vavilovВавиловский журнал генетики и селекцииVavilov Journal of Genetics and Breeding2500-3259Institute of Cytology and Genetics of Siberian Branch of the RAS10.18699/vjgb-26-80vavilov-5233Research ArticleМЕДИЦИНСКАЯ ГЕНЕТИКАMEDICAL GENETICSУнаследованная и соматическая компоненты в патогенетике многофакторных заболеванийInherited and somatic components in the pathogenetics of common diseasesНазаренкоМ. С.NazarenkoM. S.

Томск

Тюмень

Tomsk

Tyumen

maria.nazarenko@medgenetics.ruСлепцовА. А.SleptcovA. A.

Томск

Тюмень

Tomsk

Tyumen

ПузыревВ. 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 the 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 Federation202626082026305792802Copyright © Назаренко М.С., Слепцов А.А., Пузырев В.П., 20262026Назаренко М.С., Слепцов А.А., Пузырев В.П.Nazarenko M.S., Sleptcov A.A., Puzyrev V.P.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://vavilov.elpub.ru/jour/article/view/5233

Хорошо известно, что патогенез многофакторных заболеваний определяется сложным и нелинейным взаимодействием генетической предрасположенности, эпигенетических модификаций и факторов внешней среды. Однако помимо унаследованных генетических вариантов, важную роль в развитии патологического фенотипа играют соматические мутации, образуя клеточно-специфичные генетические ландшафты и влияя на регионарную предрасположенность органов-мишеней, возраст манифестации и вариабельность клинических проявлений. Таким образом, согласно современным представлениям, многофакторные заболевания формируются в результате совместного влияния унаследованных герминативных вариантов и соматических мутаций, приобретенных в течение жизни, взаимодействие которых реализуется через клеточно-специфичные молекулярные сети. В связи с этим в обзоре последовательно рассматриваются основные факторы, классические и современные модели сложных патологических фенотипов, а также достижения и перспективы анализа наследуемых генетических вариантов в отношении многофакторных заболеваний. Роль соматических мутаций в формировании патологии обсуждается на примере онтогенеза атеросклероза и концепции атероонкологии через оценку соматической вариабельности генома в гладкомышечных клетках атеросклеротической бляшки, когда последовательное накопление «драйверных» мутаций дает селективное преимущество и запускает процесс клональной эволюции в тканевом микроокружении. Отдельное внимание уделено описанию концепции «парадоминантного» наследования – особой форме неменделевской передачи сложных признаков, сочетающей унаследованную предрасположенность и соматические мутации, возникающие на ранних стадиях онтогенеза. На основе анализа современных данных нами предлагается интегративная гипотеза, постулирующая, что унаследованные генетические варианты формируют общеорганизменный фон предрасположенности к многофакторным заболеваниям, в то время как соматические мутации, возникающие и селективно увеличивающиеся в специфических клеточных компартментах органов-мишеней, являются критичным событием, объясняющим топическую специфичность, временнýю динамику (возраст манифестации) и вариабельность тяжести клинического фенотипа. Новая парадигма предиктивной медицины в отношении многофакторных заболеваний основывается на комплексной характеристике континуума генетических вариантов (унаследованных и соматических), анализе их взаимодействия с клеточно-специфичными молекулярными сетями и переходе от популяционных оценок риска к каузальным моделям индивидуального патогенеза.

It is known that the pathogenesis of common diseases (CDs) is determined by a complex and nonlinear interaction of genetic predisposition, epigenetic modifications, and environmental factors. However, in addition to inherited genetic variants, somatic mutations play a key role in the pathological phenotype, shaping cell-type-specific genetic landscapes and influencing regional predisposition of target organs, age of onset, and variability in clinical manifestations. Thus, according to current concepts, CDs develop as a result of the combined influence of inherited germline variants and somatic mutations acquired during life, the interaction of which is realized through cell-specific molecular networks. Therefore, this review sequentially examines the main factors, classical and modern models of complex pathological phenotypes, as well as the achievements and prospects of analyzing inherited genetic variants in relation to CDs. The role of somatic mutations in the development of pathology is discussed using the example of atherosclerosis ontogenesis and the concept of atherooncology through the assessment of somatic genomic variability in smooth muscle cells of atherosclerotic plaques, where the sequential accumulation of “driver” mutations confers a selective advantage and triggers clonal evolution in the tissue microenvironment. Special attention is given to the concept of “paradominant” inheritance – a special form of nonMendelian transmission of complex traits that combines inherited predisposition and somatic mutations that arise early in ontogenesis. Based on an analysis of current data, we propose an integrative hypothesis postulating that inherited genetic variants form a body-wide predisposition to CDs, while somatic mutations, arising and selectively increasing in specific cellular compartments of target organs, are critical events explaining the regional specificity, temporal dynamics (age of onset), and variability in the severity of the clinical phenotype. A new paradigm for predictive medicine for CDs is based on a comprehensive characterization of the continuum of genetic variants (inherited and somatic), an analysis of their interactions with cell-specific molecular networks, and a transition from population-based risk assessments to causal models of individual pathogenesis.

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