- Methodology article
- Open Access
Human Pol II promoter recognition based on primary sequences and free energy of dinucleotides
© Yang et al; licensee BioMed Central Ltd. 2008
- Received: 13 August 2007
- Accepted: 24 February 2008
- Published: 24 February 2008
Promoter region plays an important role in determining where the transcription of a particular gene should be initiated. Computational prediction of eukaryotic Pol II promoter sequences is one of the most significant problems in sequence analysis. Existing promoter prediction methods are still far from being satisfactory.
We attempt to recognize the human Pol II promoter sequences from the non-promoter sequences which are made up of exon and intron sequences. Four methods are used: two kinds of multifractal analysis performed on the numeric sequences obtained from the dinucleotide free energy, Z curve analysis and global descriptor of the promoter/non-promoter primary sequences. A total of 141 parameters are extracted from these methods and categorized into seven groups (methods). They are used to generate certain spaces and then each promoter/non-promoter sequence is represented by a point in the corresponding space. All the 120 possible combinations of the seven methods are tested. Based on Fisher's linear discriminant algorithm, with a relatively smaller number of parameters (96 and 117), we get satisfactory discriminant accuracies. Particularly, in the case of 117 parameters, the accuracies for the training and test sets reach 90.43% and 89.79%, respectively. A comparison with five other existing methods indicates that our methods have a better performance. Using the global descriptor method (36 parameters), 17 of the 18 experimentally verified promoter sequences of human chromosome 22 are correctly identified.
The high accuracies achieved suggest that the methods of this paper are useful for understanding the difficult problem of promoter prediction.
- Promoter Sequence
- Codon Position
- Multifractal Analysis
- Multifractal Spectrum
- Numeric Sequence
Promoter region plays an essential role in determining where the transcription of a particular gene should be initiated. Hence, promoter recognition – the computational task of finding the promoter regions on a DNA sequence, is an important problem . The accumulation of a huge amount of genome sequence data in recent years makes the annotation process more and more complicated for higher eukaryotes . The RNA polymerase II (Pol II) promoter is a key region that regulates differential transcription of protein coding genes. Computational analysis of Pol II promoters may contribute to improved gene identification and to prediction of the expression context of genes . There is a need for prediction techniques that can rapidly and accurately evaluate sequences for the presence of promoter sequences .
Existing promoter prediction methods are still far from being satisfactory [3–5]. The performance of many current eukaryote promoter prediction methods has been unreliable with poor specificity or poor sensitivity . Many methods predict promoter sequences based on the regulatory sequence elements (RSEs) in them. But the RSEs are short and not fully conserved in the promoter sequences, which results in a high probability of finding similar sequence elements elsewhere in genomes, outside the promoter regions. That is why most of the promoter prediction methods end up predicting a lot of false positions . Fickett and Hatzigeorgiou  performed an evaluation of the different promoter prediction methods on genome DNA and suggested that it would be worth attempting nonlinear recognition methods, such as neural nets or quadratic discriminant analysis. Following this direction, Gangal and Sharma  applied time series descriptors and machine learning methods to human Pol II promoter prediction and got a higher accuracy compared with other methods; Kanhere and Bansal  presented a novel prokaryotic promoter prediction method based on DNA stability showing that the changing in the stability of DNA provides a much better clue than the usual sequence motifs.
In this paper, we attempt to recognize the human Pol II promoter sequences from the non-promoter sequences which contain exon and intron sequences. It should be noted that the aim of the present paper is similar to that of Ref. , but the non-promoter sequences in Ref.  are made up of coding sequences (CDSs) and intron sequences, while we use an existing database, the Exon/Intron database, to extract non-promoter sequences. We first convert the promoter/non-promoter sequences into numeric sequences according to the 10 unified free energy parameters , which have been used to measure the stability of DNA . Then a measure representation is introduced for the numeric sequences. Multifractal analysis of the measure is next performed, which results in the first 5 parameters. Analogous multifractal analysis  is also used on the numeric sequences to achieve another 4 parameters. The Z curve method, which has been used in recent years with some successes [10, 11], yields 96 parameters for the promoter/non-promoter primary sequences. The protein-chain descriptor method was first proposed by Dubchak et al.  to predict protein folding classes. Here we propose a global descriptor for the promoter/non-promoter sequences, which yields 36 parameters for a global description of the primary sequences. Overall, a total of 141 parameters are extracted from these four different methods and categorized into seven groups (methods). Fisher's linear discriminant algorithm shows that the global descriptor method is the most effective when used separately. Complete enumerations of all the possible combinations of these seven methods (120) are tested to find possibly better results with a relatively smaller number of parameters. Numerical results show that the methods with 96 and 117 parameters can produce satisfactory results. Compared with five other existing tools, the higher sensitivity, specificity, accuracy and correlation coefficient demonstrate that the methods proposed here are useful for understanding the human Pol II promoter prediction problem. 17 of the 18 experimentally verified promoter sequences of human chromosome 22  are successfully identified by the global descriptor method (with only 36 parameters).
