Full text of DOI:10.1007/BF03343785

J. Endocrinol. Invest. 23: 616-622, 2000
Conservation of the deleted-in-azoospermia-like-1
(DAZL1) gene structure in old world monkeys points to
a homologous function of DAZL1 in this primate class
B. Grossmann*, G. Weinbauer**, P. Hirschmann*, and P.H. Vogt*
*Reproduction Genetics in Institute of Human Genetics, University of Heidelberg; and **Institute of
Reproductive Medicine, University of Münster, Germany
ABSTRACT. We isolated the complete deleted-in-
azoospermia-like-1 (DAZL1) gene of the old
world monkey Macaca fascicularis (tentatively
designated as MafaDAZL1) and compared its se-
quence structure to that of the other DAZL1
genes isolated so far. In addition to the homolo-
gous RNA recognition motif (RRM domain), we
only identified a high conservation of the Mafa-
DAZL1 coding region to the mammalian DAZL1
genes (i.e. mouse: Dazl1; and human: DAZL1)
and to that of Xenopus (xdazl). Only in the pri-
mates, Macaca fascicularis and human, sequences
and lengths of the 5´ and 3´ untranslated DAZL1
gene structures (UTRs) displayed a similar con-
servation as their coding regions (i.e. 91-94%).
Both belong to the primate class of old world
monkeys evolutionarily separated 36-55 million
years ago (1). The strong conservation of the
complete DAZL1 gene structure in both primate
species suggests a similar control and matura-
tion pathway of DAZL1 transcripts in the germ
line of old world monkeys and also indicates a
homologous function of the DAZL1 RNA-binding
protein in this primate class.
(J. Endocrinol. Invest. 23: 616-622, 2000)
©2000, Editrice Kurtis
INTRODUCTION
gene in the male germ line is complicated by the
fact that in man this gene is amplified and homol-
ogous gene copies exist on the long arm of the Y
chromosome in distal Yq11 (9-12). Indeed, the hu-
man Y gene copies were isolated first and designa-
ted as DAZ (deleted-in-azoospermia) (13) and SPGY
(spermatogenesis-gene-on-the-Y) (14). They are
clustered in distal Yq11 in the so-called AZFc re-
gion (15) and are frequently deleted in men with
non-obstructive azoospermia or severe oligo-
zoospermia (16). It has now been shown that both
DAZ and SPGY were derived from the autosomal
DAZL1 gene and are therefore both members of
the DAZ Y gene family. Consequently, DAZ was re-
cently designated as DAZ1 and SPGY as DAZ2 (17).
The amplification and transposition event of DAZL1
to the Y chromosome took place between 36 and
55 million years ago during primate evolution, i.e.
after divergence of the new world monkeys but be-
fore divergence of the old world monkeys (10, 12).
Comparative genomic hybridization experiments
with human and mouse DAZL1 probes on Noah´s
ark blots (blots of male and female DNA from dif-
ferent species) indicated male-specific cross-hy-
bridization patterns in the genomes of macaques,
The human deleted-in-azoospermia-like-1 (DAZL1)
gene seems to be highly conserved in vertebrates
and invertebrates. Molecular isolation of a similar
gene in Caenorhabiditis elegans (cedazl) (2), Dro-
sophila (boule) (3), zebrafish (zdazl) (4), Xenopus
(xdazl) (5) and mouse (Dazl1) (6, 7) revealed that
DAZL1 encodes a conserved germ line specific
RNA-binding protein of the RRM (RNA recognition
motif) class. These proteins are characterized by
two conserved peptide boxes (RNP-1, an octapep-
tide, RNP-2, a hexapeptide) in a range of about 30
amino acids (aa) near their N termini (8).
In zebrafish, Xenopus, mouse and human, DAZL1
is expressed in the male and female germ line (4-7,
9), in Drosophila only in the male germ line (3), in
Caenorhabitidis elegans only in the female germ
line (2). Functional analysis of the human DAZL1
Key-words: DAZL1 gene structure, primate evolution, germ line, con-
served 3’UTR.
Correspondence: Prof. Peter H. Vogt, Im Neuenheimer Feld 328, 69120
Heidelberg, Germany.
