Download DNA Sequence Variation in the Human Y Chromosome: Functions

Proc
Indianand
NatnDysfunctions
Sci Acad 72 No.4
pp. 231-238
(2006)
Functions
of Human
Y Chromosome
231
Research Paper
DNA Sequence Variation in the Human Y Chromosome: Functions and
Dysfunctions
SUDHIR KUMAR
Department of Zoology, University of Lucknow, Lucknow-226 007
(Received 20 September 2006; Accepted 12 October 2006)
Human Y chromosome is clonally inherited and show extensive variation owing to large-scale mutations. Studies have
shown that distal-Yq heterochromatin changed its length 12 times, the TSPY gene array, 23 times, the 3.6-Mb IR3/IR3
region underwent sequence re-orientation 12 times and the AZFc region rearranged 20 times. Molecular lineages of the Y
chromosome encompassing 1.3 million years or 52,000 generations have confirmed high rate of mutations responsible for
extensive structural polymorphism. In addition, large-scale copy number variation of the Y linked gene(s) has further
fueled this process. Some of these changes may affect fertility status of the males. Therefore, it is logical to look for a
correlation between organizational variations of the human Y chromosome and occurrence of male infertility. Information
on this line would facilitate DNA based diagnosis and augment genetic counseling to the affected patients.
Key Words: Human Y chromosome, Male infertility, Azoospermia factor(s), Paracrine control, copy number
polymorphism, microdeletions.
Introduction
Human Y chromosome contains about 70 million
nucleotides but harbors least number of genes compared
to any other chromosome. The male specific region,
MSY, comprising 95% of the Y chromosome represents
a mosaic of heterochromatic and three classes of
euchromatic (X-transposed, X-degenerate and
ampliconic) sequences (Fig. 1). Thus far, a total of 156
transcriptional units, 78 protein-coding genes and 27
distinct proteins have been ascribed to the Y
chromosome. The MSY euchromatic sequences show
frequent gene conversion. Of the eight palindromes
localized on the human Y chromosome (Fig. 1d), six
harbor vital testis specific genes. Characterization of
palindromic complexes on the long arm of Y
chromosome encompassing AZFb and AZFc regions and
Male-specific region
Yp
a
Y1
b
cen
1 Mb
Ampliconic
Heterochromatic
-transposed
-degenerate
-transposed
c
-degenerate
Pseudoautosomal
Other
Ampliconic
uchromatic MY uchromatic genome
P1
d
P
1 Mb
cen
P
PP
P
Yp
P
P
Y
Fig. 1: Schematic representation of the Y chromosome showing pseudoautosomal and heterochromatic regions (a). Enlarged view of a
24-Mb MSY extending from the proximal boundary of the Yp pseudoautosomal region to the proximal boundary of the large heterochromatic
region of Yq (b). Shown are three classes of euchromatic and heterochromatic sequences. A 1-Mb bar indicates the scale of the diagram.
Gene, pseudogene and interspersed repeat elements of three euchromatic classes are given in (c) and palindromes P1-P8 in (d). Taken
from Skaletsky et al. Nature 423, 825-837 (19 June 2003).
Author for correspondence: Email: [email protected]; Mobile: 09415110631
232
Sudhir Kumar
identification of HERV15 class of endogenous
retroviruses close to AZFa region have facilitated our
understanding on the organization of azoospermia factors
[3, 50]. Deletion of any of the three azoospermia (AZFa,
AZFb or AZFc) factor(s) and some still unidentified
regulatory elements located elsewhere in the genome
have been suspected to be responsible for male infertility.
Considerable overlap of the AZFb and AZFc regions
encompassing a number of genes and transcripts has been
detected. In a recent study, a total of 1,099 proteins, copurified with spermatogenic chromatin have been
identified and these proteins vital for DNA compaction
and chromosome segregation show high degree of
evolutionary conservation [8]. However, it is not clear
as to how many of these are encoded by the genes present
on the Y chromosome. Thus, information on the exact
number of genes or the types of mutations prevalent in
the infertile male is still not available. Similarly, effects
of loss or gain of the Y chromosome linked loci or their
copy number polymorphism in the context of infertility,
repeated abortion or sex chromosome related anomalies
are not known. In a clinical setting, a couple experiencing
repeated abortion may be subjected to DNA analysis in
addition to clinical diagnosis. If the Y chromosome
mosaicism or deletion of the DYZ1 is encountered in
the father’s DNA, that would be a cause of concern. Thus,
DNA based diagnosis would augment genetic couselling
to the affected couples. Present article provides a brief
summary on this line focusing also on the fast emerging
newer tools of genome analysis and their applications.
