An Experimental Study of the Effect of Rare Polymorphisms of Human Hbb, HBD and F9 Promoter Tata Boxes on the Kinetics of Interaction With the Tata-Binding Protein

Sharypova, Ekaterina; Драчкова, И. А.; Кашина, Е. В.; Рассказов, Д. А.; Пономаренко, П. М.; Пономаренко, М. П.; Колчанов, Н. А.; Савинкова, Л. К.

doi:10.18699/vj18.342

Cited by 6 publications

(32 citation statements)

References 18 publications

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“…Стрелками на рис. 1 указано, как с помощью (а) Webсервиса UCSC Genome Browser (Haeussler et al, 2015) и (б) базы данных dbSNP (Sherry et al, 2001) мы вводили исходные данные в наш (в) Webсервис SNP_ TATA_Ztester (Sharypova et al, 2018), где окно "Result" содержит результат обработки этих исходных данных в рамках нашей биоинформатической модели трехшагового связывания ТВР/промотор (Ponomarenko P. et al, 2008).…”

Section: материалы и методыunclassified

“…На этих рисунках можно видеть снижение сродства "ТВРODN" с 160 нМ в норме до 500 нМ для минорного аллеля rs2276109. Это свидетельствует об адекватности оценок Webсервиса SNP_TATA_Ztester (Sharypova et al, 2018) для оценки сродства ТВР к промоторам генов на хромосоме Y человека.…”

Section: результаты и обсуждениеunclassified

“…В порядке обсуждения можно ко ротко отметить, что несовпадение между шкалами вер тикальной (эксперимент) и горизонтальной (прогноз) осей на рис. 3 соответствует различию в концентрациях TBP (т. е. в неконтролируемой доле димеров TBP, которые имеют K D = 4 ± 1.5 нМ (Colemanet al, 1995) и не связывают ДНК) в этой работе (2 нМ) и ранее (Ponomarenko Р. et al, 2008) при оптимизации трехшаговой модели связывания «ТВРпромотор» (0.3 нМ), использованной Webсервисом SNP_TATA_Ztester (Sharypova et al, 2018) для прогнозов в этой работе.…”

Section: результаты и обсуждениеunclassified

“…Ранее мы создали Webсервисы SNP_TATA_Comparator (Ponomarenko M. et al, 2015) и SNP_TATA_Ztester (Sharypova et al, 2018) для оценки статистической значимости влияния SNP на сродство ТВР к промоторам генов человека и других эукариот с использованием библиотеки BioPerl (Stajich et al, 2002), доступа к базе данных En sembl (Cunningham et al, 2019) и с помощью других источников данных соответственно. На этой методической основе мы предсказали кандидатные SNPмаркеры ожирения (Ar kova et al, 2015), агрессивности (Chadaeva et al, 2016), нарушений циркадного ритма , атеросклероза (Ponomarenko M. et al, 2019), аутоиммунных заболеваний , болезни Альцгеймера , резистентности к противоопухолевой химиотерапии (Turnaev et al, 2016), предрасположенности к социальному доминированию и подчинению у людей (Chadaeva et al, 2019).…”

Section: Introductionunclassified

“…Целью настоящей работы было расширить область при менимости наших Webсервисов (Ponomarenko M. et al, 2015;Sharypova et al, 2018) для оценки SNP сайтов ТВР связывания посредством поиска кандидатных SNPмар керов на хромосоме Y человека, связанных с показателями мужского репродуктивного потенциала (МРП). Эта ме то дология была использована при изучении женского ре продуктивного потенциала (Chadaeva et al, 2018), тогда как МРП еще не получил должного внимания.…”

Section: Introductionunclassified

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Candidate 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 men

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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.

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Section: материалы и методыunclassified

Section: результаты и обсуждениеunclassified

Section: Introductionunclassified

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Candidate 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 men

et al. 2020

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Disruptive natural selection by male reproductive potential prevents underexpression of protein-coding genes on the human Y chromosome as a self-domestication syndrome

