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Detecting evolutionary strata on the human x chromosome in the absence of gametologous y-linked sequences.

Pandey RS, Wilson Sayres MA, Azad RK - Genome Biol Evol (2013)

Bottom Line: Mammalian sex chromosomes arose from a pair of homologous autosomes that differentiated into the X and Y chromosomes following a series of recombination suppression events between the X and Y.We have developed an integrative method that combines a top-down, recursive segmentation algorithm with a bottom-up, agglomerative clustering algorithm to decipher compositionally distinct regions on the X, which reflect regions of unique X-Y divergence.The older strata, from the first up to the third stratum, have remained poorly resolved due to paucity of X-Y gametologs.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Sciences, University of North Texas.

ABSTRACT
Mammalian sex chromosomes arose from a pair of homologous autosomes that differentiated into the X and Y chromosomes following a series of recombination suppression events between the X and Y. The stepwise recombination suppressions from the distal long arm to the distal short arm of the chromosomes are reflected as regions with distinct X-Y divergence, referred to as evolutionary strata on the X. All current methods for stratum detection depend on X-Y comparisons but are severely limited by the paucity of X-Y gametologs. We have developed an integrative method that combines a top-down, recursive segmentation algorithm with a bottom-up, agglomerative clustering algorithm to decipher compositionally distinct regions on the X, which reflect regions of unique X-Y divergence. In application to human X chromosome, our method correctly classified a concatenated set of 35 previously assayed X-linked gene sequences by evolutionary strata. We then extended our analysis, applying this method to the entire sequence of the human X chromosome, in an effort to define stratum boundaries. The boundaries of more recently formed strata on X-added region, namely the fourth and fifth strata, have been defined by previous studies and are recapitulated with our method. The older strata, from the first up to the third stratum, have remained poorly resolved due to paucity of X-Y gametologs. By analyzing the entire X sequence, our method identified seven evolutionary strata in these ancient regions, where only three could previously be assayed, thus demonstrating the robustness of our method in detecting the evolutionary strata.

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Strata identified across the whole X chromosome. Here, we show the clusters that are determined using the entire sequence of the human X chromosome, either unmasked or masked for repetitive elements, as defined by RepeatMasker. We also plot the position and strata delineation of X-linked genes that have previously been assayed. Previous strata are colored: 5, Red; 4, Yellow; 3, Geen; 2, Blue; 1, Violet. We used Markov model of order 2 to perform segmentation and clustering at significance thresholds of 0.4 and 10−7, respectively.
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evt139-F2: Strata identified across the whole X chromosome. Here, we show the clusters that are determined using the entire sequence of the human X chromosome, either unmasked or masked for repetitive elements, as defined by RepeatMasker. We also plot the position and strata delineation of X-linked genes that have previously been assayed. Previous strata are colored: 5, Red; 4, Yellow; 3, Geen; 2, Blue; 1, Violet. We used Markov model of order 2 to perform segmentation and clustering at significance thresholds of 0.4 and 10−7, respectively.

Mentions: We make significant improvements to predicting strata by allowing all of the sequence on the X chromosome to be utilized, instead of relying only on genic regions, and also by not limiting to regions that retain Y homology. Our algorithm identifies 12 compositionally distinct regions on the human X chromosome. Three of these occur within the first PAR (PAR1). Given the strong evidence that the PAR1 is still recombining, we do not take this as evidence of recombination suppression. These three clusters also appear to be driven by repetitive elements because when repetitive elements are masked out we observe only two clusters on the human X chromosome, one corresponding to the PAR1 and the other corresponding to the rest of the X chromosome (which is almost entirely nonrecombining in males). Outside of the PAR, our method identifies nine clusters, which we expect to correspond to distinct evolutionary strata. First, our method identifies the previously defined boundaries of the human PAR1 and the two most recent strata (fig. 2, table 1, and supplementary fig. S3, Supplementary Material online), which have been described in detail and independently confirmed by different studies (Ross et al. 2005; Lemaitre et al. 2009b). We confirm, as others have hypothesized (Lemaitre et al. 2009a; Wilson and Makova 2009), that the stratum previously described as stratum 3 is actually comprised of at least two compositionally distinct regions (fig. 2 and table 1). Finally, for the first time, we provide estimates of the positions and boundaries of strata in the oldest region of the sex chromosomes (table 1). Specifically, in humans, we show that rather than only one or two strata on the XCR (Lahn and Page 1999; Skaletsky et al. 2003; Katsura and Satta 2012), there were at least five independent recombination suppression events in the XCR (fig. 2 and table 1). Given that species with very young sex chromosomes already have several observable strata (e.g., three strata have already been identified on the <10-million-year-old sex chromosomes of Silene latifolia [Bergero et al. 2007]), the existence of many strata in the XCR is much more consistent with current theory of sex chromosome evolution than the likelihood of one or two extremely large inversions. Our method makes no assumption about the timing of any of the events, although other lines of evidence do suggest successive linear recombination suppressions. Specifically, we do not distinguish where the first recombination suppression event occurred. Current theory suggests that SOX3, from which the sex-determining SRY gene evolved, is in the oldest stratum. We do not contest this; however, the new evidence from this study suggests that the earliest two inversions might have happened in quick succession, the inversion involving SOX3 (represented by the second cluster, fig. 2) happening first, then recombination suppression proceeded in both directions along the chromosome, reaching the terminal end of Xq very quickly. Interestingly, the first cluster (∼10 Mbp in size, fig. 2) contains PAR2, which is only 320 kb long, was recently added to the X and Y, and reported to only occasionally undergo recombination, in contrast to PAR1 (Charchar et al. 2003).Fig. 2.—


Detecting evolutionary strata on the human x chromosome in the absence of gametologous y-linked sequences.