E-mail: peter_vogt@med.uni-heidelberg.de
616

B. Grossmann, G. Weinbauer, P. Hirschmann, et al.
baboons, gorillas and chimpanzees but not in the
male genome of any new world monkey (6, 10, 12).
If we assume that the Y located DAZ gene family
has evolved and been maintained in all old world
monkeys to improve or extend specifically the male
germ line function of DAZL1 in this species group,
one would expect that the DAZL1 gene structures
in old world monkeys can be distinguished from
that in all other species and remained strongly con-
served in this primate class. As a first step to verify
this basic assumption we isolated the complete
DAZL1 gene structure of the old world monkey
Macaca fascicularis (tentatively designated as
MafaDAZL1) and compared this structure to that of
the DAZL1 genes in all other species.
For species specification of the DAZL1 genes in pri-
mate species we now designated the human DA-
ZL1 gene isolated earlier (10) tentatively as
HsaDAZL1 (GenBank accession no.: U66726).
Sequence comparison of the putative amino acid (aa)
sequence encoded by MafaDAZL1 with those en-
coded by its assumed functional homologs, in human
(HsaDAZL1), mouse (Dazl1; GenBank accession no.:
U38690), Xenopus (xdazl; GenBank accession no.:
AF017778), zebrafish (zdazl; GenBank accession no.:
AB018191), Drosophila (boule, GenBank accession
no.: U51858), and Caenorhabiditis elegans (cedazl;
GenBank accession no.: AB025253) revealed a con-
tinuous homology of peptide domains along the
whole sequence only in the Xenopus (60% sequence
identity, 67% sequence similarity), mouse (88% se-
quence identity, 90% sequence similarity) and human
(98% sequence identity) DAZL1 protein sequences
(Fig. 1). Species-specific aa exchanges along the oth-
er peptide regions reflect the large evolutionarily dis-
tances between the species analyzed. However, be-
sides the RNP-1 octapeptide and RNP-2 hexapep-
tide strongly conserved in all RRM proteins (8) some
additional peptide domains in the so-called RRM re-
gion (in MafaDAZL1: aa no. 32-117) (Fig. 1) indicate a
comparable RNA-binding function via this RRM do-
main for all DAZL1 proteins. Interestingly, in com-
parison with the mouse gene, the primates´ DAZL1
genes have shifted the stop-signal of their open read-
ing frame 9 nucleotides upstream. Sequence align-
ments in that sequence region suggest that this frame
shift is possibly due to the insertion of a primate-spe-
cific 4bp-nucleotide (TTTG) which creates the ear-
lier stop codon (data not shown).
Our comparative DAZL1 protein sequence picture
(Fig. 1) raised the question as to whether all the
RRM proteins usually declared as functional DAZL1
homologs in the literature have, indeed, at the
molecular scale, a homologous function during the
pre-meiotic germ-cell phase (their mean time of ge-
netic activity), or alternatively, may have evolution-
arily altered their function(s) to the specific needs
of the various species classes. Numerous RNA-bind-
ing proteins are present during the pre-meiotic
phase of the germ line because of the high demand
of alternative spliced mRNAs and the formation of
translational repressed RNP complexes used only
later during the different phases of the post-mei-
otic differentiation process of the male germ cell,
respectively, during the maturation process of the
oocyte after puberty (folliculogenesis). Species-spe-
cific functional adaptation of conserved germ line
genes are therefore most likely.
MATERIALS AND METHODS
Gene isolation and computer software
Hybridizations of filter discs (duplicates) prepared
from a plated testis poly(A) cDNA library of Macaca
fascicularis (18) were performed with a radiolabeled
(α32PdCTP) human DAZL1 cDNA probe in sealed
plastic bags as described in Ausubel et al. (19).
Sequence analyses of selected cDNA clones from
both strands (at least 80-90% overlapping) were per-
formed on an A.L.F. express from Pharmacia using
the Sanger dideoxy chain termination method (Au-
toread kit of Pharmacia) and the strategy of primer
walking on overlapping sub-fragments. Sequence
runs were repeated with the same or homologous
clones at least three times and analyzed for possible
artificial nucleotide substitutions during cloning us-
ing the program CLUSTAL of the HUSAR software
package of the German Cancer Institute, Heidelberg,
FRG (http: genome.dkfz-heidelberg.de/ biounit/). For
alignment analyses between the DAZL1 gene se-
quences of different species we used different align-
ment tools of the HUSAR software package.
