vavilovВавиловский журнал генетики и селекцииVavilov Journal of Genetics and Breeding2500-3259Institute of Cytology and Genetics of Siberian Branch of the RAS10.18699/vjgb-25-37vavilov-4600Research ArticleМОЛЕКУЛЯРНАЯ И КЛЕТОЧНАЯ БИОЛОГИЯMOLECULAR AND CELL BIOLOGYОт цитогенетики к протеогеномике: новые горизонты в исследовании анеуплоидийFrom cytogenetics to proteogenomics: new horizons in the study of aneuploidiesЗадесенецК. С.ZadesenetsK. S.

Новосибирск

Novosibirsk

kira_z@bionet.nsc.ruРубцовН. Б.RubtsovN. B.

Новосибирск

Novosibirsk

Федеральный исследовательский центр Институт цитологии и генетики Сибирского отделения Российской академии наук; Новосибирский национальный исследовательский государственный университетРоссияInstitute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences; Novosibirsk State UniversityRussian Federation202503062025293335348Copyright © Задесенец К.С., Рубцов Н.Б., 20252025Задесенец К.С., Рубцов Н.Б.Zadesenets K.S., Rubtsov N.B.This work is licensed under a Creative Commons Attribution 4.0 License.https://vavilov.elpub.ru/jour/article/view/4600

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.

Aneuploidy is defined as the loss or gain of a whole chromosome or its region. Even at early stages of development, it usually leads to fatal consequences, including developmental defects/abnormalities and death. For a long time, it was believed that the disruption of gene balance results in pronounced effects at both the cellular and organismal levels, adversely affecting organism formation. It has been shown that the gene imbalance resulting from aneuploidy leads to proteotoxic and metabolic stress within the cell, reduced cell proliferation, genomic instability, oxidative stress, etc. However, some organisms have exhibited tolerance to aneuploidies, which may even confer adaptive advantages, such as antibiotic resistance in pathogenic fungal strains. A significant factor likely lies in the complexity of the tissue and organ organization of specific species. Polyploid organisms are generally more tolerant of aneuploidy, particularly those that have recently undergone whole-genome duplication. This review places special emphasis on the examination of sex chromosome aneuploidies in humans. In addition to primary effects, or cis effects (changes in the quantity of the transcripts of genes located on the aneuploid chromosome), aneuploidy can induce secondary or trans effects (changes in the expression levels of genes located on other chromosomes). The results of recent studies have prompted a reevaluation of the impact of aneuploidy on the structural-functional organization of the genome, transcriptome, and proteome of both the cell and the entire organism. Despite the fact that, in the cases of aneuploidy, the expression levels for most genes correlate with their altered copy numbers in the cell, there have been instances of  dosage compensation, where the transcript levels of genes located on the aneuploid chromosome remained unchanged. The review presents findings from recent studies focused on compensatory mechanisms of dosage compensation that modify gene product quantities at post-transcriptional and post-translational levels, alleviating the negative effects of aneuploidy on cellular homeostasis. It also discusses the influence of extrachromosomal elements on the spatial organization of the genome and the changes in gene expression patterns resulting from their presence. Additionally, the review specifically examines cases of segmental aneuploidy and changes in copy number variants (CNVs) in the genome. Not only the implications of their composition are considered, but also their localization within the chromosome and in various compartments of the interphase nucleus. Addressing these questions could significantly contribute to enhancing cytogenomic diagnostics and establishing a necessary database for accurate interpretation of identified cases of segmental aneuploidy and CNVs in the genome.

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