Matthew Myers, MSK SPECTRUM Consortium, Britta Weigelt, Dmitriy Zamarin, Andrew McPherson, Samuel F. Bakhoum, Sohrab P. Shah. Transient chromosomal instability as a driver of ovarian cancer genome evolution [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 102.

Molecular Pathogenesis of Colitis-associated Colorectal Cancer: Immunity, Genetics, and Intestinal Microecology.

Patients with inflammatory bowel disease (IBD) have a high risk for colorectal cancer (CRC). This cancer type, which is strongly associated with chronic inflammation, is called colitis-associated CRC (CAC). Understanding the molecular pathogenesis of CAC is crucial to identify biomarkers necessary for early diagnosis and more effective treatment directions. The accumulation of immune cells and inflammatory factors, which constitute a complex chronic inflammatory environment in the intestinal mucosa, may cause oxidative stress or DNA damage to the epithelial cells, leading to CAC development and progression. An important feature of CAC is genetic instability, which includes chromosome instability, microsatellite instability, hypermethylation, and changes in noncoding RNAs. Furthermore, the intestinal microbiota and metabolites have a great impact on IBD and CAC. By clarifying immune, genetic, intestinal microecology, and other related pathogenesis, CAC may be more predictable and treatable.

PO-2239 Remaining chromosomal and immunological changes years after prostate cancer brachy- and teletherapy

PO-2239 Remaining chromosomal and immunological changes years after prostate cancer brachy- and teletherapy

Chromosomal Instability in Genome Evolution: From Cancer to Macroevolution.

The integrity of the genome is crucial for the survival of all living organisms. However, genomes need to adapt to survive certain pressures, and for this purpose use several mechanisms to diversify. Chromosomal instability (CIN) is one of the main mechanisms leading to the creation of genomic heterogeneity by altering the number of chromosomes and changing their structures. In this review, we will discuss the different chromosomal patterns and changes observed in speciation, in evolutional biology as well as during tumor progression. By nature, the human genome shows an induction of diversity during gametogenesis but as well during tumorigenesis that can conclude in drastic changes such as the whole genome doubling to more discrete changes as the complex chromosomal rearrangement chromothripsis. More importantly, changes observed during speciation are strikingly similar to the genomic evolution observed during tumor progression and resistance to therapy. The different origins of CIN will be treated as the importance of double-strand breaks (DSBs) or the consequences of micronuclei. We will also explain the mechanisms behind the controlled DSBs, and recombination of homologous chromosomes observed during meiosis, to explain how errors lead to similar patterns observed during tumorigenesis. Then, we will also list several diseases associated with CIN, resulting in fertility issues, miscarriage, rare genetic diseases, and cancer. Understanding better chromosomal instability as a whole is primordial for the understanding of mechanisms leading to tumor progression.

Patient attitudes and preferences about expanded noninvasive prenatal testing.

Introduction: Noninvasive prenatal testing (NIPT) using cell-free DNA (cfDNA) is typically carried out to screen for common fetal chromosomal anomalies, with the option to screen for a wider range of chromosomal changes (expanded NIPT) becoming increasingly available. However, little is known about pregnant patients' attitudes and preferences regarding expanded NIPT. Methods: To address this gap, we surveyed general-risk patients having first-tier cfDNA screening at a private prenatal clinic on their expectations for expanded NIPT. Patients were asked questions regarding their current pregnancy and previous pregnancy history, their opinions on fetal DNA screenings during pregnancy and incidental findings, information and opinions on financial resources for NIPT, as well as socio-cultural questions to determine patient demographics. Results: Of the 200 survey participants, the majority were educated, self-reported as white, had a higher than average income, and reported no aneuploidy risk factors. When asked what information they would like to receive from cfDNA screening, the vast majority of participants wanted all information available that could have an immediate impact on fetal health (88%) or an immediate impact on infant health from birth (82%). Many participants also wanted information that could have a future impact on the child's health or an immediate or future impact on the pregnant woman's own health. Most participants wanted information about the sex of fetus (86%) and common trisomies (71%), with almost half of participants desiring information about rare autosomal aneuploidies and/or all genetic information that may affect the baby. In addition, participants were found to be comfortable screening for conditions that are well-known, influence care during pregnancy, and are treatable. Finally, while most respondents either had insurance coverage for NIPT or were able to afford NIPT out of pocket, the majority of our participants felt that expanded NIPT should be either free for everyone or for those considered high risk. Discussion: Our findings suggest that with appropriate pre-test counseling, pregnant patients may choose NIPT for an expanding list of conditions.

Intraspecific divergence of diploid grass Aegilopscomosa is associated with structural chromosome changes.

