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Hindawi Publishing Corporation
ISRN Computational Biology
Volume 2013, Article ID 790240, 6 pages
http://dx.doi.org/10.1155/2013/790240
Research Article
Zebra Finch Glucokinase Containing Two Homologous
Halves Is an In Silico Chimera
Khrustalev Vladislav Victorovich,1 Lelevich Sergey Vladimirovich,2
and Barkovsky Eugene Victorovich1
1
2
Department of General Chemistry, Belarusian State Medical University, Dzerzinskogo 83, 220116 Minsk, Belarus
Department of Clinical Laboratory Diagnostics, Allergology and Immunology, Grodno State Medical University,
Gorkogo 80, 230009 Grodno, Belarus
Correspondence should be addressed to Khrustalev Vladislav Victorovich; [email protected]
Received 9 September 2013; Accepted 29 September 2013
Academic Editors: P. Durrens and A. Fedorov
Copyright © 2013 Khrustalev Vladislav Victorovich et al. This is an open access article distributed under the Creative Commons
Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is
properly cited.
Chimerical nature of the gene annotated as Zebra finch (Taeniopygia guttata) glucokinase (hexokinase IV) has been proved in this
study. N-half of the protein encoded by that gene shows similarity with glucokinase from other vertebrates, while its C-half shows
similarity with C-halves of hexokinases II. We mapped 7 new exons coding for N-half of hexokinase II and 4 new exons coding for
glucokinase of Zebra finch. Finally, we reconstructed normal genes coding for Zebra finch glucokinase and hexokinase II which
are situated in “head-to-tail” orientation on the chromosome 22. Because of the error in gene annotation, exons encoding N-half
of normal glucokinase have been fused with exons encoding C-half of normal hexokinase II, even though they are separated from
each other by the sequence 98066 nucleotides in length.
1. Introduction
Methods of phylogenetic analysis are usually used for reconstruction of the relations between distinct species or between
families of homologous proteins. Nucleotide sequences of
homologous genes are used as a material for fundamental
works in computational biology and phylogenetic. In this
study, the situation is quite different. Methods of phylogenetic
analysis and methods of computational biology helped to find
an error in gene annotation.
The volume of nucleotide sequences including those of
complete prokaryotic and eukaryotic genomes is increasing
in geometric progression in the last decade. There are many
different automatic gene finding algorithms developed to
annotate those sequences. Even though most of the annotations are correct, there are still some mistakes which may lead
to wrong conclusions. The material from public databases
should not be taken as something absolutely correct. In case
if something is wrong with phylogenetic trees one should
carefully recheck all the nucleotide sequences used.
There are five types of hexokinase encoded by five
different genes in genomes of vertebrates: hexokinase I (HKI);
hexokinase II (HKII), hexokinase III (HKIII), hexokinase
domain containing protein I (HKDCI), and glucokinase (GK)
[1]. HKI, HKII, HKIII, and HKDCI consist of two homologous halves. GK, which is often referred to as hexokinase IV,
contains only a single “half ” of hexokinase. It was shown that
N-halves of HKI and HKIII are not catalytically active, unlike
their C-halves [2]. In contrast, both halves of HKII are able to
catalyze phosphorylation of hexoses [3].
Phylogenetic relations between glucokinase and two
halves of hexokinase have been studied previously with the
aim to reconstruct evolutionary history of the “standard
set” (HKI, HKII, HKIII, HKDCI, and GK) of hexokinase
formation [1, 4]. According to one of the hypotheses, divergence between common predecessor of all hexokinase and
glucokinase happened before the duplication and fusion of
the common predecessor of all hexokinase [4]. According to
the more recent hypothesis [1], the common predecessor of all
hexokinase and glucokinase has undergone the duplication
2
and fusion event. Then N-half of the glucokinase has been
lost. According to the latest hypothesis, glucokinase had
existed as a protein containing two homologous halves during
the certain period of its evolution. The major evidence of that
hypothesis would be the existence of “double” glucokinase in
some species. However, such protein has not been found yet.
In this work we showed that the gene encoding glucokinase from bird Zebra finch (Taeniopygia guttata) genome
contains two homologous halves. The initial aim of our study
was to determine the time of the divergence between two
homologous halves of the Taeniopygia guttata glucokinase.
However, results of the phylogenetic part of the study showed
that N-half of that “double” glucokinase is similar to “single”
glucokinase, while C-half is similar to C-half of hexokinase II.
Thus, the final aim of the study was to reconstruct previously
unknown hexokinase II gene of Taeniopygia guttata.
2. Material and Methods
Predicted gene (ENSTGUG00000003490) from Ensembl
database (http://www.ensembl.org/) encoding a product
annotated as “glucokinase (hexokinase 4)” of Zebra finch
(Taeniopygia guttata) has the following borders: 130,183–
236,222. There are 18 exons predicted for this gene. The
corresponding predicted protein can be found in UniProt
database (http://www.uniprot.org/) as well (H0YZB2).