The Y chromosome may be delineated into several
broad sections encompassing, (i) pseudoautosomal
boundary regions (PABY), (ii) a pericentric region on
the short arm harboring the sex determining (SRY) gene,
(iii) an euchromatic region (DYS1) on the proximal long
arm (iv) a heterochromatic region (DYZ1) on the distal
long arm and (v) an important DYZ3 region (Fig. 2).
← PABY
←Y
←Y
←Y
←Y
Fig. 2: Schematic representation showing five different loci of the
human Y chromosome encompassing both the arms. The Yqh region
is shown as a major repeat DYZ1 (For details, see Bashamboo
et al. 2005)
DYZ3 region is critical for the survival and propagation
of the Y chromosome since it harbors the centromeric
sequences. Besides these delineations, large sets of
primers encompassing palindromes [43, 45] have been
used for STS based analysis to assess genetic variation.
In the process, several DNA markers have been found to
have multiple locations in the non-recombining regions
of the human Y chromosome [57]. These STS based
markers may be used to screen patients DNA samples
encompassing critical region(s) representing gonadal sex
reversal, Turner syndrome, graft rejection and
spermatogenic failure. Similarly, screening of 100–500
DNA samples, encompassing cases of repeated abortion,
prostate cancer or males exposed to natural background
radiation may be used for establishing genotype–
phenotype correlation. With the availability of complete
sequence information (http://www.nature.com/nature/
focus/ychromosome/), more comprehensive screening
approach encompassing new genes or gene families
would go a long way to understand the genomics of the
human Y chromosome.
Repeat DNA on the Y Chromosome
A total of 44 loci linked to the human Y chromosome
have been described (http://www.ncbi.nlm.nih.gov/
Omim/mimstats.html). Besides functional genes, Y
chromosome includes the alphoid repeats, the major
human SINE (Alu repeats) and additional 15 families of
satellite sequences [1, 2, 6]. The alphoid sequences are
clustered tandemly near the centromere on the Y
chromosome and can be distinguished from those on the
other chromosomes. Majority of the Y chromosome Alu
repeats has little similarity with genomic consensus Alu
sequences. In contrast, the Y LINE repeats cannot be
distinguished from the LINEs found on the other
chromosomes. Thus, Y chromosome Alu repeat
sequences seem to have evolved together with other male
specific (heteromorphic) sequences. We identified two
such heteromorphic (male specific) sequences, though
not involved in sex determination but showed cross
hybridization with a few mammalian species [2, 6]. This
indicates that some of the repeat sequences present on
the human Y chromosome may have their homologues
across the species. In addition, Y chromosome seems to
have acted as a repository of the heterochromatic
sequences. In earlier studies, of the 758 STS markers
used for the development of high-resolution Y
chromosome map, 136 from the NRY region were based
on repetitive DNA [57]. These set of markers may be
used as potential candidates to uncover sequence
polymorphism and their possible biological roles.
Studies focused on this line have enabled
identification of palindromic complexes P1 to P8
(Fig. 1d) on the long arm of human Y chromosome
Functions and Dysfunctions of Human Y Chromosome
encompassing azoospermia (AZF) factors. Deletions of
these palindromic sequences have been found to correlate
with spermatogenic failure [42]. P5/proximal-P1
deletions encompass upto 6.2 Mb sequences and 32 genes
and transcripts whereas, P5/distal-P1 deletion encompass
upto 7.7 Mb and 42 genes and transcripts. Extensive STS
based analysis of these palindromic complexes has
demonstrated that AZFb and AZFc regions are not
independent, as reported earlier, but show overlap [42].
However, AZFa region, which spans about 0.8 Mb
sequence is independent of the AZFb and AZFc regions
[54]. Analysis of small but still undetected deletion in
the patients is envisaged to uncover the roles of individual
gene or gene families involved in regulation of
spermatogenesis. Studies have shown de novo point
mutation in the Y linked USP9Y gene in an azoospermic
man [54]. Though infertility may also be caused by
mutation(s) in the autosomal genes, the ones controlling
paracrine systems or involved in signal transduction [35].
Organization of DYZ1 Sequences
Besides alphoid repeats (Miklos and John, 1979), Y
chromosome harbors DYZ1 (Fig. 1 and 2), another major
repeat, detected as 3.4 kb fragments in HaeIII digest of
male genomic DNA [9]. This largely contains a
pentameric motif ‘‘5TTCCA3’’ and in normal males,
233
approximately, 3000–4000 copies are estimated to be
present [32]. Whether DYZ1 copy number variation has
any role to play in the processes of regulation of
spermatogenesis, male fertility, sustenance of full-term
pregnancy or overall reproductive potential of the human
males is not clear. However, DYZ1 seems to be affected
showing massive copy number variation (CNV) in cases
of repeated abortion, males exposed to natural
background radiation and prostate cancer [36, 37].
