Pseudoautosomal regions of the X chromosome showing heterozgyosity

Pseudoautosomal regions of the X chromosome showing heterozgyosity

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I've always had questions for myself about sex differentiation, mostly on account of an unusual history & puberty. I won't go into details, but needless to say it was unique.

My question is… I got results back from 23andme showing hetereozygosity at the beginning & ending of the X

I've been diagnosed as XY androgen insensitive & pseudohermaphrodite with mullerian structures intact. Born with questionable stuff internally, only definitive thing is nothing male (no prostate, no seminal etc… )

They also did show a Y, but it was apparently missing half of it (though I've read thats not unusual for half of it to be --)

Can you have a hetereozygosity at the ends of the x and not have another x?

rs6644972 X 178624 AG rs28475515 X 182276 CT rs28463388 X 191998 TT rs28669107 X 195014 CC i6033542 X 200928 CC rs6655397 X 201935 GG rs7890186 X 202458 GG i6033543 X 209741 CC i6033544 X 215805 CC rs28736870 X 220770 GG i6033545 X 228250 GG rs6603204 X 298440 GG i6033547 X 301596 CC rs2738344 X 310897 AA

A normal male can show heterozygosity in the "X" results of a 23andMe SNP test despite having only one X chromosome. This is because there are very short regions at the ends of the Y chromosome, called pseudoautosomal regions, that match up with equivalent (homologous) regions at the ends of the X chromosome.

Because the pseudoautosomal regions of the Y are homologous to the matching regions of the X, the SNP results for those areas cannot be distinguished in the SNP tests, so the results appear along with the X results in "X" chromosome file. The results in those two areas of the file can be either homozygous or heterozygous at each location. Most of the locations in the "X" file are for locations outside of those regions, so most of the file entries cannot report heterozygous results.

Human Sex Chromosomes Are Sloppy DNA Swappers

Variety is the spice of life—especially when it comes to genetics. Our species needs DNA to intermingle to create genetic diversity, which is key to population-wide health and hardiness. As cells divide and grow, all 22 pairs of chromosomes in a human can perform genetic swaps along their entire lengths, except for the sex chromosomes. Because X and Y differ in size and in the genes they carry, these two genetic bundles remain aloof.

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But research has been showing how the sex chromosomes do sometimes trade genetic data in select spots—and it seems their swapping is sloppier than originally thought.

A team led by Melissa Wilson Sayres at Arizona State University offers new details about what happens when X and Y chromosomes swap DNA during the cell division that gives rise t eggs and sperm. Intriguingly, their work confirms that when the sex chromosomes converse, a particular gene that is critical for male development sometimes gets accidentally moved around. The results could help explain why some people have female DNA—a pair of X chromosomes—but develop physically as male.

Millions of years ago, our X and Y chromosomes were roughly equivalent and were able to freely swap genetic material. In most cases, evolution favors this exchange of DNA between chromosomes because it boosts diversity. But today, the X chromosome is much longer than the Y chromosome, and only two small matching regions remain at the tips. “We often talk about how different X and Y are,” says Wilson Sayres. “But there are two regions in which they are identical,” called pseudoautosomal regions. This is where the X and Y chromosomes can partner and swap DNA.

Previous work by geneticists David Page at MIT and Bruce Lahn at the University of Chicago showed that, millions of year ago, segments of the X chromosome got cut, flipped and reinserted. The result of this mutation, called an inversion, is that the X and Y chromosomes could no longer interact in the inverted region. Analyses from Wilson Sayres’ lab also previously showed that inversions on the X chromosome have happened up to nine times in our evolutionary history.

These inversions "were favored by natural selection because they prevented the male-determining gene to recombine onto the X, and allowed X and Y to evolve independently,” says Qi Zhou, a postdoctoral fellow at the University of California, Berkeley, who studies the evolution of sex chromosomes in fruit flies and birds.

Because the process of inversion cuts genes in half, scientists can see the pseudoautosomal boundaries on the chromosomes simply by looking at the DNA sequence and identifying the chunks of truncated genes. So Wilson Sayres wondered whether genetic swapping happening inside the pseudoautosomal regions might leave a distinct signature of diversity with sharp borders. “Because recombination is happening in the pseudoautosomal regions, there should be increased diversity there relative to the other parts of the X chromosome,” says Wilson Sayres.