We used a nucleotide sequence (forward strand: 129,163–
236,222) of chromosome 22 from Taeniopygia guttata
genome (taeGut3.2.4) to show the distribution of exons along
this region of DNA. This sequence has been cut down into
windows 540 nucleotides in length. Each step of the window
was equal to 60 nucleotides. GC-content has been calculated
in each of those windows. We also performed calculation
of GC-content in three codon positions (1GC; 2GC and
3GC) for all 18 annotated exons by “VVK Protective Buffer”
algorithm [5] (http://www.barkovsky.hotmail.ru/).
We used Ensembl tool entitled “BLAST/BLAT” exclusively for Taeniopygia guttata genome (http://www.ensembl
.org/Taeniopygia guttata/blastview/) to search for nucleotide
sequences similar to Chicken (Gallus gallus) hexokinase II
and glucokinase genes. Seven additional exons encoding Nhalf of hexokinase II have been found by us in the region of
chromosome 22 upstream to eleven exons encoding its Chalf. Moreover, we found three additional exons encoding
N-terminus of glucokinase and a single exon encoding
its C-terminus. Levels of 1GC; 2GC and 3GC have been
calculated by “VVK Protective Buffer” [5] in those newly
described exons too. Splicing sites for “new” exons have been
predicted by “FSPLICE” algorithm from SoftBerry server
(http://linux1.softberry.com/). Predictions have been made
for canonical splicing sites (“AG” for donor and “GT” for
acceptor sites) using the data set of Gallus gallus.
To perform initial phylogenetic analysis for N- and Chalves of Taeniopygia guttata glucokinase we collected GK
genes from vertebrates and hexokinase genes from Homo
sapiens genome. To perform more thorough phylogenetic
analysis with reconstructed GK and HK II of Taeniopygia guttata we collected all the available genes encoding
hexokinase I, II, and III, as well as hexokinase domain
ISRN Computational Biology
containing protein I from genomes of vertebrates which can
be found in the Ensembl (http://www.ensembl.org/) data
base [6]. There should be four types of hexokinase and
a single glucokinase in each genome [1]. In case if some
of the enzymes from the abovementioned “standard set”
were absent in the Ensembl data base, we searched for
them in GenBank data base using NCBI BLAST algorithm
(http://www.ncbi.nlm.nih.gov/). Complete list of nucleotide
sequences with identifiers can be found in Supplementary
Material file. We avoided the usage of those sequences which
are partial, as well as those (mostly from Ensembl data base)
which include nucleotides designated by letter “N” (we used
to call those defects of sequences “PolyN tracts”).
N-halves of hexokinase have been separated from Chalves according to the results of the “REPRO” algorithm
which is able to find repeated regions in protein sequences
(http://www.ibi.vu.nl/programs/reprowww/) [7]. N-half of
Zebra finch glucokinase has been separated from its homologous C-half with the help of the same algorithm.
All the sequences were aligned by MUSCLE algorithm
integrated into MEGA 5 program [8]. JTT (Jones, Taylor and
Thornton) [9] amino acid evolutionary distances between
all the sequences have been calculated with the help of
MEGA 5 program [8]. Complete deletion mode has been
chosen. Phylogenetic trees have been built by ME (Minimum
Evolution) method [10] with the help of MEGA 5 program
[8].
3. Results and Discussion
In Figure 1, one can see the ME phylogenetic tree for
glucokinase from vertebrates and human hexokinase which
have been cut into two halves. N-half of the predicted Zebra
finch GK can be found on the branch with other glucokinase.
It is situated in the same clade with Gallus gallus and Anolis
carolinensis glucokinase, while two later proteins show more
similarity with each other than with N-half of Taeniopygia
guttata glucokinase (see Figure 1). C-half of Zebra finch GK
groups together with C-half of Homo sapiens HK II (see
Figure 1). So, predicted glucokinase from Zebra finch is a
chimera which is composed of glucokinase itself and C-half
of hexokinase II. Here we should highlight that gene coding
for HK II has not been found in Zebra finch genome yet.
The nature of the chimerical glucokinase/hexokinase II is not
absolutely clear. Theoretically, one cannot except that such a
chimeric protein may exist in vivo, while, in our opinion, this
chimera is the consequence of incorrect gene annotation.
