vavilovВавиловский журнал генетики и селекцииVavilov Journal of Genetics and Breeding2500-3259Institute of Cytology and Genetics of Siberian Branch of the RAS10.18699/vjgb-24-89vavilov-4403Research ArticleГЕНОМИКА И ТРАНСКРИПТОМИКАGENOMICS AND TRANSCRIPTOMICSКандидатные SNP-маркеры изменения экспрессии гена SCN9A человека в качестве интегратора генерации, чувства, ответа на боль и анестезииCandidate SNP markers of changes in the expression levels of the human SCN9A gene as a hub gene for pain generation, perception, response and anesthesiahttps://orcid.org/0009-0007-2243-9996ДоценкоП. А.DotsenkoP. A.

Новосибирск

Novosibirsk

https://orcid.org/0009-0006-3933-208XЗолотареваК. А.ZolotarevaK. A.

Новосибирск

Novosibirsk

ИвановР. А.IvanovR. A.

Новосибирск

Novosibirsk

https://orcid.org/0000-0002-2724-5441ЧадаеваИ. В.ChadaevaI. V.

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Novosibirsk

https://orcid.org/0000-0001-9132-7997ПодколодныйН. Л.PodkolodnyyN. L.

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Novosibirsk

https://orcid.org/0000-0002-1859-4631ИванисенкоВ. А.IvanisenkoV. A.

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Novosibirsk

https://orcid.org/0000-0001-9433-8341ДеменковП. С.DemenkovP. S.

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Novosibirsk

https://orcid.org/0000-0003-3138-381XЛашинС. А.LashinS. A.

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Novosibirsk

https://orcid.org/0000-0003-1663-318XПономаренкоМ. П.PonomarenkoM. P.

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Novosibirsk

pon@bionet.nsc.ruФедеральный исследовательский центр Институт цитологии и генетики Сибирского отделения Российской академии наук; Новосибирский национальный исследовательский государственный университет; Курчатовский геномный центр ИЦиГ СО РАНРоссияInstitute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences; Novosibirsk State University; Kurchatov Genomic Center of ICG SB RASRussian FederationФедеральный исследовательский центр Институт цитологии и генетики Сибирского отделения Российской академии наукРоссияInstitute of Cytology and Genetics of the Siberian Branch of the Russian Academy of SciencesRussian FederationФедеральный исследовательский центр Институт цитологии и генетики Сибирского отделения Российской академии наук; Курчатовский геномный центр ИЦиГ СО РАНРоссияInstitute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences; Kurchatov Genomic Center of ICG SB RASRussian FederationФедеральный исследовательский центр Институт цитологии и генетики Сибирского отделения Российской академии наук; Институт вычислительной математики и математической геофизики Сибирского отделения Российской академии наукРоссияInstitute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences; Institute of Computational Mathematics and Mathematical Geophysics of the Siberian Branch of the Russian Academy of SciencesRussian FederationФедеральный 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 Federation202425012025288808821Copyright © Доценко П.А., Золотарева К.А., Иванов Р.А., Чадаева И.В., Подколодный Н.Л., Иванисенко В.А., Деменков П.С., Лашин С.А., Пономаренко М.П., 20252025Доценко П.А., Золотарева К.А., Иванов Р.А., Чадаева И.В., Подколодный Н.Л., Иванисенко В.А., Деменков П.С., Лашин С.А., Пономаренко М.П.Dotsenko P.A., Zolotareva K.A., Ivanov R.A., Chadaeva I.V., Podkolodnyy N.L., Ivanisenko V.A., Demenkov P.S., Lashin S.A., Ponomarenko M.P.This work is licensed under a Creative Commons Attribution 4.0 License.https://vavilov.elpub.ru/jour/article/view/4403