Further, DYZ1 was found to undergo programmed
sequence modulation resulting in alteration of restriction
sites for RsaI enzyme, which is restored back sometimes
after fertilization [39].
The 5’TTCCA3’ sequences are the core element of
the DYZ1 fraction, organized structurally in sex specific
manner in humans but absent in the non-human
systems[2].
In our study, FISH conducted with metaphase
chromosomes of male having prostate cancer showed
DYZ1 arrays on the chromosome 10 and varying signals
of the same in the interphase nuclei (Fig. 3). In
subsequent studies on DNA samples from the cases of
repeated abortion, DYZ1 showed conspicuous loss of
the sequences at three regions (Fig. 4a-d). Similarly,
DNA samples from semen and blood of the males
1
(a)
()
2
3
4
5
6
7
8
9
10
11
13
14
15
16
17
18
19
20
21
22
Y
12
()
X
()
Fig. 3: Fluorescent in situ Hybridization (FISH) of the DYZ1 with metaphase chromosomes of human males representing prostate cancer
(a-d). Note the DYZ1 signal on autosomes 10 and Y chromosome in a-b, absence of the same in the interphase nuclei (c) and on the Y
chromosome in panel d (arrows).
234
Sudhir Kumar
Fig. 4: Schematic representation showing specific deletion points within the DYZ1 array (a) and corresponding individual deletions in
the aborted fetus (b-d) and germline and blood samples of the males exposed to background radiations (e). As control, genomic DNA
amplification with ß actin primers is shown in panel B. Sample ID is given on top of each panel and molecular marker (M) is shown in
base pairs (For details, See Pathak et al. 2006)
exposed to natural background radiation (NBR) also
showed deletion of the DYZ1 in some cases (Fig. 4e).
Thus, DYZ1 is affected in the abnormal genomes and
often show copy number variation. In cases of repeated
abortion, DYZ1 copies were found to be far below the
normal range showing as few as 95 (Fig. 5a).
Surprisingly, males exposed to NBR showed more copies
of the DYZ1 in many samples compared to that in the
normal ones (Fig. 5b). Though the mechanism is not
clear, this study suggests that DYZ1 repeat is affected in
case of repeated abortion and males exposed to NBR[34].
NBR males showing higher copies of DYZ1 were fertile
though it is not clear for how long they would be able to
maintain their fertility status. Surprisingly, all the changes
took place in somatic DNA and not in that of germline.
We construed that germline DNA is protected by some
innate mechanism. Irrespective of the mechanism
involved, copy number variation (CNV) may be used as
an important parameter to assess the status of DYZ1 in a
given cell population to establish genotype phenotype
correlation.
Y Chromosome Related Anomalies
Involvement of Y in sex chromosome related anomalies
like XY gonadal dysgenesis (Swyer syndrome), XYY
males, recurrent spontaneous abortions (RSA) and Turner
Syndrome (TS) is well established. At birth, the XY
female patients with gonadal dysgenesis (Swyer
syndrome) appear to be normal but at puberty, they
develop streak gonads, do not menstruate and lack
secondary sexual characters. Patients are of normal
stature and have no somatic stigmata of Turner syndrome.
The height of patients with XY gonadal dysgenesis
(unusually higher for females) is probably explained by
androgen production in the streak gonad whereas
clitoromegaly is present in some cases. Three forms of
Swyer syndrome have been suggested [30]. These are
(i) sporadic testicular agenesis syndrome (STAS)
detected in the H-Y negative individuals, (ii) familial
testicular agenesis syndrome (FTAS), also in the H-Y
negative individuals but showing an X-linked recessive
pedigree and (iii) familial testicular dysgenesis syndrome
(FTDS) where the patients are H-Y positive but have
female phenotype and streak gonads which may contain
testis-like tumoral structures. The phenotype of STAS
and FTAS is identical even though the mutation is
probably on the Y chromosome in STAS and on the X
chromosome in FTAS [30].
The XYY syndrome with an extra Y chromosome is
an abnormality associated with tall stature, low
intelligence, delayed speech and some learning problems.