The gene coding for Zebra finch glucokinase occupies
106039 nucleotides in the chromosome 22. Interestingly, first
7 exons (coding for glucokinase itself) are separated from the
last 11 exons (coding for C-half of hexokinase II) by a rather
long intron 98066 nucleotides in length containing several
relatively GC-poor fragments (see Figure 2). According to
the results of Ensembl BLAT/BLAST analysis, 7 “new” exons
coding for N-half of hexokinase II exist in the 3󸀠 -end of this
long “pseudointron”. Their coordinates in chromosome 22
(in nucleotides) are from 223,162 to 223,331; from 226,647 to
226,694; from 227,122 to 227,192; from 228,944 to 229,043;
from 229,153 to 229,258; from 229,519 to 229,698; from
ISRN Computational Biology
3
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0.1
Figure 1: Minimum evolution (ME) phylogenetic tree built on the basis of JTT evolutionary distances (complete deletion) between sequences
of N- and C-halves of human hexokinase, glucokinase from vertebrates, and N- and C-halves of Taeniopygia guttata glucokinase aligned by
MUSCLE algorithm.
1
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annotated exons coding for glucokinase and hexokinase II of Taeniopygia guttata. GC-content distribution between three codon positions
(1GC; 2GC; 3GC) is given for each exon. Defects of sequence (unknown nucleotides, i.e., “polyN” tracts) are also shown.
ISRN Computational Biology
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4
Figure 3: Minimum evolution (ME) phylogenetic tree built on the basis of JTT evolutionary distances (complete deletion) between sequences
of N- and C-halves of hexokinase and glucokinase from vertebrates together with reconstructed N- and C-halves of Taeniopygia guttata
hexokinase II and glucokinase aligned by MUSCLE algorithm.
C - half
In silico chimera
N-half
C-half
N-half
C-half
Parts of coding regions annotated by us
“Normal” glucokinase
“Normal” hexokinase II
containing two homologous halves
Figure 4: The scheme of the gene annotation defect which led to the in silico chimera formation.
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230,423 to 230,499 (see Figure 2). Acceptor splicing sites have
been found by “FSPLICE” algorithm for the first, fourth, fifth
and sixth exons. Donor splicing sites have been found for the
second, third, fourth, and fifth exons.
Three additional exons encoding N-terminus of the
Zebra finch glucokinase occupy the following locations in
chromosome 22 (in nucleotides): from 129,426 to 129,589;
from 129,709 to 129,767; from 129,782 to 129,889. Acceptor
splicing sites have been found for the first and second exons;
donor splicing sites have been found for the first and third
ones. There is a single nucleotide deletion in the second
exon, relative to sequences of other glucokinase. That kind of
deletion (which is, probably, a sequencing defect) resulted in
frameshifting.
We found out that 40 amino acid residues from the Cterminus of Zebra finch glucokinase N-half actually belong
to the C-terminus of hexokinase II N-half. “Original” Zebra
finch glucokinase C-terminus has been reconstructed by us. It
is encoded by newly mapped exon. That “new” exon has been
found in chromosome 22: from the nucleotide 132,945 to the
nucleotide 133,088 (see Figure 2). There is a donor splicing
site in its 5󸀠 -end and a terminal codon in its 3󸀠 -end.
There were three gaps in the reconstructed amino acid
sequence of hexokinase II N-half. It is likely that those gaps
occurred due to defects in nucleotide sequence determination: there are areas with “PolyN” tracts situated between the
first and second, between the second and third and between
the sixth and seventh exons (see Figure 2).
In general, there is specific pattern of GC-content distribution between three codon positions in both previously
mapped and newly mapped exons: 3GC > 1GC > 2GC. This
pattern is characteristic for genes which are under the
influence of mutational GC-pressure [11–13]. Exons coding
for both glucokinase and hexokinase II seem to be situated in
GC-rich isochores [14] of Zebra finch chromosome 22. 3GC
levels for three of the exons even reached 100% (see Figure 2),
while average 3GC level for both “new” and already annotated
exons encoding hexokinase II is equal to 87.91 ± 4.97%. In
case if exons encoding N-half of hexokinase II were inactive,
2GC and 1GC levels would grow to the higher level under
the influence of GC-pressure [13]. However, average 2GC
level for 7 “new” hexokinase II exons is not significantly
higher than that for 11 already annotated exons (36.38 ± 7.29%
versus 36.72 ± 4.02%; 𝑃 = 0.94). The same situation is characteristic for their average 1GC levels (53.66 ± 7.65% versus
58.43 ± 5.23%; 𝑃 = 0.34).
N-half of Zebra finch hexokinase II reconstructed by
us occupies correct branch (it groups with N-half of Gallus
gallus hexokinase II) in ME tree from Figure 3, as well as
reconstructed glucokinase and C-half of hexokinase II do.
So, in our opinion, Zebra finch possesses normal functional
glucokinase gene and normal functional hexokinase II gene
which are situated on the same chromosome 22 near each
other.
Interestingly, in Figure 3 both N- and C-halves of
Turkey hexokinase I can be found on branches with Nand C-halves of HKDCI (together with Chicken homologues). This fact is the evidence that the gene from
Turkey genome annotated as that coding for hexokinase I is
5
actually coding for hexokinase domain containing protein I
(HKDCI).
