Full text of DOI:10.1007/BF03343787

J. Endocrinol. Invest. 23: 630-645, 2000
The role of human and mouse Y chromosome genes
in male infertility
N.A. Affara* and M.J. Mitchell**
*
Department of Pathology, University of Cambridge, U.K.; **INSERM U.491, Génétique Médicale et
Dévelopement, Faculté de Médecine, Marseille Cedex, France
ABSTRACT. It was suggested by Ronald Fisher
in 1931 that genes involved in benefit to the
male (including spermatogenesis genes) would
accumulate on the Y chromosome. The analysis
of mouse Y chromosome deletions and the dis-
covery of microdeletions of the human Y chro-
mosome associated with diverse defective sper-
matogenic phenotypes has revealed the pres-
ence of intervals containing one or more genes
controlling male germ cell differentiation. These
intervals have been mapped, cloned and exam-
ined in detail for functional genes. This review
discusses the genes mapping to critical sper-
matogenesis intervals and the evidence indicat-
ing which are the most likely candidates under-
lying Y-linked male infertility.
(J. Endocrinol. Invest. 23: 630-645, 2000)
©
2000, Editrice Kurtis
INTRODUCTION
mosome (NRY) (6, 7). Secondly, the male-specific na-
ture of the Y chromosome may promote the accu-
mulation of male-enhancing/female-damaging alle-
les, sexually antagonistic (SA) alleles (8), leading to
the Y chromosome becoming a specialized male
chromosome. In this review, we will discuss the role
of the Y chromosome in spermatogenesis as eluci-
dated from studies of the human and mouse NRYs.
It has been estimated that up to 10% of couples
worldwide suffer from infertility or reduced fertility
and that in approximately half of these cases the
cause is defective spermatogenesis (1). In 60% of
these men, the failure to produce mature germ cells
(
azoospermia) or the formation of low numbers of
sperm (oligozoospermia) can be ascribed to a ge-
netic etiology (2). Few of the loci associated with
male infertility have been mapped in humans; how-
ever in mice, a number of genetic models of de-
fective germ cell development and differentiation
has been described (3-5). In both species it has
been shown that the Y chromosome plays an im-
portant role in male gametogenesis and that sev-
eral loci are located within the genetically isolated
non-recombining regions of the chromosome.
Two (but not mutually exclusive) principal theories
for the evolution of genes on the Y chromosome
have been formulated, each based on one of its two
distinctive properties, that is, its failure to recombine
along the majority of its length and its presence on-
ly in the male. Firstly, it has been theorized that the
absence of recombination prevents the segregation
of deleterious mutations from advantageous muta-
tions, thus leading to an inevitable deterioration in
the genetic content of the non-recombining Y chro-
DELETIONS OF THE Y CHROMOSOME
DEFINE THE LOCATION OF KEY
SPERMATOGENESIS GENES
Deletions of the human Y chromosome
The involvement of the human Y chromosome in
male infertility was first suggested by cytogeneti-
cally detectable terminal deletions of the long arm
where the entire Yq heterochromatin was lost (9).
In some men, this did not appear to impair sper-
matogenesis, whereas in others it led to infertility.
The simple explanation for these observations lay in
suggesting that a key locus (or loci) resided close
to the boundary between the Yq euchromatin and
genetically inert heterochromatin. More extensive
deletions (not capable of being resolved by cyto-
genetic analysis) remove this locus in some men,
causing infertility. However, it could be argued that
such large structural changes to the Y chromosome
may perturb its normal pairing and segregation be-
havior with the X chromosome during meiosis and
that this, rather than the loss of a key locus, is the
cause of spermatogenic failure in these men.
Key-words: Y chromosome, male fertility, deletions candidate genes.
Correspondence: Prof. Nabeel A. Affara, Department of Pathology,
University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, U.K.
630

Human and mouse Y chromosome
Through the use of molecular markers that have
been mapped at high density on the Y chromo-
some, numerous deletion-mapping studies have
defined at least three distinct non-overlapping in-
tervals each associated with variable degrees of
spermatogenic impairment (10-14). These intervals
have been named AZFa, AZFb and AZFc for azoo-
spermia factors a, b and c (Fig. 1) and clearly indi-
cate that there are at least three different loci on
the Y chromosome long arm that are critical for
germ cell differentiation. Similar deletion analysis
has defined critical intervals of the mouse Y chro-
mosome (see below) (15). Genotype/phenotype
correlations in patients shown to have AZFa, b and
c deletions have revealed considerable variations
in the nature and degree of spermatogenic failure.
Deletions of the AZFa region (the least common class
of deletion) are most frequently associated with
azoospermia manifested by Sertoli cell-only syndrome
(SCOS) and less often with oligozoospermia (11, 16,
17). In SCOS, there is a complete absence of germ
cells within seminiferous tubules. Two types of SCOS
phenotype have been described: SCOS I, where
none of the tubules in a section contains germ cells,
and SCOS II, where there is a mixture of some tubules
being devoid of germ cells and others containing re-
duced numbers (11). SCOS I is likely to arise from an
early-acting primary defect in spermatogenesis,
whereas SCOS II is believed to develop as a sec-
ondary effect from a primary defect affecting sper-
matogenesis at a latter stage of differentiation.
Deletions of the AZFb region are associated with
azoospermia, oligozoospermia and normozoosper-
mia (normal spermatogenesis) (11, 12, 18). Azoo-
spermia is accompanied not only by SCOS, but al-
so by meiotic and maturation arrest at the sperma-
tocyte and spermatid stages of male germ cell dif-
ferentiation.
Fig. 1 - Schematic representation of the euchromatic region of the human Y chromosome and the mouse Y chromosome. The map
of the human Y shows the intervals defined by deletion mapping. The diagram of the mouse Y chromosome summarizes the dele-
tion intervals associated with spermatogenesis. On both maps the intervals associated with various spermatogenic phenotypes have
been marked. A) Map of the human Y chromosome. B) Map of the mouse Y chromosome. PAR: pseudoautosomal region.