To test the idea, she and her undergraduate collaborators at Arizona State analyzed patterns of genetic diversity across the X chromosomes from 26 unrelated women. To their surprise, the team did not observe a clear border. “Diversity decreases at almost a linear rate across the pseudoautosomal boundary, which suggests that recombination boundaries are not very strict,” says Wilson Sayres. Instead, it seems that when pseudoautosomal regions trade snippets of DNA, nearby pieces of the inverted region sometimes get taken along for the ride. The team is presenting their results this week at the 2015 meeting of the Society of Molecular Biology and Evolution in Vienna.  

The finding “is really important, because one of the genes on the Y chromosome that is very close to that boundary is SRY, the Sex-determining Region of the Y,” says Wilson Sayres. SRY is a gene that is key for initiating testes development in males. “If the boundary is not set, you can pull the SRY gene over onto the X chromosome," she says. In that case, an individual with an XX genotype, which is typically female, may instead develop as male. XX male syndrome, also called de la Chapelle syndrome, occurs in 1 of 20,000 people who appear outwardly male. Individuals with this rare condition are usually sterile.

“Lots of mammal species have SRY, and it is at very different places on the Y chromosome, because the inversions happened many times independently in different lineages,” adds Wilson Sayres. “It’s just bad luck that, in humans, the SRY gene happens to be close to the inversion boundary.”

A 2012 study by Terje Raudsepp at Texas A&M University and her colleagues had already suggested that errors in X-Y recombination can move SRY to the X chromosome in humans and chimpanzees. The new work boosts that result and shows a probable mechanism. Also, because the swapping region boundaries are so fuzzy, it's likely that XX male syndrome is not a recent "fluke" phenomenon in modern humans but has occurred for at least thousands of years. “XX males likely occurred with this frequency throughout human evolution,” says Wilson Sayres.

The new analysis also shows an unexpected peak of genetic diversity in an inverted section of the X chromosome that, in humans, was copied and added to the Y chromosome. One of the genes within that peak is called protocadherin 11, a gene thought to be involved in brain development. “People usually assume that this region is X-specific, but actually we show that there is swapping between X and Y in that region,” says Wilson Sayres. This is important because “the X-transposed region looks like a new third pseudoautosomal region. This could lead to a new process for male-biased genes from the Y to hop onto the X, where they don't belong, leading to additional sex-chromosome genetic disorders.”

“The work by Dr. Wilson Sayres’ group certainly adds to the depth of analysis of the curious features of human sex chromosomes,” says Raudsepp.

The Location of the Pseudoautosomal Boundary in Silene latifolia

11 million years ago, to study the location of the boundary between the NRY and the recombining pseudoautosomal region (PAR). The previous work devoted to the NRY/PAR boundary in S. latifolia was based on a handful of genes with locations approximately known from the genetic map. Here, we report the analysis of 86 pseudoautosomal and sex-linked genes adjacent to the S. latifolia NRY/PAR boundary to establish the location of the boundary more precisely. We take advantage of the dense genetic map and polymorphism data from wild populations to identify 20 partially sex-linked genes located in the &ldquofuzzy boundary&rdquo, that rarely recombines in male meiosis. Genes proximal to this fuzzy boundary show no evidence of recombination in males, while the genes distal to this partially-sex-linked region are actively recombining in males. Our results provide a more accurate location for the PAR boundary in S. latifolia , which will help to elucidate the causes of PAR boundary shifts leading to NRY expansion over time.

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Evolution of the threespine stickleback Y chromosome

Using a combination of long-read sequencing and chromosome conformation capture (Hi-C) sequencing for scaffolding, we were able to assemble a highly accurate Y chromosome reference assembly for the threespine stickleback, concordant with sequenced BAC inserts and known cytogenetic markers [32]. Our new reference assembly revealed several patterns of sequence evolution that were not accurately resolved using short-read sequencing [18]. First, synonymous divergence was underestimated throughout the Y chromosome by relying on single-nucleotide polymorphisms ascertained through short-read sequencing. This effect was greatest in the oldest region of the Y chromosome (stratum one). Median dS was approximately 8.7-fold greater within stratum one when long-read sequences were used. Synonymous divergence was approximately 2.8-fold greater across the younger strata in the new reference assembly compared to the dS estimates from short-read sequencing. The short-read sequencing was also unable to distinguish two independent strata within this region, likely from a bias against aligning reads in divergent regions, leading to an under estimation of the true number of SNPs. Our results argue for caution in using short-read sequencing technologies to characterize sex-specific regions of Y or W chromosomes.