Similar error has already been described by us for pyruvate kinases. A protein annotated as Lamprey liver pyruvate
kinase shows more similarity with muscle pyruvate kinases of
vertebrates than with liver pyruvate kinases [15].
Wrong determination of isoenzyme type is relatively
common mistake in gene annotation, while the error
described in the present work is a weird one.
One of the benefits of automatic gene annotation is the
absence of mistakes caused by so-called “human factor”.
However, in certain cases, such as in the case described
in this work, corrections of automatic annotations should
be introduced “manually” with the help of computational
biology methods.
4. Conclusions
Gene annotation algorithm “fused” most of the exons coding
for glucokinase of Zebra finch with exons coding for Cterminus (C-terminus of N-half and the whole C-half) of its
hexokinase II situated downstream on the same chromosome
22 (as it is schematically represented in Figure 4) and
predicted a relatively long “pseudointron” in the place of
intergenic spacer.
References
[1] D. M. Irwin and H. Tan, “Molecular evolution of the vertebrate
hexokinase gene family: identification of a conserved fifth
vertebrate hexokinase gene,” Comparative Biochemistry and
Physiology D, vol. 3, no. 1, pp. 96–107, 2008.
[2] H. J. Tsai, “Functional organization and evolution of mammalian hexokinases: mutations that caused the loss of catalytic
activity in N-terminal halves of type I and type III isozymes,”
Archives of Biochemistry and Biophysics, vol. 369, no. 1, pp. 149–
156, 1999.
[3] K. J. Ahn, J. Kim, M. Yun, J. H. Park, and J. D. Lee, “Enzymatic
properties of the N-and C-terminal halves of human hexokinase
II,” BMB Reports, vol. 42, no. 6, pp. 350–355, 2009.
[4] M. L. Cárdenas, A. Cornish-Bowden, and T. Ureta, “Evolution
and regulatory role of the hexokinases,” Biochimica et Biophysica
Acta, vol. 1401, no. 3, pp. 242–264, 1998.
[5] V. V. Khrustalev, M. Arjomandzadegan, E. V. Barkovsky, and L.
P. Titov, “Low rates of synonymous mutations in sequences of
mycobacterium tuberculosis GyrA and KatG genes,” Tuberculosis, vol. 92, no. 4, pp. 333–344, 2012.
[6] P. Flicek, M. R. Amode, and K. Beal, “Ensembl 2012,” Nucleic
Acids Research, vol. 40, pp. D84–D90, 2012.
[7] R. A. George and J. Heringa, “The REPRO server: finding
protein internal sequence repeats through the web,” Trends in
Biochemical Sciences, vol. 25, no. 10, pp. 515–517, 2000.
[8] K. Tamura, D. Peterson, N. Peterson, G. Stecher, M. Nei, and
S. Kumar, “MEGA5: molecular evolutionary genetics analysis
using maximum likelihood, evolutionary distance, and maximum parsimony methods,” Molecular Biology and Evolution,
vol. 28, no. 10, pp. 2731–2739, 2011.
[9] D. T. Jones, W. R. Taylor, and J. M. Thornton, “The rapid
generation of mutation data matrices from protein sequences,”
6
[10]
[11]
[12]
[13]
[14]
[15]
ISRN Computational Biology
Computer Applications in the Biosciences, vol. 8, no. 3, pp. 275–
282, 1992.
M. Nei and S. Kumar, Molecular Evolution and Phylogenetics,
Oxford University Press, New York, NY, USA, 2000.
N. Sueoka, “Directional mutation pressure and neutral molecular evolution,” Proceedings of the National Academy of Sciences of
the United States of America, vol. 85, no. 8, pp. 2653–2657, 1988.
O. K. Clay and G. Bernardi, “GC3 of genes can be used as a proxy
for isochore base composition: a reply to Elhaik et al,” Molecular
Biology and Evolution, vol. 28, no. 1, pp. 21–23, 2011.
V. V. Khrustalev and E. V. Barkovsky, “An in-silico study of
alphaherpesviruses ICP0 genes: positive selection or strong
mutational GC-pressure?” IUBMB Life, vol. 60, no. 7, pp. 456–
460, 2008.
M. Costantini and G. Bernardi, “Replication timing, chromosomal bands, and isochores,” Proceedings of the National Academy
of Sciences of the United States of America, vol. 105, no. 9, pp.
3433–3437, 2008.
S. V. Lelevich, V. V. Khrustalev, E. V. Barkovsky, and T. A.
Shedogubova, “The influence of ethanol on pyruvate kinases
activity in vivo, in vitro, in silico,” American Journal of Medical
and Biological Research, vol. 1, pp. 6–15, 2013.
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