The characteristics of XYY syndrome are often very
subtle and do not indicate any serious disorder. Therefore,
males with XYY chromosomes are either undiagnosed
or misdiagnosed. Thus far, the XYY syndrome has been
diagnosed on the basis of chromosomal analysis. It would
be informative if such cases are subjected to FISH and
6f
7f
2000
8f
9f
95
1000
0
0
2000
1887
500
3000
1577
DYZ1 copies
550
1000
3900
3933
4000
1372
DYZ1 copies
1500
345B
5000
2000
3930
5010
6000
4210
2000
2500
5700
235
2237
Functions and Dysfunctions of Human Y Chromosome
RA1
0
RA2
RA3
RA4
Sample ID
RA9
PC2
(a)
1b
2f
3f
4f
5f
Sample ID
10f
(b)
Fig. 5: A bar diagram showing copy number status of the DYZ1 arrays in samples representing cases of repeated abortion, (RA), prostate
cancer (PC) (a) and males exposed to natural background radiation (NBR) (b). Note the copy number variations of the DYZ1 arrays
amongst different RA and NBR samples (For details, See Pathak et al. 2006)
Real Time PCR analyses to assess if both the Ys are
identical with respect to Y-linked loci and their major
repeat elements. Since all the cells may not have XYY
chromosome constitution, it is likely that some patient
show mosaicism. These mosaicism may be detected by
FISH as reported earlier [34]. DNA analysis to assess
loss/gain or sequence modulation of the critical Y linked
loci from the couple experiencing repeated abortions and
that from the aborted fetus might generate useful
information. Studies have shown that long Y
chromosome may affect the viability of the zygote but
not the fertility of its carrier [15]. Studied conducted on
DNA samples from repeat abortion showed distinct
deletion in the DYZ1 [34]. Thus, it is reasonable to infer
that intact human Y chromosome is needed for the
sustenance of full term pregnancies of the male fetus.
Candidate Turner Syndrome Genes
Turner syndrome (TS) with 45, XO karyotype is the only
monosomy of the X chromosome known to occur 1 in
2000–5000 female live births [17]. Over 90% of the pure
O concept uses are eliminated during prenatal
development and postnataly, chromosomal mosaicism
of both X and Y chromosomes are observed. The most
common karyotypes are, 45,X, isochromosome X, 45,X/
45,XX, 45,X/46,XY, 45,X,i(Xq), 46,Xi(Yp), 46,Xt(X;X);
46,Xi(X;Y), 46,Xi(Xp), 46,X,del(Xq), r(X), 46,Xr(X)
(including small ring X chromosome), 45,/X/46.XX,
45,X/ 47,XXX, 46,X/46,XX/47,XXX, 45,X/46,XY, and
45,X/ 51446,XXq + 46,X + mar(X) 47,XXq+, + mar(X)
46,X + mar(Y) 47,XXq+, + mar(Y). In a patient with
stigmata of Turner syndrome, a Y-derived aberrant
marker chromosome showed rare indels in the DYS1
region [7].
Several molecular mechanisms have been proposed
to explain the Turner syndrome (TS) phenotype including
the chromosome imbalance, genomic imprinting and
haploinsufficiency. In normal women with two X’s in
each cell, genes on one X are permanently switched off
to give women the same dose of X-based genes as that
in men. The exceptions to this rule are the X-linked
housekeeping genes having their counterparts on the Y
chromosome [38]. The housekeeping genes remain
switched on in both the X’s so as to equal the male cell’s
dose from its X and Y chromosomes. Thus, the
abnormalities in Turner’s syndrome may arise due to
haploinsufficiency because the product of single X
chromosome is only half the dose needed for various
housekeeping functions [60]. In accordance with this
hypothesis, Turner syndrome loci were originally
assigned to be present in the pseudoautosomal region
on the short arm of X and Y chromosomes [33, 21, 49].
The only TS feature consistently present in patients with
small distal Xp deletions is short stature, suggesting that
loci responsible for other features lie outside of the
pseudoautosomal region [53].
One reason for poor genotype–phenotype correlation
may be the high prevalence of mosaicism, essential for
the viability of the X chromosome monosomy (Held
et al. 1992). There are evidences favoring Yq and distal
Yp as the site for TS lymphedema gene (Fisher et al.
1990; Barbaux et al. 1995). Apart from ZFY, RPS4Y
seems to be another candidate gene in this region for
TS. There are evidences against RPS4Y
haploinsufficiency as the sole cause of TS [14]. However,
these findings do not rule out a role for RPS4X/RPS4Y
haploinsufficiency in certain phenotypes associated with
236
monosomy of the X chromosome including lethality or
lymphatic abnormalities [60]. Owing to a broad spectrum
of physical and physiological abnormalities observed in
TS and inconsistent phenotypes, it is reasonable to infer
that a large number of autosomal genes but relatively
fewer Y-linked genes are involved in these anomalies.
However, much effort would be required to uncover the
exact number of genes implicated in TS. In our study
focusing on five loci encompassing both the arms of the
Y chromosome (see Fig. 2), we screened 19 TS samples.
Of these, 8 were positive for PABY, 7 SRY, 11 DYZ3, 9
DYS1 and 7 DYZ1. No two TS samples showed identical
pattern but maximum number of samples were positive
for DYZ3 [39]. Screening of a large number of samples
is envisaged to uncover better picture with respect to
most frequently affected loci in case of TS.