631

N.A. Affara and M.J. Mitchell
Deletions of the AZFc interval are associated with
azoospermia, severe-to-mild oligozoospermia and
the production of sufficient mature sperm to en-
able reproduction (11, 19, 20). As with AZFb dele-
tions, azoospermia reflects a spectrum of sper-
matogenic phenotypes from SCOS to meiotic and
maturation arrest.
which are associated with a reduction in fertility.
del
The B10.BR-Y deletion arose and in the B10.BR
strain of mice is seen as a small chromosome, about
25% the size of the normal Y chromosome, and
pairs normally with the X chromosome. This indi-
del
cates that Y has a pseudoautosomal region, and
must therefore have arisen through interstitial dele-
tion of most of the long arm (25).
From these genotype/phenotype correlations, it
has emerged that very similar or identical deletions
in patients can cause a different spermatogenic im-
pairment. This variation in phenotype could be ex-
plained in a number of ways. First, the accumula-
tion on this chromosome of amplified families of
DNA sequences makes it difficult to be sure that a
marker has only one location on the chromosome,
leading to scoring errors. Second, variation be-
tween individuals may reflect modification of phe-
notype as a consequence of X-Y mosaicism in the
germline (absent from lymphocytes), with some
germ cells possessing an intact Y chromosome.
Third, alleles of modifying genes within the genet-
ic background of the individual may be able to
compensate for lost function of Y-linked genes.
The human Y chromosome has now been mapped
in considerable detail through a combination of
deletion-mapping studies that define Y intervals,
and a series of overlapping yeast, P1 and bacterial
artificial chromosome clones (21-23) that cover the
entire active euchromatic DNA. This has enabled a
detailed search for candidate genes within the
clones covering key intervals associated with dis-
ease phenotypes.
del
B10.BR-Y males are fertile, but produce increased
numbers of spermatozoa with abnormal head struc-
tures (25, 27). In vitro tests further indicated that
even the spermatozoa with normal morphology
del
from B10.BR-Y mice fertilize with reduced effi-
ciency, when compared with those from B10.BR
(28, 29). In normal B10.BR ejaculate ~22% of sperm
are abnormal, but this rises to ~64% in mice carry-
del
ing the Y . This increase is largely due to the pres-
ence of spermatozoa with an almost normal head
structure but a flattened acrosome (25, 27). This
type of spermatozoon is not found at all in the ejac-
ulate of normal B10.BR mice, but represents ~28%
del
of all the spermatozoa in the Y ejaculate. A slight-
ly increased frequency is also seen in two types of
more grossly deformed spermatozoa which are pre-
sent in the normal ejaculate.
In the case of RIII Y-del (26), a similar 3-fold increase
in the percentage of abnormal sperm was ob-
served, although cytogenetically the deletion was
slightly smaller, removing about half the long arm.
A slight distortion in the sex ratio in favor of females
was observed in the offspring of the males carrying
the Y-del chromosome. This was measured on two
different genetic backgrounds, and the percentage
of males dropped from 57% with the undeleted Y
to 46% with the Y-del on a C57BL/10 background,
and from 51% to 38% on an MF1 background. The
sex-ratio distortion suggests that the deleted re-
gion contains factors that act during the haploid
stages of spermatogenesis and favor transmission
of the Y-bearing gamete.
Deletions of the mouse Y chromosome
XO germ cells in the testis of XO/XY chimeric males
can develop normally as far as the post-natal sper-
matogonial stage, but they proliferate poorly and
rarely enter meiosis (24). This shows that the Y chro-
mosome produces a cell-autonomous factor which
is necessary for the successful post-natal develop-
ment of the mitotically dividing spermatogonial
germ cells. This factor has been named Spy (sper-
matogenesis on the Y chromosome).
Five deletion mutations (with no noticeable effect
on somatic development) have provided a more
precise localization of Spy to the minute short arm,
and have led to the identification of a spermio-
genesis factor on the long arm, Smy (sperm head
morphology on the Y chromosome), which is nec-
essary for the production of spermatozoa with func-
tional heads.
Deletion of the pericentric region
The primary phenotype of the Yd1 deletion is sex-re-
versal, caused by the transcriptional silencing of Sry
d1
which remains intact on Y (30, 31). To see the ef-
fect of the deletion on spermatogenesis, an Sry
transgene was introduced to allow determination
d1
of the testis, and the resulting XY Sry male mice
were analyzed (32). This analysis showed that like
del
d1
the B10.BR-Y and the RIII Y-del mice, XY Sry
mice are fertile, but produce increased number of
abnormal spermatozoa. The profile of spermatozoa
morphology is different from that associated with
the interstitial long arm deletions, with slightly ab-
normal forms being only marginally increased and
Deletion of the long arm
Two partial deletions of the mouse long arm have
del
been reported: B10.BR-Y (25) and RIII Y-del (26),
632

Human and mouse Y chromosome
grossly abnormal forms greatly increased. The con-
concluded that Y-borne spermiogenesis factors,
necessary for normal sperm head morphogenesis,
del
verse being observed in B10.BR-Y and RIII Y-del,
a
this suggests that the Y chromosome may act at
least at two different stages in the spermiogenic
process.
are located outside the Sxr region, but are not lim-
ited to a single locus. It can also be concluded that
a
the tiny Sxr region contains sufficient Y chromo-
some genetic material for the production of sper-
matozoa in normal numbers.
Deletion of the long arm and the
pericentric region
a
Deletion of the short arm
The Sxr mutation has allowed an evaluation of the
spermatogenesis in male mice lacking the long arm
Spy has been further localized by a deletion vari-
a
a
b
and the pericentric region. The Sxr (sex-reversed)
ant of the Sxr region which has been termed Sxr .
b
mutation was originally described as an autosomal
dominant sex-reversal mutation that caused the de-
velopment of testis in embryos lacking a Y chro-
mosome (33). The molecular basis for this mutation
is a translocated fragment of the Y chromosome.