В настоящей работе впервые проведен комплексный биоинформатический анализ генов человека, связанных с генерацией, чувством и ответом на боль наряду с обезболиванием, которые были представлены 568 генами человека согласно базе данных NCBI Gene (дата обращения 15.09.2024). Ген SCN9A человека (sodium voltage-gated channel α subunit 9) передачи сигналов о повреждении тканей от сенсорных нейронов в центральную нервную систему был единственным среди исследуемых 568 генов, который вовлечен во все анализируемые процессы как ген-интегратор для них. Сначала с использованием созданного нами ранее инструмента OrthoWeb для каждого гена оценили таксон ближайшего общего предка всех организмов, у которого расшифрована ДНК этого гена (т. е. индекс филостратиграфического возраста, PAI). Среднеарифметическая оценка PAI для всех анализируемых генов, а также его значение для гена SCN9A, интегратора генерации, чувства и ответа на боль наряду с анестезией, оказались равными 4. На эволюционной шкале Киотской энциклопедии генов и геномов (KEGG) это соответствует таксону Chordata, у одних из самых древних представителей которого произошла специализация центральной и периферической нервной системы. Далее с помощью созданной нами системы ANDSystem мы выявили фосфорилирование ионных каналов как краеугольного камня в генерации, чувстве, ответе на боль и обезболивание, которое определяет эффективность передачи сигналов из периферической в центральную нервную систему. Этот вывод согласуется с литературными данными о ключевой роли эффективной передачи сигналов периферической нервной системы в центральную при коррекции циркадного ритма человека через фактическую детекцию фоторецепторами смены ночной темноты на дневное освещение, а также при определении направления на источник звука слуховыми ядрами мозга, формировании ответа на холодовой стресс и при координации движений у человека. Затем с использованием ранее созданной нами базы данных Human_SNP_TATAdb был предложен 21 кандидатный SNP-маркер значимого увеличения и уменьшения экспрессии гена SCN9A человека. Наконец, отношение встречаемости этих SNP-маркеров сравнили с полногеномным отношением, которое было оценено консорциумом «1000 геномов». В результате обнаружено, что SCN9A как ген-интегратор генерации, чувства, ответа на боль наряду с анестезией подвержен естественному отбору против снижения его экспрессии для поддержания высокого уровня контроля состояния организма и параметров внешней среды.

In this work, we for the first time performed a comprehensive bioinformatics analysis of 568 human genes that, according to the NCBI Gene database as on September 15, 2024, were associated with pain generation, perception and anesthesia. The SCN9A gene encoding the sodium voltage-gated channel α subunit 9 and expressed in sensory neurons for transferring signals to the central nervous system about tissue damage was the only one involved in all the processes of interest at once as a hub gene. First, with our tool called OrthoWeb, we estimated the phylostratigraphic age indices (PAIs) for each of the genes, that is, identified the taxon of the most recent common ancestor of the organisms for which that gene has been sequenced. The mean PAI for all genes under study, including SCN9A as a hub gene for pain generation, perception, response and anesthesia, was ‘4’. On the evolutionary scale by the Kyoto Encyclopedia of Genes and Genomes (KEGG), the ancestor is the phylum Chordata, some of the most ancient of which evolved the central and the peripheral nervous system. Next, with our tool called ANDSystem, we found that phosphorylation of ion channels is a centerpiece in pain generation, perception, response and anesthesia, on which the efficiency of signal transduction from the peripheral to the central system depends. This conclusion was consistent with literature data on a key role an efficient signal transduction from the peripheral to the central system from the peripheral to the central system for adjusting the human circadian rhythm through detection of a change from the dark of night to the light of day and for identification of the direction of the source of sound by auditory brainstem nuclei, for generating the response to cold stress and for physical coordination. 21 candidate SNP marker of significant SCN9A over- and underexpression. Finally, the ratio of SCN9A upregulating to downregulating SNPs was compared to that for all known human genes estimated by the 1000 Genomes Project Consortium. It was found that SCN9A as a hub gene for pain generation, perception, pain response and anesthesia is acted on by natural selection against its downregulation, to keep the nervous system highly informed on the status of the organism and the environment.

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