Ribosomal, Satellite III (1q12) and Telomere Repeat Copy Number Variations in Cystic Fibrosis Patients Used as a Model of Permanent Stress and Survivability

Introduction: Ribosomal (rDNA), satellite III (f-SatIII) and telomere (TR) tandem repeats perform a variety of functions in the human cell. Copy number variations (CNVs) of these repeats contributes to the global chromatin architecture and genome expression changes in response to stress or pathology. An elevated rDNA abundance and lowered contents of f-SatIII and TR were found in blood leukocytes of patients with schizophrenia. The main question of the study was: are the CNVs of the three repeat types in blood leukocytes a universal phenomenon linked to a pathology associated with chronic oxidative stress? Cystic fibrosis (CF), a monogenic disease was chosen as an object of the study. Materials and Methods: We determined the rDNA, f-SatIII and TR content in the blood leukocyte genomes of 545 subjects aged 0.2 to 50 years. The subjects were divided into three groups: Control (HC-group, N = 267), CF group (N= 186) and CF(d) group (severe patients, who died after some time upon sampling, aged 17 to 40 years, N = 92). For each patient, the type of the mutation in CFTR gene had been determined earlier. Non-radioactive quantitative hybridization technique was applied to quantify the repeats. Results: the rDNA abundance was elevated in the DNA of CF and CF(d) groups (565+/-105 copies per genome, N=278) compared to HC group (445+/-112 copies, N=267). A patient's age 3 to 16 years was associated with "severe" mutations in CFTR (98% of cases), increased f-SatIII repeat counts and decreased telomere repeat (TR) contents in genome DNA compared to the age-matched controls. The genomes of deceased patients from CF(d) group also harbored increased numbers of f-SatIII and decreased numbers of TR. Patients above 16 years with a milder course of the disease and relatively low content of "severe" CFTR mutations contained less f-SatIII and more TR in their genomic DNA. A parameter rDNA*(f-SatIII/TR) showed a maximum difference between patients with relatively mild (age 17 to 40) and severe (age 17 to 40) forms of the pathology according to ROC analysis data (AUC = 0.86). Conclusion: Cystic fibrosis was associated with an increase in rDNA abundance and altered f-SatIII and TR contents in the DNA of cases compared to the controls. The severe course of the disease was characterized with high f-SatIII contents and shortened telomeres, whereas mild CF cases were associated with low contents of f-SatIII and normal or slightly reduced telomere length. The index rDNA*(f-SatIII/TR) might be a predictor of the patient's life expectancy. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study did not receive any funding ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee of Research Centre for Medical Genetics gave ethical approval for this work I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors