Wide Genome Comparisons Reveal the Origins of the Human X Chromosome
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Opinion TRENDS in Genetics Vol.20 No.12 December 2004 Wide genome comparisons reveal the origins of the human X chromosome Matthias Kohn1, Hildegard Kehrer-Sawatzki1, Walther Vogel1, Jennifer A.M. Graves2 and Horst Hameister1 1Department of Human Genetics, University of Ulm, D-89070 Ulm, Germany 2Comparative Genomics Research Group, Research School of Biological Sciences, Australian National University, Canberra ACT 2601, Australia The eutherian X chromosome has one of the most mammalian X and Y chromosomes originated from an conserved gene arrangements in mammals. Although ancestral pair of autosomes in a reptile ancestor [9], which earlier comparisons with distantly related mammalian diverged over time as the Y chromosome progressively groups pointed towards separate origins for the short degraded [1,10]. This hypothesis is supported by regions of and long arms, much deeper comparisons are now homology between the X and Y, within and outside the possible using draft sequences of the chicken genome, pseudoautosomal regions (PAR1 and PAR2). A starting in combination with genome sequences from pufferfish point for the divergence is given by the observation and zebrafish. This enables surprising new insights into that birds and reptiles, from which mammals diverged the origins of the mammalian X chromosome. w310 million years ago (Mya) [11], do not share the mammal X and Y chromosomes [9]. The origin and evolution of the X chromosome is fascinat- The observation that genes on the short arm of the ing for several reasons, including its unique dosage human X chromosome distal to Xp11.2, many with copies compensation mechanism, and its role as the origin of on the Y, are autosomal in marsupial and monotreme most male-specific genes on the human Y chromosome [1]. mammals (which diverged independently from eutherians We are particularly interested in how the X chromosome w180 and 210 Mya, respectively) implies that an auto- managed to become enriched for sex- and reproduction- somal region was added to both the X and Y sometime related genes [2], as well as for genes engaged in the between the divergence of the marsupials and eutherians development of higher cognitive abilities [3], yet simul- 180 Mya, and the radiation of eutherians 105 Mya [1]. taneously be devoid of tumor- and growth-related genes Some intermixture of ancient and added genes on the [4,5]. This might be caused either by the relocation of a short arm implies at least one rearrangement around the specialized set of genes from elsewhere in the genome to fusion point [8]. This addition enlarged the pseudoauto- the X chromosome, or by co-option of extant X chromo- somal region, which subsequently degraded on the Y in somal genes to new functions. Analysis of the evolutionary two or more steps. Comparisons of the DNA sequences of history of the human X chromosome can distinguish genes with copies on the X and Y are consistent with an between these two hypotheses. ancient region on the long arm of the human X, and In 1967, Ohno pointed out the exceptional conservation stepwise differentiation of the short arm [12] (Box 1). of the size and gene content of the mammalian X Early events in the evolution of the human X chromosome [6]. Comparative gene mapping over the chromosome can be reconstructed by comparing genomes four decades since has confirmed Ohno’s Law, and from species that diverged from mammals early in the extended it to the conservation of gene order. Indeed, the history of vertebrates. Mammals diverged from birds and X chromosome represents by far the largest and most reptiles w310 Mya [11] and from fish w450 Mya [13]. conserved gene arrangement across eutherian (‘placental’) Data from whole genome sequencing of chicken, Gallus mammals [7]. However, comparisons of the X chromosome gallus (GGA), and several fish species are now becoming between eutherians and the other two major mammalian available, and this enables us to trace the ultimate origins groups (marsupials and monotremes) showed that only of regions of the human X. Genome sequences from part of the X chromosome is conserved between all three pufferfish and zebrafish were not immediately informative major mammal groups [8]. for comparisons with the human X because these genomes are highly rearranged with respect to mammalian Comparative gene mapping genomes. However, a comparison with the chicken genome Comparisons are now possible between eutherian genome was highly informative, and enabeled us to interpret data sequences and chicken, pufferfish and zebrafish, providing from the fish species. surprising new insights into the origins of the mammalian The chicken karyotype probably represents that of an X chromosome. It has long been accepted that the ancient bird, or even reptile, ancestor, because it is Corresponding author: Horst Hameister ([email protected]). virtually