We use two different data sets downloaded from two databases. The first set is the human Pol II promoter sequences from Release 90 of the Eukaryotic Promoter Database (EPD) . The EPD is an annotated non-redundant collection of eukaryotic Pol II promoters, experimentally defined by a transcription start site (TSS) . The EPD is a useful database when one wants to deal with the Pol II promoter prediction problem and it is broadly tested by different prediction tools [7, 16–19]. A total of 1871 entries of human Pol II promoter sequences with window size of 499 bp upstream and 100 bp downstream of TSS, which is the same as that used in Ref. , are obtained from EPD. The sequences containing 'N' are manually filtered out, which results in a total of 1856 sequences. The second set is the non-promoter sequences of the human genome. For this data set, we consider using the Exon/Intron Database (EID), which incorporates information on the exon/intron structure of eukaryotic genes  (, hs35p1.EID.tar.gz). Firstly, the exon/intron sequences with 'n' and length less than 600 are filtered out. Then, we randomly select 1000 intron sequences from the file hs35p1.intrEID and 500 exon sequences from the file hs35p1.exEID. A fragment of length 600 is then selected randomly from each exon/intron sequence with length larger than 600. As the intron sequences are represented by lower-case letters in the file hs35p1.intrEID, we transform them into upper-case letters to be consistent with the promoter and exon sequences.
From the four different methods described in the Methods section, we get a total of 141 parameters. We will test their contributions in the promoter/non-promoter problem. Then we will try to combine some of them to see whether better results can be achieved.
For comparison of various methods, a benchmark should be set up. We use Fisher's linear discriminant algorithm [22–24] to calculate the discriminant accuracies. We divide all promoter and non-promoter sequences into two sets randomly. A set of 90% of promoter/non-promoter sequences is regarded as a training set, and the set of remaining 10% of promoter/non-promoter sequences as a test set.
The discriminant accuracies for various methods with Fisher's discriminant. The method marked "3+6+7" in the 8th row means the combination of the methods listed in the 3rd, 6th and 7th rows. The meanings of the methods marked for the 9th row is similar.
p c (%)
p nc (%)
q c (%)
q nc (%)
No. of parameters
ZC Eq.(21), k = 12
ZC Eq.(21), k = 23
ZC Eqs.(20, 22)
Firstly, seven groups of parameters are derived from the four methods: (i) 9 parameters from fractal methods (MFA and AMFA); (ii) 9 parameters from ZC representing the codon-position-dependent frequencies of mononucleotides; (iii) 12 parameters from ZC representing the frequencies of phase-specific dinucleotides (codon positions 1–2); (iv) 12 parameters from ZC representing the frequencies of phase-specific dinucleotides (codon positions 2–3); (v) 15 parameters for the phase-independent mononucleotides and dinucleotides from ZC; (vi) 36 parameters from GD; (vii) 48 parameters for the frequencies of phase-independent tri-nucleotides from ZC. From Table 1, it is seen that the results from the multifractal analyses seem to be better than that from ZC with an equal number of parameters, namely 9. We have successfully applied multifractal analyses in the clustering of large protein structures [9, 25] and the distinction of coding and non-coding sequences in complete genomes , where the length of protein sequences and coding and non-coding sequences are larger than 300. It is well-known that the promoter sequences are highly diverse, which makes it notoriously difficult to generate patterns and rules for promoter prediction. It is expected that multifractal analyses can unfold some useful information on promoter sequences. The results from the frequencies of phase-specific dinucleotides at codon positions 2–3 in ZC indicate a better performance than that at codon positions 1–2. In addition, the accuracies from ZC with the frequencies of phase-independent mononucleotides and dinucleotides are improved but the number of parameters is increased to 15. The GD method shown in boldface in Table 1, denoted as M1, turns out to be especially useful as the accuracies are all larger that 85%. Compared with this, the results from the 48 parameters in ZC are not as good even though the number of parameters is increased.
