Journal of Heredity 2006:97(3):279–284
doi:10.1093/jhered/esj024
Advance Access publication February 22, 2006
ª The American Genetic Association. 2006. All rights reserved.
For permissions, please email: [email protected].
Identification and Characterization of
a Tandem Repeat in Exon III of the
Dopamine Receptor D4 (DRD4) Gene
in Cetaceans
LINE MOGENSEN, CARL CHRISTIAN KINZE, THOMAS WERGE,
AND
HENRIK BERG RASMUSSEN
From the Research Institute of Biological Psychiatry, H:S Sct. Hans Hospital, Copenhagen University, 2 Boserupvej,
DK-4000 Roskilde, Denmark; and CC Konsult, 35 Falkoner Allé, DK-2000 Frederiksberg, Denmark.
Address correspondence to H. B. Rasmussen at the address above, or e-mail: [email protected].
A large number of mammalian species harbor a tandem repeat
in exon III of the gene encoding dopamine receptor D4 (DRD4),
a receptor associated with cognitive functions. In this study,
a DRD4 gene exon III tandem repeat from the order Cetacea
was identified and characterized. Included in our study were
samples from 10 white-beaked dolphins (Lagenorhynchus albirostris), 10 harbor porpoises (Phocoena phocoena), eight sperm
whales (Physeter macrocephalus), and five minke whales (Balaenoptera acutorostrata). Using enzymatic amplification followed
by sequencing of amplified fragments, a tandem repeat composed of 18-bp basic units was detected in all of these species.
The tandem repeats in white-beaked dolphin and harbor porpoise were both monomorphic and consisted of 11 and 12 basic
units, respectively. In contrast, the sperm whale harbored
a polymorphic tandem repeat with size variants composed
of three, four, and five basic units. Also the tandem repeat
in minke whale was polymorphic; size variants composed of
6 or 11 basic units were found in this species. The consensus
sequences of the basic units were identical in the closely related
white-beaked dolphin and harbor porpoise, and these sequences differed by a maximum of two changes when compared to the remaining species. There was a high degree of
similarity between the cetacean basic unit consensus sequences
and those from members of the horse family and domestic
cow, which also harbor a tandem repeat composed of 18bp basic units in exon III of their DRD4 gene. Consequently,
the 18-bp tandem repeat appears to have originated prior
to the differentiation of hoofed mammals into odd-toed and
even-toed ungulates. The composition of the tandem repeat
in cetaceans differed markedly from that in primates, which is
composed of 48-bp repeat basic units.
Introduction
Dopamine is a neurotransmitter implicated in the control of
intellectual skills, motivational behavior, language, and motor
activity (Nieoullon and Coquerel 2003). The importance of
this transmitter in terms of cognition and conceptual skills
has nourished the idea that development of human intelligence has been dependent on the expansion of the dopamine
system (Previc 1999).
The dopamine receptor D4 (DRD4) is expressed at high
levels in the prefrontal cortex, that is, a region of the brain
associated with cognitive abilities (Oak et al. 2000; Tarazi
and Baldessarini 1999). Observations with DRD4 knockout
mice have associated this receptor with the trait termed
novelty seeking (Dulawa et al. 1999). More recently, DRD4
has been implicated in working memory in rats (Zhang et al.
2004).
Exon III of the DRD4 gene harbors a tandem repeat in
several mammalian species. This tandem repeat is composed
of 48-bp basic units in humans (Lichter et al. 1993; Van
Tol et al. 1992), nonhuman primates (Livak et al. 1995;
Matsumoto et al. 1995), and prosimians (Inoue-Murayama
et al. 1998). A DRD4 gene exon III tandem repeat consisting of 18-bp or 36-bp basic units has been identified in domestic cow (Larsen et al., 2005) and in members of the
horse family (Hasegawa et al. 2002). The repeat structure
is complex in the dog family (Canidae) because it consists
of basic units of different sizes, namely 39, 27, and 12 bp
(Niimi et al. 2001). Recently, tandem repeats composed of
18-bp basic units were identified in exon III of the DRD4
gene in other members of the mammalian order Carnivora,
including domestic cat (Felis catus), polar bear (Ursus maritimus), Asiatic bear (Ursus thibetanus), and common raccoon
(Procyon lotor), implying that this repeat size is not restricted
to hoofed animals (Larsen et al., 2005). A repeat structure
has not been identified in the DRD4 gene of mouse
(Fishburn et al. 1995).
