Perspective The Conflict within and the Escalating War between the Sex Chromosomes Jeffrey M. Good* Division of Biological Sciences, University of Montana, Missoula, Montana, United States of America Selfish genetic elements that distort Mendelian segregation to favor their own transmission are common in eukaryotic genomes [1,2]. Segregation distortion can reduce whole organism fitness, resulting in strong counter selection for genes that suppress distorters. Such intragenomic conflicts have the potential to drive recurrent bouts of antagonistic co-evolu- tion [3]. Theory predicts that genetic conflicts should be particularly intense between the sex chromosomes [4,5]. The expectation that sex-linked conflict should be rampant has led to a renewed emphasis on the importance of antagonistic co- evolution for driving genome evolution [6]. However, while numerous examples of genes involved in intragenomic conflict now exist [1], evidence for antagonistic co- evolution between the mammalian X and Y chromosomes has remained elusive. In this issue of PLOS Genetics, Cocquet et al. have demonstrated a genetic basis for X–Y conflict acting during a crucial stage of mouse spermatogenesis [7]. The sex chromosomes are silenced via chromatin remodeling during the initiation of meiosis (meiotic sex chromosome inactivation or MSCI) [8]. Gene silencing persists through the remainder of spermatogenesis (post- meiotic sex chromatin or PMSC), save for a subset of genes that escape inactivation [9]. Considerable progress has been made recently on the epigenetic regulation of MSCI and PMSC, including the identifi- cation of a multicopy Y-linked gene, Sly, involved in the maintenance of PMSC [10]. Male mice with Sly deficiency show up-regulation of several sex-linked genes during PMSC, are sub-fertile, and pro- duce female-biased litters. Thus, Sly is a strong candidate for being involved in X– Y conflict due to its repressive interaction with other genes and its potential to bias sex chromosome transmission. Intriguing- ly, there are two X-linked genes (Slx and Slxl1; hereafter Slx/Slxl1) that are closely related to Sly. Both are regulated by Sly, occur in large multicopy clusters on the X, and are crucial for spermatogenesis [11]. To test for genetic conflict between these genes, Cocquet et al. generated transgenic mice expressing short hairpin RNA (shRNA) that knockdown Sly or Slx/ Slxl1 transcript levels without completely knocking out gene function [7]. Both Sly- and Slx/Slxl1-deficient mice showed im- paired spermatogenesis, but Slx/Slxl1 de- ficiency led to a slight reduction in sex- linked gene expression in postmeiotic cells and male-biased litters (Figure 1A). Strik- ingly, mice deficient for both Sly and Slx/ Slxl1I showed a complete rescue of XY expression, male fertility, and sex ratio phenotypes. That is, the genes have antagonistic roles during spermatogenesis: Sly represses XY expression during PMSC and promotes the transmission of the Y, while Slx/Slxl1 activates XY expression and promotes the transmission of the X. The surprising conclusion is that antago- nism depends on the relative expression of these genes and not their total abundance. Several questions remain regarding the mechanistic and genetic bases of distor- tion. For example, segregation distortion in the Sly-Slx/Slxl1 system appears to be caused by the differential fertilization ability of X- and Y-bearing sperm. Dis- torter genes often skew transmission through epistatic interactions with one or more responder genes [12]. In this context both Sly and Slx/Slxl1 appear to be distorters acting on one or more responder genes to impair the function of the X- or Y-bearing sperm, respectively [7]. Which raises the question, what are the respond- ers? Even more interesting are the evolu- tionary consequences of recurrent sex- linked conflict. If Sly and Slx/Slxl1I were locked in an antagonistic conflict, then we would predict that each would be rapidly evolving on some level. The relevant metric here seems to be gene copy number. Sly and Slx/Slxl1I are recent additions to the mouse genome, appearing within the past 3 million years (Figure 1B). Since that time they have rapidly expand- ed in some, but not all, lineages [13]. Why? Is genetic conflict more intense in some species? Or is the antagonistic interaction a consequence of novel func- tions that have evolved more recently? The Mus musculus X is enriched for dozens of other multicopy gene families expressed primarily in postmeiotic cells, which is thought to be a mechanism for escaping PMSC [14]. This interpretation now appears to be correct, with the added caveat that the entire process may be a side effect of genetic conflict between Sly and Slx/Slxl1I. Most of these X-linked amplicons are repressed by Sly during PMSC. Thus, the rapid expansion of Sly— driven by conflict with Slx/Slxl1I—may in turn drive compensatory expansion of other sex-linked genes in order to maintain proper expression levels [13]. One important consequence of recur- rent sex-linked conflict is its potential to drive speciation [6]. Several of the mice presented in Figure 1B can hybridize, often resulting in hybrid male sterility (HMS). In particular, some reciprocal crosses between M. m. musculus and M. m. domesticus yield asymmetric HMS; males are only sterile when a M. m. musculus female is crossed with an M. m. domesticus male. Moreover, sterile males show wide- spread over-expression of the X, presum- ably due to a failure of MSCI and/or PMSC [15]. Cocquet et al. [7] propose that interactions between Sly and Slx/ Citation: Good JM (2012) The Conflict within and the Escalating War between the Sex Chromosomes. PLoS Genet 8(9): e1002955. doi:10.1371/journal.pgen.1002955 Editor: Michael W. Nachman, University of Arizona, United States of America Published September 13, 2012 Copyright: 2012 Jeffrey M. Good. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: JMG is supported by a National Institutes of Health grant (1-R01HD73439-01). The funder had no role in the preparation of the manuscript. Competing Interests: The author has declared that no competing interests exist. * E-mail: jeffrey.good@mso.umt.edu PLOS Genetics | www.plosgenetics.org 1 September 2012 | Volume 8 | Issue 9 | e1002955