The Sxr deletion arose in a stock of mice carrying
a
the Sxr mutation (38, 42, 43), and the deleted in-
b
a
terval has been termed ꢀSxr . Unlike XSxr O mice,
b
XSxr O mice have a severe block in spermatogen-
esis (39), affecting the proliferation of the differen-
tiating A spermatogonia shortly after the exit of the
germ cells from mitotic arrest, at birth. The fact that
this deletion is a transmissible mutation, being com-
a
XYSxr carrier males have a duplication of most of
the Y short arm, translocated to the distal end of
the Y chromosome pseudoautosomal region (34-
a
b
37). The duplicated segment is called Sxr region,
plemented by the Y short arm in XYSxr carrier
b
and during male meiosis it is transferred to the X
chromosome by pseudoautosomal recombination,
males, has allowed post-natal XSxr O germ cell de-
velopment to be precisely characterized (44). The
earliest effect is evident 3 days after birth as re-
duced numbers of A spermatogonia precursors, the
T2 prospermatogonia. Decreased mitotic activity
among the differentiating A spermatogonia results
in the effective absence of B spermatogonia, and
only very rare germ cells are seen to enter meiosis.
The abnormal proliferation of spermatogonia in
a
d1
giving rise to XXSxr progeny (35). Like the Y chro-
a
mosome, the Sxr region has a reduced number of
copies of the Rbmy/Sx1 repeat (see below) and so
a
it is likely that the Sxr translocation breakpoint lies
within the Rbmy/Sx1 cluster (32, 38). Thus, the Sxra
region consists of an estimated 3 to 7 copies of the
Rbmy/Sx1 repeat, together with all distally located
short arm sequences.
b
XSxr O mice appears to activate a control system
a
XXSxr mice develop as males because of the ex-
that eliminates the aberrantly dividing germ cells,
leaving the adult testis tubules essentially empty of
a
pression of Sry from the Sxr region, but have a lim-
b
ited post-natal germ cell development due to the
presence of two X chromosomes (39). This latter ef-
germ cells. The ꢀSxr gene or genes encoding the
spermatogenesis factor necessary for normal sper-
matogonial development have been equated with
Spy. The role of the different intervals of the mouse
and human Y chromosomes in spermatogenesis is
summarized in Figure 1 together with the genes as-
signed to these intervals.
a
fect is not present in XSxr O mice, where all stages
of spermatogenesis are present (33), thus showing
that the gene, or genes, for Spy must be located in
a
the Sxr region. Despite the presence of Spy,
a
XSxr O mice are nevertheless sterile, producing on-
ly a few malformed sperm. The reduced number of
a
spermatozoa produced by XSxr O mice was shown
CANDIDATE GENES MAPPING TO KEY
REGIONS OF THE HUMAN AND MOUSE Y
CHROMOSOMES
to result from the absence of a meiotic pairing part-
ner when genetic crosses were used to introduce
*X
*X
a rearranged chromosome, Y (40). The Y is com-
posed of a pseudoautosomal region attached to an
Human deletion intervals
a
*X
unknown X or autosomal centromere (41). XSxr Y
Much focus has now been placed on identifying
candidate genes that map to the AZFa, b and c in-
tervals, which will be considered in historical order
below.
mice produce almost normal numbers of sperma-
tozoa, but all are grossly deformed and the mice
a
*X
are infertile (40). The XSxr Y spermatozoa are
equivalent to the more grossly deformed types pro-
duced with increased frequency in mice carrying
long arm or pericentric deletions of the Y chromo-
some. Thus, the deletion of long arm and pericen-
tric sequences provokes a more severe phenotype
than either deletion individually. It can therefore be
The AZFb interval
The first Y-linked gene to be isolated as a strong
candidate for a role in spermatogenesis came from
the AZFb interval. Ma et al. (45) described two tran-
scripts mapping to this region that are part of a
633

N.A. Affara and M.J. Mitchell
larger gene family located on the Y chromosome.
The transcripts encode potential RNA-binding pro-
teins related to the autosomal gene HnRNP G and
contain a single N-terminal RNA-binding motif (the
RNP motif) and four tandem repeats of 37 amino
acids (known as the SRGY box – rich in serine, argi-
nine, glycine and tryptophan residues) in the mid-
dle of the protein. The family of genes has been
named RBM (for RNA-binding motif) and contains
at least 30 genes and pseudogenes that fall into
different sub-classes mapping to several locations
on the short and long arms of the human Y chro-
mosome, including the AZFb interval (46). Similar
studies in mice have shown that there are multiple
copies of the Rbm gene family on the mouse Y
chromosome short arm, but that these (unlike the
human RBM family) are clustered at a single loca-
tion just proximal to the Sry sex-determining gene
stages, but AZFb deletions that abolish RBMY1 ex-
pression and cause meiotic arrest suggest that it is
not essential for germ cells to reach meiosis but
that it is necessary for them to pass successfully to
the haploid state.
Comparative analysis of RBM and related genes in
different eutherian mammals and marsupials reveals
details of how this gene family has evolved (52).
The original data indicated that the Y-borne genes
arose by translocation from an ancestral autosomal
HnRNP G gene on to the Y and that this was fol-
lowed by independent amplification events in dif-
ferent species. Two amplification events can be dis-
tinguished: 1) an internal amplification of the exon
that encodes the SRGY box in the human lineage,
giving rise to four tandem repeats; and 2) whole
gene amplification leading to the multi-copy fam-
ily. In mice, there has been amplification of the Rbm
gene on the Y, but not of the SRGY box. In marsu-
pials, it would appear that in some species the gene
is amplified on the Y but that there is a single copy
of the SRGY box. These findings suggest that SRGY
box amplification occurred after the divergence of
the human and mouse lineages and before ampli-
fication of the gene on the Y, since different mem-
bers of the human gene family contain the four tan-
dem SRGY box repeats. The recent discovery that
there is a widely expressed RBMY1 homologue
possessing introns on the X chromosome in both
mice (53) and humans (Xq26) (54), and that the au-
tosomal loci (on chromosome 6 in humans and 14
in mice) have proved to represent X-derived pseu-
dogenes (53, 54) has altered our thinking about the
evolution of this gene family. It is clear that these
genes date from the ancestral homologues that
gave rise to the sex chromosomes and that the au-
tosomal loci have been generated by retrotrans-
position. The locus on the Y has become amplified
during evolution and the selection for a role in
spermatogenesis. The X-linked gene is known as
RBMX.
