Полногеномное исследование генетических детерминант преждевременного старения крыс OXYS

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.

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