От цитогенетики к протеогеномике: новые горизонты в исследовании анеуплоидий

Анеуплоидией принято считать потерю или приобретение копии целой хромосомы или ее района. Уже на ранних стадиях развития она, как правило, приводит к фатальным последствиям, включая гибель организма и пороки/аномалии развития. Длительное время предполагалось, что именно нарушение баланса генов приводит к выраженным эффектам как на клеточном, так и на организменном уровне, негативно сказываясь на формировании организма. Было показано, что возникший вследствие анеуплоидии дисбаланс генов индуцирует протеотоксический и метаболический стресс в клетке, ее замедленную пролиферацию, нестабильность ее генома, оксидативный стресс и пр. Однако для некоторых организмов была описана толерантность к анеуплоидиям, которая даже могла способствовать возникновению у них адаптивных преимуществ (например, резистентность к антибиотикам у патогенных штаммов грибов). Вероятно, значимым фактором является сложность тканевой и органной организации особей конкретного вида. К анеуплоидии преимущественно более толерантны полиплоидные организмы и виды, относительно недавно прошедшие полногеномную дупликацию. Особое внимание в обзоре уделено рассмотрению анеуплоидий половых хромосом человека. Помимо первичных эффектов или цис-эффектов (изменение количества транскриптов генов, находящихся на анеуплоидной хромосоме), анеуплоидия может вызывать вторичные или транс-эффекты (изменение уровня экспрессии генов, расположенных на других хромосомах). Результаты исследований последних лет заставили по-новому взглянуть на влияние анеуплоидии на структурно-функциональную организацию генома, транскриптом и протеом как клетки, так и целого организма. Несмотря на то что при анеуплоидии уровень экспрессии для большинства генов коррелирует с измененным числом копий генов в клетке, были описаны случаи дозовой компенсации, при которой уровень транскриптов генов, расположенных на анеуплоидной хромосоме, оставался неизменным. В обзоре приводятся результаты последних исследований, посвященных изучению компенсаторных механизмов дозовой компенсации изменения количества продуктов генов на посттранскрипционных и пострансляционных уровнях, снижающих негативный эффект анеуплоидии на гомеостаз клетки, а также влиянию экстрахромосом на пространственную организацию генома, изменению паттернов экспрессии генов вследствие ее наличия. Кроме того, отдельно обсуждаются варианты сегментных анеуплоидий и изменения числа копий участков генома. Рассмотрено не только значение их состава, но также его локализация в хромосоме и в разных компартментах интерфазного ядра. Решение поднятых вопросов может внести большой вклад в совершенствование цитогеномной диагностики и в создание необходимой базы данных для корректной интерпретации выявленных случаев и сегментной анеуплоидии, и варьирующих по числу копий участков генома.

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