Y Chromosome and Gonadoblastoma
Despite all efforts, mapping of the GBY gene has proven
to be unexpectedly complex. It is likely that several genes
present in multiple copies distributed across the Y
chromosome are responsible for gonadoblastoma [58].
Isolation of many Y-linked genes and high resolution
physical map of the Y chromosome are envisaged to be
helpful for studying multiple candidate genes for GBY
locus [26, 57]. The small region defined by Tsuchiya et
al.1995 contains seven known genes, amelogenin Y
(AMELY), RNA binding motif (RBM), protein kinase
Y (PRKY), protein tyrosine phosphatases (PTP)-BL
related Y (PRY), testis transcripts Y1 and Y2 (TTY1 and
TTY2) also referred to as TTTY1 andTTTY2, and testis
specific protein Y-encoded (TSPY). Both TTY1 and
TTY2 consist of repetitive DNA lacking any apparent
protein coding sequences [26]. AMELY, like its X-linked
homologue, AMELX, encodes an enamel protein [28]
expressed exclusively in the developing tooth bud [48].
Thus, these gene products are unlikely to affect cell
proliferation in the gonad. RBM is a repeated gene with
functional sequences that are mostly located in the
interval 6 on the long arm [41]. Only a few copies are
located within the postulated GBY critical region. The
PRKY and its X homologue, PRKX, encode members
of the c-AMP dependent serine-threonine protein kinase
family [22, 47]. The PRY is a repeated gene whose
product displays some similarity to PTP-BL gene [26].
Other copies of PRY are found in the interval 6 outside
of the GBY critical region. Protein kinases are known to
act as signal transducers for growth factors and cytokine
receptors, whereas phosphatases counter balance their
effects [18, 31]. Thus, an imbalance in the expression
between PRKY and PRY may hamper normal growth
regulatory functions. However, biological significance
of these proteins in the context of gonadoblastoma is yet
to be understood. The remaining candidate locus for
gonadoblastoma is a multicopy TSPY (gene for testis
Sudhir Kumar
specific protein on Y) located primarily in the GBY
critical region at the interval 3 [4, 59]. Several
homologous copies have also been mapped on proximal
intervals 4 and 5 of the long arm. TSPY expresses in
gonadoblastoma tissues and has several features fitting
the profile of the GBY locus [58]. Most of its repeat
units have been mapped to the critical region of GBY
including intervals 3E–3G and 4/5 [46, 58]. Further, its
expression in spermatogonial cells in normal testis
suggests a function during early spermatogenesis. TSPY
is unregulated in gonadoblastoma tissues as well as in
certain testicular and prostate cancers [58]. Interestingly,
TSPY expression is drastically reduced in the dysgenetic
gonads of the patients with 46, XY Tfm, who rarely
develops gonadoblastoma. Despite evidences pointing
towards a number of genes as possible candidates for
the postulated GBY locus, there is no conclusive
evidence in support of any such gene(s). Thus, it would
be relevant to monitor the presence/absence and if
possible, expression of several recently uncovered Ylinked genes using STS based marker systems [48].
Coupled with this, assessment of copy number status of
candidate genes using Real Time PCR and FISH may be
yet another complementary approach to nail the GBY
locus on the Y chromosome.
Y Chromosome Haplotyping and SNP
A correlation between the occurrences of Y chromosome
related SNPs with their resultant diseased phenotypes is
useful to develop understanding on its biological roles.
SNPs in the repetitive sequences have been described in
males with deletion of azoospermia complex,
highlighting the significance of these repeat elements in
male infertility [44, 56]. Based on Y chromosome SNP
haplotypes, gene flow among caste, tribe, and the migrant
Siddi populations of Southern part of India has been
reported [40]. This approach was adopted to uncover Ychromosome variation in a Norwegian population [11].
In addition, micro- and minisatellites have been used to
unravel the evolutionary history of the Y chromosome
since changes in microsatellite length occur more
frequently than the emergence of new unique event
polymorphisms (UEPs) [20].
Conclusions
Perusal of literature provides an understanding on the
genes/factors associated with human male infertility
albeit without throwing light on the exact number and
type of such genes and their overall mutational status.
Although infertility is seen in both the sexes, but in
majority of the cases, it remains confined to males
contributing to about 10–15% in a given population.
Characterization of additional Y- linked and autosomal
candidate genes with respect to mutations prevalent
therein would provide a better picture on the actual
Functions and Dysfunctions of Human Y Chromosome
genesis of infertility. A comprehensive physiological and
genetic testing of the patients would establish a more
meaningful genotype phenotype correlation. Finally,
copy number polymorphism of Y-linked loci and major
repeat elements using real time PCR in normal males
and those suffering from sex chromosome related
anomalies would prove to be informative. The male
infertility is caused due mutations in the genes not only
on the Y chromosome but also on the autosomes in
addition to failures of several physical and physiological
attributes including paracrine controls. Thus, search for
candidate genes on the autosomes would equally be
useful.
