Vol.3, No.9, 577-583 (2011)
doi:10.4236/health.2011.39099
C
opyright © 2011 SciRes. Openly accessible at http://www.scirp.org/journal/HEALTH/
Health
In vitro examining the existing prognoses how TBP
binds to TATA with SNP associated with human
diseases
Irina A. Drachkova1, Petr M. Ponomarenko1, Tatyana V. Arshinova1, Мikhail P. Ponomarenko1*,
Valentin V. Suslov1, Ludmila K. Savinkova1, Nikolay А. Kolchanov1,2
1Institute of Cytology and Genetics, Siberian Division, Russian Academy of Sciences, Novosibirsk, Russia;
*Corresponding Author:
2Novosibirsk State University, Novosibirsk, Russia.
Received June 18th, 2011; revised July 12th, 2011; accepted August 1st, 2011.
ABSTRACT
We in vitro examined the existing prognoses of
the dissociation constant, KD, between ТАТА-
Binding Protein (TBP) and ТАТА box with single
nucleotide polymorphism (SNP) associated with
human diseases. Five SNPs of the genes for
cytochrome P450 2A6 (associated with lung
cancer), β-globin (associated with β-thalassemia),
mannose binding lectin (associated with vari-
able immunodeficiency), superoxide dismutase
1 (associated with amyotrophic lateral sclerosis)
and triosephosphate isomerase (associated with
anemia) fell within the range of –ln(KD;M/KD;W T)
between –1.5 and –1 (here KD;WT and KD;M denote
the normal ТАТА box and with SNP). The meas-
urements using EMSA demonstrated that: 1) all
the predictions stating that the affinity between
ТВР and ТАТА boxes with SNPs would be re-
duced were correct; 2) the departures of three
predictions from the measurements fell within
the confidence interval; 3) all the predictions
consistently underestimated actual mutational
damage caused to ТАТА boxes with SNPs (
 <
0.05; binomial law) and two of these predictions
did so significantly (
 < 0.05, Student’s t-test).
This consistent underestimation seems to be
associated with the damage to the context that
modulates ТВP/ТА ТА affinity, for example, the
contact between the nucleosomal histone H3-Н4
dimer and the core promoter immediately near
ТАТА boxes.
Keywords: Disease; Polymorphism; ТАТА Box;
TATA-Binding Protein; Affinity; In Vitro; In Silico
1. INTRODUCTION
Variome is largely composed of single nucleotide
polymorphisms (SNPs). Consequently, no study of their
role in ontogenesis or evolution could be efficient with-
out computer-aided support, which would facilitate
searches for SNPs, their documentation and systematiza-
tion, and prediction of their effects on the phenotype.
Over the past 10 years of the coordinated development
of SNP databases and tools [1], anything outside the
phenotype prediction problem has been successfully
addressed [2]. In particular, SNPs responsible for the
propensity for diseases, susceptibility to therapy, sensi-
tivity to regulatory signals, etc. have been identified.
Phenotype prediction has only been successful for the
SNPs that are located in coding gene regions. The com-
mon molecular mechanism that can be proposed for
them is mutational damage made to the gene product [3].
It is still difficult to propose the same for SNPs in regu-
latory gene regions because of the diversity of such re-
gions and a multi-step sequence of assembly, rear-
rangement and degradation of DNA-protein complexes
in them [4]. Examination of the computer-aided methods,
developed on such a diverse material, requires an ex-
perimental examination in standardized conditions (the
standardized examination throughout). Because different
authors set different experimental conditions, the sole
analysis of experimental results in databases will be of
little help. For avoidance of doubt, there is a need for a
coordination of bioinformatic and experimental studies
of each type of site. For that purpose we conduct an in-
tegrated study of regulatory SNPs, especially those in
ТАТА boxes.