(see below) (47). What is not clear for both species
is how many of the genes within the family are ac-
tually functional. Analysis of genomic and cDNA
clones and RT-PCR products indicates that there
are possibly 6 human RBM sub-classes (RBMI-RBMVI
now renamed RBMY1-RBMY6), but that only mem-
bers of the RBMY1 sub-class are transcribed (48).
The pattern of expression of the RBMY1 genes is
complex, with several different transcripts and po-
tential protein isoforms being produced due both
to base substitutions and to alternative splicing that
results in 3 or 4 SRGY boxes (48). This complexity
makes functional analysis difficult.
The use of RBM antibodies to detect RBM expres-
sion in human testis sections has shown that the
protein is localized to the nucleus, confined to germ
cells, and appears to occur at all stages of sper-
matogenesis except in elongating spermatids (49).
Analysis of RBM protein in testis sections from in-
fertile men has indicated a correlation between ac-
tive protein expression uniquely to deletions that
cover the AZFb region and, most particularly, in-
terval 6B (49) (Fig. 1). This is an important result as
it suggests that other RBM loci on the human Y
chromosome do not produce a protein product es-
sential for spermatogenesis and that the key RBM
genes lie in the AZFb interval.
The fact that the RBMY1 genes form a multi-copy
family makes it difficult to provide direct genetic
and functional evidence that they are critical to
spermatogenesis. There is strong indirect evidence
to support their involvement in germ cell differen-
tiation, based primarily on the correlation between
the AZFb interval and expression of the RBMY1
protein in germ cells. A number of questions arise
in attempting to make correlations of genotype to
phenotype. How many RBM genes are involved in
the critical deletions that abolish RBM protein ex-
pression? What contribution (if any) do other genes
mapped to the AZFb interval make to spermato-
genic phenotypes associated with this region?
It is likely that RBMY1 functions as an RNA-binding
protein and its location in the nucleus in associa-
tion with splicing factors (50) implies that it may
have an important role in RNA metabolism, per-
haps in RNA processing. Post-transcriptional and
translational control is important in spermatogen-
esis (51), especially during post-meiotic stages
where almost all transcriptional activity has ceased.
RBMY1 expression throughout most of spermato-
genesis indicates that the protein has a role at all
634

Human and mouse Y chromosome
What further genes are encompassed within the
AZFb interval? Two X-Y homologous genes that are
expressed ubiquitously have been mapped to the
AZFb region; SMCY, which encodes a protein with
male-specific H-Y antigen epitopes (55); and
EIF1AY, a translation elongation initiation factor
tion that DAZLA could be a candidate for autoso-
mal recessive forms of male infertility. The mouse
gene (Dazla) has been mapped to chromosome 17
and is also expressed in male germ cells and the
female gonad (65, 66) but, unlike Rbm, has a cyto-
plasmic rather than a nuclear location (67). The tem-
poral pattern of Dazla expression indicates that it
is present throughout spermatogenesis and thus
may have a critical function at all stages of germ
cell differentiation. Reijo et al. (66) have suggested
that this may explain the range of phenotypes as-
sociated with AZFc deletions, but it has not been
demonstrated that the human Y transcript has the
same pattern of expression. Thus it may be pre-
mature to extrapolate from observations made with
the mouse autosomal gene. Disruption of the
mouse Dazla gene has provided functional evi-
dence of the critical role that the gene plays in both
male and female germ cell production (67): loss of
Dazla function leads to a complete ablation of ga-
mete production, demonstrating that it is essential
for successful gametogenesis.
As mentioned above, the DAZ gene family con-
trasts to the RBM gene family in that no DAZ genes
have been found on the Y chromosome of mice or
any non-primate species tested (57, 65, 64). There
is also no evidence for any sequences on the X
chromosome in humans and mice. DAZ sequences
are relatively recent arrivals on the Y chromosome,
having appeared on the primate NRY some time
after the divergence of the New World monkeys
but before the splitting of the lineage that gave rise
to Old World monkeys. It has been suggested that
this was achieved by direct transposition from the
autosomal locus to the NRY, with subsequent am-
plification (57). Thus, this amplified gene family has
a quite different evolutionary history to that of RBM.
Two points are worth noting in relation to this find-
ing. First, Lahn and Page (56) have suggested that
amplified genes on the Y all arose by recruitment
from an autosomal homologue. DAZ and RBM il-
lustrate that this is not the case and that a second
class of Y-linked amplified gene family can arise
from an ancestral X homologue. This may be the
case for other Y-linked amplified gene families, as
has been shown recently for BPY1 now renamed
VCX/Y (68). Second, X-Y homologous genes and
not just Y-specific genes must be considered as po-
tential candidate genes involved in regulating sper-
matogenesis (see discussion below).
(
56). Two other transcripts, TTY2 and PRY, both
members of amplified gene families on the Y, have
also been assigned to the AZFb interval (56). No
functional open reading frames are to be found in
TTY2 transcripts; PRY is related to PTP-BL, a pro-
tein tyrosine phosphatase.
The AZFc interval
The first suggestion of a candidate gene in the
AZFc interval came from a systematic exon-trap-
ping analysis of DNA clones covering about 500 Kb
of the region. Reijo et al. (20) isolated expressed
exons which formed part of a gene that contains an
N-terminal RNA recognition motif and a repetitive
internal structure composed of a series of seven
tandem 72 bp repeats. These features indicate that
the gene encodes an RNA-binding protein that may
have a regulatory role concerned with RNA meta-
bolism. The gene has been named DAZ (deleted
in azoospermia) and was at first claimed to be sin-
gle copy and the only functional gene in the AZFc
interval (20). Subsequent analysis of the DAZ locus
in the AZFc region demonstrated that it represents
a clustered amplified gene family with considerable
variation between gene family members in the
number of DAZ repeats, and polymorphism in the
population in the number and sequence of DAZ re-
peats (57, 58). A diverse spectrum of DAZ tran-
scripts is produced, reflecting the transcriptional
activity of all members of the gene family (58).
