vavilovВавиловский журнал генетики и селекцииVavilov Journal of Genetics and Breeding2500-3259Institute of Cytology and Genetics of Siberian Branch of the RAS10.18699/VJ17.312vavilov-1267Research ArticleСИСТЕМНАЯ БИОЛОГИЯ ЧЕЛОВЕКА И ЖИВОТНЫХHUMAN AND ANIMAL SYSTEMS BIOLOGYРоль генов апоптоза в контроле агрессивного поведения, выявленная с помощью комбинированного анализа ассоциативных генных сетей, экспрессионных и геномных данных по серым крысам с агрессивным поведениемRole of apoptosis genes in aggression revealed using combined analysis of ANDSystem gene networks, expression and genomic data in grey rats with aggressive behaviorБрагинА. О.BraginA. O.

Новосибирск.

Novosibirsk.

ibragim@bionet.nsc.ruСайкО. В.SaikO. V.

Новосибирск.

Novosibirsk.

ЧадаеваИ. В.ChadaevaI. V.

Новосибирск.

Novosibirsk.

ДеменковП. С.DemenkovP. S.

Новосибирск.

Novosibirsk.

МаркельА. Л.MarkelA. L.

Новосибирск.

Novosibirsk.

ОрловЮ. Л.OrlovYu. L.

Новосибирск.

Novosibirsk.

РогаевЕ. И. RogaevE. I.ЛаврикИ. Н.LavrikI. N.

Магдебург.

Magdeburg.

ИванисенкоВ. А.IvanisenkoV. A.

Новосибирск.

Novosibirsk.

Федеральный исследовательский центр Институт цитологии и генетики Сибирского отделения Российской академии наук.РоссияInstitute of Cytology and Genetics SB RAS.Russian FederationФедеральный исследовательский центр Институт цитологии и генетики Сибирского отделения Российской академии наук; Новосибирский национальный исследовательский государственный университет.РоссияInstitute of Cytology and Genetics SB RAS; Novosibirsk State University.Russian FederationФедеральный исследовательский центр Институт цитологии и генетики Сибирского отделения Российской академии наук.РоссияInstitute of Cytology and Genetics SB RASRussian FederationФедеральный исследовательский центр Институт цитологии и генетики Сибирского отделения Российской академии наук; Медицинская школа Массачусетского университета в Вустере; Институт общей генетики Российской Академии наук; Центр генетики и генетических технологий, биологический факультет, факультет биоинженерии и биоинформатики, Московский государственный университет им. М.В. Ломоносова.РоссияInstitute of Cytology and Genetics SB RAS; University of Massachusetts Medical School, Worcester; Institute of General Genetics RAS; Center for Genetics and Genetic Technologies, Faculty of Biology, Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University.Russian FederationФедеральный исследовательский центр Институт цитологии и генетики Сибирского отделения Российской академии наук; Магдебургский университет имени Отто фон Гуерике.ГерманияInstitute of Cytology and Genetics SB RAS; 6 Otto von Guericke University.Germany201720012018218911919Copyright © Брагин А.О., Сайк О.В., Чадаева И.В., Деменков П.С., Маркель А.Л., Орлов Ю.Л., Рогаев Е.И., Лаврик И.Н., Иванисенко В.А., 20182018Брагин А.О., Сайк О.В., Чадаева И.В., Деменков П.С., Маркель А.Л., Орлов Ю.Л., Рогаев Е.И., Лаврик И.Н., Иванисенко В.А.Bragin A.O., Saik O.V., Chadaeva I.V., Demenkov P.S., Markel A.L., Orlov Y.L.,  Rogaev E.I., Lavrik I.N., Ivanisenko V.A.This work is licensed under a Creative Commons Attribution 4.0 License.https://vavilov.elpub.ru/jour/article/view/1267