The binding of the ТАТА-binding protein (ТВР) to
the ТАТА box initiates assembly of the pre-initiation
complex on the ТАТА-containing promoters of eu-
karyotic genes, which is a critical step in transcription

I. A. Drachkova et al. / Health 3 (2011) 577-583
Copyright © 2011 SciRes. Openly accessible at http://www.scirp.org/journal/HEALTH/
578
initiation [5]. We had previously [6] proposed a method
for in silico prediction of TBP/TATA affinity on the
basis of the equation of equilibrium of ТВР/ТАТА
binding over four subsequent steps: 1) non-specific ТВР/
DNA binding [7]; 2) TBP sliding along DNA [8]; 3)
molecular identification of ТВР/ТАТА [9] and 4) stabi-
lization of the ТВР/ТАТА complex [10] by endothermic
DNA rearrangement [11] with the helix axis bent at 90˚
[10]. This equation allows the relative affinity, Δ =
–ln(KD;M/KD;WT), that is, the ratio of the dissociation
constant of TBP and the normal TATA box (KD;WT) to
that of TBP and the mutant ТАТА box (KD;M), to be
estimated in logarithms. This equation puts together the
commonly accepted criterion associated with TATA
boxes for arbitrary DNA [9] (step 3), which only ac-
counts for 33% of the variance of the measured ТВР/
ТАТА affinity [12], original criteria associated with
TBP affinity estimates for single-strand DNA [13] and
double-strand DNA [14] (step 4 and step 2) and an in-
dependent measurement of the non-specific affinity of
ТВР and DNA [7] (step 1). Stepwise binding of ТВР to
ТАТА, predicted by this equation [6], has now been
confirmed experimentally [15].
Although the ТАТА box is a “semi-conservative” site,
no-neutral SNPs in it are quite a common occurrence in
various species. Thus, in silico analysis of the current
content of the GenBank database revealed 146 SNPs of
the HIV-1 TATA box, of which 63 could significantly
modify the replicative potential of the virus and were
associated with the regional patterns of the AIDS pan-
demic in 70 countries [16]. Literature data suggest that
53 SNPs in the ТАТА boxes of various human genes are
associated with the propensity for diseases [17], 38
SNPs are associated with various animal and plant traits
valuable with respect to breeding purposes [18]. In both
cases we predicted in silico significant departures of
ТВР/ТАТА affinity. The aim of the present work was to
perform a standardized experimental examination of the
strongest reductions in ТВР/ТАТА affinity as predicated
among 53 disease-associated SNPs in human TATA
boxes [19]. The measurements of KD;M and KD;WT using
EMSA demonstrated that: 1) all the predictions stating
that the affinity between ТВР and ТАТА boxes with
SNPs would be reduced were correct; 2) the departures
of three predictions from the measurements fell within
the confidence interval; 3) all the predictions consis-
tently underestimated actual mutational damage caused
to ТАТА boxes with SNPs (
 < 0.05; binomial law) and
two of these predictions did so significantly (
 < 0.05,
Student’s t-test).
2. EXPERIMENTAL PROCEDURES
For the standardized experimental examination of the
predicted ТВР/ТАТА affinity, we used recombinant
human ТВР expressed in E. coli BL21 (DE3) cells from
plasmid pAR3038-hTBP (courtesy of Professor B. Puhg,
Center for Gene Regulation, Department of Biochemis-
try and Molecular Biology, The Pennsylvania State
University, University Park, Pennsylvania, USA). E. coli
BL21 (DE3) transformation was performed as per Pe-
terson and the co-workers [20]. The expression and puri-
fication of TBP were done as [21]. A 26-bp strand of
oligodeoxyribonucleotides (Biosset, Novosibirsk) was
labeled with γ32P-ATP (Biosan, Novosibirsk, Russia)
using Т4 polynucleotide kinases (SibEnzime, Novosi-
birsk, Russia), annealed at 95˚C with the non-labeled
strand and cooled slowly to room temperature. The equi-
librium dissociation constants, KD, of the ТВР/DNA
complexes were measured using EMSA, titration of a
fixed amount of ТВР with the oligonucleotide in in-
creasing concentrations and isotopic dilution [22] as
shown in Figure 1. In doing so, we used two standard
tools, Gel-Pro Analyzer 3.1 for the densitometry of
autoradiographs and OriginPro 8 for obtaining KD from
densitometry data (Figure 1).
The confidence intervals of the 5% boundary (
 <
0.05) for each prediction were in silico estimated using
Student’s t-test as [19]. For all the in vitro measurements,
the confidence interval, KD, commonly acceptable for
the above two standard tools, was set as ±0.37 in relative
natural logarithms, which corresponds to a confidence
interval of ±30% of the KD value in nM, commonly ac-
cepted for EMSA-measurements of the parameters of the
protein/DNA complex.