With the presence of both an X and Y chromosome reference, we were able to show that this mapping bias is alleviated, and short-read sequences can be correctly partitioned between the two chromosomes in males and females. When we analyzed nucleotide divergence between the reference Y chromosome and the short-read sequenced Y chromosomes from various populations, we found divergence was an order of magnitude lower than what was observed on the autosomes or X chromosome. Thus, threespine stickleback fish also exhibit reduced Y chromosome diversity as observed in other species [63,64,65,66,67,68,69]. However, there is some evidence for population divergence on the Y chromosome, as read depth was slightly lower when mapping reads from males of different populations to the Y chromosome assembly than when reads from a male of the same population were used. Additional work will be necessary to understand whether patterns of Y chromosome diversity are consistent with neutral expectations or whether nucleotide diversity is being reduced through strong selection on linked sites [63,64,65].

Divergence times for each of the strata can be approximated based on divergence rates between the threespine stickleback fish and the ninespine stickleback fish (Pungitius pungitius), which last shared a common ancestor as many as 26 million years ago [28, 30, 31]. Combined with a mean genome-wide estimate of synonymous divergence between the two species (0.184 [70]), we determined stratum one likely arose less than 21.9 million years (i.e., generations) ago, close to when the two species diverged. Using the same calibration, stratum two formed less than 5.9 million years ago and stratum three formed less than 4.7 million years ago.

Y chromosome centromere evolution

Due to their highly repetitive nature, centromeric arrays have been challenging to sequence and assemble using traditional approaches. However, long-read technologies have shown recent promise in traversing these inaccessible regions [14, 71, 72]. Using long-read sequencing, we were also able to recover two contigs in our assembly that contained arrays of an alpha satellite monomeric repeat that had sequence similarity to a monomeric repeat isolated from the remainder of the genome [34]. Centromeres across species are highly variable both at the level of the individual monomer and how monomers are organized at a higher level [37, 38, 73,74,75,76]. This incredible variability can even occur within species. For example, in humans, centromeric HORs are not identical between nonhomologous chromosomes [77, 78], and the Y chromosomes of mouse and humans contain divergent or novel centromeric repeats relative to the autosomes [79,80,81]. Consistent with these patterns, we observed a decrease in sequence similarity between the Y chromosome monomeric repeat and the consensus repeat identified from the remainder of the threespine stickleback genome [34]. We found the Y chromosome was also ordered into a complex HOR however, we cannot determine if the structure of the Y chromosome HOR is similar or dissimilar from other threespine stickleback chromosomes. The centromere sequence from other chromosomes is currently limited to short tracts of monomeric repeats [34].

Cytogenetic work has shown the threespine stickleback Y chromosome centromere may contain a divergent satellite repeat relative to the X chromosome and autosomes [34, 82]. This hypothesis was based on a weak fluorescent in situ hybridization signal on the Y chromosome from DNA probes designed from the consensus repeat. Our Y chromosome assembly indicates a mechanism driving this pattern may be the reduced sequence identity shared between the Y chromosome monomeric repeat and the consensus monomeric repeat. An alternative explanation is that the weak hybridization signal is not due to the differences in monomeric repeat sequence, but it is actually caused by a reduction in overall size of the Y chromosome centromere. Although we isolated

87 kb of centromere sequence, we did not identify a contig that spans the complete centromere, leaving the actual size of the centromere unknown. Additional sequencing work is necessary to test this alternative model.

The genetic architecture of the threespine stickleback Y chromosome is rapidly evolving

The threespine stickleback Y chromosome is at an intermediate stage of degeneration, with the retention of a total of 44.1% of the genes present on the X chromosome, compared to the highly degenerate Y chromosomes of mammals in which only

1–5% of ancestral X-linked genes remain [10, 11]. The rate of gene loss on the oldest stratum of the threespine stickleback Y, in which 82% of genes have been lost, is approximately 3.7% per million generations. This is similar to the rate of gene loss per million generations estimated for other heteromorphic sex chromosomes with similarly aged strata, such as Rumex hastatulus (1.1–2%) [83], Silene latifolia (4–8%) [17, 84], and the Drosophila miranda neo-Y (1.7–3.4%) [1, 84, 85]. A somewhat higher rate of gene loss (8.4–11.5%) is found on the Rumex rothschildianus Y [83], but none of these systems have experienced rates of gene loss as rapid as on the similarly aged strata 4 and 5 of the primate Y chromosome (60% per million generations) [84, 86], possibly due to a lower effective population size in primates. The consistent estimates of rate of gene loss in the other plant and animal systems suggest that haploid selection in pollen is unlikely to play a major role in rates of degeneration in the plant systems examined so far (Rumex and Silene), although there is evidence that haploid-expressed genes are maintained on plant Y chromosome, just as dosage-sensitive genes are retained on animal Y chromosomes, including the threespine stickleback [10, 13, 18, 19, 83, 84, 87].

