vavilovВавиловский журнал генетики и селекцииVavilov Journal of Genetics and Breeding2500-3259Institute of Cytology and Genetics of Siberian Branch of the RAS10.18699/VJ20.674vavilov-2822Research ArticleГЕНЕТИКА ЧЕЛОВЕКАHUMAN GENETICSКандидатные SNP-маркеры, изменяющие сродство ТВР к промоторам Y-связанных генов CDY2A, SHOX, ZFY, снижают ряд показателей репродуктивного потенциала мужчинCandidate SNP-markers altering TBP binding affinity for promoters of the Y-linked genes CDY2A, SHOX, and ZFY are lowering many indexes of reproductive potential in menhttps://orcid.org/0000-0003-1663-318XПономаренкоМ. П.PonomarenkoM. P.

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Novosibirsk

pon@bionet.nsc.ruШарыповаЕ. Б.SharypovaE. B.

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Novosibirsk

ДрачковаИ. А.DrachkovaI. A.

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Novosibirsk

СавинковаЛ. К.SavinkovaL. K.

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Novosibirsk

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

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Novosibirsk

https://orcid.org/0000-0003-4795-0954РассказовД. А.RasskazovD. A.

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Novosibirsk

https://orcid.org/0000-0003-2715-9612ПономаренкоП. М.PonomarenkoP. M.

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Novosibirsk

https://orcid.org/0000-0002-7597-9204ОсадчукЛ. В.OsadchukL. V.

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Novosibirsk

https://orcid.org/0000-0002-4210-7354ОсадчукА. В.OsadchukA. V.

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Novosibirsk

Федеральный исследовательский центр Институт цитологии и генетики Сибирского отделения Российской академии наук; Новосибирский национальный исследовательский государственный университетРоссияInstitute of Cytology and Genetics of Siberian Branch of the Russian Academy of Sciences; Novosibirsk State UniversityRussian FederationФедеральный исследовательский центр Институт цитологии и генетики Сибирского отделения Российской академии наукРоссияInstitute of Cytology and Genetics of Siberian Branch of the Russian Academy of SciencesRussian Federation202006122020247785793Copyright © Пономаренко М.П., Шарыпова Е.Б., Драчкова И.А., Савинкова Л.К., Чадаева И.В., Рассказов Д.А., Пономаренко П.М., Осадчук Л.В., Осадчук А.В., 20202020Пономаренко М.П., Шарыпова Е.Б., Драчкова И.А., Савинкова Л.К., Чадаева И.В., Рассказов Д.А., Пономаренко П.М., Осадчук Л.В., Осадчук А.В.Ponomarenko M.P., Sharypova E.B., Drachkova I.A., Savinkova L.K., Chadaeva I.V., Rasskazov D.A., Ponomarenko P.M., Osadchuk L.V., Osadchuk A.V.This work is licensed under a Creative Commons Attribution 4.0 License.https://vavilov.elpub.ru/jour/article/view/2822

Репродуктивный потенциал – уровень физического и психического состояния организма, позволяющий при достижении социальной зрелости воспроизводить здоровое потомство. В узком биомедицинском смысле определение включает комплекс функциональных показателей репродуктивной системы, но в более широком смысле его можно рассматривать как совокупность физиологических, поведенческих, адаптивных, ментальных, антропометрических и генетических характеристик особи, способствующих размножению. Целью настоящей работы было расширить область применимости созданного ранее Web-сервиса SNP_TATA_Z-tester для поиска кандидатных маркеров однонуклеотидного полиморфизма (SNP) на хромосоме Y человека, связанных с мужским репродуктивным потенциалом (МРП). В поиске кандидатных SNP-маркеров для МРП мы сосредоточились на генах хромосомы Y человека. Изучены 35 SNP в промоторах генов CDY2A, SHOX и ZFY, представляющих все три типа генов хромосомы Y человека: уникальный, псевдоаутосомный и паралог гена хромосомы X человека соответственно. Предсказаны 11 кандидатных SNP-маркеров ослабления МРП из-за изменения сродства TATA-связывающего белка (TBP) к этим промоторам. Выборочно верифицированы in vitro величины сродства «TBP-промотор», предсказанные в этой работе. Установлена достоверная корреляция (r = 0.94, p < 0.005) между ними и результатами измерения in vitro сродства ТВР человека к олигонуклеотидам, идентичным сайтам ТВР-связывания исследуемых промоторов. Проведя поиск в базе данных PubMed по ключевым словам, мы нашли клиническое описание патологических состояний человека, соответствующих изменению экспрессии генов, несущих предсказанные нами кандидатные SNP-маркеры. Среди них оказались такие патологии, как нарушение сперматогенеза (ZFY: rs1388535808 и rs996955491), задержка полового созревания (CDY2A: rs200670724), нарушения эмбриогенеза (SHOX: rs28378830) и непропорционально низкий рост с деформациями Маделунга (SHOX: rs1452787381). Они свидетельствуют, что в случае SNP-промоторов генов хромосомы Y человека следует ожидать изменений широкого круга показателей МРП, выходящих далеко за рамки генетического контроля собственно мужской репродуктивной функции.