3. RESULTS AND DISCUSSIONS
The predicted in silico [19] and experimentally meas-
ured in vitro relative affinity of ТВР for ТАТА boxes
containing SNPs for the genes encoding cytochrome
P450 2A6 (associated with lung cancer), β-globin (asso-
ciated with β-thalassemia), superoxide dismutase 1 (as-
sociated with amyotrophic lateral sclerosis), mannose
binding lectin (associated with variable immunodefi-
ciency) and triosephosphate isomerase (associated with
anemia) are presented in Table 1. In all cases, the ex-
periment confirmed the in silico predicted reduction in
the affinity of ТВР to the ТАТА box containing the
SNPs associated with the respective diseases. In three of
the five SNPs, namely cytochrome P450 2A6 (associated
with lung cancer), β-globin (associated with β-thalas-
semia) and superoxide dismutase 1 (associated with
amyotrophic lateral sclerosis), the departures of the pre-
dicted values from those measured experimentally fell
within the confidence interval.
In the rightmost column of Table 1, we compared the
affinity range from –3.72 ± 037 to –1.03 ± 0.14, which .

I. A. Drachkova et al. / Health 3 (2011) 577-583
Copyright © 2011 SciRes. http://www.scirp.org/journal/HEALTH/Openly accessible at
579579
Figure 1. An example of the EMSA measurement of the mutation-induced change in the affinity of ТВР to the ТАТА box in the
gene for triosephosphate isomerase containing a SNP associated with anemia [33]. ТВР/ТАТА binding isotherms inferred from
electrophoregrams (insets): upper, for the –24T allele, unaffected, KD;WT = 7 nM; lower, for the –24 g, allele, anemia, KD;M = 290 nM.
The result of the measurement is presented in Table 1, –ln(KD;M/KD;WT) = –ln(290/7) = –3.72.
corresponds to the highest amounts of damage to the
TATA boxes with SNPs evaluated in silico [19] and in
vitro, with the affinity range from –8.60 ± 2.33 to –5.52 ±
2.31, which corresponds to the differences between the
affinity of TBP for non-specific DNA [19] and the
affinity of TBP for the five TATA boxes in the focus of
this work [7]. Lack of overlap between these two ranges
implies that not even the strongest damage to any TATA
box with SNPs can affect affinity so much as can total
destruction of that TATA box.
Nevertheless, we were surprised to observe an under-
estimation of the effect that mutational damage to the
TATA box had on the numerical value for any of the
five SNPs (Table 1:
 < 0.05; binomial law), and that in
two of the five, namely mannose binding lectin (associ-
ated with variable immunodeficiency) and triosephos-
phate isomerase (associated with anemia), this underes-
timation reached significance (
 < 0.05, t-test). Because
the measurement was done in standard conditions, this
underestimation cannot have been due to local natural
factors (as tissue-specificity) or laboratory factors. There-
fore, in all the five genes, not only did the SNPs affect
ТВР/ТАТА affinity, but also damaged the nucleotide
context, which modulates this affinity, but does not im-
mediately affect any of the ТВP/ТАТА steps included in
the equilibrium equation [6]. Since it was discovered [23]
that whether or not TBP will bind to the TATA box ab-
solutely depends upon the position of the TATA box
relative to the histone octamer and, hence, the promoter
nucleosome should undergo a rearrangement to enable
transcription, the universal contexts, which, being com-
mon to all the genes, modulates their expression and
interferes with transcription factor binding sites, is nu-
cleosomal context.
It is commonly considered that the optimum seat site
(145 bp) for the specific nucleosome of the core pro-
moter of eukaryotic genes is at position –43 [24]. Up-
stream and downstream of the nucleosome center (be-
tween positions ±13 and ±17 relative to it) are located
two 5-bp (А + Т)-rich regions, which make contact with

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Table 1. The existing prognoses in silico [19] and in vitro measurements the change, Δ ± δ5%, in the TBP affinity for the known
natural ТАТА boxes with SNPs associated with human disease.
Literature: five known ТАТА boxes with SNP associated with
human diseases considered
Reduction in ТВР/TATA affinity
caused by SNP, ln
Human gene SNP Disease
26-bp sequence of the promoter
DNA with TATA boxes
(CAPITALIZED)
Ref.