In addition to this extensive gene loss, we found acquisition of novel genes throughout all strata of the threespine stickleback Y chromosome. Although we did not detect massive amplification of gene families as observed on mammalian sex chromosomes [7, 8, 11, 20,21,22], many genes that had translocated from the autosomes or were present in the common ancestor of the sex chromosomes had multiple copies on the Y chromosome. The copy numbers we observed are on the same order as the duplicated genes on the sex chromosomes of multiple species of Drosophila [23, 49]. The gene duplications on the threespine stickleback sex chromosomes may reflect selection on the early amplification of genes important for male fertility [43] or to prevent degradation by providing a repair template through gene conversion [7, 11, 49, 54, 88,89,90,91,92,93,94,95,96]. Alternatively, the duplications we observe on the threespine stickleback Y chromosome may simply reflect recent translocations and duplications that have yet to degenerate and pseudogenize.

Gene expression patterns of duplicated and translocated genes suggest this process is not entirely neutral. We observed strong testis-biased expression among genes that had duplicated and translocated to the Y chromosome, similar to patterns observed on other Y chromosomes [7, 8, 11, 20,21,22, 46, 47, 97]. Interestingly, we observed multiple ways that testis-biased genes can accumulate on the Y chromosome. For one, many genes exhibit ancestral testis-biased expression. Genes that have translocated from the autosomes to the Y chromosome had a similar degree of testis-biased expression as the ancestral autosomal paralog. The X-linked gametologs of genes that are duplicating on the Y chromosome also had testis-biased expression ancestrally. This suggests genes can be selected to be retained on the Y chromosome because of existing male-biased expression patterns. Our observations mirror translocations on the ancient human Y chromosome the amplified DAZ genes arose from an autosomal paralog that was expressed in the testis [44]. Examples of autosome-derived translocations to the Y chromosome also exist in Drosophila and can have ancestral testis-biased functions [46]. On the other hand, we also found that autosome-derived translocated genes evolved stronger testis-biased expression in a tissue-specific context compared to ancestral expression. The variation in testis-biased expression observed among tissue comparisons suggests the acquisition of testis functions for many genes is incomplete. This makes the threespine stickleback Y chromosome a useful system to understand the regulatory changes required for genes to evolve novel functions in the testis.

Genes that translocate to the Y chromosome either arise through RNA-mediated mechanisms or through DNA-based translocations (reviewed in [52]). Of the translocations we observed, we only detected DNA-based translocations. Work in other species has shown that DNA-based duplications occur more frequently than RNA-mediated mechanisms [49, 52, 98, 99]. Our results support this bias on younger sex chromosomes. It is possible that the frequency of DNA-based duplications is even higher on young sex chromosomes compared to ancient sex chromosomes. DNA-based duplications are driven by erroneous double-strand break repair. On the ancient sex chromosomes of rodents, double-strand break initiation is suppressed on the sex chromosomes of males [100, 101]. This would limit the opportunity for DNA-based translocations to occur due to aberrant double-strand break repair during meiosis. However, on younger sex chromosomes, double-strand break frequencies may still be occurring at an appreciable frequency. Coupling a diverging Y chromosome with accumulating repetitive DNA would create additional opportunities for double-strand break repair through non-allelic processes, increasing the number of duplications and translocations [102].

Amhy is a candidate sex determination gene

We identified the Amhy gene as a candidate for male sex determination in the threespine stickleback. Amh has been co-opted as a male sex determination gene in multiple species of fish [57,58,59]. The master sex determination gene is one of the primary genes that initiate evolution of a proto-Y chromosome (reviewed in [1]). Consistent with this, Amhy is located in the oldest region of the stickleback Y chromosome (stratum one), adjacent to the pseudoautosomal region, and synonymous divergence with its paralog is within the range of other genes in the oldest stratum. Amhy is expressed in developing stickleback larvae, consistent with a role in early sex determination. Finally, the amino acids that are highly conserved across vertebrates in the functional domains of the protein are also conserved on the Y chromosome paralog in stickleback fish, suggesting Amhy is functional. Based on the known role of AMH signaling in sex determination in other fish, and the location, expression, and sequence of the Y chromosome paralog in stickleback fish, we propose that Amhy is the threespine stickleback master sex determination gene. Additional functional genetics work is underway to test this hypothesis.