Reproductive potential is the most important conditional indicator reflecting the ability of individuals in a population to reproduce, survive and develop under optimal environmental conditions. As for humans, the concept of reproductive potential can include the level of the individual’s mental and physical state, which allows them to reproduce healthy offspring when they reach social and physical maturity. Female reproductive potential has been investigated in great detail, whereas the male reproductive potential (MRP) has not received the equal amount of attention as yet. Therefore, here we focused on the human Y chromosome and found candidate single-nucleotide polymorphism (SNP) markers of MRP. With our development named Web-service SNP_TATA_Z-tester, we examined in silico all 35 unannotated SNPs within 70-bp proximal promoters of the three Y-linked genes, CDY2A, SHOX and ZFY, which represent all types of human Y-chromosome genes, namely: unique, pseudo-autosomal, and human X-chromosome gene paralogs, respectively. As a result, we found 11 candidate SNP markers for MRP, which can significantly alter the TATA-binding protein (TBP) binding affinity for promoters of these genes. First of all, we selectively verified in vitro the values of the TBP-promoter affinity under this study, Pearson’s linear correlation between predicted and measured values of which were r = 0.94 (significance p < 0.005). Next, as a discussion, using keyword search tools of the PubMed database, we found clinically proven physiological markers of human pathologies, which correspond to a change in the expression of the genes carrying the candidate SNP markers predicted here. These were markers for spermatogenesis disorders (ZFY: rs1388535808 and rs996955491), for male maturation arrest (CDY2A: rs200670724) as well as for disproportionate short stature at Madelung deformity (e. g., SHOX: rs1452787381) and even for embryogenesis disorders (e. g., SHOX: rs28378830). This indicates a wide range of MRI indicators, alterations in which should be expected in the case of SNPs in the promoters of the human Y-chromosome genes and which can go far beyond changes in male fertility.

человекрепродуктивный потенциалхромосома YгенпромоторTATA-связывающий белок (TBP)TBP-связывающий сайт (ТATA-бокс)однонуклеотидный полиморфизм (SNP)SNP-маркерверификация in vitrohumanreproductive potentialchromosome YgenepromoterTATA-binding protein (TBP)TBP-binding site (TATA-box)single nucleotide polymorphism (SNP)candidate SNP markerverification in vitroИдея, общая координация работы, компьютерные прогнозы и их биологическая интерпретация (ЛВО и АВО) осуществлены при поддержке гранта Российского научного фонда (проект № 19-15-00075). Текст рукописи написан МПП и ИВЧ при поддержке Минобрнауки РФ по Программе повышения конкурентоспособности российских университетов среди мировых научно-образовательных центров (Проект 5-100), Web-сервис (ПМП и ДАР) и эксперимент in vitro (ЕБШ, ИАД и ЛКС) – при поддержке бюджетных проектов № 0324-2019-0040-C-01 и № 0324-2019-0042-C-01 соответственно.ReferencesAmberger J., Bocchini C., Schiettecatte F., Scott A., Hamosh A. 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The authors declare that there are no conflicts of interest present.