It is possible that there are functional implications of size
variation of the tandem repeat in exon III in the DRD4 gene.
Recent observations suggest that the length of the polymorphic repeat modulates the level of expression of the human
279
Journal of Heredity 2006:97(3)
DRD4 gene (Schoots and Van Tol 2003). This could be important because an altered cell-surface density of DRD4 may
affect the magnitude of the receptor response. A previous
study associated a size variant of the human DRD4 gene with
a blunted dopamine response (Asghari et al. 1995). This size
variant has been implicated in susceptibility to psychiatric diseases (Holmes et al. 2002; Millet et al. 2003), while its association with novelty seeking is more uncertain (Kluger et al.
2002).
So far, studies of the tandem repeat in exon III of the
DRD4 gene have focused on primates and other terrestrial
animals, while no attempts have been done to identify and
characterize this tandem repeat in cetaceans. This is surprising because whales, in particular dolphins, possess highly
developed cognitive skills, including advanced means of
communication, abstract thinking abilities, and excellent
working memories (Previc 1999). In this study, a tandem
repeat in DRD4 exon III of four whale species was identified
and characterized.
Materials and Methods
Skin samples were obtained from 10 white-beaked dolphins
(Lagenorhynchus albirostris), 10 harbor porpoises (Phocoena phocoena), eight sperm whales (Physeter macrocephalus), and five
minke whales (Balaenoptera acutorostrata). Two of the harbor
porpoises originated from Greek waters. All other animals
had been found dead along the coasts of Denmark. Some
of these animals came ashore in small groups. Genomic
DNA was extracted from the skin samples using the DNeasy
kit (Qiagen GmbH, Hilden, Germany).
Primers[5#-CTACTCGTCCGTGTGCTCCT-3#(forward)
and 5#-ACCACAGGCAGGACTCTCAT-3# (reverse)] for
amplification of a fragment of exon III of the cetacean
DRD4 gene were designed on the basis of a sequence from
white-beaked dolphin deposited under accession number
DQ132799 in GenBank. Amplification mixtures contained
60 mM Tris-SO4 (pH 9.1), 18 mM (NH)4SO4, 400 nM of both
upstream and downstream primers, 200 lM of each deoxynucleoside triphosphate, 1.5 mM MgCl2, 5% dimethyl sulphoxide, 1 unit Elongase Enzyme Mix (Invitrogen, Carlsbad, CA,
USA), and 50 ng genomic DNA. Initially, the amplification
mixtures were heated to 94C for 3 min. Then followed 35
cycles, each consisting of 30 s at 94C, 45 s at 55C, and 45
s at 68C. After the last cycle, elongation was allowed to proceed for 10 min at 72C.
Amplified fragments were subjected to agarose gel electrophoresis. Fragments of interest were excised from the gel,
purified using the Geneclean III Kit (Qbiogene, Inc., Carlsbad, CA, USA), and sequenced on both strands. Some of the
amplified samples produced two fragments of nearly the
same size. In these cases, excision from the gel was omitted
to avoid cross-contamination of one of the polymerase chain
reaction fragments with the other. Instead, the amplified
fragments were cloned by insertion into the pDrive Cloning
Vector (Qiagen GmbH, Hilden, Germany) followed by transformation using NovaBlue Singles Competent cells (Merck
280
Biosciences, Darmstadt, Germany). Plasmids were isolated
from the bacterial clones, and their inserts were sequenced.
Sequences were analyzed by the TANDEM REPEAT
FINDER (TRF), a program that identifies tandem repeats
(Benson 1999). The weight for match is þ2 in this program,
while three different weights can be chosen for mismatch and
indels, namely 3, 5, and 7. In this study, the alignment
parameters þ2, 5, and 7 (match, mismatch, and gap) were
used. Lower numbers permit the detection of tandem copies
with more mismatches or indels; higher weight numbers increase the search stringency. If successful in identifying a tandem repeat, TRF reports its compositional characteristics,
including the size, number of basic units, consensus sequence
of the basic units, percentage of matches between adjacent
basic units (a measure of their degree of identity), and percent
GC. Often the number of basic units reported by TRF is not
a whole number. This may reflect an accumulation of nucleotide substitutions in ends of the tandem repeat, resulting in
a partial disappearance of the repeat motif in these portions
of the tandem repeat. For example, a tandem repeat, which is
reported to be composed of 18-bp basic units in an array of
4.7 copies, has four full-size18-bp basic units followed by
a partial basic unit of 13 bp (13/18 ; 0.7). The consensus
sequence of the basic units in a tandem repeat is determined
by the majority rule and is the sequence, which produces the
best alignment. All full-length and partial basic units are utilized in this alignment.