Secondly, we want to test whether the results can be improved by increasing the number of parameters. It is not possible to test all the subsets of the 141 parameters but we can test all the combinations of the above seven methods (120 altogether). In our test, the accuracies do not simply increase as the number of parameters becomes larger, which indicates there might be some redundancy/correlation among the 141 parameters. For example, the accuracies with the 141 parameters are similar to those with only 117 parameters, suggesting the information from the mononucleotides and phase-independent dinucleotides in ZC is contained in the other methods. Therefore, all these parameters are not really needed. Nevertheless, in some circumstances the results do improve when the number of parameters is increased. Especially, among the 120 combinations, the results are relatively satisfactory in the cases of 96 and 117 parameters, which is shown in boldface in Table 1. We denote them by M2 and M3, respectively. In order to see whether multifractal analysis brings out useful information, we remove the 9 parameters of MFA and AMFA from M3 and test the results for such new combination. The p c , p nc , q c , and q nc calculated from this combination are: 86.05% 92.67%, 86.02% and 92.00% respectively. They are similar to those from M3 (86.89%, 93.11%, 86.02% and 92.67%), which demonstrates that multifractal analysis does not significantly improve the performance in M3.
where TP denotes the number of correctly recognized promoter sequences, FN the number of promoter sequences recognized as non-promoter sequences, FP the number of non-promoter sequences recognized as promoter sequences, TN the number of correctly recognized non-promoter sequences.
The accuracies of the prediction for promoter sequences by Fisher's discriminant algorithm. The S n , S p , A c and CC are the results for the training set and S' n , S' p , A' c and CC' are the results for the test set. The rows are related to those in Table 1 according to the mark order.
S n (%)
S p (%)
A c (%)
Overall, from Tables 1 and 2, when the methods are used independently, we can see that M1 is the best one. The combined methods M2 and M3 improve the results. However, the number of parameters is too high in M3. Taking this aspect into account, a preferred method would be M1 or M2.
The promoter prediction accuracies for the test data set made up of 186 promoter sequences and 150 non-promoter sequences using five kinds of tools and our methods.
S n (%)
S p (%)
A c (%)
Promoter Scan version 1.7
Dragon Promoter Finder version 1.5
Promoter 2.0 Prediction Server
Our method (M3)
The accuracies for M1, M2 and M3 with 50% sequences as training and the remaining 50% as test set in Fisher's discriminant algorithm.
S n (%)
S p (%)
A c (%)
The accuracies for M1, M2 and M3 with 80% sequences as training and the remaining 20% as test set in Fisher's discriminant algorithm.
S n (%)
S p (%)
A c (%)
Finally, it is important to test our method with real human DNA sequences. For example, a sliding window technique with window size of 600 bp and step size of 10 bp can be used to recognize promoter sequences in the human DNA sequences, similar to the technique adopted by Gao and Zhang  to recognize exons. However, because promoter sequences are not clearly marked in the human DNA sequences, we can't use this approach to test our method. Nevertheless, similar to that performed in Ref. [7, 33], we use the human chromosome 22, in which 20 promoters are experimentally verified . One can refer to Table 1 in Ref.  to get the sequences with the accession numbers. However, as AB016655 and D86746 are not clearly annotated, we do not use them in the test. We use 50% of the promoter (from EPD) and non-promoter (from EID) sequences to train M1. The coefficients in Fisher's algorithm w = (w1, w2, ⋯, w36) are determined based on the training set. The choice of a promoter/non-promoter sequence is determined by the criterion Z(x) > 0/Z(x) <0. Except for AF047576, the other 17 promoter sequences are correctly identified. This suggests that the global descriptor GD (M1), with a smaller number of parameters (36), is a practical method.
