Meiotic Consequences of Genetic Divergence Across the Murine Pseudoautosomal Region

Total Page:16

File Type:pdf, Size:1020Kb

Meiotic Consequences of Genetic Divergence Across the Murine Pseudoautosomal Region Genetics: Early Online, published on January 18, 2017 as 10.1534/genetics.116.189092 Meiotic Consequences of Genetic Divergence across the Murine Pseudoautosomal Region Beth L. Dumont Department of Biological Sciences, Initiative in Biological Complexity, North Carolina State University, Raleigh, NC, 27695 Previous Address: North Carolina State University Initiative in Biological Complexity 112 Derieux Place 3510 Thomas Hall Campus Box 7614 Raleigh, NC 27695-7614 e-mail: [email protected] fax: 919-515-3355 Current Address: The Jackson Laboratory 600 Main Street Bar Harbor, ME 04609 email: [email protected] phone: 207-288-6647 Running Header: Sex chromosome meiosis in hybrid mice Key words: pseudoautosomal region, aneuploidy, recombination, meiosis, Mus musculus 1 Copyright 2017. 1 ABSTRACT 2 The production of haploid gametes during meiosis is dependent on the 3 homology-driven processes of pairing, synapsis, and recombination. On the mammalian 4 heterogametic sex chromosomes, these key meiotic activities are confined to the 5 pseudoautosomal region (PAR), a short region of near-perfect sequence homology 6 between the X and Y chromosomes. Despite its established importance for meiosis, the 7 PAR is rapidly evolving, raising the question of how proper X/Y segregation is buffered 8 against the accumulation of homology-disrupting mutations. Here, I investigate the 9 interplay of PAR evolution and function in two interfertile house mouse subspecies 10 characterized by structurally divergent PARs, Mus musculus domesticus and M. m. 11 castaneus. Using cytogenetic methods to visualize the sex chromosomes at meiosis, I 12 show that intersubspecific F1 hybrids harbor an increased frequency of pachytene 13 spermatocytes with unsynapsed sex chromosomes. This high rate of asynapsis is due, 14 in part, to the premature release of synaptic associations prior to completion of 15 prophase I. Further, I show that when sex chromosomes do synapse in intersubspecific 16 hybrids, recombination is reduced across the paired region. Together, these meiotic 17 defects afflict ~50% of spermatocytes from F1 hybrids and lead to increased apoptosis 18 in meiotically dividing cells. Despite flagrant disruption of the meiotic program, a subset 19 of spermatocytes complete meiosis and intersubspecific F1 males remain fertile. These 20 findings cast light on the meiotic constraints that shape sex chromosome evolution and 21 offer initial clues to resolve the paradox raised by the rapid evolution of this functionally 22 significant locus. 2 23 INTRODUCTION 24 The processes of meiotic pairing, synapsis, and recombination are essential for 25 progression through the first meiotic division and the formation of haploid gametes. 26 Unpaired, asynapsed chromatin is transcriptionally silenced (SHIU et al. 2001; BAARENDS 27 et al. 2005), and the aberrant repression of key genes regulating meiotic progression 28 can cause premature arrest of the meiotic cell cycle (TURNER et al. 2005; BURGOYNE et 29 al. 2009). A minimum of one crossover per bivalent is needed to ensure its stable 30 orientation at the metaphase plate (MATHER 1938; NICKLAS 1974), and homologous 31 chromosome pairs that lack an obligate crossover are susceptible to nondisjunction at 32 the first meiotic division (HAWLEY et al. 1994; LAMB et al. 1996; ROSS et al. 1996). As a 33 consequence, meiotic pairing, synapsis, and recombination defects are directly linked to 34 infertility and chromosome aneuploidy (HASSOLD and HUNT 2001; COHEN et al. 2006; 35 BURGOYNE et al. 2009; HANDEL and SCHIMENTI 2010), outcomes with severe 36 consequences for organismal fitness. 37 The mammalian sex chromosomes present a notable deviation to these general 38 rules of meiosis. Although the X and Y are derived from an ancestral pair of 39 homologous autosomes, the long-term suppression of recombination between them has 40 eroded sequence homology across most of their length (GRAVES et al. 1995; 41 CHARLESWORTH 1996; LAHN and PAGE 1999). In most mammals, the only vestige of this 42 ancestral identity is a short region of terminal homology known as the pseudoautosomal 43 region (PAR). The key homology-driven steps of meiotic pairing and recombination are 44 confined to this narrow zone of residual sequence identity (BURGOYNE 1982; MANGS and 45 MORRIS 2007), rendering the PAR one of the most functionally important regions of the 3 46 genome. Failure to initiate or maintain pairing across the PAR is associated with meiotic 47 arrest (MATSUDA et al. 1982, 1992) and reduced recombination across this region has 48 been directly linked to sex chromosome nondisjunction in humans (HASSOLD et al. 1991; 49 SHI et al. 2001). Expectedly, mutations that disrupt sequence homology across the PAR 50 or interfere with sex chromosome pairing are often associated with male infertility and 51 elevated rates of sex chromosome aneuploidy (GABRIEL-ROBEZ et al. 1990; MATSUDA et 52 al. 1992; MOHANDAS et al. 1992; KOROBOVA et al. 1998; BURGOYNE and EVANS 2000; 53 JORGEZ et al. 2011). 