vavilovВавиловский журнал генетики и селекцииVavilov Journal of Genetics and Breeding2500-3259Institute of Cytology and Genetics of Siberian Branch of the RAS10.18699/vjgb-26-90vavilov-5296Research ArticleГЕНЕТИКА ЖИВОТНЫХANIMAL GENETICSПолногеномное исследование генетических детерминант преждевременного старения крыс OXYSWhole genome sequencing identifies genetic variants associated with senescence-accelerated phenotype of OXYS ratsПетроваВ. М.PetrovaV. M.

Федеральная территория «Сириус», Краснодарский край

Sirius Federal Territory, Krasnodar region

petrova.vm@talantiuspeh.ruПротасоваМ. С.ProtasovaM. S.

Федеральная территория «Сириус», Краснодарский край,

Москва

Sirius Federal Territory, Krasnodar region, Moscow

МанаховА. Д.ManakhovA. D.

Федеральная территория «Сириус», Краснодарский край,

Москва

Sirius Federal Territory, Krasnodar region. Moscow

СтефановаН. А.StefanovaN. A.

Новосибирск

Novosibirsk

КолосоваН. Г.KolosovaN. G.

Новосибирск

Novosibirsk

РогаевЕ. И.RogaevE. I.

Шрусбери

Shrewsbury

evivrecc@gmail.comНаучно-технологический университет «Сириус»РоссияSirius University of Science and TechnologyRussian FederationНаучно-технологический университет «Сириус»; Институт общей генетики им. Н.И. Вавилова Российской академии наукРоссияSirius University of Science and Technology; Vavilov Institute of General Genetics of the Russian Academy of SciencesRussian FederationФедеральный исследовательский центр Институт цитологии и генетики Сибирского отделения Российской академии наукРоссияInstitute of Cytology and Genetics of the Siberian Branch of the Russian Academy of SciencesRussian FederationМедицинская школа Чан Массачусетского университета, департамент психиатрииСоединённые Штаты АмерикиUMass Chan Medical School, Department of PsychiatryUnited States202613102026306883898Copyright © Петрова В.М., Протасова М.С., Манахов А.Д., Стефанова Н.А., Колосова Н.Г., Рогаев Е.И., 20262026Петрова В.М., Протасова М.С., Манахов А.Д., Стефанова Н.А., Колосова Н.Г., Рогаев Е.И.Petrova V.M., Protasova M.S., Manakhov A.D., Stefanova N.A., Kolosova N.G., Rogaev E.I.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://vavilov.elpub.ru/jour/article/view/5296

Возраст – основной фактор риска ассоциированных со старением заболеваний, раннее развитие которых лежит в основе преждевременного старения, а более позднее – обеспечивает долголетие. Неблагоприятные генетические варианты способствуют преждевременному старению и его множественным проявлениям – увеличению числа коморбидных состояний. Установление предпосылок преждевременного старения и разработка подходов к его профилактике – основной резерв увеличения здорового периода жизни людей, что обусловливает необходимость в фундаментальных исследованиях на моделях животных. Нами проведено полногеномное секвенирование (с глубиной покрытия >25×) крыс линии OXYS – модели преждевременного старения, которое сопровождается ранним развитием комплекса гериатрических заболеваний: катаракты, ретинопатии, аналогичной возрастной макулярной дегенерации (ВМД), признаков болезни Альцгеймера (БА), остеопороза, саркопении и гипертрофической кардиомиопатии (контроль – родительская линия крыс Wistar/Icgn). Поиск однонуклеотидных вариантов, инсерций-делеций (инделов) и вариаций числа копий геномных регионов (CNV) и сравнительный геномный анализ выявили генетические варианты, уникальные для крыс OXYS и не встречающиеся среди других линий крыс. Обнаружены: крупная делеция в энхансере гена Fat1; делеции в промоторных регионах генов Abcf1 и Gsta6; а также миссенс-варианты в генах Cic, Akap6, Nqo2, Cerkl, Bfsp1 и Cmya5, приводящие к аминокислотным заменам в высококонсервативных регионах белков. Проведенный биоинформатический анализ показал, что данные варианты, вероятно, вносят вклад в развитие ключевых проявлений преждевременного старения у линии крыс OXYS. А именно: делеции в энхансере Fat1 и промоторе Gsta6, а также миссенс-замены в Cic, Akap6 и Nqo2 могут способствовать ранней нейродегенерации и когнитивному дефициту, нарушая нейрогенез, снижая выживаемость нейронов и их антиоксидантную защиту; делеция в промоторной области Abcf1 и миссенс-варианты в Cerkl могут приводить к возникновению признаков ВМД, нарушая гомеостаз сетчатки и ослабляя защиту фоторецепторов и клеток пигментного эпителия сетчатки (РПЭ) от окислительного стресса и апоптоза соответственно, а миссенс-замена в Bfsp1 – к раннему развитию катаракты через снижение стабильности промежуточных филаментов хрусталика. Миссенс-варианты в Cmya5 и Akap6 могут способствовать развитию саркопении и кардиомиопатии: замена в Cmya5 – за счет дестабилизации миофибрилл в кардиомиоцитах и скелетных мышцах, а замена в Akap6 – за счет нарушения регенерации скелетных мышц и структурной организации кардиомиоцитов.

Age is the primary risk factor for age-related diseases, the early onset of which manifests as premature aging, whereas delayed development forms the basis for healthy aging and longevity. Adverse genetic variants contribute to premature aging and its diverse manifestations, including increased multimorbidity. Identifying the genetic underpinnings of premature aging and developing preventive approaches are essential to extending the human healthspan, which requires fundamental research using animal models. In this study, we performed whole-genome sequencing (coverage depth >25×) of OXYS rats – a unique model of premature aging characterized by the early onset of geriatric disorders, including cataracts, AMD-like retinopathy, Alzheimer’s disease-like pathology, osteoporosis, sarcopenia, and hypertrophic cardiomyopathy – using the parental Wistar/Icgn rat strain as a control. The screening for singlenucleotide variants (SNVs), short insertions/deletions (indels), and copy number variations (CNVs) and comparative genomic analysis revealed genetic variants unique to OXYS rats that are absent in other rat strains. Specifically, we identified a large deletion in the Fat1 enhancer, deletions in the promoter regions of Abcf1 and Gsta6, and missense variants in Cic, Akap6, Nqo2, Cerkl, Bfsp1, and Cmya5 that lead to amino acid substitutions in highly conserved protein regions. Bioinformatic analysis suggested that these variants may contribute to the key features of premature aging in OXYS rats. Notably, deletions in the Fat1 enhancer and Gsta6 promoter, alongside missense substitutions in Cic, Akap6, and Nqo2, may drive early neurodegeneration and cognitive deficits by disrupting neurogenesis, reducing neuronal survival, and impairing antioxidant defense. The deletion in the Abcf1 promoter and the missense variants in Cerkl may induce retinopathy features by disrupting retinal homeostasis and weakening the protection of photoreceptors and retinal pigment epithelium (RPE) cells against oxidative stress and apoptosis. Furthermore, the missense substitution in Bfsp1 likely contributes to early cataract development by reducing the stability of lens intermediate filaments. Finally, missense variants in Cmya5 and Akap6 may promote sarcopenia and cardiomyopathy via the destabilization of myofibrils in skeletal muscles and cardiomyocytes (Cmya5) and through impaired skeletal muscle regeneration and structural disorganization of cardiomyocytes (Akap6).

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The authors declare that there are no conflicts of interest present.