Results for the pseudoautosomal regions

Genetic features of the PARs are summarized in Table 2. Both regions, although very small in size, display a higher gene density than the X chromosome and the average of seven genes per Mb on autosomes. The male recombination activity in PAR1 is much higher than in the autosomes. The female recombination activity is within the autosomal range for PAR1 and probably also for PAR2. In 493 female meiosis, no recombinant has been observed in PAR2 (based on 48 families from the Kong et al study 30 , data not shown). The approximate 95% confidence interval 42 extends from 0.0000 to 0.0093 for the female recombination rate corresponding to an estimated recombination activity of 0–2.8 cM/Mb. The sequence of PAR2 is completely known, however in PAR1 six gaps with an estimated combined size of 370 kb could not be filled up to now. 11, 43, 44

Physical locations of loci within PAR1 from different available SNP chips and genetic mapping projects are shown in Figure 2. In some studies markers sets are sparse and do not offer a good coverage of the telomeric region. In Figure 2 one can notice some larger regions that are not covered by SNPs, and these regions correspond to the sequence gaps. Estimated genetic map lengths in men vary in different studies between 12 and 55 cM in PAR1 and between 0.3 and 1.6 cM in PAR2 (Table 1). The very small value of PAR1 in the Rutgers map is because the most telomeric marker is still approximately 900 kb off the telomere. The ratio of male to female total map length in PAR1 is approximately 10, varying in single studies between 2.8 and 14.6. The deCODE map is not included because the PARs are not covered. The Marshfield map harbors few markers in PAR1 and one in PAR2 but at the time of map estimation the order of the markers was not well determined and, therefore, the map was omitted.

Physical location (build 35.1) for genetic markers in PAR1 from different mapping projects. Affymetrix and Illumina are represented by the Genome-Wide Human SNP Array 5.0 and Humhap550, respectively. Single nucleotide polymorphisms (SNPs) are shown as triangles with peak up and short tandem repeats (STRs) as triangles with peak down, squares indicate markers within the genes CSF2RA and MIC2.

Figure 3 illustrates three selected male genetic maps in PAR1 in more detail: the Duffy map 45 (sperm typing), the HapMap 34 map (unrelated individuals), and the map created by Henke et al 6 (CEPH three-generation families). The sex-averaged estimate from HapMap was converted to a male map by using a male/female map ratio of 10:1. All maps are well in concordance for the first 750 kb whereas for the last 750 kb the HapMap estimate is much lower. This could indicate a systematic map estimation bias, a varying male/female map ratio, data errors, or random differences.

Three different genetic maps for the men. The Duffy map, 45 the HapMap map, 46 and the map created by Henke et al 6 HapMap estimated sex-averaged map distances, male distances were obtained using a male/female map ratio of 10:1.


In the first genetic studies no apparent double crossover events in male meioses were observed and the question was raised whether multiple crossover events can occur at all within human PAR1. 7, 9 In larger studies however, male double recombinants were found: 1 in 330 meiosis by Rappold et al, 38 3 among 555 single sperms by Schmitt et al, 32 and 21 among 1912 single sperms by Lien et al. 33 The expected number under the assumption of no interference was 12, 15, and 177, respectively. Under Kosambi's assumption about interference, nearly 96 double recombinants would have been expected in Lien's data, significantly more than the observed number. We conclude that the absence of interference (I=0) can be rejected. Kosambi's assumption does not fit well in PAR1 and on the other hand there is no complete interference (I=1) since double recombinants have been observed. The estimated interference, I=0.96 (calculated from Lien's data) is very close to 1 indicating that the identity (1% recombination rate corresponds to 1 cM) might be the most suitable mapping function for PAR1.