For comparative purposes, sequences of DRD4 exon III
from domestic cow (Bos taurus), wild horse (Equus prezewalskii), wild ass (Equus hemionus), and mountain zebra (Equus
zebra) with the GenBank accession numbers AB069666,
AB080628, AB080631, and AB080635, respectively, were
also analyzed by TRF. Although these sequences previously
have been subjected to analysis by TRF (Larsen et al., 2005),
they have not been analyzed using the stringency applied in
the present study. A consensus sequence of the basic units
of DRD4 exon III tandem repeats from various primate
species (Livak et al. 1995) was included for comparative
purposes.
The start of a tandem repeat as determined by TRF may
vary with several nucleotides between different species. This
complicates a comparison of the consensus sequences. To
compensate for this, consensus sequences from different tandem repeats were subjected to cyclic alignment, which allows
every position in one of two sequences to be the first.
Results
Fragments of DRD4 exon III from four different cetacean
species were amplified and analyzed. The approximate sizes
of the amplified fragments from white-beaked dolphin and
harbor porpoise were 480 and 500 bp, respectively. Analysis
of amplification products from the sperm whales revealed
three different fragment sizes ranging from about 320 to
370 bp. Fragment sizes of about 390 and 490 bp were detected
on analysis of amplified samples from the minke whales.
The sequences of the amplified fragments were determined and deposited in GenBank under the accession
Heterozygosity is the probability that a given individual is heterozygous.
Percent matches is an overall measure of the degree of sequence identity between adjacent basic units in a tandem repeat.
Alignment of the equine basic unit consensus sequences with those from cetaceans changed the start position and other properties of the equine tandem repeats, including percent matches.
d
c
b
a
Domestic cow (Bos taurus)
Wild horse (Equus przewalskii)d
Wild ass (Equus hemionus)d
Mountain zebra (Equus zebra)d
Nucleotide number 14 is a G in the consensus sequence of the short allele and a C in that from the medium-sized and long alleles.
CCCGCCCCCGACGCCGGC
CCGCCCCCCGACGCCATC
CCGCCCCCCGACGCCACC
CCGCCCCCCGACGCCATC
data
data
data
data
No
No
No
No
0.48
CCGGCCCCCGACGGCATC
AY615861
AY615862
AY615863
AY615864
AY615865
AY615866
AY615867
AB069666
AB080628
AB080631
AB080635
CCGGCCCCCGACGCCATC
CCGGCCCCCGACGCCATC
CCGCCCCCCGACG[G/C]CACCc
0
0
0.53
78
80
88
89
87
82
81
86
74
75
75
69
73
86
91
81
71
72
68
68
69
69
11.3
12.3
3.1
4.1
5.1
6.6
11.6
5.6
19.1
16.7
19.1
Minke whale (Balaenoptera acutorostrata)
Species
White-beaked dolphin (Lagenorhynchus albirostris)
Harbor porpoise (Phocoena phocoena)
Sperm whale (Physeter macrocephalus)
Heterozygosityb
Consensus sequence of 18-bp
basic units
Percent
GC
Percent
matchesa
Number of 18-bp
basic units
Table 1. Properties of the tandem repeat in exon III of the DRD4 gene from cetaceans and modern ungulates
numbers AY615861–AY615867. Analysis of these sequences
revealed tandem repeats composed of 18-bp basic units in all
four cetacean species. Important characteristics of these tandem repeats are shown (Table 1). Suggestions for basic unit
sizes of 36 or 51 bp were also provided by TRF, but these
alternatives achieved inferior scores and were not considered
further.
The number of 18-bp basic units was 11.3 in all 20 of the
white-beaked dolphin tandem repeat sequences examined.