Acknowledgements
The Author is grateful to Vice-Chancellor and Head,
Department of Zoology, University of Lucknow,
Lucknow for encouragement and Dr. Sher Ali, National
Institute of Immunology, New Delhi for his critical
comments on the manuscript. Thanks are also due to
DST, New Delhi for the award of SERC Visiting
Fellowship.
References
1.
S Ali and S Gangadharan Differential evolution of coding and
non-coding sequences in related vertebrates, implications in
probe design Proc Ind Nat Sci Acad (PINSA)-B 66 (2000)
49-67, 768
2. S Ali, S Gauri and S Bala A synthetic oligonucleotide probe
(5VTTC- CA3V) n uncovers a male specific hybridization
pattern in the human genome Mol Cell Probes 6 (1992)
521-525
3. S Ali and S E Hasnain Molecular dissection of the human Y
chromosome Gene 383 (2002) 1-10
4. J Arnemann, J T Epplen, H J Cooke, U Sauermann, W Engel
and J Schmidtke A human Y-chromosomal DNA sequence
ex-pressed in testicular tissue Nucleic Acids Res 15 (1987)
8713-8724
5. S Barbaux, E Vilain, O Raoul, S Gilgenkrantz, E Jeandidier,
D Chadenas, N Souleyreau, M Fellous and K McElreavey
Proximal deletions of the long arm of the Y chromosome
suggest a critical region associated with a specific subset of
characteristic Turner stigmata Hum Mol Genet 4(9) (1995)
1565-1568
6. A Bashamboo and S Ali Minisatellite associated sequence
amplification (MASA) of the hyper variable repeat marker
33.15 reveals a mass specific band in humans Mol Cell Probes
15 (2001) 89-92
7. A Bashamboo, S Bhatnagar, A Kaur, V K Sarhadi, J R Singh
and S Ali Molecular characterization of a Y-derived marker
chromosome and identification of indels in the DYS1 region
in a patient with stigmata of Turner syndrome Curr Sci 84
(2003) 219-224
8. D S Chu, H Liu, P Nix, T F Wu, E J Ralston J R Yates and B
J Meyer Serm chromatin proteomics identifies evolutionarily
conserved fertility factors Nature 443 (2006) 101-105
9. H Cooke Repeated sequence specific to human males Nature
262 (1976)
10. P L Deininger, D J Jolly, C M Rubin, T Friedmann and C W
Schmid Base sequence studies of nucleotide renatured repeated
human DNA clones J Mol Biol 151 (1981) 17-33
237
11. B M Dupuy, R Andreassen, A G Flones, K Tomassen, T
Egeland, M Brion, A Carracedo and B Olaisen Y-chromosome
variation in a Norwegian population sample Forensic Sci Int
117 (2001) 163-173
12. J T Epplen On simple repeated GATA/GACA sequences, a
critical reappraisal J Hered 79 (1988) 409-417
13. E M Fisher, P Beer-Romero, L G Brown, A Ridley, J A McNeil,
J B Lawrence, H F Willard, F R Bieber and D C Page
Homologous ribosomal protein genes on the human X and Y
chromosomes: escape from X inactivation and possible
implications for Turner syndrome Cell 63(6) (1990) 12051218
14. C Geerkens, W Just , K R Held and W Vogel Ullrich-Turner
syndrome is not caused by haploinsufficiency of RPS4X. Hum
Genet 97(1) (1996) 39-44
15. P Genest and F B Genest The influence of the length of the
human Y chromosome on spontaneous abortions. A
prospective study in family lines with inherited polymorphic
Y chromosomes Ann Genet 28 (1985) 143-148
16. K R Held, S Kerber, E Kaminsky, S Singh, P Goetz, E
Seemanova and H W Goedde Mosaicism in 45, X Turner
syndrome: does survival in early pregnancy depend on the
presence of two sex chromosomes? Hum Genet 88(3) (1992)
288-294
17. E B Hook and D Warburton The distribution of chromosomal
genotypes associated with Turner’s syndrome, live birth
prevalence rates and evidence for diminished fetal mortality
and severity in genotypes associated with structural X
abnormalities or mosaicism Hum Genet 64 (1983) 24-27 866
18. T Hunter Anti-phosphatases take the stage Nat Genet 18 (1998)
303-305
19. W R Jelinek, T P Toomey, L Leinwand, C H Duncan, P A Biro,
P V Choudary, S M Weissman, C M Rubin, C M Houck, P L
Deininger and C W Schmid Ubiquitous, interspersed repeated
sequences in mammalian genomes Proc Natl Acad Sci USA
