Footprints of inversions at present and past pseudoautosomal boundaries in human sex chromosomes - PubMed (original) (raw)

Footprints of inversions at present and past pseudoautosomal boundaries in human sex chromosomes

Claire Lemaitre et al. Genome Biol Evol. 2009.

Abstract

The human sex chromosomes have stopped recombining gradually, which has left five evolutionary strata on the X chromosome. Y inversions are thought to have suppressed X-Y recombination but clear evidence is missing. Here, we looked for such evidence by focusing on a region--the X-added region (XAR)--that includes the pseudoautosomal region and the most recent strata 3 to 5. We estimated and analyzed the whole set of parsimonious scenarios of Y inversions given the gene order in XAR and its Y homolog. Comparing these to scenarios for simulated sequences suggests that the strata 4 and 5 were formed by Y inversions. By comparing the X and Y DNA sequences, we found clear evidence of two Y inversions associated with duplications that coincide with the boundaries of strata 4 and 5. Divergence between duplicates is in agreement with the timing of strata 4 and 5 formation. These duplicates show a complex pattern of gene conversion that resembles the pattern previously found for AMELXY, a stratum 3 locus. This suggests that this locus--despite AMELY being unbroken--was possibly involved in a Y inversion that formed stratum 3. However, no clear evidence supporting the formation of stratum 3 by a Y inversion was found, probably because this stratum is too old for such an inversion to be detectable. Our results strongly support the view that the most recent human strata have arisen by Y inversions and suggest that inversions have played a major role in the differentiation of our sex chromosomes.

Keywords: duplication; evolutionary strata; inversion; recombination; sex chromosomes.

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Figures

F<sc>IG</sc>. 1.—

FIG. 1.—

A possible scenario for the X–Y rearrangements and the evolution of recent human strata (adapted from Ross et al. 2005). This scenario has been obtained by GRIMM using 12 markers covering PAR, stratum 5, stratum 4, and the beginning of stratum 3. Strata definitions are from Ross et al. (2005). See the list of markers in table 1. Inversions that coincide with strata and that could have formed them are indicated in red. Other inversions are in brown.

F<sc>IG</sc>. 2.—

FIG. 2.—

Distributions of the number of optimal scenarios consistent with the human strata 4 and 5 over the total number of optimal scenarios (#strata_scen/#total_scen) for free and strata-constrained simulated sequences. Free simulations have been obtained by random inversions (black boxes). Strata-constrained simulations have been obtained by simulating formation of strata by inversions (using currently defined strata 3, 4, and 5 for humans) with additional small inversions occurring within strata after their formation (white boxes). See main text (Materials and Methods, Results, and Discussion) for more details. #strata_scen/#total_scen values for simulated sequences have been obtained using the Braga et al. (2008) program. The value observed for the true X–Y sequences is indicated by a red arrow.

F<sc>IG</sc>. 3.—

FIG. 3.—

Analysis of breakpoints at strata and PAR boundaries in humans. (A) Dot plot for the PAR/stratum 5 boundary. This shows the similarities between the X region at the PAR/stratum 5 boundary with two “broken” regions on the Y. It clearly shows that the X region is duplicated on the Y (with one duplicate being inverted). Total length of the region = 45 kb. (B) Dot plot for the strata 4/5 boundary. This shows the similarities between the X region at the strata 4/5 boundary with two broken regions on the Y. It clearly shows that the X region is duplicated on the Y (both Y duplicates are in inverted orientation compared with the X homologous region). Total length of the region = 110 kb. See main text (Materials and Methods, Results, and Discussion) for more details. (C) Picture showing the location and orientation of the duplications on the chromosomes X and Y. On the Y chromosome, stratum 5 is flanked by duplication of the PAR/stratum 5 region of the X (shown in red), which indicates a large inversion spanning the entire stratum 5. Duplicates of the strata 4/5 region of the X are found at the ends of stratum 5 and stratum 4 (shown in green). This defines a large inversion spanning the whole stratum 4. Importantly, duplicates are in an orientation consistent with two large inversions that have formed stratum 4 first and then stratum 5. (D) Sketch showing the scenario with two inversions for the formation of strata 4 and 5 under the isochromatid model with staggered single-strand breaks (see Ranz et al. 2007). The first inversion reduces the size of the PAR and forms stratum 4 with two inverted duplicates flanking the inversion. The second inversion reduces further the size of the PAR and forms stratum 5 with two inverted duplicates flanking the inversion. Note that duplicates associated with the formation of stratum 4 are no longer inverted because one of them is involved in the inversion that has formed stratum 5. Lines with arrows indicate inversions. In (C) and (D): Blocks of similarities are indicated by blue boxes and shadows. Black lines indicate large stretches of nonhomologous sequences. Sizes of boxes and lines are not in scale.

F<sc>IG</sc>. 4.—

FIG. 4.—

Divergence patterns among XG copies. The three copies of XG are shown—the X copy (XG-X) and two Y copies: the one in the PAR (XG-Y1) and the entire copy in the NRY (XG-Y2). XG-Y1 and XG-Y2 are the inverted duplicates shown in red in figure 3. XG-X and XG-Y2 have been compared. Two regions were defined: XG-5′ (1–29,500) and XG-3′ (29,500–63,854). _d_S and _d_N were estimated using PAML and the percentage of similarity for total DNA was obtained using BlastZ (see Material and Methods). Gray arrows indicate possible events of gene conversion.

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