vavilovВавиловский журнал генетики и селекцииVavilov Journal of Genetics and Breeding2500-3259Institute of Cytology and Genetics of Siberian Branch of the RAS10.18699/VJ15.089vavilov-485Research ArticleГеномика и анализ полиморфизмовGenomics and Polymorphism AnalysisВлияние однонуклеотидных полиморфных замен в районах позиционирования РНК -полимеразы II на сродство к ним TBP в генах циркадных часов человекаThe effects of SN Ps in the regions of positioning RNA polymerase II on the TBP/promoter affinity in the genes of human circadian clockПодколоднаяО. А.PodkolodnayaO. A.opodkol@bionet.nsc.ruРассказовД. А.RasskazovD. A.ПодколодныйН. Л.PodkolodnyyN. L.ПодколоднаяН. Н.PodkolodnayaN. N.СусловВ. В.SuslovV. V.СавинковаЛ. К.SavinkovaL. K.ПономаренкоП. М.PonomarenkoP. M.ПономаренкоМ. П.PonomarenkoM. P.Федеральное государственное бюджетное научное учреждение «Федеральный исследовательский центр Институт цитологии и генетики Сибирского отделения Российской академии наук», Новосибирск, РоссияРоссияInstitute of Cytology and Genetics SB RA S, Novosibirsk, RussiaRussian FederationФедеральное государственное бюджетное научное учреждение «Федеральный исследовательский центр Институт цитологии и генетики Сибирского отделения Российской академии наук», Новосибирск, Россия Федеральное государственное бюджетное учреждение науки Институт вычислительной математики и математической геофизики Сибирского отделения Российской академии наук, Новосибирск, Россия Федеральное государственное автономное образовательное учреждение высшего образования «Новосибирский национальный исследовательский государственный университет», Новосибирск, РоссияРоссияInstitute of Cytology and Genetics SB RA S, Novosibirsk, Russia Institute of Computational Mathematics and Mathematical Geophysics SB RA S, Novosibirsk, Russia Novosibirsk State University, Novosibirsk, RussiaRussian FederationФедеральное государственное бюджетное научное учреждение «Федеральный исследовательский центр Институт цитологии и генетики Сибирского отделения Российской академии наук», Новосибирск, Россия Федеральное государственное автономное образовательное учреждение высшего образования «Новосибирский национальный исследовательский государственный университет», Новосибирск, РоссияРоссияInstitute of Cytology and Genetics SB RA S, Novosibirsk, Russia Novosibirsk State University, Novosibirsk, RussiaRussian FederationФедеральное государственное бюджетное научное учреждение «Федеральный исследовательский центр Институт цитологии и генетики Сибирского отделения Российской академии наук», Новосибирск, РоссияРоссияChildren’s Hospital Los Angeles, University of Southern California, USARussian Federation201502012016196682690Copyright © Подколодная О.А., Рассказов Д.А., Подколодный Н.Л., Подколодная Н.Н., Суслов В.В., Савинкова Л.К., Пономаренко П.М., Пономаренко М.П., 20162016Подколодная О.А., Рассказов Д.А., Подколодный Н.Л., Подколодная Н.Н., Суслов В.В., Савинкова Л.К., Пономаренко П.М., Пономаренко М.П.Podkolodnaya O.A., Rasskazov D.A., Podkolodnyy N.L., Podkolodnaya N.N., Suslov V.V., Savinkova L.K., Ponomarenko P.M., Ponomarenko M.P.This work is licensed under a Creative Commons Attribution 4.0 License.https://vavilov.elpub.ru/jour/article/view/485

Генетическая вариабельность в системе циркадных часов проявляется в фенотипической изменчивости физиологических функций и поведения, а также в нарушениях функционирования не только самих часов, но и других систем, приводящих к развитию серьезных патологических состояний. В данной работе был проведен анализ влияния однонуклеотидных полиморфных замен (ОНП), локализованных в области [–70, –20] от старта транскрипции, на сродство TATA-связывающего белка (TATA-binding protein, TBP) к промотору в двух группах генов, являющихся компонентами системы циркадных часов человека. Первую группу составляют гены ядра циркадного осциллятора (11 генов), вторую – гены ближайшего регуляторного окружения циркадного осциллятора (21 ген), для сравнения взята группа функционально отличающихся генов (31 ген). Для оценки in silico изменения константы диссоциации и, следовательно, сродства TBP/промотор при мутациях был использован Web-сервис SNP_TATA_Comparator. В результате показано, что в первой группе генов количество ОНП-маркеров снижения сродства TBP/ промотор значимо ниже количества ОНП-маркеров увеличения сродства (α < 10–3), в то время как в группе сравнения наблюдается противоположная картина: ОНП-маркеров уменьшения сродства TBP/промотор значимо больше, чем ОНП-маркеров увеличения сродства (α < 10–6). Наблюдаемая особенность может быть специфической характеристикой генов циркадного осциллятора, влияющей на его устойчивость при генетической вариабельности анализируемой области промоторов. Полученные предсказания могут играть важную роль для отбора кандидатных ОНП- маркеров различных патологий, связанных с нарушением системы циркадных часов, для дальнейшей проверки их в экспериментальных исследованиях, а также при верификации математических моделей циркадного осциллятора.

Genetic variability in the genes of circadian clock is manifested as the phenotypic variability of physiological functions and behavior as well as disorders of the function of not only the clock but also other systems, leading to the development of a pathologies. We analyzed the influence of SNPs localized in the [–70, –20] region from the transcription start site of the gene on TBP / promoter affinity in two groups of genes that are components of the system of human circadian clock. The first group comprises the genes of the circadian oscillator core (11 genes); the second, the genes of the nearest regulatory environment of the circadian oscillator (21 genes). A group for comparison included genes with another function (31 genes). The SNP_TATA_Comparator web service was used for prediction of the effect of SNPs in the regions of positioning of RNA polymerase II on the dissociation constant for TBP / promoter. It was shown that the number of SNP markers reducing the TBP / promoter affinity in the first group of genes significantly lower than the number of SNP markers increasing affinity (α < 10–3). The reverse was true of the comparison group: SNP markers reduced TBP / promoter affinity to a significantly greater extent than the SNP marker increased affinity (α < 10–6). This property may be a characteristic feature of genes  of the circadian oscillator. These predictions are important for identification of candidate SNP markers of various pathologies associated with the dysfunction of circadian clock genes for further testing them in experimental and clinical studies, as well as for verification of mathematical models of the circadian oscillator.

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