vavilovВавиловский журнал генетики и селекцииVavilov Journal of Genetics and Breeding2500-3259Institute of Cytology and Genetics of Siberian Branch of the RAS10.18699/vjgb-26-68vavilov-5185Research ArticleМЕДИЦИНСКАЯ ГЕНЕТИКАMEDICAL GENETICSПарадигма соматического мозаицизма при многофакторных заболеванияхThe paradigm of somatic mosaicism in complex diseaseshttps://orcid.org/0000-0003-3226-1750СлепцовА. А.SleptcovA. A.

Томск; Тюмень

Tomsk; Tyumen

alexei.sleptcov@medgenetics.ruhttps://orcid.org/0000-0002-0673-4094НазаренкоМ. С.NazarenkoM. S.

Томск; Тюмень

Tomsk; Tyumen

https://orcid.org/0000-0002-2113-4556ПузыревВ. П.PuzyrevV. P.

Томск

Tomsk

Научно-исследовательский институт медицинской генетики Томского национального исследовательского медицинского центра Российской академии наук; Тюменский кардиологический научный центр – филиал Томского национального исследовательского медицинского центра Российской академии наукРоссияResearch Institute of Medical Genetics, Tomsk National Research Medical Center of the Russian Academy of Sciences; Tyumen Cardiology Research Center – Branch of Tomsk National Research Medical Center of the Russian Academy of SciencesRussian FederationНаучно-исследовательский институт медицинской генетики Томского национального исследовательского медицинского центра Российской академии наукРоссияResearch Institute of Medical Genetics, Tomsk National Research Medical Center of the Russian Academy of SciencesRussian Federation202624072026304676684Copyright © Слепцов А.А., Назаренко М.С., Пузырев В.П., 20262026Слепцов А.А., Назаренко М.С., Пузырев В.П.Sleptcov A.A., Nazarenko M.S., Puzyrev V.P.This work is licensed under a Creative Commons Attribution 4.0 License.https://vavilov.elpub.ru/jour/article/view/5185

Многофакторные заболевания (МФЗ) характеризуются сложной этиологией, включающей взаимодействие полигенных/олигогенных наследственных детерминант и факторов среды, а также выраженным клиническим полиморфизмом, генетической гетерогенностью, плейотропией генетических вариантов, вариабельной пенетрантностью и экспрессивностью. Достижения в области секвенирования геномов популяций существенно расширили понимание наследственной архитектуры МФЗ, однако герминативные варианты объясняют лишь часть наблюдаемой фенотипической вариабельности. Внедрение методов глубокого секвенирования ДНК и мультиомиксного анализа отдельных клеток позволило выявить дополнительную, ранее недооцененную категорию факторов риска, а именно соматические мутации, непрерывно накапливающиеся в клетках на протяжении онтогенеза и формирующие мозаичную генетическую конституцию организма (соматический мозаицизм). В настоящем обзоре рассматривается роль соматических мутаций в этиопатогенезе МФЗ с позиции их сочетанного вклада с герминативными детерминантами в формирование патологического фенотипа. Особое внимание уделено феномену клонального гемопоэза неопределенного потенциала как наиболее изученной модели соматического мозаицизма, ассоциированного с возраст-зависимой патологией. Показано, что взаимодействие соматических и герминативных вариантов реализуется в клетках в специфических тканевых контекстах через механизмы клональной селекции, стохастического клонального дрейфа и эпигенетической дисрегуляции, приводящих к дисфункции органов. В рамках концепции соматического мозаицизма в работе обосновывается механизм селекции, альтернативный классическому онкогенезу. Данный путь определяется как «пассивная клональная доминантность» и описывает селекцию как персистенцию клонов, получивших преимущество не за счет пролиферации, а благодаря резистентности к апоптозу в условиях хронического стресса. Такой механизм может быть особенно важен для постмитотических тканей, таких как миокард и нервная ткань. С практической точки зрения рассмотренные соматические варианты представляют потенциальный интерес в качестве кандидатных биомаркеров для предиктивной диагностики и стратификации риска МФЗ, что требует дальнейшей клинической валидации. Более того, они указывают на патофизиологические пути, потенциально открывающие мишени для таргетной терапии, направленной на модуляцию клонального состава и предотвращение прогрессирования заболеваний. В заключение даны перспективы и направления изучения соматического мозаицизма в контексте МФЗ, включая потенциал технологий динамического отслеживания клеточных линий для экспериментальной верификации предложенных механизмов клональной селекции. Отмечена важность интеграции данных о соматических и герминативных генетических вариантах в единые модели оценки индивидуального риска заболеваний.

The multifactorial etiology of complex diseases involves the interplay of polygenic/oligogenic susceptibility loci and environmental factors. Complex diseases are characterized by pronounced phenotypic variability, genetic heterogeneity, pleiotropy of genetic variants, variable penetrance, and expressivity. Advances in population-wide genomic sequencing have expanded our understanding of the genetic architecture of complex diseases significantly; however, germline variants explain only a fraction of the observed phenotypic variability. The introduction of deep DNA sequencing and single-cell multi-omics analysis has revealed an additional, previously underestimated category of risk factors: somatic mutations that continuously accumulate in cells throughout an individual’s lifespan, giving rise to genetic mosaicism. This review considers the role of somatic mutations in the pathogenesis of complex diseases in the context of their combined contribution with germline determinants to the formation of disease phenotypes. Particular attention is paid to clonal hematopoiesis of indeterminate potential as the best-studied model of somatic mosaicism associated with age-related conditions. It is demonstrated that the interaction of somatic and germline variants occurs within specific tissue contexts through mechanisms of clonal selection, stochastic clonal drift, and epigenetic dysregulation, causing organ dysfunction. Within the concept of somatic mosaicism, this work suggests a selection mechanism alternative to classical oncogenesis. This pathway, defined as “passive clonal dominance”, describes selection through the persistence of clones that gain advantage not via proliferation but through resistance to apoptosis under chronic stress, which may be particularly relevant to post-mitotic tissues such as the heart muscle and nervous tissue. From a practical standpoint, the somatic variants discussed herein are of interest as candidate biomarkers for predictive diagnostics and risk stratification of complex diseases, pending clinical validation. Moreover, they point to pathophysiological pathways that may reveal targets for therapies aimed at modulating clonal composition and preventing disease progression. The paper also discusses prospects for studying somatic mosaicism in the context of complex diseases, including the potential of dynamic lineage tracing technologies for experimental verification of the proposed clonal selection mechanisms, as well as the need to integrate somatic and germline genetic variant data into unified models for individual disease risk assessment.

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