Acceleration of X-chromosome gene order evolution in the cattle lineage
Acceleration of X-chromosome gene order evolution in the cattle lineage
BMB Reports. 2013. Jun, 46(6): 310-315
Copyright © 2013, Korean Society for Biochemistry and Molecular Biology
This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
  • Received : September 07, 2012
  • Accepted : December 19, 2012
  • Published : June 30, 2013
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About the Authors
Woncheoul, Park
C&K Genomics, Seoul 151-742, Korea
Hee-Seok, Oh
Department of Statistics, Seoul National University, Seoul 151-747, Korea
Heebal, Kim
C&K Genomics, Seoul 151-742, Korea

The gene order on the X chromosome of eutherians is generally highly conserved, although an increase in the rate of rearrangement has been reported in the rodent lineage. Conservation of the X chromosome is thought to be caused by selection related to maintenance of dosage compensation. However, we herein reveal that the cattle (Btau4.0) lineage has experienced a strong increase in the rate of X-chromosome rearrangement, much stronger than that previously reported for rodents. We also show that this increase is not matched by a similar increase on the autosomes and cannot be explained by assembly errors. Furthermore, we compared the difference in two cattle genome assemblies: Btau4.0 and Btau6.0 (Bos taurus UMD3.1). The results showed a discrepancy between Btau4.0 and Btau6.0 cattle assembly version data, and we believe that Btau6.0 cattle assembly version data are not more reliable than Btau4.0. [BMB Reports 2013; 46(6): 310-315]
The difference in the X-chromosome number between heterogametic and homogametic individuals requires some form of dosage compensation to ensure equal levels of X-linked gene activity. In mammals, dosage compensation occurs in the form of X inactivation. The X inactivation process is initially dependent on an RNA gene, Xist, located in the X inactivation center (XIC) (1) . Xist is upregulated in the inactivated chromosome, and gene silencing then occurs in Cis along the chromosome. While Xist silencing may also happen on autosomes, it is most efficient on the X chromosome, leading to the suggestion that X inactivation is boosted by genomic elements on the X chromosome. Because LINE elements, and L1 elements in particular, are much more common on the X chromosome than on autosomes, it has been hypothesized that they serve as boosters of the X inactivation signal (2 - 4) .
Ohno (5) suggested that the establishment of a dosage compensation mechanism in somatic cells of a mammalian ancestor may have conferred constraints on rearrangements between the X chromosome and autosomes during evolution. It was later shown that there is an almost identical set of genes on the X chromosome of many eutherian mammals (6 - 8) . The gene order on the X chromosome is also highly conserved, with only rodents showing large changes in the gene order on the X chromosome (9 - 11) . Comparative maps between cattle and human X chromosomes based on radiation hybrid mapping have shown a highly conserved gene order (12) . However, Raudsepp et al . (11) reported several evolutionary rearrangements on the cattle X chromosome in the context of an analysis of the horse genome. Here, we estimated the rate of rearrangements on the X chromosome and on autosomes in the cattle lineage to evaluate the degree of conservation of the gene order in cattle. We show that the cattle lineage has experienced an acceleration in the rate of rearrangements on the X chromosome compared with other mammals. We also discuss possible implications of these findings.
Two assemble version in cattle which were Btau4.0 and Btau6.0 (UMD3.1) was many differences. Because of assemble group and method are clearly differences. as a result, Number of SNPs on Btau4.0 and Btau6.0 were different from 46,760 and 48,284 (13) . Chromosome size was too striking differences. Among them, X-chromosome size on Btau4.0 and Btau6.0 were striking differences from 83Mbp and 136Mbp (14) . Unknown chromosomes information in Btau4.0 was many involved in X-chromosome of Btau6.0 (15) .
- The most spectacular gene order changes on the X chromosome among boreoeutherian species have occurred in the cow (Artiodactyla) lineage
As seen in Fig. 1 , the gene order on the X chromosome of primates, dogs, and horses is conserved almost perfectly. This observation is consistent with previous reports describing the human X chromosome as identical to the putative ancestral mammalian X chromosome (16) and the X chromosome gene order of humans, dogs, and horses being highly conserved (17) . As described previously (11 , 18) , the gene order in the rodent lineage is less conserved on the X chromosome. However, somewhat surprisingly, we found that the cattle lineage is the least conserved among the genomes examined herein. Using the parsimony estimate of the number of rearrangements for our set of markers divided by time as an estimate of rate, we found a rate of 0.56/MY/GB in cattle but a rate that varies between 0 and 0.2/MY/GB in the other species ( Fig. 2 A). Notably, a similar increase in the rate of rearrangements on autosomes was not observed in cattle ( Fig. 2 B). Analyses based on signed gene order provided similar X chromosome results in cattle, but not in mice (Supplementary Fig. 1A); and similar autosome results were found in cattle and mice (Supplementary Fig. 1B). The parsimony inferred number of rearrangements will always be an underestimate of the true number. This bias will be stronger for long lineages than for short lineages. However, because the cattle lineage is one of the longest lineages in the phylogeny, this bias cannot explain our results.