DAZ is expressed specifically in testis (20, 59) and is
closely related to a Drosophila fertility gene named
boule (60). Loss-of-function mutations of boule
cause azoospermia. Thus it seems reasonable to
expect that DAZ is a candidate for involvement in
the AZFc phenotype(s) although is not necessarily
the only gene required. The protein is found main-
ly in post-meiotic germ cells (late spermatids and
sperm) (61) and this may reflect a role in post-tran-
scriptional control during the transcriptionally inac-
tive stages of germ cell differentiation.
An autosomal homologue of DAZ containing a sin-
gle DAZ repeat has been described in both humans
and mice but no DAZ-related sequences have been
found on the mouse Y chromosome. The human
gene (named DAZLA) which maps to chromosome
Although DAZ is an attractive candidate for the
AZFc phenotype, it is dogged by the same prob-
lems that confront a functional analysis of the RBM
genes. No discrete mutations have been found in
DAZ genes that are associated with infertility, and
3
p24 is expressed specifically in the testis and at
lower levels (detectable by RT-PCR) in ovary (57,
2-64); this observation has prompted the sugges-
6
635

N.A. Affara and M.J. Mitchell
the existence of a gene family exacerbates efforts
to establish such genetic evidence. The picture be-
comes even more complex as a consequence of
new data showing that DAZ is not the only gene
family to map to the AZFc region (56). At least three
other gene families are encompassed by AZFc
deletions: BPY1 and BPY2 transcripts encode basic
proteins of unkown function; PRY has been men-
tioned above and CDY contains a chromodomain
found specifically in testis (56). The function of UTY
(ubiquitous transcribed tetratricopeptide repeat
gene on the Y) is unknown, but this gene can be
excluded from involvement in the AZFa phenotype
as it has been found to be present in all patients
studied to date. Detailed annotation of the se-
quence covering the AZFa interval by Sargent et al.
(71) and Sun et al. (77) has also identified several
pseudogenes related to gene sequences mapping
to Xp22.3.
(
chromatin-binding domain) and a potential CoA-
substrate catalytic domain. Members of the CDY1
gene family may modify chromatin during sper-
matogenesis. Stuppia et al. (69) reported infertili-
ty-causing deletions of the AZFc region that do not
remove DAZ genes but may remove other genes
The position of breakpoints in patients with respect
to the location of genes has placed focus upon the
DFFRY and DBY genes as potential candidates for
the AZFa phenotype. The milder oligozoospermic
phenotype observed in patients retaining a tran-
scriptionally active DBY gene but a deleted DFFRY
gene (71), may reflect the combined requirement of
these two genes to avoid the more severe SCOS
seen in other patients where both genes are delet-
ed. More patients are required to investigate this
possibility, particularly cases where there is genetic
evidence of point mutations affecting both genes. A
recent study of 500 infertile men has described in
one case a 4-bp deletion in DFFRY affecting a splice
donor site in intron 7 leading to premature termi-
nation of the polypeptide chain (77). This patient
has an oligozoospermic phenotype, supporting the
notion that DFFRY and DBY may act synergistically
to enable full fertility. It should be noted that none
of the 500 patients studied by Sun et al. (77) showed
any evidence of mutation in the DBY gene.
(
e.g. CDY1 and BPY1). This finding suggests that
there are other loci in the AZFc interval that con-
tribute to fertility in addition to DAZ and this might
explain some of the diverse phenotypes associat-
ed with different deletions.
The AZFa interval
Several deletion studies have defined an approxi-
mately 400 Kb segment correlated with the AZFa
phenotype in Yq11.2 (11, 70, 71). The frequency of
deletions defining AZFa is much lower than that
found for AZFb and c. With the exception of one
study (72), all the laboratories that have reported
AZFa deletions agree that 1-2% of Y chromosome
deletions involve the AZFa region. Recently, just
over 1 Mb of DNA covering the AZFa region has
been sequenced by the Whitehead Institute/MIT
Center of Genome Research and this has allowed
the accurate positioning of breakpoints in relation
to functional genes that have been mapped to the
region. These include the DFFRY (56, 70, 71, 73),
the DBY (56) and the UTY gene, (56, 74). All three
genes have ubiquitously expressed X homologues
Mouse deletion intervals
The long arm
A large proportion of the long arm chromatin con-
sists of sequences that have been amplified specif-
ically on the Y chromosome. There are an estimat-
ed 300-500 copies of a complex element com-
posed of at least two Y-specific proviral genomes:
a murine retrovirus, MuRVY, and an intracisternal A
particle, IAPE-Y (78, 79). The full extent of the re-
peat unit has not been defined, but it is greater
than 25 kb, and therefore accounts for a minimum
of 9-12% of the Y-chromatin. FISH analysis shows
that both the proviral components of this repeat
are spread throughout the Y chromatin (79).
Attempts to isolate low-copy number sequences
specifically from the Y chromosome have led to the
isolation of Y-specific low-level repeat sequences
which are present on the Y chromosome in 10 to
250 copies. Analysis of the distribution of these el-
ements by FISH shows that they are mostly dis-
persed throughout the long arm of the chromo-
some (80, 81). In the majority of cases, Southern
analysis with these Y-fragments reveals a single in-
(
DFFRX, DBX and UTX) that map in the interval
Xp11.3-p11.4 and have been shown to escape X.
DFFRY (Drosophila fat facets related, also known
as USP9Y) is also expressed ubiquitously and en-
codes a ubiquitin-specific hydrolase closely related
to the Drosophila faf gene (75) known to be in-
volved in photoreceptor and oocyte development.
