Мозаичная потеря Y-хромосомы при нейродегенеративных и онкологических заболеваниях человека

Одно из наиболее актуальных направлений современной генетики и геномики человека – разработка новых биомаркеров для прогнозирования и раннего выявления заболеваний человека, а также для мониторинга ответа на терапию. До недавнего времени считалось, что функция генов Y-хромосомы человека ограничена определением пола и контролем сперматогенеза. Благодаря созданию крупных баз данных, полученных на основе метода поиска ассоциаций (GWAS), произошел переход к использованию больших выборок при анализе генетических изменений в норме и при патологиях, в том числе стало возможно оценить связь мозаичной анеуплоидии по Y-хромосоме в соматических клетках с более короткой продолжительностью жизни у мужчин по сравнению с женщинами. На основе данных Британского биобанка (UK Biobank) была обнаружена ассоциация между мозаичной потерей Y-хромосомы (mLOY) в лейкоцитах периферической крови с возрастом мужчин старше 70 лет, а также с рядом онкологических, сердечных, метаболических, нейродегенеративных и психических заболеваний. В результате mLOY в клетках периферической крови стала рассматриваться в качестве потенциального маркера биологического возраста мужчин и как маркер определенных возрастных болезней. На сегодняшний день определено множество ассоциаций между mLOY и генами, выявленными на основании данных GWAS и транскриптомов в пораженных тканях, однако не установлены ни точная причина возникновения mLOY, ни влияние и последствия этого феномена на уровне всего организма. В частности, неясно, влияет ли анеуплоидия по Y-хромосоме в клетках крови на развитие патологий, проявляющихся в других органах, например на мозг при болезни Альцгеймера, или представляет собой нейтральный биомаркер общей геномной нестабильности. В обзоре рассмотрены основные патологии и генетические факторы, ассоциированные с mLOY, и гипотезы их взаимосвязи. Особое внимание уделено последним исследованиям, посвященным mLOY в клетках мозга при болезни Альцгеймера.

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