identical to that of ratite birds from which they Available online 12 October 2004 diverged w80 Mya, and even turtles, which are thought to www.sciencedirect.com 0168-9525/$ - see front matter Q 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.tig.2004.09.008 Opinion TRENDS in Genetics Vol.20 No.12 December 2004 599 that the 230 segments shared by human and mouse Box 1. Strata on the human X chromosome genomes [21].Thisrateofgenomechange(w0.3 There are two ways in which the human X chromosome can be rearrangements per MY) places the chicken genome into subdivided into evolutionary distinct regions. The first divides the a class of slowly evolving genomes [19]. The human X regions according to their separate evolutionary origin, and the second according to the time at which X and Y chromosome ceased chromosome arrangement is especially conserved in recombining. How these regions correspond with each other is chicken, and conventional gene mapping revealed two shown in Figure I. segments of common synteny on chicken chromosomes 1q13–q31 and 4p [17]. While we were engaged in mapping key human X-borne genes in chicken [22], our work was (a)Evolutionary origins by (b) X–Y divergence by comparative mapping recombination suppression overwhelmed by new data appearing from the chicken genome sequencing. We have now retrieved the chicken Marsupials and homologs of w300 genes from human Xpter to Xqter monotremes Chicken Human (see supplementary data online). The locations of chicken PAR1 homologs of representative human X genes are summar- Xp22.2 4 ized in Figure 1. Xp22.1 3 A 1 Two major regions of shared synteny between the human X chromosome and the chicken genome Xp11.2 2 12 As expected, genes from human Xpter–p11.2 (0–46.0 Mb), including those from the pseudoautosomal region PAR1, CEN are conserved on chicken chromosome GGA 1q13–q31. Although the 46-Mb human region is compressed more than twofold to 18.6 Mb in the chicken genome, these genes maintain an identical order on human Xp and X 4 1 chicken 1q (Figure 1, Table 1, supplementary data online). Proximal Xp11.2–cen and the entire long arm, except for part of Xq28, of the human X chromosome to SYBL1, within the Xq terminal PAR2, is completely conserved in a Xq28 single syntenic segment on GGA 4p (Figure 1, Table 1, PAR2 supplementary data online). This 99.6-Mb region of the TRENDS in Genetics human genome is compressed about five times to !20 Mb in the chicken genome. Remarkably, the gene order is Figure I. Comparative mapping reflects regions of the human X chromosome with a different evolutionary origin. (a) Comparisons with marsupials and completely different in the human and chicken genomes, monotremes revealed an ancient region (X) conserved on the X chromosome in as is apparent from the complete non-correspondence of all mammals, and a region that is autosomal in other mammals (marsupials, pairs of neighboring human genes (Figure 1). monotremes), and therefore must have been added recently to the X chromosome [1]. Comparison with chicken (present study) confirms the The extraordinary contrast between the co-linear independent origin of these regions, which are orthologous to chicken chicken 1q–human Xp and the completely scrambled chromosome 1 and 4, and reveals a third and fourth block of genes, chicken 4p–human Xq might reflect the evolutionary predominantly derived from chicken chromosome 12. (b) X–Y divergence of gene pairs on the human X chromosome reflects regions in which X–Y history of GGA 4p. This region is represented by a recombination was suppressed at different times. Differences in the divergence microchromosome in the ancient ratites [14] and in all rate of 19 gene pairs on the human X and Y chromosomes divided the X into four regions called strata 1, 2, 3 and 4 [12]. Divergence of eight gene pairs in the bird orders except Galliformes, in which it is found fused mouse divided the mouse X chromosome into the corresponding strata 1, 2 and to GGA 4 [23,24]. A scrambled gene order might be (3C4) [31], which in the mouse are rearranged by several inversions [32]. common to microchromosomes, because Crooijmans et al. Stratum 4 separated from stratum 3 only in the primate lineage [27] and therefore is not present in mouse. A similar divergence rate based on [25] found that the order of genes on microchromosome subdivision into two evolutionary strata has been proposed for the chicken Z GGA 10 was completely scrambled with respect to a and W chromosome [33]. segment of shared synteny on Homo sapiens (HSA) chromosome 15. We suggest, therefore, that the scrambled gene order observed in GGA 4p reflects the recent have diverged early in the reptile radiation [14,15]. evolutionary history of this chromosome arm as a Karyotypes of birds (and most reptiles) consist of macro- microchromosome. chromosomes, which are structurally similar to mamma- lian chromosomes, and microchromosomes, which are A new evolutionary stratum of the human X small, gene-rich elements.