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HIGHLIGHTED ARTICLE | INVESTIGATION Instability of the Pseudoautosomal Boundary in House Mice Andrew P. Morgan,*,†,1 Timothy A. Bell,*,† James J. Crowley,*,†,‡,§ and Fernando Pardo-Manuel de Villena*,†,1 *Department of Genetics, †Lineberger Comprehensive Cancer Center, and ‡Department of Psychiatry, University of North Carolina, Chapel Hill, North Carolina 27514, and §Department of Clinical Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden ORCID IDs: 0000-0003-1942-4543 (A.P.M.); 0000-0002-5738-5795 (F.P.-M.d.V.) ABSTRACT Faithful segregation of homologous chromosomes at meiosis requires pairing and recombination. In taxa with dimorphic sex chromosomes, pairing between them in the heterogametic sex is limited to a narrow interval of residual sequence homology known as the pseudoautosomal region (PAR). Failure to form the obligate crossover in the PAR is associated with male infertility in house mice (Mus musculus) and humans. Yet despite this apparent functional constraint, the boundary and organization of the PAR is highly variable in mammals, and even between subspecies of mice. Here, we estimate the genetic map in a previously documented expansion of the PAR in the M. musculus castaneus subspecies and show that the local recombination rate is 100-fold higher than the autosomal background. We identify an independent shift in the PAR boundary in the M. musculus musculus subspecies and show that it involves a complex rearrangement, but still recombines in heterozygous males. Finally, we demonstrate pervasive copy-number variation at the PAR boundary in wild populations of M. m. domesticus, M. m. musculus, and M. m. castaneus. Our results suggest that the intensity of recombination activity in the PAR, coupled with relatively weak constraints on its sequence, permit the generation and maintenance of unusual levels of polymorphism in the population of unknown functional significance. KEYWORDS meiosis; recombination; pseudoautosomal region; sex chromosome evolution AIRING, synapsis, and crossing-over between homolo- faithful segregation of the sex chromosomes in both humans Pgous chromosomes is a requirement for orderly progres- and mice (Rouyer et al. 1986; Hassold et al. 1991; Matsuda sion through meiosis that is broadly conserved in eukaryotes et al. 1991; Burgoyne et al. 1992), although not in some other (Mather 1938; Mirzaghaderi and Hörandl 2016). In most mammals (Ashley and Moses 1980; Wolf et al. 1988; Carnero organisms, pairing is facilitated by sequence homology. The et al. 1991). We limit our discussion here to the placental — sex chromosomes of mammals which are divergent in se- mammals; the sex chromosomes of marsupials and mono- quence and structure over most of their length (Graves tremes are distinct, and have more complex meiotic behavior — 2006) thus pose a unique challenge for males, the hetero- (Sharman et al. 1950; Sharp 1982; Graves and Watson 1991; gametic sex. Homology between the X and Y chromosomes is Page et al. 2005). limited to remnant “pseudoautosomal regions” (PARs) that Despite the putative functional importance of the PAR, its are a vestige of the sex chromosomes’ origins as an ancestral boundary and structure appear to evolve rapidly in eutherian autosome pair (Ohno 1966). Synapsis and crossing-over in mammals (Raudsepp and Chowdhary 2015). PARs have been this relatively small territory appears to be necessary for defined at the sequence level for only a handful of organisms, due in large part to the challenges of assembling repeat- and Copyright © 2019 by the Genetics Society of America GC-rich sequences. The human X chromosome has two PARs: doi: https://doi.org/10.1534/genetics.119.302232 PAR1 on Xp and PAR2 on Xq (Figure 1A). Only PAR1 repre- Manuscript received March 4, 2019; accepted for publication April 23, 2019; published sents the remnant of the ancestral autosome, while PAR2 Early Online April 26, 2019. Supplemental material available at FigShare: https://doi.org/10.25386/genetics. arose via several rearrangements within the primate lineage 7798889. (Charchar et al. 2003); PAR1 recombines avidly in male mei- 1Corresponding authors: Department of Genetics, 5049C Genetic Medicine Bldg., University of North Carolina, Chapel Hill, NC 27514. E-mail: andrew.parker. osis (Hinch et al. 2014), while PAR2 recombines infrequently [email protected]; and [email protected] and has sequence properties similar to the rest of the X Genetics, Vol. 212, 469–487 June 2019 469 Figure 1 Schematic organization of the pseudoautosomal region (PAR) in human and the house mouse. (A) Synteny map of the human and mouse X chromosomes. Orthologous genes are shown in black, non- orthologous genes in gray, and the gene marking the end of the human–mouse syn- teny block (MID1) in red. PARs shown as gray boxes. Not all human genes are shown. (B) The mouse PAR. The canonical PAR de- fined in the C57BL/6J reference strain (top) encompasses at least