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Background In population ecology, the concept of reproductive potential denotes the most vital indicator of chances to produce and sustain a healthy descendant until his/her reproductive maturity under the best conditions. This concept links quality of life and longevity of an individual with disease susceptibilities encoded by his/her genome. Female reproductive potential has been investigated deeply, widely, and comprehensively in the past, but the male one has not received an equal amount of attention. Therefore, here we focused on the human Y chromosome and found candidate single-nucleotide polymorphism (SNP) markers of male reproductive potential. Results Examining in silico (i.e., using our earlier created Web-service SNP_TATA_Z-tester) all 1206 unannotated SNPs within 70 bp proximal promoters of all 63 Y-linked genes, we found 261 possible male-reproductive-potential SNP markers that can significantly alter the binding affinity of TATA-binding protein (TBP) for these promoters. Among them, there are candidate SNP markers of spermatogenesis disorders (e.g., rs1402972626), pediatric cancer (e.g., rs1483581212) as well as male anxiety damaging family relationships and mother’s and children’s health (e.g., rs187456378). First of all, we selectively verified in vitro both absolute and relative values of the analyzed TBP–promoter affinity, whose Pearson’s coefficients of correlation between predicted and measured values were r = 0.84 (significance p < 0.025) and r = 0.98 (p < 0.025), respectively. Next, we found that there are twofold fewer candidate SNP markers decreasing TBP–promoter affinity relative to those increasing it, whereas in the genome-wide norm, SNP-induced damage to TBP–promoter complexes is fourfold more frequent than SNP-induced improvement (p < 0.05, binomial distribution). This means natural selection against underexpression of these genes. Meanwhile, the numbers of candidate SNP markers of an increase and decrease in male reproductive potential were indistinguishably equal to each other (p < 0.05) as if male self-domestication could have happened, with its experimentally known disruptive natural selection. Because there is still not enough scientific evidence that this could have happened, we discuss the human diseases associated with candidate SNP markers of male reproductive potential that may correspond to domestication-related disorders in pets. Conclusions Overall, our findings seem to support a self-domestication syndrome with disruptive natural selection by male reproductive potential preventing Y-linked underexpression of a protein.

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Unannotated single nucleotide polymorphisms in the TATA box of erythropoiesis genes show in vitro positive involvements in cognitive and mental disorders

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Background Hemoglobin is a tetramer consisting of two α-chains and two β-chains of globin. Hereditary aberrations in the synthesis of one of the globin chains are at the root of thalassemia, one of the most prevalent monogenic diseases worldwide. In humans, in addition to α- and β-globins, embryonic zeta-globin and fetal γ-globin are expressed. Immediately after birth, the expression of fetal Aγ- and Gγ-globin ceases, and then adult β-globin is mostly expressed. It has been shown that in addition to erythroid cells, hemoglobin is widely expressed in nonerythroid cells including neurons of the cortex, hippocampus, and cerebellum in rodents; embryonic and adult brain neurons in mice; and mesencephalic dopaminergic brain cells in humans, mice, and rats. Lately, there is growing evidence that different forms of anemia (changes in the number and quality of blood cells) may be involved in (or may accompany) the pathogenesis of various cognitive and mental disorders, such as Alzheimer’s and Parkinson’s diseases, depression of various severity levels, bipolar disorders, and schizophrenia. Higher hemoglobin concentrations in the blood may lead to hyperviscosity, hypovolemia, and lung diseases, which may cause brain hypoxia and anomalies of brain function, which may also result in cognitive deficits. Methods In this study, a search for unannotated single-nucleotide polymorphisms (SNPs) of erythroid genes was initially performed using our previously created and published SNP-TATA_Z-tester, which is a Web service for computational analysis of a given SNP for in silico estimation of its influence on the affinity of TATA-binding protein (TBP) for TATA and TATA-like sequences. The obtained predictions were finally verified in vitro by an electrophoretic mobility shift assay (EMSA). Results On the basis of these experimental in vitro results and literature data, we studied TATA box SNPs influencing both human erythropoiesis and cognitive abilities. For instance, TBP–TATA affinity in the HbZ promoter decreases 6.6-fold as a result of a substitution in the TATA box (rs113180943), thereby possibly disrupting stage-dependent events of “switching” of hemoglobin genes and thus causing erythroblastosis. Therefore, rs113180943 may be a candidate marker of severe hemoglobinopathies with comorbid cognitive and mental disorders associated with cerebral blood flow disturbances. Conclusions The literature data and experimental and computations results suggest that the uncovered candidate SNP markers of erythropoiesis anomalies may also be studied in cohorts of patients with cognitive and/or mental disorders with comorbid erythropoiesis diseases in comparison to conventionally healthy volunteers. Research into the regulatory mechanisms by which the identified SNP markers contribute to the development of hemoglobinopathies and of the associated cognitive deficits will allow physicians not only to take timely and adequate measures against hemoglobinopathies but also to implement strategies preventing cognitive and mental disorders.

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An Experimental Study of the Effect of Rare Polymorphisms of Human Hbb, HBD and F9 Promoter Tata Boxes on the Kinetics of Interaction With the Tata-Binding Protein

Cited by 6 publications

References 18 publications

Candidate 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 men

Candidate 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 men

Disruptive natural selection by male reproductive potential prevents underexpression of protein-coding genes on the human Y chromosome as a self-domestication syndrome

Unannotated single nucleotide polymorphisms in the TATA box of erythropoiesis genes show in vitro positive involvements in cognitive and mental disorders

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