The Drosophila gene has been shown to be in-
volved in ubiquitin-dependent degradation of pro-
tein and to target specifically the D-Jun transcrip-
tion factor and other members of the signal trans-
duction cascade involved in regulating D-Jun ac-
tivity (76). DBY (DEAD box on the Y) encodes a pro-
tein containing the DEAD box motif found in RNA
helicases and, therefore, may be involved in RNA
metabolism (see below for further discussion). Two
transcripts are evident for DBY, one of which is
636

Human and mouse Y chromosome
The pericentric region
tense male-specific band, suggesting that the am-
plification of these sequences occurred recently in
the evolution of the Muridae, and that the se-
quences defined are part of a larger element. Thus,
it is reasonable to conclude that most of the 94.7
Mb of the mouse Y chromosome have arisen re-
cently through amplification events, and that the
long arm of the mouse Y chromosome is predomi-
nantly composed of several hundred copies of one
large composite element, interspersed with a vari-
ety of low-to-medium copy elements.
A composite repeat element has been partially de-
fined, which is present in 20-50 copies in the peri-
centromeric region of the mouse Y chromosome
(32, 81). It is known to comprise in part the Rbmy
gene (31, 47), together with a sequence defined by
the anonymous marker pSx1 (38), and these two
sequences are located within the same 15 kb
stretch of DNA (32). Thus, copies of this element
cover at least 1 Mb. It is not known whether the
Rbmy/Sx1 repeats are arranged as a single block
or are split into multiple blocks. FISH analysis, using
pSx1 as a probe, shows a hybridization signal ex-
clusively at the centromeric end of the chromosome
(81). The Sry gene is located close to the main
Rbmy/Sx1 repeat cluster (31, 87), and the deletion
of some copies of this repeat can lead to the tran-
scriptional silencing of Sry, causing the develop-
ment of sex-reversed XY females (30).
One of the most interesting findings of the recent
systematic cDNA selection performed in humans was
that many human Y chromosome genes are in fact
encoded by low-copy repeat elements (56). In the
mouse, one such gene, Ssty, has been isolated from
the Y chromosome, where it is present as a hetero-
geneous multi-copy gene family dispersed along the
long arm (82-84). Two sub-classes of transcript which
have only 84% nucleotide identity have been de-
fined and a related multi-copy family (DXF34) has
been identified on the human and mouse X chro-
mosome (85). Ssty shares homology (75% amino acid
similarity) with the Spindlin gene, which represents
a more distantly related autosomal homologue. The
Spindlin gene encodes a protein that associates with
the meiotic spindle in the unfertilized egg and per-
sists in the embryo until some time between 2 to 8
cell stage (86). Unlike Ssty and its X homologue,
Spindlin contains introns, suggesting that the sex
chromosome genes arose through retroposition of
a Spindlin transcript. The expression of Ssty is limit-
ed to the spermatids, consistent with its having a role
in spermiogenesis (83). Presently, the Ssty genes rep-
resent the only long arm sequences known to be
transcribed, and so it remains to be determined
whether any of the other repeats encode similar
gene families. At the molecular level, the RIII Y-del
deletion removes approximately half the Ssty copies
from the Y chromosome, and this translates to a
threefold decrease in the levels of Ssty transcripts.
This reduction in Ssty expression could underlie the
increase in abnormal spermatozoa, but the deletion
intervals are very large and may contain other genes.
Nevertheless, the diminished expression of Ssty in
the RIII Y-del deletion makes it a candidate for the
sperm-head morphology gene, Smy. Given the ap-
parent multi-copy nature of the majority of se-
quences on the long arm of the mouse Y chromo-
some, it is tempting to conclude that the spermio-
genesis functions of the Y chromosome are fulfilled
by such amplified gene families. The role of the
testis-specific amplified gene families that have been
identified on the human Y chromosome may there-
fore also have a role in spermiogenesis.
d1
a
The Y mutation arose in an XSxr Y mouse which
carries a duplicated segment of the short arm, the
a
Sxr region, on the X chromosome. The deletion
is probably the result of unequal crossing-over be-
a
tween the Sxr region and the short arm of the Y
chromosome (30-32). The unequal crossing-over is
believed to have occurred within the Rbmy/Sx1
tandem repeats situated on the short arm, be-
d1
tween the centromere and Sry. The resulting Y
carries an estimated two to four copies of this re-
peat. If the repeat is arranged in a single block on
the Y chromosome then it is only copies of this re-
peat that have been deleted, but if it is split be-
tween two blocks then interstitial sequences will
d1
also have been deleted. Y carries only about 10%
of the normal number of copies of Rbmy, and there
is a drastic reduction in the level of Rbmy tran-
scripts.
The mouse Rbmy gene is the homologue of the hu-
man RBMY Y chromosome gene. As mentioned
above, the Rbmy gene is transcribed specifically in
the testis, and its expression is limited to germ cells
(32, 47). The mouse and human RBMY protein are
found predominately in the nucleus (32, 49). Both
are present in spermatogonia and early spermato-
cytes, but while human RBMY protein persists until
the round spermatid stage, the mouse protein dis-
appears from the primary spermatocytes and does
not reappear until the elongating spermatid stages.
The association of Rbmy deletions with maturation
defects indicates that the protein may be essential
for post-meiotic maturation of germ cells, where it
could be required for post-transcriptional control,
and that the human and mouse proteins have dis-
tinct roles during the meiotic and spermiogenesis
stages of spermatogenesis (32).
637

N.A. Affara and M.J. Mitchell
The short arm
8
9% nucleotide identity with Dbx and has main-
The most fully characterized region of the mouse Y
chromosome is the short arm. Relative to the rest of
the chromosome, however, it appears to have a
high density of single copy segments and almost
all the genes so far identified on the mouse Y chro-
mosome. There are several segments that have
been amplified from two to six copies and dis-
persed on the short arm, representing region-spe-
cific repeats (87, 88). These segments include the X-
Y homologous genes Zfy (two copies) (89) and
Ube1y (five to six copies) (90). Thus, much of the
DNA content of the short arm may have arisen by
duplication events during murine evolution. Zfy1
and Ube1y are separated by less than 20 kb and lie
adjacent to a segment of >600 kb of single copy
sequences which encodes five functional X-Y ho-
mologous genes (91). No other X-Y homologous
genes have yet been identified on any other part
of the mouse NRY.
tained an open reading frame but, unlike Dbx that
is ubiquitously expressed, it is only expressed in
the testis (102). In the yeast, Saccharomyces ceriv-
isiae, it has been shown that the DED1 gene,
which encodes a polypeptide that has 53% amino
acid identity to PL10, is required for the initiation
of translation at the ribosome. A deletion of the
DED1 gene can be complemented by PL10, sug-
gesting that the mouse genes are involved in
translation initiation (99).