Promoter prediction is a difficult but important problem in gene finding, and it is critical for elucidating the regulation of gene expression . We use two kinds of multifractal analysis on the free energy sequences of promoter/non-promoter, Z curve analysis, and the global descriptor for the primary sequences of promoter/non-promoter. A total of 141 parameters are extracted from these four methods. These parameters are used in both independent and combined ways to distinguish promoter sequences from non-promoter sequences.
Fisher's linear discriminant algorithm provides a quantitative assessment of the recognition methods. If we use these methods independently, the global descriptor of the promoter/non-promoter sequences is the best method based Fisher's algorithm. Combinations of various methods show that the accuracies can be improved in some cases but the improvements are not simply due to the increase of parameter numbers. With all 141 parameters together, the results are satisfactory. However, the number of parameters is too high in this condition. The number is reduced as there is some redundancy/correlation among these parameters. In the case of 117 parameters, similar results are achieved, with the discriminant accuracies p c , p nc , q c , and q nc reaching 86.89% 93.11%, 86.02% and 92.67%, respectively. The related sensitivity S n , specificity S p , accuracy A c and correlation coefficient CC for the test set reach 86.02%, 93.57%, 89.79% and 0.78, respectively. A smaller number of parameters (96) also produces relatively satisfactory results. The global descriptor method with only 36 parameters successfully identifies 17 of the 18 experimentally verified promoters in human chromosome 22 . Recognition of promoter sequences with such satisfactory accuracy indicates that the methods is promising for human Pol II promoter prediction.
The main aim of this work is to develop efficient algorithms that can discriminate between promoters and non-promoters in a given sequence. Another challenge being addressed is the localization of promoters rather than a simple classification considered in current methods . Multifractal analysis, which is especially useful in many other fields [25, 26, 35, 36], seems to reflect some information for promoter recognition (see first line in Table 1). But if we use method M3, multifractal analysis does not significantly improve the performance. The methods considered in this paper seem promising in enhancing the performance of biomolecular sequence analysis and promoter prediction in particular. It is a challenge to predict promoter sequences directly from the real human genome. However, it would be helpful to use first the ENCODE pilot project data set, which spans about 1% of the human genome sequence . Our following work aims to contribute towards this challenging problem.
Conversion of the original data
Multifractal analysis (MFA)
to be the frequency of T t . It follows that . We define a measure μ on the interval [0, 1) byμ(dx) = Y(x) dx,
where the sum runs over all different nonempty boxes B of a given side ε in a grid covering of the support E, that is,B = [kε, (k + 1)ε).
where . The generalized fractal dimensions are numerically estimated through a linear regression of ln Z ε (q)/(q - 1) against ln ε for q ≠ 1, and similarly through a linear regression of Z1, εagainst ln ε for q = 1 [25, 42, 45]. D(1) is called the information dimension and D(2) the correlation dimension [43, 44].
He showed that the form of C q resembles a classical phase transition at a critical point for financial time series.
Analogous multifractal analysis (AMFA)
Linear regressions of ln and ln M q (L) against ln L will yield the exponents h' (q) and h(q) respectively.
The exponent h(q) has a nonlinear dependence on q. When q = 1, the methods are just those reported in Refs. [48, 49] and these methods are used to study the length sequences from the complete genomes by Yu et al. . M'(L) may be assessed to determine long-range correlation . From Ref. , the linear fit to get the exponent h(1) is better than that to get the exponent h'(1). Our numerical results show that the exponents h(q) are more robust than the exponents h'(q), so we suggest to use the exponents h(q). We have used h(q) in clustering the structure of large proteins and it turns out to be a useful method .
Z curve (ZC)
The concept of the Z curve representation of a DNA sequence was first proposed by Zhang and Zhang , and was used to distinguish coding and noncoding DNA sequences [52, 53]. A new system based on ZC, Z CURVE 1.0, for finding protein-coding genes in bacterial and archaeal genomes has been proposed . Recently, another new self-training system based on the ZC method, ZCURVE_V , for recognizing protein-coding genes in viral and phage genomes was reported.
where x i , y i , z i ∈ [-1, 1], i = 1, 2, 3.
where x, y, z ∈ [-1, 1], a, c, g and t are the frequencies for the bases A, C, G and T in a promoter/non-promoter sequence, respectively.