All these repeat sequences were completely identical (only
one unique allele was found), implying that the white-beaked
dolphin tandem repeat was monomorphic. The harbor porpoise tandem repeat was composed of 12.3 of 18-bp basic
units. Also this tandem repeat was monomorphic. In contrast, the sperm whale tandem repeat was polymorphic with
respect to the number of 18-bp basic units; three size variants
composed of 3.1, 4.1, and 5.1 basic units were found in this
species. On analysis of the minke whale sequences, two size
variants with 6.6 and 11.6 basic units were identified.
All tandem repeats were imperfect, that is, the sequences
of the 18-bp basic units differed within each of the tandem
repeats (Figure 1). Further examination revealed that none of
the 18-bp basic units were present in a number higher than
two in any of the tandem repeats. The degree of identity between adjacent copies of the 18-bp basic units in the tandem
repeats ranged from 69% in white-beaked dolphin to 91% in
sperm whale. Comparison of the two tandem repeat variants
from minke whale revealed that the short variant differed
from its longer counterpart by the lack of the five 3# terminal
basic units. The relationship between the alleles of the sperm
whale was more complex as the 3# terminal basic unit in the
two shortest alleles was absent in the long allele.
Several of the 18-bp basic units were present in two or
more cetacean species, including three consecutive 18-bp
basic units in white-beaked dolphin and harbor porpoise.
Overall, the tandem repeats from these two closely related
species had seven 18-bp basic unit sequences in common.
Comparison of the 18-bp basic unit consensus sequences
from the four different cetacean species revealed that those
from harbor porpoise and white-beaked dolphin were identical. These consensus sequences differed from those of
minke whale and sperm whale at one and two nucleotide
positions, respectively (Table 1).
We determined the consensus sequences of the 18-bp
basic units in tandem repeats from domestic cow and members of the horse family (Table 1). A subsequent comparison of the 18-bp basic unit consensus sequences from
domestic cow and cetaceans revealed differences at three
or four nucleotide positions. In contrast, the 18-bp basic unit
consensus sequences from sperm whale and wild ass were
completely identical. Those from the other cetaceans differed
from the equine consensus sequences at one or two nucleotide positions
The number of basic units was lower in the tandem repeats from the cetacean species and domestic cow than in
the members of the horse family. The GC content of the
various tandem repeats ranged from 0.74 to 0.89. The highest value was found in the tandem repeat from sperm whale.
GenBank
accession
numbers
Brief Communications
281
Journal of Heredity 2006:97(3)
Figure 1. Alignment of 18-bp basic units of DRD4 exon III tandem repeats from different whale species. Tandem repeats were
split into their 18-bp basic units; these units were listed consecutively below their consensus sequences. Partial basic units in the
3# ends of the repeat regions are also shown. The numbers of basic units are listed in parentheses; they are not whole numbers
due to the presence of the partial basic units. Dots indicate nucleotides identical with the consensus. The dolphin basic unit
numbers 2 and 3, which TRF reported to consist of 17 and 19 bp, respectively, were manually edited to create two 18-bp basic
units. This resulted in an equal number of nucleotide G and C at position four among the basic units from dolphin; the dolphin
consensus was listed with a G at that position in accordance with the harbor porpoise and minke whale 18-bp basic unit consensus
sequences. Both size variants of minke whale (6.6 and 11.6 basic units) and the three size variants of sperm whale (3.1, 4.1, and
5.1 basic units) are shown. The basic unit consensus sequence of the short allele from sperm whale has not been included.
On alignment of the 18-bp dolphin consensus sequence
with the 48-bp consensus sequence deduced on the basis of
DRD4 exon III tandem repeats from various primate species
(Livak et al. 1995), a consecutive stretch of seven identical
nucleotides was found. No other similarities were found.
Discussion
This is the first study to identify and characterize a tandem
repeat in exon III of the DRD4 gene within the order Ceta-
282
cea. The species included in the study derived from four
different cetacean families with both suborders being represented, that is, Odontoceti (white-beaked dolphin, harbor
porpoise and sperm whale), and Mysticeti (minke whale).
Imperfect tandem repeats composed of 18-bp basic units
were detected in all species. These tandem repeat were
GC rich, a property characteristic of some hypermutable
tandem repeats (Denoeud et al. 2003).