77 (1980) 1398-1402
20. M A Jobling, E Heyer, P Dieltjes and P de KnijffY-chromosome
specific microsatellite mutation rates re-examined using a
minisatellite, MSY1 Hum Mol Genet 8 (1999) 2117-2120
21. M Joseph, E S Cantu, G S Pai, S M Willi, P R Papenhausen
and L Weiss Xp pseudoautosomal gene haploinsufficiency
and linear growth deficiency in three girls with chromosome
Xp22; Yq11 translocation J Med Genet 33(11) (1996)
906-911
22. A Klink, K Schiebel, M Winkelmann, E Rao, B Horsthemke,
H J Lu-decke, U Claussen, G Scherer and G Rappold The
human protein kinase gene PKX1 on Xp22.3 displays Xp/Yp
homology and is a site of chromosomal instability Hum Mol
Genet 4 (1995) 869-878
23. K Kobayashi, K Mizuno, A Hida, R Komaki, K Tomita, I
Matsushita, M Namiki, T Iwamoto, S Tamura and S Minowada
PCR analysis of the Y chromosome long arm in azoospermic
patients, evidence for a second locus required for
spermatogenesis Hum Mol Genet 3(11) (1994) 1965-1967
24. C Krausz and K McElreavey Y chromosome and male
infertility Front Biosci 4 (1999) E1-E8
25. T Kuroda-Kawaguchi, H Skaletsky, L G Brown, P J Minx,
H S Cordum, R H Waterston, R K Wilson, S Silber, R Oates,
S Rozen and D C Page The AZFc region on the Y chromosome
features massive palindromes and uniform recurrent deletions
in infertile men Nat Genet 29 (2001) 279-286
26. B T Lahn and D C Page Functional coherence of the human
Y chromosome Science 278 (1997) 675-680
27. E S Lander, L M Linton, B Birren, C Nusbaum, M C Zody, J
Baldwin, K Devon, K Dewar, M Doyle, W Fitz Hugh et al.
238
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
Sudhir Kumar
Initial sequencing and analysis of the human genome Nature
409 (2001) 860-921
E C Lau, T K Mohandas, L J Shapiro, H C Slavkin and M L
Snead 1989 Human and mouse amelogenin gene loci are on
the sex chromosomes Genomics 4(2) (1989) 162-168
G L Miklos and B John Heterochromatin and satellite DNA
in man, properties and prospects Am J Hum Genet 31 (1979)
264-280
C A Moreira-Filho, S P Toledo, V R Bagnolli, O Frota-Pessoa,
H Bisi and A Wajntal H-Y antigen in Swyer syndrome and
the genetics of XY gonadal dysgenesis Hum Genet 53
(1979) 51-56
M P Myers and NK Tonks PTEN, sometimes taking it off can
bebetter than putting it on Am J Hum Genet 61 (1997)
1234-1238
Y Nakahori, K Mitani, M Yamada and Y Nakagome A human
Y-chromosome specific repeated DNA family (DYZ1) consists
of a tandem array of pentanucleotides Nucleic Acids Res 14
(1986) 7569-7580
T Ogata, K Tomita, A Hida, N Matsuo, Y Nakahori and Y
Nakagome Chromosomal localisation of a Y specific growth
gene(s) J Med Genet 32(7) (1995) 572-575
D Pathak, S Premi, J Srivastava, P J Chandy and S Ali Genomic
Instability of the DYZ1 Repeat in Patients withY chromosome
Anomalies and Males Exposed to Natural Background
Radiation. DNA Res (2006) 00:000-000 (in press)
S G Prasanth and S Ali Expression of Protooncogene c-kit
receptor in rats Rattus norvegicus and identification of a mutant
mRNA transcript implicated in spermatogenic failure. DNA
Cell Biol 22 (2003) 447-456
S Premi, J Srivastava, P J Chandy J Ahmad and S Ali Tandem
Duplication and Copy Number Polymorphism of the SRY
Gene in Patients with Sex Chromosome Related Anomalies
and Males Exposed to Natural Background Radiation Molec
Human Reprod 12 (2006) 113-121
J L Pryor, M Kent-First, A Muallem, A H Van Bergen, W E
Nolten, L Meisner and K P Roberts Microdeletions in the Y
chromosome of infertile men N Engl J Med 336 (1997)
534-539
L Quintana-Murci and M Fellous The human Y chromosome:
the biological role of a ‘‘functional wasteland’’ J Biomed
Biotechnol 1 (2001) 18-24
M M Rahman, A Bashamboo, A Prasad, D Pathak and S Ali
Organizational Variation of DYZ1 Repeat Sequences on the
Human Y Chromosome and its Diagnostic Potentials DNA
and Cell Biol 23 (2004) 561-571
G V Ramana, B Su, L Jin, L Singh, N Wang, P Underhill and