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Gene order of 169 concordant orthologous genes on the X chromosomes between Btau4.0 (A) and Btua6.0 (B). Red lines indicate orthologous genes in the X-added region (XAR), and the blue line indicates orthologous genes in the X-conserved region (XCR) according to annotations of the human chromosome. The number to the right of each chromosome represents the chromosomal length.
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Rates of unsigned gene order rearrangements on the X chromosomes (A) and autosomes (B) of five mammals. The evolutionary tree is based on the estimation of divergence times provided by the TIMETREE database ( Gene order distances are based on 169 and 10,196 orthologous gene sets of the mammals on the X chromosome and autosomes, respectively. Rates are depicted as a color gradient from minimum to maximum, and the color scale is shown at bottom. The number on each lineage is the parsimony-inferred number of rearrangements, and the rates are indicated in parentheses. The rate is estimated only for external lineages. Internal lineages are striped.
A more serious challenge to our results is genome assembly errors. The cattle genome has been sequenced for a male animal (XY), resulting in a sequencing coverage on the X chromosome of only half that of the autosomes. In addition, it is a relatively recently sequenced genome, possibly suggesting that quality might be a concern. To address this problem, we repeated our analyses of the X chromosome using only markers showing a concordant marker order in independently generated genetic and physical maps in cattle. As described in the Methods, we collected 51 concordant markers in terms of orders on linkage and physical maps ( Table 1 ) of the cattle X chromosome. The physical map was generated independently of the linkage map (19) using a radiation hybrid physical map for scaffolding. Using these markers, we again identified a strong increase in the rate of rearrangement in the cattle lineage, indicating that possible assembly errors in the cattle X chromosome did not affect our main results (Supplementary Fig.S2 and S3). We conclude that there is a strong increase in the rate of rearrangement on the cattle X chromosome compared with that of other eutherian species that is not matched by a similar increase in the rate of rearrangement on the autosomes.
A list of the 51 concordant markers of the cattle X chromosome and their corresponding positions in the other mammals. Genome assembly versions of each species are the following: GRCh37 (human), NCBIM37 (mouse), BROADD2 (dog), EquCab2 (horse), and Btau4.0 (cow)
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A list of the 51 concordant markers of the cattle X chromosome and their corresponding positions in the other mammals. Genome assembly versions of each species are the following: GRCh37 (human), NCBIM37 (mouse), BROADD2 (dog), EquCab2 (horse), and Btau4.0 (cow)
A number of different factors may explain differences in the rate of rearrangement. The increase in the rodent lineage may, for example, be explained by the short generation time of rodents (20) . However, this explanation does not seem to apply to the cattle lineage because artiodactyls do not in general tend to have shorter generation times than other eutherian mammals (21 , 22) .
In addition, generation-time effects cannot explain the differences between autosomes and X chromosomes. Changes in mutational processes likewise seem unlikely explanations because they should apply to both X chromosomes and autosomes as well. Rather, we should explore potential X-specific explanations.
- Significant differences in each cattle genome assembly (Btau4.0 and Btau6.0)
We found many differences in the comparison of Btau4.0 and Btau6.0. First, we showed that much of the chromosome mapping information in Btau4.0 is not matched to Btau6.0, as shown by the chromosome X size ( Fig. 1 ) and genome mapping results ( Fig. 3 ) in the two cattle genome assemblies. The X chromosome size in Btau4.0 and Btau6.0 showed a difference of about 61 Mb (88 and 149 Mb, respectively). Orthologous gene sets of mammalian X chromosomes and autosomes were 257 and 11,479 for Btau4.0, respectively, and 372 and 11740 for Btau6.0, respectively. The differences in the X chromosomes and autosomes were 115 and 261, respectively. The result of concordant markers was not similar increases in the X chromosome and autosomes were seen in cattle (Supplementary Fig. 3). However, Btau6.0 differed in that similar increases in the X chromosome and autosomes were seen in cattle, and analyses based on unsigned and signed gene order provided similar results (Supplementary Fig. 4, 5). The results of concordant orthologous gene sets between Btau4.0 and Btau6.0 were similar to the results of Btau4.0 and Btau6.0 in chromosome X, and the Btau4.0 results were similar to the concordant orthologous gene set results in autosomes. However, the Btau6.0 results were not matched to the concordant orthologous gene set results in autosomes. Thus, we assume that Btau6.0 contains more errors and incorrect information than Btau4.0. Consequentially, we have so far determined that the cattle assembly data of Btau4.0 and Btau6.0 are not completely reliable. Thus more care must be taken when using Btau6.0 data than when using Btau4.0 data.