54 Despite its central role in mammalian meiosis, the PAR is rapidly evolving, both 55 at the level of DNA sequence and structure (KIPLING et al. 1996; PERRY and ASHWORTH 56 1999; SCHIEBEL et al. 2000; FILATOV and GERRARD 2003; BUSSELL et al. 2006; WHITE et 57 al. 2012a). A comparative sequence analysis of human-orangutan orthologs found that 58 non-coding divergence in PAR-linked genes is more than twice the rate of evolution at 59 autosomal genes (FILATOV and GERRARD 2003). Similarly, the rate of nucleotide 60 substitution across the mouse PAR is several-fold higher than that for adjacent X-linked 61 regions (PERRY and ASHWORTH 1999; WHITE et al. 2012a). PAR length polymorphisms 62 have been characterized in both human and mouse (KIPLING et al. 1996; WHITE et al. 63 2012a; MENSAH et al. 2014), and there is rapid structural rearrangement of the PAR in 64 closely related vole species (ACOSTA et al. 2011; BORODIN et al. 2012). Owing to 65 challenges associated with genotyping and sequencing this region of the genome, the 66 full extent of natural genetic variation in the mammalian PAR is still in active discovery 67 phase (MENSAH et al. 2014). 68 Together, the PAR’s essential meiotic roles and dramatic evolutionary trends 4 69 present an intriguing biological conundrum: How does such a functionally significant 70 region of the genome – and, notably, one whose function is directly dependent upon the 71 preservation of homology between two chromosomes – evolve so rapidly? Answers to 72 this question could provide important new insights into the general requirements for 73 sequence homology and pairing at meiosis, as well as clues into the selective forces 74 that constrain the evolution of sex chromosomes. 75 Toward this goal, one potentially informative experimental approach is to directly 76 assess the meiotic consequences of PAR divergence in hybrids characterized by 77 distinct X- and Y-linked PAR sequences. House mice of the genus Mus represent an 78 especially powerful model system for studying the interplay of PAR function and 79 evolution from this perspective. The pseudoautosomal boundary (PAB) has been 80 subject to considerable repositioning across the Mus phylogeny, including significant 81 PAR divergence between inter-fertile taxa. Within the M. musculus species complex, 82 two closely related subspecies, M. m. domesticus and M. m. castaneus, are 83 characterized by a ~430kb shift in the pseudoautosomal boundary (PAB) (WHITE et al. 84 2012a). The M. m. domesticus PAB, which appears to coincide with that of the standard 85 laboratory mouse strain C57BL6/J, is located ~700kb from the distal end of the X 86 chromosome in intron 3 of Mid1 (PALMER et al. 1997). In contrast, the M. m. castaneus 87 PAR is ~1.1Mb long and encompasses the entire Mid1 locus (WHITE et al. 2012a). 88 Numerous indel mutations within introns of Mid1 further distinguish the M. m. 89 domesticus and M. m. castaneus PARs (WHITE et al. 2012a). 90 The marked shift in the PAB between M. m. castaneus and M. m. domesticus is 91 associated with a reduced frequency of X/Y synapsis in spermatocytes from F1 hybrids 5 92 (WHITE et al. 2012b). Whereas 95% of heterogametic sex chromosomes are synapsed 93 along their PARs at late pachytene in both M. m. castaneus and M. m. domesticus, the 94 X and Y are synapsed in only ~70% of F1 spermatocytes at this early meiotic sub-stage. 95 Surprisingly, however, reduced X/Y synapsis does not appear to elicit downstream 96 consequences for F1 hybrid fertility. F1 animals have testis weights, sperm densities, 97 and measures of sperm morphology that are comparable to or exceed fertility 98 parameters in the inbred parental strains (WHITE et al. 2012b). These findings are in line 99 with observations from other intersubspecies house mouse hybrids, in which the X and 100 Y experience premature dissociation at metaphase I, without obvious repercussions for 101 male fertility (IMAI et al. 1981; MATSUDA et al. 1982, 1983). However, given the 102 established significance of synapsis and recombination for meiotic progression, it 103 remains puzzling that organisms with impaired meiotic sex chromosome associations 104 suffer no apparent fitness consequences. One possible explanation is that animals with 105 reduced XY pairing exhibit subtle spermatogenic defects, but that the associated 106 reduction in fertility is matched or exceeded by fitness gains associated with 107 outbreeding. A second alternative is that the resulting gametes are of reduced genetic 108 quality, harboring elevated rates of sex chromosome aneuploidy. 109 Here, I apply cytogenetic methods and immunofluorescence imaging to conduct 110 an in-depth study of sex chromosome synapsis, recombination, meiotic progression, 111 and aneuploidy in M. m. domesticus, M. m. castaneus, and their reciprocal inter- 112 subspecific F1 hybrids. My findings reveal the phenotypic consequences of PAR 113 divergence on X/Y dynamics at meiosis, with important implications for our 114 understanding the functional constraints governing the evolution of the heterogametic 6 115 mammalian sex chromosomes.