Using one polymorphic marker in PAR2 and sex it has been shown that crossover events in PAR2 are possible and occur in about 2% of male meioses, 2 no recombinants have been observed for PAR2 in women. In PAR2, male recombination rate is higher than in female and higher than the autosomal average but lower than in PAR1 (Table 1). This has been confirmed by other groups. 30, 39

Linkage disequilibrium

In PAR1, LD and the corresponding block structures have not been analyzed in detail. Cox et al 47 explored the LD in PAR1 and the remainder of the X chromosome with only seven SNPs in PAR1 and found a significant difference in LD decay. May et al 48 analyzed an interval of 43 kb around the SHOX gene. Using 61 SNPs they found a rapid decline of LD, markers displaying only very low pairwise LD, and the largest block of high LD, D′>0.8, being only about 3 kb long.

In PAR2, LD has been studied with tree markers that show high allelic association between each other but not with sex-specific loci on X and Y. 35 Given the male recombination rate of about 2%, this result is surprising since LD is reduced exponentially with the number of generations.

Results and Discussion

We identified two families (families A and B) with large terminal deletions of PAR1 ( fig. 1A). These families were found through molecular analyses of SHOX, an osteogenic gene located in PAR1 at a position ∼600 kb from the end of Xp/Yp ( Rao et al. 1997 the UCSC Genome Browser, [GRCh37/hg19]). The probands of these families (II-1 of family A and III-4 of family B) presented with mesomelic short stature and skeletal deformity indicative of SHOX haploinsufficiency ( Belin et al. 1998). Multiplex ligation-dependent probe amplification showed decreased copy number of all SHOX exons and their flanking regions in both individuals. The same copy-number losses were also identified in their relatives ( fig. 1A). Microarray-based comparative genomic hybridization (CGH) detected PAR1 terminal deletions of ∼1.24 Mb (maximum interval, chrXY:1–1,256,608 minimum interval, chrXY:1–1,235,344) in family A and of ∼2.30 Mb (maximum interval, chrXY:1–2,309,402 minimum interval, chrXY:1–2,297,925) in family B ( fig. 1B). Fluorescent in situ hybridization revealed that the deletion in family A was located on the X chromosome of the proband and on the Y chromosome of her father (A-I-1) ( supplementary fig. 1 , Supplementary Material online), whereas the deletion in family B resided on the X chromosome of the proband, his elder sister (B-II-3), mother (B-II-2), and maternal grandfather (B-I-1) ( fig. 1A). All deletion-positive individuals exhibited skeletal features indicative of SHOX haploinsufficiency ( Belin et al. 1998), but no other congenital anomalies. Allegedly, another individual of family B (III-2) also had short stature, although genomic DNA samples and detailed clinical information of this individual were unavailable.

Molecular findings of families A and B. (A) The pedigrees of families A and B. Black boxes and circles indicate individuals with mesomelic short stature and/or skeletal deformities, whereas the white box and circles depict unaffected family members. The striped circle indicates an individual with short stature, whose genomic DNA sample and detailed clinical information were unavailable. Red stars on the X and Y chromosomes indicate SHOX-containing deletions in the pseudoautosomal region 1 (PAR1). (B) Representative results of microarray-based comparative genomic hybridization for the probands of families A and B. PAR1 is indicated by the red arrow. Black, green, and red dots denote signals indicative of the normal, decreased (<−0.8) and increased (>+0.4) copy numbers, respectively. Green arrows indicate the deleted regions in families A and B. Genomic positions refer to the human genome database (GRCh37/hg19). The position of SHOX is indicated by the black box. (C) Schematic representation of PAR1. The deleted regions in families A and B, together with those in the three previously reported cases with normal fertility ( Ogata et al. 2002 Kant et al. 2011) and two cases with spermatogenic failure ( Gabriel-Robez et al. 1990 Mohandas et al. 1992), are shown as black arrows. The broken lines depict dosage-unknown regions. The position of SHOX is indicated by the black box. The panel at the bottom shows the recombination rates of normal males (in cM) calculated by Hinch et al. (2014).

Molecular findings of families A and B. (A) The pedigrees of families A and B. Black boxes and circles indicate individuals with mesomelic short stature and/or skeletal deformities, whereas the white box and circles depict unaffected family members. The striped circle indicates an individual with short stature, whose genomic DNA sample and detailed clinical information were unavailable. Red stars on the X and Y chromosomes indicate SHOX-containing deletions in the pseudoautosomal region 1 (PAR1). (B) Representative results of microarray-based comparative genomic hybridization for the probands of families A and B. PAR1 is indicated by the red arrow. Black, green, and red dots denote signals indicative of the normal, decreased (<−0.8) and increased (>+0.4) copy numbers, respectively. Green arrows indicate the deleted regions in families A and B. Genomic positions refer to the human genome database (GRCh37/hg19). The position of SHOX is indicated by the black box. (C) Schematic representation of PAR1. The deleted regions in families A and B, together with those in the three previously reported cases with normal fertility ( Ogata et al. 2002 Kant et al. 2011) and two cases with spermatogenic failure ( Gabriel-Robez et al. 1990 Mohandas et al. 1992), are shown as black arrows. The broken lines depict dosage-unknown regions. The position of SHOX is indicated by the black box. The panel at the bottom shows the recombination rates of normal males (in cM) calculated by Hinch et al. (2014).