Aegilopscomosa Smith in Sibthorp et Smith, 1806 is diploid grass with MM genome constitution occurring mainly in Greece. Two morphologically distinct subspecies - Ae.c.comosa Chennaveeraiah, 1960 and Ae.c.heldreichii (Holzmann ex Boissier) Eig, 1929 are discriminated within Ae.comosa, however, genetic and karyotypic bases of their divergence are not fully understood. We used Fluorescence in situ hybridization (FISH) with repetitive DNA probes and electrophoretic analysis of gliadins to characterize the genome and karyotype of Ae.comosa to assess the level of their genetic diversity and uncover mechanisms leading to radiation of subspecies. We show that two subspecies differ in size and morphology of chromosomes 3M and 6M, which can be due to reciprocal translocation. Subspecies also differ in the amount and distribution of microsatellite and satellite DNA sequences, the number and position of minor NORs, especially on 3M and 6M, and gliadin spectra mainly in the a-zone. Frequent occurrence of hybrids can be caused by open pollination, which, along with genetic heterogeneity of accessions and, probably, the lack of geographic or genetic barrier between the subspecies, may contribute to extremely broad intraspecific variation of GAAn and gliadin patterns in Ae.comosa, which are usually not observed in endemic plant species.

Abstract 1185: Mosaic chromosomal alterations are independent predictors of chronic lymphocytic leukemia risk

Abstract Chronic lymphocytic leukemia (CLL) is strongly associated with mosaic chromosomal alterations (mCAs), a type of clonal hematopoiesis characterized by large structural chromosomal changes (e.g., gains, losses and copy neutral loss of heterozygosity). We aim to identify specific chromosomal regions that, when impacted by mCAs, are most predictive of CLL risk and evaluate their predictive utility in models that include established CLL risk factors. We utilized genotype array data from 436,784 participants in the UK Biobank (UKBB) and 35,382 participants in the Prostate, Lung, Colorectal, and Ovarian (PLCO) screening trial to identify mCAs. UKBB was split (90/10) into training and test sets, and PLCO served as an external validation set. We developed sequential regression models to predict risk of CLL, with a baseline model consisting of age, age-squared, sex, smoking status, and ancestry. Additional models evaluated mCAs, a CLL polygenic risk score (PRS), and blood cell counts. Area under the receiver operating characteristic curve (AUC) was used to evaluate the predictive utility for both 5-year and 10-year CLL risk. Any detectable mCA was associated with incident CLL (Hazards Ratio (HR)=26, 95% Confidence interval (CI)=21-31), and mCAs on each individual chromosome were associated with increased CLL risk. mCAs on segments of chromosomes 13, 12, 22, 14, and 11 had the largest effect size (e.g., chr 13q14 HR=199, 95%CI=155-257). The CLL prediction model, including baseline factors, CLL PRS, and any autosomal mCA status, showed strong predictive utility in independent UKBB (AUC=0.88) and PLCO (AUC=0.88) samples. Restricting to a subset of mCAs strongly associated with CLL did not improve performance over including any detectable autosomal mCA. After the inclusion of blood cell traits, predictive utility further increased in UKBB (AUC=0.91; no count data available in PLCO). We observed the strongest CLL predictive utility in 5-year risk compared to 10-year risk across all models. mCAs genome-wide are associated with CLL risk, with variable effects across chromosomes and specific chromosomal regions. Autosomal mCAs are strong independent predictors of CLL risk and substantially add to predictive utility over standard clinical measures. The predictive utility of autosomal mCAs is strongest within the first 1-5 years of sample collection. Evaluation of mCAs could provide added utility for risk stratification in populations at high risk of CLL. Citation Format: Aubrey K. Hubbard, Alexander DePaulis, Sruthi Srinivasan, Ian D. Buller, Shu-Hong Lin, Weiyin Zhou, Stephen J. Chanock, Neal D. Freedman, Derek W. Brown, Mitchell J. Machiela. Mosaic chromosomal alterations are independent predictors of chronic lymphocytic leukemia risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1185.

Structural changes in chromosomes driven by multiple condensin motors during mitosis

We create a computational framework that utilizes loop extrusion (LE) by multiple condensin I/II motors to predict changes in chromosome organization during mitosis. The theory accurately reproduces the experimental contact probability profiles for the mitotic chromosomes in HeLa and DT40 cells. The LE rate is smaller at the start of mitosis and increases as the cells approach metaphase. Condensin II-mediated mean loop size is about six times larger than loops because of condensin I. The loops, which overlap each other, are stapled to a central dynamically changing helical scaffold formed by the motors during the LE process. A polymer physics-based data-driven method that uses the Hi-C contact map as the only input shows that the helix is characterized as random helix perversions (RHPs) in which the handedness changes randomly along the scaffold. The theoretical predictions, which are testable using imaging experiments, do not contain any parameters.