RESULTS
Isolation and sequence analysis of the
Macaca fascicularis DAZL1 gene
Isolation of the DAZL1 gene from Macaca fascicu-
laris was performed by cross-hybridization of a com-
plete human DAZL1 cDNA probe (CT355) (10) to a
series of clones on filters of a poly(A) cDNA library
(here designated as pcTMf library) prepared from
a testis tissue sample of this primate species (see
Materials and Methods). Sequence analyses of all
clones identified the clone pcTMf2 as a complete
DAZL1 gene of Macaca fascicularis (tentatively des-
ignated as MafaDAZL1) encoding a putative pro-
tein of 295 aa (Genbank accession no.: AF144132).
In this context it is interesting to note that only the
zDazll, xdazl1, Dazl1 and HsaDAZL1 genes were
617

Conserved DAZL1 gene structure in old world monkeys
Comparative analyses of protein sequences of putative MafaDAZL1 homologs
Fig.1 - Comparative analyses of the protein sequences of the putative MafaDAZL1 homologs isolated in Caenorhabiditis elegans
(cedazl), Drosophila (boule), zebrafish (zdazl), Xenopus (xdazl), mouse (Dazl1), Macaca fascicularis (MafaDAZL1) and human (HsaDAZL1).
The cedazl protein further extends with a unique C-peptide of 141 aa at its C-terminal end. Two highly conserved RNP- boxes (RNP-1,
RNP-2) mark their conserved RRM domain (underlined). Numbers of amino acid sequence positions are given at the right. Protein se-
quences were aligned by the software PRETTYBOX, highlighting identical aminoacids by black boxes. Conservative amino acid ex-
changes are marked by grey boxes according to a matrix scale based on the Dayhof table (in Atlas of Protein Sequence and Structure,
1979, pp. 353-358).
shown to be expressed in the male and female
germ line as well (4-7, 9), whereas the Drosophila
gene, boule, is functional only during spermatoge-
nesis (3) and the Caenorhabiditis elegans gene,
cedazl, is functional only during oogenesis (2).
Only in old world monkeys, the DAZL1 gene has
been amplified and transposed some gene copies
to the Y chromosome (9-13). Putative functional in-
teractions between the autosomal DAZL1 gene and
the Y chromosomal DAZ gene family can be as-
sumed but have not yet been proven. If they exist,
the DAZL1 gene structures in old world monkeys
are expected to contain a conserved structure also
in their 5´ and 3´ untranslated regions (UTRs) which
is probably different from that in the other species
only containing the autosomal single copy gene.
We therefore compared in detail all DAZL1 se-
quence structures not only in their coding regions
but also in their 5´ UTRs and 3´ UTRs.
Comparison of DAZL1 coding sequence regions
The lengths of the coding regions (ORFs) of the
DAZL1 homologs vary significantly and range be-
tween 684 (boule) and 1497 (cedazl) nucleotides
(Table 1). Consequently, the encoded DAZL1 pro-
teins contain only 228 aa in Drosophila but 499 aa
618

B. Grossmann, G. Weinbauer, P. Hirschmann, et al.
in Caenorhabiditis elegans and their molecular
weights are not comparable (Table 1). Other mo-
lecular parameters of the proposed homologous
DAZL1 proteins (overall surface charges and the re-
lated isoelectric points) also displayed a significant
variability suggesting that the hydrophilicity of the
DAZL1 protein is different in each species analyzed,
except for primates. They encode DAZL1 proteins
of identical molecular weights, identical surface
charges and identical isoelectric points although
macaques and humans were separated during evo-
lution at least 36 million years ago (1). Similar values
were only found for the mouse gene (Table 1). The
protein of the Xenopus homolog (xdazl) was the on-
ly with a negative surface charge. Consequently, its
isoelectric point shifted significantly from that found
in all other vertebrates although its molecular
weight was comparable to that of the mouse and
primates DAZL1 protein and their sequence simi-
larities could be shown along the whole coding se-
quence (Fig. 1).
similarity of 91%. Given comparable evolutionary
distances between mice and macaques of 50 mil-
lion years and between macaques and human of
36 million years (1) the higher rate of 5´UTR se-
quence exchanges observed between the rodent
and primate lines might be explained by the short-
er generation times of rodents compared to that of
primates. The divergence of orthologous (i.e. func-
tional homologous) mouse and human genes in
their 5´ untranslated sequence parts was reported
to range between 41-100% (20). The value of 42%
sequence similarity between the Dazl1 and Mafa-
DAZL1 5´UTRs therefore suggests a low selection
pressure on the evolutionary conservation of this
DAZL1 gene region.
