Однонуклеотидные замены в геноме человека, влияющие на связывание факторов транскрипции, и их роль в развитии патологий

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.

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