Агрессивное поведение животных играет важную роль при защите территории, потомства, установлении социально­иерархических отношений и т. д. При ряде заболеваний (шизофрения, маниакально­депрессивный психоз, нейродегенеративные заболевания) наблюдается повышенная агрессия. В нейрогенезе большое значение в поддержании клеточного гомеостаза имеет нейрональный апоптоз. Нарушения нейронального апоптоза отмечаются при старении и различных нейропатологиях (эпилепсия, болезнь Альцгеймера, нейротравмы), сопровождающихся изменениями психоэмоционального состояния. Известно, что в мозге высокоагрессивных крыс значительно изменяется уровень экспрессии ключевых генов нейронального апоптоза (Casp3, Bax и Bcl-xl). В связи с этим актуальным является изучение связей нейронального апоптоза и агрессивного поведения. Целью данной работы был анализ ассоциативных сетей, описывающих молекулярно­генетические взаимодействия между генами/белками, вовлеченными в нейрональный апоптоз, дифференциально экспрессированными генами и генами, имеющими полиморфизмы, у серых крыс с агрессивным поведением. Выявлено 819 дифференциально экспресси рующихся генов в гипоталамусе, вентральной тегментальной об ласти и в сером веществе периакведуктума у крыс с агрессивным и дружелюбным поведением. Анализ ассоциативной сети диффе ренциально экспрессирующихся генов позволил выявить три вершины с максимальной центральностью, которые соответство вали генам Stx1a, Mbp и Th. При анализе генома было  обнаружено 137 полиморфных генов, три из которых (Lig4, Parp1 и Pigt) вовлечены в нейрональный апоптоз. Показано, что среди генов, взаимодей ствующих в ассоциативной сети с генами, вовлеченными в нейро нальный апоптоз, статистически значимо представлены полиморфные и дифференциально экспрессированные гены (p-value < 0.01). Реконструированы три молекулярно­генетические цепочки, описывающие связи между полиморфными генами и генами/белками нейронального апоптоза, опосредованные через дифференциально экспрессированные гены. Цепочки включали полиморфные гены Tsc1, Adamts4 и Lgals3, дифференциально экспрессированные гены Ezr, Acan, Th и 19 генов нейронального апоптоза. Было показано, что процесс нейронального апоптоза тесно связан с агрессивным поведением у животных.

Aggressive behavior in animals plays an important role in protecting the territory, offspring, establishing social hierarchical relations, etc. Increased aggression is observed in a number of diseases ( schizophrenia, bipolar disorder, brain degenerative disorders). Neuronal apoptosis is crucial in the maintenance of developmental processes during neurogenesis. Alterations in neuronal apoptosis are observed in aging and neuropathologies accompanied by changes in psycho­emo­ tional state (epilepsy, Alzheimer’s disease, neurotrauma). The expression of key neuronal apoptosis genes (Casp3, Bax and Bcl-xl) in the brain of highly aggressive rats is significantly altered. The aim of this work was to analyze associative networks that describe genetic interactions between genes/proteins involved in neuronal apoptosis, differentially expressed genes and genes with polymorphisms in grey rats with aggressive behavior. Analysis revealed 819 differentially expressed genes in the hypothalamus, ventral tegmental region and periaqueductus Sylvii grey matter in grey rats with aggressive and tame behavior. The Stx1a, Mbp and Th genes have the highest index of betweenness centrality in the associative network of differentially expressed genes. Genome analysis revealed 137 polymorphic genes. Three of them (Lig4, Parp1 and Pigt) were involved in neuronal apoptosis. It was shown that polymorphic and differentially expressed genes were statistically significantly overrepresented among ge nes interacting with neuronal apoptosis genes (p value < 0.01). Three molecular­genetic chains describing connections between polymorphic and neuronal apoptosis genes mediated by differentially expressed genes were reconstructed. Chains included the polymorphic genes Tsc1, Adamts4 and Lgals3, differentially expressed genes Ezr, Acan, Th and 19 neuronal apoptosis genes. It was shown that neuronal apoptosis is closely related to aggressive behavior in animals.

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