Existing
prognoses
in silico [19]
In vitro
examining
[this work]
Deviation between
unspecific affinity TBP
to random DNA [7] and
specific one in the case
of TBP/TATA, ln
in silico and in vitro
norm tttcaggcagТАТАААggcaaaccac
cytochrome
P450 2A6 T–48g
lung cancer tttcaggcagТАgАААggcaaaccac
[42]–1.49 ± 0.15–1.60 ± 0.37 –8.36 ± 2.31
–6.38 ± 2.33
norm cagggctgggCATAAAAgtcagggca
β-globin T–30a
β-thalassemia cagggctgggCAaAAAAgtcagggca
[43]–1.46 ± 0.11–1.91 ± 0.37 –6.96 ± 2.31
–6.17 ± 2.33
norm aggtctggccТАТАААgtagtcgcgg
superoxide
dismutase 1 A–27g amyotrophic
lateral sclerosis aggtctggccТgТАААgtagtcgcgg
[44]–1.17 ± 0.13–1.45 ± 0.37 –7.70 ± 2.31
–5.52 ± 2.33
norm catctatttcТАТАТАgcctgcaccc
mannose
binding lectin T–35c variable
immunodeficiency catctatttcТАcАТАgcctgcaccc
[41]–1.11 ± 0.14–1.74 ± 0.37* –8.17 ± 2.31
–5.88 ± 2.33
norm cgcggcgctcТАТАTААgtgggcagt
triosephosphate
isomerase T–24g
anemia cgcggcgctcТАТАgААgtgggcagt
[33]–1.03 ± 0.14–3.72 ± 0.37* –8.60 ± 2.31
–7.27 ± 2.33
*Asterisks are the significant differences between the prognoses in silico [19] and the measurements in vitro [this work],
 < 0.05 (Student’s t-test).
two nucleosomal histone H3-Н4 dimers [25]. Whichever
of the two DNA/(Н3-Н4) contacts is closer to the tran-
scription start site overlaps the commonly accepted op-
timum location of the TATA box, namely: T–30A–29T–28
A–27A–26A–25A–24 [9]. Consequently, it is likely that
SNPs in TATA boxes (Table 1: (A or T) → (G or C)
substitutions) can damage not only the TATA box itself
but also the (A + T)-rich context, which forms the con-
tact between the promoter and the nucleosomal histone
H3-Н4 dimer [26]. The observed significant consistent
underestimation of the affinity of TBP and mutant
TATA boxes by in silico prediction revealed in our
standardized experimental measurements is indicative of
a likely cooperative influence of the contextual damages
to the DNA/(Н3-Н4) contact on the ТВР/ТАТА com-
plex which overlaps this contact (similarly to that de-
scribed previously for the composite element NFATp/
AP-1 [27]). This suggests that eukaryotic promoters
might possess the composite element ТАТА/(Н3-Н4)
(Н2А-Н2В)2(Н3- Н4), which has been indicated experi-
mentally [26] and which is still not yet considered in the
tools intended for in silico analysis.
So, after we performed the standardized experimental
examination of the in silico predictions for the ТВР/
ТАТА affinity, we found in all the five cases that
non-mutant ТАТА boxes in these genes had a high
ТВР/ТАТА affinity (which suggests a high was consis-
tently potential for expression); however, the relative
affinity, Δ underestimated. Except rarely, it is not the
absolute value of the gene expression level that is an
evolutionarily important parameter, rather it is the scope
of the norm of reaction—or the ability to modify this
value. Dynamical systems theory considers two modes
of modification, external and parametric [28]. In the
former case, any change represents an unambiguous re-
flection of the impact made. This is consistent with the
formation of a mosaic of transcriptional factors on the
promoter, which allows expression to be finely regulated.
However, this is a relatively slow process, which re-
quires, if nothing else, the presence of the pre-initiation
complex. Typically, the phenotypic effects of the poly-
morphisms damaging the mechanisms of fine transcrip-
tional regulation are specific.
In the latter case, a change in the values of the pa-
rameters destabilizes the system, leading to a change in
the probability of what its function will be afterwards.
This is consistent with disruption of the multistep regu-
latory process as a whole rather than disturbances in
some single steps [29-31]. The phenotypic effect of the
polymorphisms that influence this variability is non-
specific and general. This change in the norm of reaction
may be adaptive for a large population when in stressful
conditions: if environmental changes occur very rapidly
or are multiple (in which case some often are mutually
exclusive), the level of expression in part of the popula-
tion may—just for random reasons—turn out to be adap-

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Copyright © 2011 SciRes. Openly accessible at http://www.scirp.org/journal/HEALTH/
581581
tive.
In particular, a change in nucleosome packaging is
capable of non-specifically changing the probability of
the gene expressing in many tissues at a time. A poly-
morphism that changes nucleosome packaging affects at
least two parameters: the “layout” of the transcription-
ally active genomic regions [23] and the order of bind-
ing/affinity of transcriptional factors for DNA due to
chemical modification of histones [32]. It is commonly
accepted that the housekeeping gene promoters have a
special nucleosomal context, which ensures a looser nu-
cleosome packaging and thus makes the promoter acces-
sible by various regulatory proteins in a large variety of
tissues. Destruction of one of the few nucleosomes
should considerably affect regulation. True is, it was a
housekeeping gene, the only one in our check, for which
we observed the largest departure of Δ from the in silico
prediction (Table 1: triosephosphate isomerase associ-
ated with anemia [33]).