The consensus sequences of the tandem repeats in the
four species were identical or differed slightly. The finding
Brief Communications
of an identical consensus sequence in white-beaked dolphin
and harbor porpoise probably reflects the close evolutionary
relationship between these two species. The consensus sequence from minke whale (a Mysticeti) appeared to be more
similar to that identified in dolphin and harbor porpoise
than the consensus sequence from sperm whale. Probably,
this reflects limitations adherent to the use of these short sequences for comparative purposes.
The tandem repeat appeared to be monomorphic in the
white-beaked dolphin and harbor porpoise. Because several
of the dolphin and harbor porpoise samples derived from
strandings of single individuals, the lack of genetic variation
within these two species is probably not a result of a family
relationship. Moreover, the harbor porpoises originated from
two different geographical localities, namely, Danish and
Greek waters, supporting the notion that the tandem repeat
in this species is truly monomorphic.
Different size variants were detected in sperm whale and
minke whale. The tandem repeat of sperm whale exhibited
a relatively high degree of heterozygosity with three different
allele sizes. Presence of several basic units with identical or
nearly identical sequences in a tandem repeat is an indication
that there has been several rounds of expansions and that the
tandem repeat in question exists in multiple allelic forms
(Benson 1999). In agreement with this, the degree of identity
between the basic units in the sperm whale tandem repeat
(polymorphic with three size variants) was higher than in
the three other species, especially the two monomorphic species. The presence of a basic unit with a unique nucleotide
sequence in the two short alleles of sperm whale and a basic
unit with a sequence specific for the long allele suggests
that the short alleles are evolutionarily more closely related
to each other than they are to the long allele. The long allele
of the minke whale, the sole representative of the suborder
Mysticeti, differed from the short allele in this species by the
presence of five consecutive basic units in the 3# end, suggesting a marked degree of polarity in expansion/retraction
events.
Molecular evidence places cetaceans and their terrestrial
ancestors within the order of even-toed ungulates (Graur and
Higgins 1994). This order also includes domestic cow, while
horses belong to another order, the odd-toed ungulates. The
presence of a DRD4 gene exon III tandem repeat composed
of closely related 18-bp basic units in whales, domestic cow,
and horses suggests that this structure originated prior to the
differentiation of hoofed mammals into even-toed and oddtoed ungulates. The indication that the consensus sequences
from cetaceans were more closely related with those identified in the horse family than they were with the consensus
sequence from domestic cow was surprising. However, only
a single tandem repeat from even-toed ungulates was available, and whether this tandem repeat is typical is not known.
We also compared the basic unit consensus sequence of
the DRD4 exon III tandem repeat from dolphin with that
from primates assuming that the DRD4 tandem repeat modulates cognitive abilities. If this assumption holds, structural
similarities should exist between the tandem repeats from
the cetacean and primate lineages because members of both
lineages possess advanced cognitive skills (Previc 1999).
Similarities in gene sequences from different phylogenetic
lineages reflecting shared functional properties have been
observed previously. For example, the langur stomach lysozyme, which is involved in degradation of microorganisms
that pass from the foregut to the stomach, has acquired sequence similarity to that of cow after the langur acquired its
foregut fermentation ability (Stewart et al. 1987). The observations in the present study revealed that the composition of
the tandem repeat in cetaceans differed profoundly from that
in primates, which is composed of 48-bp basic units (Lichter
et al. 1993; Van Tol et al. 1992). Consequently, there is no
evidence that the advanced conceptual skills in cetaceans
are reflected in a composition of the tandem repeat in the
DRD4 gene similar to that of primates.
Acknowledgments
The samples were kindly provided by Drs. Hans Baagøe, Natural History Museum of Denmark, University of Copenhagen, Denmark, Aimilia Drougas,
Department of Civil Engineering, Technological Education Institute of
Piraeus, Greece, and Anastasia Komnenou, Department of Clinical Sciences,
Aristotle University of Thessaloniki, Greece. The study was financed by
grants from Copenhagen Hospital Corporation Research Fund and The
Danish National Psychiatric Research Foundation.
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Received January 20, 2005
Accepted December 9, 2005
Corresponding Editor: William Modi