The X homologues of all these genes are widely
transcribed, but not all the Y genes are expressed
like their X homologues: Zfy1, Zfy2, Ube1y and
Dffry (see below) are only expressed in the testis.
Thus, it would appear that one step in the evolu-
tion of a gene on the Y chromosome is the limita-
tion of its expression to the germ cells, through the
loss of expression in somatic tissues. The interval
of the mouse Y chromosome required for the pro-
liferation and survival of the mitotic spermatogonia
is dense in X-Y homologous genes. The transcrip-
Eight of the 11 genes isolated from the mouse
b
b
NRY map into the ꢀSxr interval. The Sxr dele-
b
tion has been shown to be the result of unequal
crossing-over between duplicated Sxr region
tion map of the Sxr deletion remains incomplete,
a
nevertheless it seems likely that X-Y homologous
genes are required for normal spermatogenesis in
the mouse. The primary cause of the phenotype as-
genes, Zfy1 and Zfy2, which therefore define the
limits of the deleted interval estimated at greater
than 1.2 Mb (Simpson and Page, 1991). Seven
b
sociated with the Sxr deletion seems to be ineffi-
b
functional ꢀSxr genes, in addition to the Zfy
cient mitotic proliferation. Four of the genes in the
b
genes, have now been identified by a variety of
approaches (55, 70, 74, 90-94), and they have all
been localized to the 750 kb contig which in-
cludes Zfy1. One of the seven genes isolated is
the mouse Tspy that is a decayed, non-function-
al gene. Like the Zfy genes, the other six genes
appear to be functional and have a homologue
on the X chromosome. These genes are arranged
in the order Tel-Zfy1-Ube1y-Smcy-Eif2γy-Tspyps-
Uty-Dby-Dffry-Cen (Fig. 1).
ꢀSxr interval are homologues of confirmed or
probable housekeeping genes – Ube1y, Eif2γy,
Dffry and Dby – and thus, it could be envisaged
that the expression of these genes is critical for
spermatogenesis, because they improve the effi-
ciency of the mitotic cell-cycle in spermatogonia.
b
The ꢀSxr genes may function by augmenting the
dose of their X homologue to achieve the critical
level of product for the normal proliferation of the
spermatogonial germ cells. The genes could each
be critical at a separate point in the process, or may
all act together, or in various combinations (as sug-
gested for the human DFFRY and DBY genes), to
allow the proliferation, differentiation and survival of
the spermatogonia.
The functions of the proteins coded by some of
these genes can be extrapolated from the known
functions of their X homologues: activation of ubiq-
uitin (Ube1y) (95), initiation of translation (Eif2γy)
(
96), deubiquitination of proteins (Dffry, also see
above) (97). In other cases, clues are provided by
the functional analyses of homologous genes in
yeast: transcriptional repression (Uty) (98) and initi-
ation of translation (Dby) (99).
It is rather intriguing to note the co-localization of
b
Ube1y and Dffry within the Sxr deletion interval.
Ube1y and Dffry are concerned with the addition
(Ube1y – ubiquitin-activating enzyme) and removal
(Dffry – ubiquitin hydrolase) of ubiquitin from pro-
teins. Ubiquitination marks a protein for degrada-
tion; the degradation process occurs following re-
moval of the ubiquitin just before entry into the 26S
proteasome. It is possible that Ube1y and Dffry act
together in germ cells to permit fine control over
the turnover of a protein(s) necessary for successful
spermatogenesis.
With respect to Dby, a closely related mouse gene
has been used to complement a loss of function
mutation in yeast. The X homologue of Dby is Dbx
(
also known as ERH, mDEAD2 and mDEAD3), an
RNA helicase containing a DEAD box motif (100,
1
01), and on mouse chromosome 1 there is a Dbx
retroposon (N. Saut and M.J. Mitchell, unpub-
lished data). This retroposon, called PL10, shares
638

Human and mouse Y chromosome
b
THE MOUSE Sxr REGION SHARES
critical role in spermatogenesis and only a very mi-
nor role in somatic development. Furthermore,
some of the mouse X-Y homologous genes are not
expressed ubiquitously like their human counter-
parts, but are expressed only in the testis. Deletion
mapping suggests that in the mouse, X-Y homolo-
gous genes are required for the proliferation of the
germ cells, while the multi-copy Y-specific genes
are necessary for spermiogenesis.
HOMOLOGY WITH THE HUMAN
AZFa INTERVAL
The mouse spermatogenic phenotype (Spy) asso-
ciated with deletion of the Sxr region resembles
b
that found in those human AZFa patients where the
function of both the DFFRY and DBY genes has
been lost (44). In both cases, the block in sper-
matogenesis is at an early mitotic stage. The X-Y
homologous genes coding for DFFRY, DBY and
UTY are closely linked on the Y chromosome and
retain the same centromere to telomere order (DF-
FRY-DBY-UTY) in both species (70, 91). This indi-
DISTINCT GENE ORGANIZATION
Of the 11 genes that have been mapped to the
mouse NRY, 8 have homologues on the human Y
chromosome. A comparison of the mouse and hu-
man Y chromosome transcription maps stresses just
how different the organization of genes is between
the two species (Fig. 1). In the mouse, all such
b
cates that the Sxr interval and proximal Yq11.2
represent a conserved syntenic segment and an an-
cient organization on the Y chromosome that pre-
dates the divergence of the human and mouse lin-
eages. This suggests that the DFFRY-DBY-UTY
genes, and/or closely linked genes that have yet to
be identified, are required for the early stages of
spermatogonial proliferation in mouse and man.