The MBL2 gene, too, is characterized by a large de-
parture of Δ from the in silico prediction. Mannose
binding lectin (MBL) is a key protein in the develop-
ment of the innate immune response. The polymor-
phisms that reduce MBL expression are associated with
variable immunodeficiency, which is a risk factor (espe-
cially in the tender age [34,35]) for a variety of infec-
tious diseases [34-36]. In lower primates, both copies of
the MBL gene are under stabilizing selection [37]. In the
anthropoid lineage, one of the copies has underwent
pseudogenization [38], and man has additionally ac-
quired a high frequency of polymorphisms that reduce
the MBL level in the tissues, disrupt folding (codon 52
Arg → Cys, codon 54 Gly → Asp, codon 57 Gly → Glu)
or transcription (–2550 - H/L polymorphism, –2221 -
X/Y polymorphism, –2427, –2349, –2336, –270, +4 -
P/Q polymorphism; –2324 - –2329 deletion) [34,36,38].
A low level of MBL eases the after-effects of the stroke
[39] and pre-eclampsia [40]. Thus, it is adaptive for the
humanoids, with their actively working brain and diffi-
cult child-birth, to have strong variation of the
within-tissue level of MBL across populations by com-
bination of these polymorphisms in the heterozygotes.
In addition to the common polymorphisms mentioned
above, local human populations may have other, inde-
pendently fixed polymorphisms [41], the effect of one of
which, located in the area of the ТАТА box (T-35c, Ta-
ble 1), has been reported here. This polymorphism is
likely to serve the same purpose as the common SNPs;
specifically, it expands the norm of reaction, but does it
somewhat differently, namely, by modulation of a trig-
ger-like regulator based on the composite ТАТА/(Н3-Н4)
(Н2А-Н2В)2(Н3-Н4) unit.
Importantly, this modulation of the norm of reaction is
mild. The polymorphisms that disrupt folding or tran-
scription [34,36,38] inhibit MBL gene expression. Con-
sequently, the norm of reaction widens only at a popula-
tion-wide level. Individuals homozygous for such poly-
morphisms are vulnerable to infection at all times, that is,
the individual norm of reaction is narrow and these indi-
viduals will not survive any attack by viruses or mi-
crobes. The lack of overlap between the affinity of ТВР
for the TATA box in the MBL gene with the T-35c
polymorphism and the affinity of TBP for non-specific
DNA indicates that the expression of this gene is not
totally suppressed even in the individuals that were ho-
mozygous for this polymorphism. Decrease in ТВР af-
finity means decrease in the probability that the expres-
sion of the MBL gene will be initiated; however, if ini-
tiation does take place, the gene will be expressed to the
extent that it will be in any wild-type individual. In other
words, if some individuals in a population carry the
T–35c polymorphism, the norm of reaction will be wid-
ening not only at a population-wide level, but also at an
individual level―specifically, in those carriers. Thus,
even when under a viral or microbial attack, such indi-
viduals are given a chance.
Identification of the previously unidentified source of
the consistent in silico underestimation of the amount of
damage caused to the regulatory regions of genes with
SNPs makes us expect that a standardized examination
of all the 237 TATA box SNPs, associated with human
diseases [17], regional patterns of the AIDS pandemic
[16], animal and plant traits, which are valuable with
respect to breeding purposes [18], and newly discovered
mutations in TATA boxes will allow us to look into the
mechanisms of ТВР/ТАТА binding and improve the
research quality of the computer-aided tools used for
analysis and prediction of SNPs in the regulatory regions
of human genes.
4. ACKNOWLEDGEMENTS
We are grateful to Prof. Tatyana Merkulova for her valuable advice.
This work was supported by grants 10-04-00462, 11-04-01254, and
11-04-01888 from Russian Foundation for Basic Research, grant 119
(Siberian Branch of the Russian Academy of Sciences), grant B.27
“Biological diversity” (Russian Academy of Sciences), “Molecular and
Cell Biology” and “Origin and evolution of biosphere” programs (Rus-
sian Academy of Sciences), grant 2447.2008.4 from the Scientific
School Program, State contract 10104-37/P-18/110-327/180608/015,
contract 07.514.11.4003 (Russian Ministry of Education and Science).
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