R Chakraborty Y-chromosome SNP haplotypes suggest
evidence of gene flow among caste, tribe, and the migrant
Siddi populations of Andhra Pradesh, South India Eur J Hum
Genet 9 (2001) 695-700
R Reijo, T Y Lee, P Salo, R Alagappan, L G Brown, M
Rosenberg, S Rozen, T Jaffe, D Straus and O Hovatta Diverse
spermat0genic defects in humans caused by Y chromosome
deletions encompassing a novel RNA-binding protein gene
Nat Genet 10 (1995) 383-393
S Repping, H Skaletsky, J Lange, S Silber, F Van der Veen, R
D Oates, D C Page and S Rozen Recombination between
palindromes P5 and P1 on the human Y chromosome causes
massive deletions and spermatogenic failure Am J Hum Genet
71 (2002) 906-922
S Rozen, H Skaletsky, J D Marszalek, P J Minx, H S Cordum,
R H Waterston, R K Wilson and D C Page Abundant gene
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
conversion between arms of palindromes in human and ape Y
chromosomes Nature 423 (2003) 873- 876
L M Ruiz, M N Szmulewicz and R J Herrera Single-nucleotide
polymorphism in repetitive sequences of the human deleted
in azoospermia complex Electrophoresis 23 (2002) 1021-1024
E C Salido, P H Yen, K Koprivnikar, L C Yu and L J Shapiro
The human enamel protein gene amelogenin is expressed
from both the X and the Y chromosomes Am J Hum Genet
50(2) (1992) 303-316
P Salo, H Kaariainen, V Petrovic, P Peltomaki, D C Page and
C A de la Molecular mapping of the putative gonadoblastoma
locus on the Y chromosome Genes Chromosomes Cancer 14
(1995) 210-214
K Schiebel, M Winkelmann, A Mertz, X Xu, D C Page,
D Weil, C Petit and G A Rappold Abnormal XY interchange
between a novel isolated protein kinase gene, PRKY, and its
homologue, PRKX, accounts for one third of all (Y+) XX
males and (Y-) XY females Hum Mol Genet 6(11) (1997)
1985-1989
C W Schmidt and W R Jelinek. The Alu family of dispersed
repetitive sequences Sci 216 (1982) 1065-1070
E Schwinger, F Schaaff and H Wedemann Analysis of sex and
delta F508 in single amniocytes using primer extension
preamplification Hum Genet 98(2) (1996) 158-161
Sher Ali and Seyed E Hasnain Genomics of the human Y
chromosome: 1- Association with male infertility Gene 321
(2003) 25-37
J R Silber, D A Lundin, A Blank and M S Berger Microsatellite
instability is infrequent in sporadic adult gliomas Oncol Res
10(8) (1998) 421-428
H Skaletsky et al. The male-specific region of the human Y
chromosome is a mosaic of discrete sequence classes Nature
423 (2003) 825-837
S Spranger, S Kirsch, A Mertz, K Schiebel, G Tariverdian and
G A Rappold Molecular studies of an X; Y translocation
chromosome in a woman with deletion of the pseudoautosomal
region but normal height Clin Genet 51(5) (1997) 346-350
C Sun, H Skaletsky, B Birren, K Devon, Z Tang, S Silber, R
Oates and D C Page. An azoospermic man with a de novo
point mutation in the Y-chromosomal gene USP9Y Nat Genet
23 (1999) 429-432
C Sun, H Skaletsky, S Rozen, J Gromoll, E Nieschlag, R Oates
and D C Page Deletion of Azoospermia factor a (AZFa) region
ofhuman Y chromosome caused by recombination between
HERV15 proviruses Hum Mol Genet 9 (2000) 2291-2296
M N Szmulewicz, L M Ruiz, E P Reategui, S Hussini and R
J Herrera Single-nucleotide variant in multiple copies of a
deleted in azoospermia (DAZ) sequence-a human Y
chromosome quantitative polymorphism Hum Hered 53
(2002) 8-17
CA Tilford, T Kuroda-Kawaguchi, H Skaletsky, S Rozen, L
G Brown, M Rosenberg, J D McPherson, K Wylie, M Sekhon,
T A Kukaba, R H Waterston and D C Page A physical map of
the human Y chromosome Nature 409 (2001) 943-945
K Tsuchiya, R Reijo, D C Page and C M Disteche
Gonadoblastoma, molecular definition of the susceptibility
region on the Y chromosome Am J Hum Genet 57 (1995)
1400-1407
P H Vogt Human Y chromosome deletions in Yq11 and male
fertility Adv Exp Med Biol 424 (1997) 17-30
A R Zinn and J L Ross Turner syndrome and haploinsufficiency
Curr Opin Genet Dev 8(3) (1998) 322-327