b
genes are clustered within the ꢀSxr interval, but in
the human, they are spread out along 30 Mb (56,
9
1). This difference probably results from both a
compression of the X-Y component during rodent
evolution, and from a dispersal of the X-Y compo-
nent during primate evolution. The X homologues
COMPARISON OF THE MOUSE AND
HUMAN Y CHROMOSOME MAPS
b
of the ꢀSxr X-Y homologous genes do not co-lo-
calize on the mouse or human X chromosome as
they do on the mouse Y chromosome, and com-
parative analyses show that these X-Y homologous
genes have at least two distinct evolutionary ori-
gins. This, taken together with the presence of
Tspy, a Y-specific gene at the center of the cluster,
indicates that these genes have been condensed
The recent publication of an extensive transcription
map of the human Y chromosome stressed that the
majority of human Y chromosome genes fall into
one of two categories (56). Firstly, there are ubiq-
uitously expressed, single copy genes with a read-
ily detectable homologue on the X chromosome.
These genes escape X-inactivation, suggesting that
the X-Y homologous pair function as non-recom-
bining autosomal genes to produce two doses of
the appropriate gene product in males and fe-
males. Secondly, there are genes that do not have
a readily detectable homologue on the X chromo-
some, and whose expression is limited to the testis.
These latter genes are present in multiple copies
on the human Y chromosome. Given that the hu-
man Y chromosome is required for both somatic
and germ cell development, it is tempting to con-
clude that the X-Y homologous genes are somatic
factors, while the Y-specific genes are spermato-
genesis factors. A comparison with the transcrip-
tional and genetic maps of the mouse Y chromo-
some suggest, however, that this view may be too
reductionist, and may hinder our understanding of
the relationship between the genes of the Y chro-
mosome and spermatogenesis. The gene map of
the mouse Y chromosome is very similar to the hu-
man Y chromosome, particularly in terms of its com-
plement of X-Y homologous genes, but it is more
specialized than its human counterpart, having a
b
in the ꢀSxr interval. There is also convincing evi-
dence that, recently in primate evolution, there
have been insertions, inversions and amplifications
within the euchromatin that now lies between the
X-Y homologous genes on the human Y chromo-
some (103-110).
With respect to the distinct organization of the two
chromosomes, it is interesting to note that no re-
ported deletion of the human Y chromosome is as-
sociated exclusively with an increase in the pro-
duction of spermatozoa with abnormal heads. This
may be because human spermiogenesis or fertility
factors are intermingled with X-Y homologous
genes, and deletions removing the former also re-
move genes which act earlier in development or
spermatogenesis and so their effects on spermio-
genesis are obscured.
IMPLICATIONS FOR SPERMATOGENESIS
b
The outstanding feature of the current ꢀSxr inter-
val transcription map is its high density of X-Y ho-
mologous genes. With the exception of Zfy and
639

N.A. Affara and M.J. Mitchell
Dffry, these genes have been isolated indepen-
dently of the human gene map. Therefore, the
strong correlation with the transcription map of the
human Y chromosome indicates that most, if not
all, such genes map into this interval of the mouse
Y chromosome. This then raises the possibility that
the deletion of X-Y homologous genes underlies
specific multi-copy genes as germ cell factors. It
should, however, be remembered that a ubiquitously
expressed house-keeping gene will also be ex-
pressed in, and have a role in, the germ cells. The
data from the mouse suggests that a restriction of
the expression and function to the germline of the
X-Y component can occur during evolution. This is
manifested in the mouse by the testis-specific ex-
pression of Dffry, Ube1y and Zfy, which is in sharp
contrast to the situation in the human, where all X-Y
homologous genes are expressed in a wide range
of tissues, like their X-homologue. This difference
between mouse and man is all the more striking be-
cause Dffry and Zfy have a ubiquitously expressed
homologue on the human Y chromosome. Thus, the
mouse Y chromosome may be at a later evolutionary
stage than the human Y chromosome, a stage where
the functions of some genes have become limited
to spermatogenesis.
b
impaired spermatogenesis not only in the XSxr O
mouse, but also in certain cases of human infertili-
ty where a drastically reduced sperm count, caused
by reduced numbers of mitotic germ cells, is asso-
ciated with a deletion of the Y chromosome. The
unique syntenic homology of DFFRY-DBY-UTY be-
tween the human and mouse Y chromosomes
strongly suggests that this is the case with deletions
of the AZFa interval, and the recent demonstration
that there is an RBMX gene (see above) indicates
this is the case for the AZFb deletions too. This in
turn raises the question of whether the deletion of
X-Y homologous genes is likely to underlie the
AZFc spermatogenesis block.
ACKNOWLEDGMENTS
The AZFb deletion is associated with a very pre-
cise block which takes place during meiosis that
does not seem to affect the numbers of sper-
matogonia or primary spermatocytes in the testis
tubule, although no post-meiotic germ cells can
be detected (11). AZFc deletions are, however, fre-
quently associated with a severe reduction in the
population of mitotic germ cells (11, 20). Four
genes, DAZ, BPY2, PRY and CDY, have now been
mapped into AZFc, and it is implied that all four
genes have been recently inserted into the Y chro-
mosome from an autosome (56), although this has
only been shown to be the case for DAZ (57). The
mouse model would suggest that these genes are
more likely to be spermiogenesis factors, as op-
posed to being genes required for efficient mitot-
ic germ cell proliferation, and would, moreover, in-
dicate the presence of an X-Y homologous gene
in the AZFc interval. This view has received sup-
port by the recent demonstration that BPY1 (now
known as VCX/Y) previously reported by Lahn and
Page (56) to be Y-specific is, in fact, a member of
an X-Y homologous gene family (68). The tran-
N.A. Affara is supported by grants from the BBSRC and the Isaac
Newton Trust and PIC. M.J. Mitchell is supported by INSERM.
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