Pandey RS, Wilson Sayres MA, Azad RK - Genome Biol Evol (2013)

Strata identified across the whole X chromosome. Here, we show the clusters that are determined using the entire sequence of the human X chromosome, either unmasked or masked for repetitive elements, as defined by RepeatMasker. We also plot the position and strata delineation of X-linked genes that have previously been assayed. Previous strata are colored: 5, Red; 4, Yellow; 3, Geen; 2, Blue; 1, Violet. We used Markov model of order 2 to perform segmentation and clustering at significance thresholds of 0.4 and 10−7, respectively.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3814197&req=5

evt139-F2: Strata identified across the whole X chromosome. Here, we show the clusters that are determined using the entire sequence of the human X chromosome, either unmasked or masked for repetitive elements, as defined by RepeatMasker. We also plot the position and strata delineation of X-linked genes that have previously been assayed. Previous strata are colored: 5, Red; 4, Yellow; 3, Geen; 2, Blue; 1, Violet. We used Markov model of order 2 to perform segmentation and clustering at significance thresholds of 0.4 and 10−7, respectively.
Mentions: We make significant improvements to predicting strata by allowing all of the sequence on the X chromosome to be utilized, instead of relying only on genic regions, and also by not limiting to regions that retain Y homology. Our algorithm identifies 12 compositionally distinct regions on the human X chromosome. Three of these occur within the first PAR (PAR1). Given the strong evidence that the PAR1 is still recombining, we do not take this as evidence of recombination suppression. These three clusters also appear to be driven by repetitive elements because when repetitive elements are masked out we observe only two clusters on the human X chromosome, one corresponding to the PAR1 and the other corresponding to the rest of the X chromosome (which is almost entirely nonrecombining in males). Outside of the PAR, our method identifies nine clusters, which we expect to correspond to distinct evolutionary strata. First, our method identifies the previously defined boundaries of the human PAR1 and the two most recent strata (fig. 2, table 1, and supplementary fig. S3, Supplementary Material online), which have been described in detail and independently confirmed by different studies (Ross et al. 2005; Lemaitre et al. 2009b). We confirm, as others have hypothesized (Lemaitre et al. 2009a; Wilson and Makova 2009), that the stratum previously described as stratum 3 is actually comprised of at least two compositionally distinct regions (fig. 2 and table 1). Finally, for the first time, we provide estimates of the positions and boundaries of strata in the oldest region of the sex chromosomes (table 1). Specifically, in humans, we show that rather than only one or two strata on the XCR (Lahn and Page 1999; Skaletsky et al. 2003; Katsura and Satta 2012), there were at least five independent recombination suppression events in the XCR (fig. 2 and table 1). Given that species with very young sex chromosomes already have several observable strata (e.g., three strata have already been identified on the <10-million-year-old sex chromosomes of Silene latifolia [Bergero et al. 2007]), the existence of many strata in the XCR is much more consistent with current theory of sex chromosome evolution than the likelihood of one or two extremely large inversions. Our method makes no assumption about the timing of any of the events, although other lines of evidence do suggest successive linear recombination suppressions. Specifically, we do not distinguish where the first recombination suppression event occurred. Current theory suggests that SOX3, from which the sex-determining SRY gene evolved, is in the oldest stratum. We do not contest this; however, the new evidence from this study suggests that the earliest two inversions might have happened in quick succession, the inversion involving SOX3 (represented by the second cluster, fig. 2) happening first, then recombination suppression proceeded in both directions along the chromosome, reaching the terminal end of Xq very quickly. Interestingly, the first cluster (∼10 Mbp in size, fig. 2) contains PAR2, which is only 320 kb long, was recently added to the X and Y, and reported to only occasionally undergo recombination, in contrast to PAR1 (Charchar et al. 2003).Fig. 2.—

Bottom Line: Mammalian sex chromosomes arose from a pair of homologous autosomes that differentiated into the X and Y chromosomes following a series of recombination suppression events between the X and Y.We have developed an integrative method that combines a top-down, recursive segmentation algorithm with a bottom-up, agglomerative clustering algorithm to decipher compositionally distinct regions on the X, which reflect regions of unique X-Y divergence.The older strata, from the first up to the third stratum, have remained poorly resolved due to paucity of X-Y gametologs.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Sciences, University of North Texas.

ABSTRACT
Mammalian sex chromosomes arose from a pair of homologous autosomes that differentiated into the X and Y chromosomes following a series of recombination suppression events between the X and Y. The stepwise recombination suppressions from the distal long arm to the distal short arm of the chromosomes are reflected as regions with distinct X-Y divergence, referred to as evolutionary strata on the X. All current methods for stratum detection depend on X-Y comparisons but are severely limited by the paucity of X-Y gametologs. We have developed an integrative method that combines a top-down, recursive segmentation algorithm with a bottom-up, agglomerative clustering algorithm to decipher compositionally distinct regions on the X, which reflect regions of unique X-Y divergence. In application to human X chromosome, our method correctly classified a concatenated set of 35 previously assayed X-linked gene sequences by evolutionary strata. We then extended our analysis, applying this method to the entire sequence of the human X chromosome, in an effort to define stratum boundaries. The boundaries of more recently formed strata on X-added region, namely the fourth and fifth strata, have been defined by previous studies and are recapitulated with our method. The older strata, from the first up to the third stratum, have remained poorly resolved due to paucity of X-Y gametologs. By analyzing the entire X sequence, our method identified seven evolutionary strata in these ancient regions, where only three could previously be assayed, thus demonstrating the robustness of our method in detecting the evolutionary strata.

Show MeSH
Related in: MedlinePlus