where p k (XY) = n k (XY)/[n k (XA) + n k (XC) + n k (XG) + n k (XT)], n k (XY) are the occurring times of dinucleotides XY, X, Y = A, C, G, T, k = 12, 23.
where x X , y X , z X ∈ [-1, 1], p(XY) = n(XY)/[n(XA) + n(XC) + n(XG) + n(XT)], n(XY) are the occurring times of dinucleotides XY, X, Y = A, C, G, T.
where x XY , y XY , z XY ∈ [-1, 1], p(XYZ) = n(XYZ)/[n(XYA) + n(XYC) + n(XYG) + n(XYT)], n(XY Z) are the occurring times of trinucleotides XYZ, X, Y, Z = A, C, G, T. The difference between Ref.  and here is in the calculation of n(XYZ); the present method can be regarded as a phase-independent method.
Global descriptor of promoter/nonpromoter sequence (GD)
Dubchak et al.  proposed a method for predicting protein folding classes based on a global protein chain description. The protein-chain descriptor includes overall composition, transition, and distribution of amino acid attributes. Similar methods have also been used in Refs. [55–58]. In this paper, we propose the global descriptor of promoter/non-promoter sequences.
The global description contains three parts: composition (Comp), transition (Tran) and distribution (Dist). In order to explain the method, we suppose that a sequence consists of only two kinds of letters (A and B). The composition is used to measure the frequency of occurrence of each kind of letters in the sequences. For example, for the sequence: BABBABABBABBAABABABBAAAB-BABABA, there are 14 As and 16 Bs, hence the frequencies for A and B are 100.00 × 14/(14+16) = 46.67, 100.00 × 16/(14+16) = 53.33, respectively. These two numbers represent the first part of the global description, Comp. The second part, Tran, characterizes the percent frequency with which A is followed by B or B is followed by A. For example, for the above sequence, there are 21 transitions of this type, that is, (21/29) × 100.00 = 72.14. The third part of the global description, Dist, measures the chain length within which the first, 25%, 50%, 75% and 100% of certain type of letters is located, respectively. For example, for the above sequence, the first, 25%, 50%, 75% and 100% of Bs are located within the first, 6th, 12th, 20th and 29th nucleotides, respectively. The Dist descriptor for Bs is thus: 1/30 × 100.00 = 3.33, 6/30 × 100.00 = 20.00, 12/30 × 100.00 = 40.00, 20/30 × 100.00 = 66.67 and 29/30 × 100.00 = 96.67. Likewise, the Dist descriptor for As is 6.67, 23.33, 53.33, 73.33 and 100.00. As a result, the global description for the above sequence is (Comp; Tran; Dist) = (46.67, 53.33; 72.14; 6.67, 23.33, 53.33, 73.33, 100.00, 3.33, 20.00, 40.00, 66.67, 96.67). A more detailed description of global description of sequences is given in Refs. [12, 55–58].
The global description for the promoter/non-promoter sequences can be computed by a similar procedure. As the sequences consist of four types of nucleotides (A, C, G and T), there are 4 parameters for Comp, 6 parameters for Tran and 20 parameters for Dist. Overall, a total of 30 parameters are used to give a global description of a promoter/non-promoter sequence.
where is the Shannon entropy.
It was shown that is a useful statistical quantity for analysis of DNA sequences [54, 60], which was called a nucleotide composition constraint of genomes . As a result, we obtain 6 parameters s1, s2, s3, s4, H and P from EDP.
Overall, combining the above two description systems, we get 36 parameters for the global descriptor of a promoter/non-promoter sequence.
The authors would like to thank Dr. Feng-Biao Guo of Tianjin University for his helpful discussions about the Z curve method and Dr. Jun Lu in Inner Mongolia University for his help with the promoter data on human chromosome 22, and the referees for their detailed comments and useful suggestions to improve the paper. Financial support was provided by the Chinese National Natural Science Foundation (grant no. 30570426), Fok Ying Tung Education Foundation (grant no. 101004), the Youth Foundation of Educational Department of Hunan Province in China (grant no. 05B007) (Z.-G. Yu), the Australian Research Council (grant no. DP0559807) (V.V. Anh), and the Scientific Research Fund of the Department of Education in Hunan Province of China (no. 06C830) (L.Q. Zhou).
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