Comparison of DAZL1 3´ untranslated
sequence regions (3’UTRs)
The 3´UTR sequences of the macaque and human
DAZL1 gene were identical in their lengths (1872
nt) (Table 1) and their sequence comparison re-
vealed a high homology (95%) along the whole se-
quence, comparable to that found in their coding
regions (98%). A significant homology was also ob-
served to the 3´UTR of the mouse Dazl1 gene (73%)
although the length of the published mouse Dazl1
3´UTR sequence was short with 218 nucleotides
(Table 1). On blots of mouse testis RNA the Dazl1
cDNA probe mainly cross-hybridized to a testis
RNA population of 3 kb (6). We therefore assume
that the published Dazl1 gene sequence (1438 nt:
U38690) does not contain the complete 3´UTR se-
quence or only represents a rare variant of the com-
plete mouse Dazl1 mRNA population.
Comparison of DAZL1 5’ untranslated
sequence regions (5’ UTRs)
With the aid of 5´RACE experiments and sequence
analyses we estimated a length of 216 nucleotides
for the human DAZL1 gene (A. Kühn, unpublished
results). A length of 226 nucleotides was estimat-
ed by Yen et al. (11). The 5´UTR of the Drosophila
boule gene (minmal 769 nt) is not comparable to
these values and also the mouse Dazl1 gene con-
tains a 5´UTR sequence which is at least 100 nu-
cleotides longer (Table 1). A comparative sequence
analysis between the different 5´UTR sequences re-
vealed numerous indel (insertion, deletion) muta-
tions in the different 5´UTRs inhibiting a detailed
comparative estimation of their real homology.
Between the mouse and macaque DAZL1 genes
we estimated a 42% sequence similarity, between
the macaque and human DAZL1 genes a sequence
The duplicated canonical polyadenylation signal
(AAUAAAAAUAAA) 13-25 nucleotides upstream of
the poly(A) addition site in the MafaDAZL1 and
HsaDAZL1 gene suggests a conserved polyadeny-
lation process for DAZL1 transcripts in macaques
and humans and therefore probably in all old world
Table 1 - Comparison of DAZL1 gene structure.
DAZL1 mRNA lengths
DAZL1 proteins
Gene
5‘UTR
ORF
3‘UTR
Total
Number
of aa
Mol-weight
Isolectric
Surface
charge
kda
point
cedazl
76
1497
684
687
858
894
885
885
464
1066
1221
1355
218
1987
2519
2166
2275
1438
2973
2974
499
228
229
286
298
295
295
56.15
24.68
25.55
32.30
33,31
33.11
33.18
10.05
7.6
9+
0
boule
769
258
62
zdazl
8.41
6.98
8,61
9.21
9,21
5+
2-
xdazl
Dazl1
326
211
216
4+
5+
5+
MafaDAZL1
HsaDAZL1
1872
1872
619

Conserved DAZL1 gene structure in old world monkeys
monkeys. All other DAZL1 homologs, besides the
mouse Dazl1 gene, contained only a single canon-
ical polyadenylation signal (AATAAA) at their 3´
ends. The putative polyadenylation signal of the
mouse Dazl1 gene, a run of AAAGAAA 15-21 nu-
cleotides upstream of its polyadenylation site might
be only functional with a low efficiency (21). Our da-
ta suggest an improvement of the efficiency of the
polyadenylation process of DAZL1 transcripts dur-
ing mammalian evolution.
DAZL1 gene of the old world monkey Macaca fa-
scicularis separated from the human line at least 36
million years ago (1) and compared in detail its
complete gene structure to those published of the
other DAZL1 homologs in the database. Our com-
parative analyses predict some changes in the func-
tional structures of the DAZL1 protein homologs in
each species analysed (Fig. 1) (Table 1) and its high
conservation in the old world monkey primate class.