two genetically mapped protein-coding genes (Sts and Asmt) and the 39 fragment of Mid1. Its phys- ical size is 750 kb, most of which consists of unassembled repetitive sequence. The ex- tended PAR of CAST/EiJ (bottom) involves the duplication of 400 kb of ancestrally X-unique sequence onto the Y, including the 59 fragment of Mid1 (White et al. 2012a). chromosome (Cotter et al. 2016). At least one well-described mate by the Genome Reference Consortium), and includes structural polymorphism of PAR1 segregates in human pop- the sequences of Mid1 and Asmt. ulations (Mensah et al. 2014). The allele is a translocation of The PAR boundary is variable even within the Mus genus. It X-linked sequence onto the Y chromosome, and arose via falls between the eighth and ninth exons of Mid1 in the Mus nonhomologous recombination between repetitive elements spretus-derived strain SPRET/Ei (Perry et al. 2001). White present on the X and the male-specific portion of the Y chro- et al. (2012a) showed that in the Mus musculus castaneus- mosome. The duplicated segment recombines in male meio- derived strain CAST/EiJ, the PAR boundary is shifted sis at rates similar to single-copy PAR1 (Poriswanish et al. 400-kb proximally so that the entire sequence of Mid1 is 2018). The PARs of simian primates, such as the rhesus ma- present on both sex chromosomes. This implies translocation caque, have sequence homology and conserved synteny with of previously X-unique sequence into the Y chromosome at human PAR1 on Xp (Ellis et al. 1990), and are in the order of the PAR boundary. Recombinants in this “extended PAR” 3 Mb in physical size, while those of ruminants extend further were recovered from F2 crosses with the M. m. domesticus- into the ancestral X chromosome and are closer to 10 Mb in derived WSB/EiJ strain, and heterozygosity in the PAR was size (Das et al. 2009). associated with spermatogenic failure (White et al. 2012b). However, the mouse PAR is dissimilar to those of humans Hereafter, we refer to the PAR defined in C57BL/6J as the or other mammals. Its basic organization is shown in Figure “canonical PAR” and the CAST/EiJ allele as an extended PAR 1B. Its boundary falls in the third intron of the mouse ortho- (Figure 1B). Unlike the canonical PAR, the extended portion log of human Opitz syndrome (Online Mendelian Inheri- of the PAR in CAST/EiJ consists mostly of unique sequence, tance in Man #300000) gene MID1 (Palmer et al. 1997). with GC content and repeat density similar to the genomic Restriction mapping has shown that the mouse PAR is background. 750 kb in size in the C57BL/6J inbred strain, most of which Gain or loss of pseudoautosomal identity is predicted to consists of arrays of GC-rich satellite and other repetitive have several important consequences for molecular evolution. sequences (Perry et al. 2001), and is exquisitely prone to in- First, since pseudoautosomal genes are diploid in both sexes, ternal rearrangement in male meiosis (Kipling et al. they are subject to a different dosage-compensation regime 1996a,b). Two genes, Sts (Kipling et al. 1996a) and Asmt than the rest of the X chromosome and are more likely to (Kasahara et al. 2010), have been genetically mapped distal escape X-inactivation (Graves et al. 1998). Second, to the to Mid1. Two further genes (Ngln4x and Sfrs17a) have been extent that recombination is mutagenic (Hellmann et al. localized to the PAR in comparative studies (Bellott et al. 2003), the intensity of pseudoautosomal recombination in 2014) but lie in an assembly gap, the sequence of which male meiosis means that pseudoautosomal sequences are has not yet been finished (https://www.ncbi.nlm.nih.gov/ expected to diverge more quickly across species than grc/mouse/issues/MG-3246). The representation of the strictly X- or Y-linked sequences. Diversity within popula- PAR in the current version of the reference genome tions should also be higher than at sex-linked sites, due to (mm10/GRCm38) comprises 961; 540 bases (of which both higher mutational input, and mitigation of hitchhik- 800; 000 lie in two gaps whose sizes represent a rough esti- ing and background-selection effects by the high local 470 A. P. Morgan et al. recombination rate in males. Finally, the spectrum of muta- progeny using either a standard phenol–chloroform method tions in pseudoautosomal sequences should be biased by the (Green and Sambrook 2012), or DNeasy Blood & Tissue Kits locally increased effects of GC-biased gene conversion (Lamb (catalog no. 69506; QIAGEN, Valencia, CA). Approximately 1984; Eyre-Walker 1993). These expectations have generally 1.5 mg of DNA per sample was shipped to Neogen (Lincoln, been borne out in empirical studies of the human (Schiebel NE) for hybridization to one of two Mouse Universal Geno- et al. 2000; Filatov and Gerrard 2003; Cotter et al. 2016) and typing Arrays, MegaMUGA (77K probes) or MiniMUGA (11K mouse (Perry and Ashworth 1999; Huang et al.
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