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Genome mapping of Btau4.0 and Btau6.0 using the Circos tool. Chromosome mapping information in Btau4.0 is largely unmatched to that of Btau6.0.
Furthermore, Btau4.6.1, an upgraded version (latest Gen-Bank, latest RefSeq) of Btau4.0, has been released on the NCBI and UCSC websites. We believe that the Btau4.6.1 results are similar to the Btau4.0 results because Btau4.6.1 is an upgraded version of Btau4.0, and is not much different. Thus, the Btau4.6.1 results differ from the Btau6.0 results. We plan to perform more research using the new cattle assembly data.
Predictions of orthology between species (1:1 relationship) were based on the Ensembl ( ) database. We analyzed five species representing five mammalian orders of Eutheria: the human (primate), mouse (rodentia), dog (carnivore), horse (perissodactyla), and cattle (artiodactyla). The genome assemblies used were GRCh37 (human), NCBIM37 (mouse), BROADD2 (dog), EquCab2 (horse), and Btau4.0 (cow). A total of 257 and 11,479 orthologous gene sets for the five species were retrieved from X chromosome and autosomes, respectively. Btau4.0 (cow) was changed to Btau6.0 (cow) in the orthologous gene sets, and a total of 372 and 11,740 orthologous gene sets for the five species were retrieved from the X chromosome and autosomes, respectively. Concordant orthologous gene sets between Btau4.0 (cow) and Btau6.0 (cow) totaling 169 and 10,196 for the five species were retrieved from the X chromosome and autosomes, respectively. Estimates of tree topology and divergence times were retrieved from the TIMETREE database ( ).
To calculate the genomic distance between species based on gene order, the genomic distance on the X chromosome and autosomes was calculated by the Hannenhalli and Pevzner (23) algorithm implemented in the GRIMM program (24) . To calculate the rate of X chromosomal gene order evolution in each lineage, we use the neighbor-joining (NJ) method with a minor modification. The NJ method (25) is used to reconstruct phylogenies from a matrix (M) of pairwise distances by iterative clustering. Initially, each leaf node is associated with a column and a row of M. In each iteration, a pair of nodes is chosen to cluster based on an optimality criterion calculated from M. The branch lengths of the associated edges are likewise calculated based on M. Of the two nodes chosen to cluster, the rows and columns in M are then eliminated from M, while a row and a column is added corresponding to the new node representing the new cluster. The process is repeated until all nodes have joined a cluster. We used this algorithm to calculate branch lengths based on genomic distances. However, to ensure that the topology was in accordance with that reported in TIMETREE, we disallowed clusters that were in conflict with the TIMETREE topology. In this way, we ensured that the a priori known topology was chosen while using the distances criterion from the NJ algorithm to determine branch lengths in terms of genomic distance. The method provided an estimate of the number of genome rearrangements on each lineage from the pairwise genomic distances.
To address the problem of genome assembly, a set of concordant markers from genetic maps and physical maps were obtained. The genetic map information was from a high-density cattle linkage map. These markers were mapped onto the other mammalian genomes based on the comparative genome alignment information from the UCSC genome browser ( ). A total of 51 and 2,634 concordant markers were extracted from the X chromosome and autosomes, respectively. We emphasize that the map by Arias et al . (19) was not used in the generation of the physical genome assembly (Btau4.0) and that the two maps, therefore, are independent.
We found concordant genes between Btau4.0 and Btau6.0 by the same method used to find the concordant marker. A total of 169 and 10,196 concordant genes were extracted from the X chromosome and autosomes, respectively.
To determine the L1 content elements of the mammalian genomes, we used the latest available RepeatMasked annotations ( ). To avoid over-counting of fragmented L1, elements with the same name that overlapped the same location were counted as one element.
The genome mapping method in Btau4.0 and Btau6.0 uses the circus of visualization tool (26) after alignment by the LAST program (27) . In the LAST method, the first DB was Btau6.0 and the query used was Btau4.0. In the second stage, we edited the alignment data using Python, to generate a simple structure from which duplications had been deleted (selection of high-score values) and merged the small-align set. In the next stage, we used bundlelinks which Circos tutorial program that is make a Circos input file. More details can be found on the Circos Web site ( ).
This study was also supported by Next-Generation BioGreen 21 Program (PJ0090192013) from the Rural Development Administration of Korea.
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