The most striking finding from these families was that two adult men, that is, the proband’s father in family A (A-I-1 hereafter referred to as case 1) and the proband’s grandfather in family B (B-I-1 case 2), were fertile and transmitted their PAR1 deletions to daughters ( fig. 1A). Cases 1 and 2 retained only ∼1.44-Mb and ∼400-kb segments of PAR1, respectively ( fig. 1B). In case 1, homologous recombination between the X and Y chromosomes must have occurred within the ∼1.44-Mb segment in the most centromeric part of PAR1, because during meiosis, the SHOX-containing deletion was translocated from the Y chromosome to the X chromosome ( fig. 1A and supplementary fig. 1 , Supplementary Material online). The normal female phenotype of the daughter of case 1 (A-II-1) provides evidence that the X–Y crossover in case 1 occurred telomeric to SRY, the sex-determining gene located in the Y-specific region only ∼5 kb from the PAR1 boundary (the UCSC Genome Browser). It is known that male meiotic homologous recombination occurs predominantly in the telomeric part of PAR1, with the hottest hotspot being at the SHOX locus ( May et al. 2002 Flaquer et al. 2009 Hinch et al. 2014). Moreover, in several species, telomeric regions are predicted to play an important role in the meiotic chromosomal pairing ( McKee 2004). However, the results of case 1 indicate that loss of the telomeric half of PAR1 does not necessarily lead to spermatogenic failure. Consistent with this, previous studies have identified three fertile men with PAR1 partial deletions, in whom meiotic homologous recombination occurred between SHOX and the centromeric end of PAR1 ( fig. 1C) ( Ogata et al. 2002 Kant et al. 2011). In case 2, furthermore, the site of meiotic recombination was restricted to a ∼400-kb region at the most centromeric part of PAR1. The SHOX-containing deletion in this individual resided on the X chromosome throughout meiosis, indicating that the recombination occurred between the Y chromosome and the nontransmitted sister chromatid of the X chromosome. We cannot completely exclude the possibility that the sex chromosomal recombination in case 2 occurred outside PAR1. For example, PAR2 on Xq/Yq also has the potential to mediate male meiotic recombination ( Ciccodicola et al. 2000 Raudsepp and Chowdhary 2015). However, this probability is low, because 1) complete loss of X chromosomal PAR1 was observed in two men with spermatogenetic arrest ( Gabriel-Robez et al. 1990 Mohandas et al. 1992), 2) the estimated genetic size of PAR1 in normal males is ∼50 cM ( Flaquer et al. 2009 Evers et al. 2011 Otto et al. 2011), suggesting that virtually all spermatocytes leading to live births undergo homologous recombination in this region, and 3) in midpachytene spermatocytes, chiasmata were observed exclusively in PAR1 ( Sarbajna et al. 2012). Of note, the ∼400-kb PAR1 segment retained in case 2 accounts for only 14.8% of normal PAR1 and corresponds to 0.26% and 0.68% of the length of the X and Y chromosomes, respectively (the UCSC Genome Browser). The estimated genetic size of this segment in normal males is <5 cM ( fig. 1C Hinch et al. 2014), indicating that during normal spermatogenesis, this short segment is rarely involved in sex chromosomal recombination. Nevertheless, in case 2, this segment is likely to have hosted homologous recombination in most spermatocytes, because animal studies have shown that X–Y pairing in 50% of germ cells, but not in 30% of cells, permits sperm production ( Faisal and Kauppi 2016).

