vavilovВавиловский журнал генетики и селекцииVavilov Journal of Genetics and Breeding2500-3259Institute of Cytology and Genetics of Siberian Branch of the RAS10.18699/VJGB-23-77vavilov-3938Research ArticleГЕНЕТИКА ЧЕЛОВЕКАHUMAN GENETICSОднонуклеотидные замены в геноме человека, влияющие на связывание факторов транскрипции, и их роль в развитии патологийHuman-genome single nucleotide polymorphisms affecting transcription factor binding and their role in pathogenesishttps://orcid.org/0000-0002-4214-7153АнтонцеваЕ. В.AntontsevaE. V.

Новосибирск

Novosibirsk

antontseva@bionet.nsc.ruhttps://orcid.org/0000-0001-8586-2256ДегтяреваА. О.DegtyarevaA. O.

Новосибирск

Novosibirsk

https://orcid.org/0000-0002-7460-5892КорболинаЕ. Е.KorbolinaE. E.

Новосибирск

Novosibirsk

https://orcid.org/0000-0002-3883-3054ДамаровИ. С.DamarovI. S.

Новосибирск

Novosibirsk

https://orcid.org/0000-0002-2707-0127МеркуловаТ. И.MerkulovaT. I.

Новосибирск

Novosibirsk

Федеральный 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 Federation202302112023276662675Copyright © Антонцева Е.В., Дегтярева А.О., Корболина Е.Е., Дамаров И.С., Меркулова Т.И., 20232023Антонцева Е.В., Дегтярева А.О., Корболина Е.Е., Дамаров И.С., Меркулова Т.И.Antontseva E.V., Degtyareva A.O., Korbolina E.E., Damarov I.S., Merkulova T.I.This work is licensed under a Creative Commons Attribution 4.0 License.https://vavilov.elpub.ru/jour/article/view/3938

Однонуклеотидные замены, также называемые однонуклеотидными полиморфизмами (single nucleotide polymorphism, SNP), – это наиболее распространенный тип вариаций генома человека. Подавляющая часть выявленных в геноме человека SNP не оказывает какого-либо воздействия на молекулярный фенотип, однако некоторые способны приводить к изменению функции гена или уровня его экспрессии. В то же время большинство SNP, ассоциированных с некими признаками или патологиями, картируются в регуляторных областях генома, изменяют потенциальные сайты связывания транскрипционных факторов и, соответственно, могут влияют на экспрессию генов. В последние десятилетия значительные усилия были направлены на поиск таких регуляторных SNP (rSNP), а так же на понимание механизмов, посредством которых они приводят к фенотипическим различиям, в первую очередь к разной предрасположенности к заболеваниям и индивидуальной чувствительности к лекарственным препаратам. Развитие технологии NGS (next generation sequencing) способствовало не только выявлению огромного количества SNP и поиску их ассоциации (genome wide association studies, GWAS) с некими заболеваниями или фенотипическими проявлениями, но и развитию более производительных подходов для их функциональной аннотации. Стоит отметить, что наличие ассоциации не позволяет выделить функциональный, действительно связанный с болезнью вариант последовательности ДНК из множества маркерных, которые выявляются за счет неравновесия по сцеплению. Более того, установление ассоциаций генетических вариантов с заболеванием не дает сведений о функциональности этих вариантов, что необходимо для выяснения молекулярных механизмов развития патологии и разработки эффективных методов ее лечения и профилактики. В связи с этим функциональный анализ SNP, аннотированных в GWAS каталоге, как на полногеномном уровне, так и на уровне отдельных SNP в последние годы стал особенно актуальным. В настоящее время активно развивается полногеномный поиск потенциально регуляторных SNP без каких- либо предварительных знаний об их ассоциации с признаком. Так, картирование локусов количественных признаков экспрессии (eQTL, expression quantitative trait loci) позволяет выявить SNP, для которого в транскриптомах гомозигот по разным его аллелям, а также гетерозигот наблюдаются различия в уровне экспрессии неких генов, причем как близко расположенных, так и на значительном удалении. Для предсказания регуляторных SNP используют также подходы, основанные на поиске аллель-специфических событий в данных RNA-seq, ChIP-seq, DNase-seq, ATAC- seq, MPRA и т. д. Однако для более полной характеристики таких rSNP необходимо устанавливать их ассоциацию с признаком, в частности с предрасположенностью к некой патологии или с чувствительностью к лекарственным препаратам. Таким образом, именно комплексное использование двух основанных на противоположных принципах подходов к поиску значимых для развития признака (патологии) SNP: с одной стороны, исходящего из данных по ассоциации SNP с неким признаком, а с другой стороны, идущего от определения аллель-специфичных изменений на молекулярном уровне (в транскриптоме или регуломе) – существенно обогащает картину наших знаний о роли генетических детерминант в молекулярных механизмах формирования признаков, включая предрасположенность к многофакторным заболеваниям.

Single nucleotide polymorphisms (SNPs) are the most common type of variation in the human genome. The vast majority of SNPs identified in the human genome do not have any effect on the phenotype; however, some can lead to changes in the function of a gene or the level of its expression. Most SNPs associated with certain traits or pathologies are mapped to regulatory regions of the genome and affect gene expression by changing transcription factor binding sites. In recent decades, substantial effort has been invested in searching for such regulatory SNPs (rSNPs) and understanding the mechanisms by which they lead to phenotypic differences, primarily to individual differences in susceptibility to di seases and in sensitivity to drugs. The development of the NGS (next-generation sequencing) technology has contributed not only to the identification of a huge number of SNPs and to the search for their association (genome-wide association studies, GWASs) with certain diseases or phenotypic manifestations, but also to the development of more productive approaches to their functional annotation. It should be noted that the presence of an association does not allow one to identify a functional, truly disease-associated DNA sequence variant among multiple marker SNPs that are detected due to linkage disequilibrium. Moreover, determination of associations of genetic variants with a disease does not provide information about the functionality of these variants, which is necessary to elucidate the molecular mechanisms of the development of pathology and to design effective methods for its treatment and prevention. In this regard, the functional analysis of SNPs annotated in the GWAS catalog, both at the genome-wide level and at the level of individual SNPs, became especially relevant in recent years. A genome-wide search for potential rSNPs is possible without any prior knowledge of their association with a trait. Thus, mapping expression quantitative trait loci (eQTLs) makes it possible to identify an SNP for which – among transcriptomes of homozygotes and heterozygotes for its various alleles – there are differences in the expression level of certain genes, which can be located at various distances from the SNP. To predict rSNPs, approaches based on searches for allele-specific events in RNA-seq, ChIP-seq, DNase-seq, ATAC-seq, MPRA, and other data are also used. Nonetheless, for a more complete functional annotation of such rSNPs, it is necessary to establish their association with a trait, in particular, with a predisposition to a certain pathology or sensitivity to drugs. Thus, approaches to finding SNPs important for the development of a trait can be categorized into two groups: (1) starting from data on an association of SNPs with a certain trait, (2) starting from the determination of allele-specific changes at the molecular level (in a transcriptome or regulome). Only comprehensive use of strategically different approaches can considerably enrich our knowledge about the role of genetic determinants in the molecular mechanisms of trait formation, including predisposition to multifactorial diseases.

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