Only both primates DAZL1 genes encode proteins
of identical molecular weights, identical surface
charges and identical isoelectric points although
macaques and humans were separated during evo-
lution at least 36 million years ago (1). Does this
specificity perhaps explain the recent observation of
a primate specific transient localization of DAZL1
proteins in the nucleus of spermatogonia (25)?
The different homologies between the macaque
DAZL1 sequence and the mouse Dazl1 sequence
in their 5´UTRs and 3´UTRs cannot be explained by
the different contents of GC nucleotides in both
UTRs but suggest a different selection pressure on
both sequence regions. Only the 3´UTR seems to
contain an evolutionary conserved structure, but
this is restricted to the mammalian species ana-
lyzed, i.e. mouse and primates. Our comparative
analysis of the DAZL1 3´UTRs in Caenorhabditis el-
egans, Drosophila, zebrafish and Xenopus failed to
detect any conserved sequence domains. Although
it is too early to assign any distinct functional as-
pect with the 3´UTRs of the mammalian DAZL1
genes, we know that this structure generally con-
tains conserved sequence elements which are im-
portant for the efficiency of the nuclear maturation
process of nuclear transcripts (26). Therefore, a con-
servation of the complete DAZL1 3´UTR in se-
quence and length in both old world monkeys com-
parable to their coding regions implies a conserved
pathway of the nuclear DAZL1 mRNA maturation
in this primate class. Taking this into account as well
as the results obtained of homologous 5’UTRs
(91%) and putative identical structures we can con-
clude that the DAZL1 genes in old monkeys are
probably functional homologous in the germ line.
DISCUSSION
The DAZL1 gene encodes a germ line specific RNA
binding protein of the RRM class which is required
for germ line function. Targeted mutation analyses
of the homologous boule gene in Drosophila and
of the Dazl1 gene in mouse have shown that in both
species the germ line becomes disrupted (3, 22).
In human DAZL1 mutations disrupting the male or
female germ line are not known and its exon-spe-
cific mutation analysis is hampered by the fact that
homologous DAZ gene copies exist on the Y chro-
mosome (9-12). This primate-specific amplification
step of the DAZL1 locus occurred after divergence
of the new world monkeys but before divergence of
the old world monkeys, i.e. 36-55 million years ago.
We wanted to know whether this genomic rear-
rangements were triggered by some functional con-
straints specific for the germ line of old world mon-
keys or represent a neutral mutation event hap-
pening during evolution of the old world monkeys
chromosome structures.
Functional aspects might be considered when look-
ing at the large increase in body and testis weights
observed in all old world monkeys when compared
to the new world monkeys (23). It can be expected
that this major morphological evolution step also
has some influence on the production rate of ma-
ture spermatozoa in the different species classes
and an increased requirement of DAZL1 proteins
for this process in old world monkeys might be pos-
tulated. If this holds true, amplification of the DAZL1
gene and transposition of these genes to the Y
chromosome would be an attractive possibility to
reach this goal, as any gene transposed to the Y
chromosome with a slight influence on the male
germ cell function will be strongly selected for (24).
On the other hand, some evidence exists that at
least in humans, the DAZ genes on the Y chromo-
some are not essential for spermatogenesis and
therefore were found to be frequently deleted (16).
In order to collect more arguments for or against
functional aspects of the unique DAZL1 amplifica-
tion step in old world monkeys, we isolated the
ACNOWLEDGMENTS
We are indebted to Jörg Gromoll (Institute of Reproductive
Medicine, University of Münster) for providing us with the
MafaDAZL1 cDNA clones for sequence analysis. Under the term
cynDAZLA he and Carani et al. (27) also sequenced earlier some
RT-PCR products of the Macaca fascicularis DAZL1 gene. Katrin
Christophers-Genzmer is thanked for support in the preparation
of this manuscript and improving our English grammar. This work
was supported by a grant (Vo403/12-1) from the DFG (Deutsche
Forschungsgemeinschaft) to P.H. Vogt.
620

B. Grossmann, G. Weinbauer, P. Hirschmann, et al.
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