The aforementioned results indicate that the minimal size requirement of human PAR1 to maintain spermatogenesis is fairly small. In this regard, it is noteworthy that the size of PARs is highly variable among mammalian species ( Graves et al. 1998 Raudsepp and Chowdhary 2015). PARs are believed to be under the constant evolutionary pressure to shrink, yet such PAR attrition can be counteracted by the insertion of DNA fragments through chromosomal translocation ( Graves et al. 1998 Mensah et al. 2014). Indeed, recent studies have shown that a small percentage of healthy men carry a ∼110-kb insertion polymorphism in PAR1 that expands the size of the recombination platform to some extent ( Mensah et al. 2014 Poriswanish et al. 2018). Thus, human PAR1 is still evolving. The present study provides evidence that human PAR1 is highly tolerant to size reduction. These data are consistent with the prior observation that the size of murine PARs is only 700 kb or less ( Perry et al. 2001 Raudsepp and Chowdhary 2015). The high recombinogenic activity of mammalian PARs is likely to reflect their long chromosome axes, which leads to the frequent occurrence of double-strand DNA breaks ( Kauppi et al. 2011 Acquaviva et al. 2020).

In summary, the results indicate that a ∼400-kb segment at the centromeric end of PAR1 is sufficient to produce homologous recombination during human spermatogenesis. This study highlights the extreme recombinogenic activity of PARs in the maintenance of male fertility.

The Communicating junctions, roles and dysfunctions Shox2

Shox2 encodes a member of a small subfamily of paired, related homeodomain transcription factors that has been identified by virtue of its sequence similarity to the short-stature homeobox gene SHOX, causing various short-stature syndromes.

Blaschke et al. [88] generated Shox2 knockout mice. Homozygous mutant embryos were embryonic lethal at 11.5 to 13.5 dpc and exhibited severe hypoplasia of the sinus venosus myocardium. They showed aberrant expression of Cx40, Cx43, and Nkx2.5 within the SAN region. Similarly, Espinoza-Lewis et al. [89] reported that Shox2 is restrictedly expressed in the sinus venosus region including the SAN and the sinus valves during embryonic mouse heart development. Shox2 null mutation resulted in embryonic lethality due to cardiovascular defects, including bradycardia and severely hypoplastic SAN and sinus valves. Cx40 together with Nkx2.5 and natriuretic precursor peptide A (Nppa) was ectopically activated in the mutant SAN, where Tbx3 expression was lost. As described below, Tbx3 represses Cx40 expression by directly binding to the promoter of Cx40 gene. Thus, it has been suggested that Shox2 operates upstream of Nkx2.5, Tbx3, Cx40, and Cx43 to regulate the SAN genetic program.


The most important aspect of the characterization of the Xp22.33Yp11.2 translocation in our unique XX male patient with severe SLE is in the identification of genes that are important in the predisposition to the development of SLE in the general population. Since this translocation is unique, it is unlikely that the same mechanism would be operational in a significant proportion of subjects. However, if one of the causes of SLE in this patient is the overexpression of the triplicated genes, one could hypothesize that certain nucleotide variations located in the regulatory regions of one or several of the triplicated genes could influence the level of expression of those genes and modulate susceptibility to the more common form of SLE. Sequencing and genotyping analyses of several single-nucleotide polymorphisms in a large cohort of SLE patients would be required to test this hypothesis. It would also be of great interest to study the expression of CD99 (and of the other triplicated genes) in a large cohort of lupus patients.

We can further speculate about other potential causes of SLE in this young male patient. First, the fact that the prevalence of SLE is higher in women suggests that some X chromosome genes could be implicated in the disease etiology. Consequently, a male who possesses 2 X chromosomes is genetically very similar to females and would therefore have a higher predisposition to the development of SLE as compared with normal XY men. However, the precocity and the severity of SLE in this patient set him apart from the classic postpubertal female presentation. There is also the possibility that the predisposition to SLE is related to the loss of some protective Y chromosome genes, since >90% of the patient's Y chromosome is missing. It is also possible that his XY chromosome abnormalities are irrelevant to the etiology of his SLE and are only coincidental, such that the patient is in fact affected by 2 extremely rare conditions. Estrogens or sex hormones should also be considered as a potential cause of the SLE. However, the fact that the patient developed the disease at the age of 6 years is evidence against the sex hormone hypothesis of SLE induction, although his hypogonadism may have contributed to its maintenance.

In view of the data presented herein, we conclude that the XY translocation we describe is a highly probable contributing factor to SLE in this patient with a family history of autoimmune disease. Analysis of a large cohort of male and female SLE patients will be necessary to determine if the identified candidate genes may predispose, and be relevant, to the development of SLE in the general population.

Watch the video: Pseudoautosomal Genes and Pseudoautosomal Regions Genetics (September 2022).


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