Recommended publications
  • Instability of the Pseudoautosomal Boundary in House Mice
    Genetics: Early Online, published on April 26, 2019 as 10.1534/genetics.119.302232 Article/Investigation Instability of the pseudoautosomal boundary in house mice Andrew P Morgan∗, Timothy A Bell∗, James J Crowley∗; y; z, and Fernando Pardo-Manuel de Villena∗ ∗Department of Genetics and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC yDepartment of Psychiatry, University of North Carolina, Chapel Hill, NC zDepartment of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden April 26, 2019 Corresponding authors: Andrew P Morgan ([email protected]) Fernando Pardo-Manuel de Villena ([email protected]) 5049C Genetic Medicine Building Department of Genetics University of North Carolina Chapel Hill NC 27599-7264 Keywords: meiosis, recombination, pseudoautosomal region, sex chromosome evolution 1 Copyright 2019. 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 inter- val 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 ex- pansion of the PAR in the Mus 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 Mus musculus musculus subspecies and show that it involves a complex rearrangement but still recombines in heterozygous males.
    [Show full text]
  • A Case of Syndromic X-Linked Ichthyosis with Léri-Weill Dyschondrosteosis
    Acta Derm Venereol 2016; 96: 814–815 SHORT COMMUNICATION A Case of Syndromic X-linked Ichthyosis with Léri-Weill Dyschondrosteosis Claire Abasq-Thomas1, Sébastien Schmitt2, Emilie Brenaut1, Chantal Metz3, Jean Chiesa4 and Laurent Misery1 Departments of 1Dermatology and 3Paediatrics, University Hospital of Brest, FR-29609 Brest, 2Department of Genetics, University Hospital of Nantes, Nantes, and 4Department of Genetics, University Hospital of Nîmes, Nîmes, France. E-mail: [email protected] Accepted Feb 1, 2016; Epub ahead of print Feb 2, 2016 Léri-Weill dyschondrosteosis (LWD) is a skeletal dys- tention deficit hyperactivity disorder (ADHP) was suspected plasia marked by disproportionate short stature and initially, but only the patient’s depression, which was probably related to the disease as well as his short stature and skin ap- characteristic Madelung wrist deformity, which is an pearance, was evident after hospitalization. epiphyseal growth plate disturbance characterized by At the dermatology consultation, he presented with dark- dorsal and radial bowing of the radius. In approximately brown scales on the extensor surfaces and a dirty appearance 70% of cases, LWD is caused by haploinsufficiency of the neck. Grey polygonal scales predominated on the lower of the short stature homeobox (SHOX) gene, which limbs. Flexures were affected, but the palms, soles, hairs and nails were spared. An X-linked ichthyosis (XLI) was suspected. maps to the pseudoautosomal region 1 (PAR1) of the Given the associated abnormalities, a contiguous gene syn- sexual chromosomes (Xp22.33 and Yp11.32). Haplo- drome caused by a deletion in Xp was suspected and appropriate insufficiency results from heterozygous mutations and additional investigations were initiated.
    [Show full text]
  • A Strategic Research Alliance: Turner Syndrome and Sex Differences
    A strategic research alliance: Turner syndrome and sex differences The MIT Faculty has made this article openly available. Please share how this access benefits you. Your story matters. Citation Roman, Adrianna K. San and David C. Page. “A strategic research alliance: Turner syndrome and sex differences.” American journal of medical genetics. Part C, Seminars in medical genetics 181 (2019): 59-67 © 2019 The Author(s) As Published 10.1002/AJMG.C.31677 Publisher Wiley Version Author's final manuscript Citable link https://hdl.handle.net/1721.1/125103 Terms of Use Creative Commons Attribution-Noncommercial-Share Alike Detailed Terms http://creativecommons.org/licenses/by-nc-sa/4.0/ HHS Public Access Author manuscript Author ManuscriptAuthor Manuscript Author Am J Med Manuscript Author Genet C Semin Manuscript Author Med Genet. Author manuscript; available in PMC 2019 March 12. Published in final edited form as: Am J Med Genet C Semin Med Genet. 2019 March ; 181(1): 59–67. doi:10.1002/ajmg.c.31677. A strategic research alliance: Turner syndrome and sex differences Adrianna K. San Roman1 and David C. Page1,2,3 1Whitehead Institute, Cambridge, MA 02142, USA 2Howard Hughes Medical Institute, Whitehead Institute, Cambridge, MA 02142 3Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139 Abstract Sex chromosome constitution varies in the human population, both between the sexes (46,XX females and 46,XY males), and within the sexes (for example, 45,X and 46,XX females, and 47,XXY and 46,XY males). Coincident with this genetic variation are numerous phenotypic differences between males and females, and individuals with sex chromosome aneuploidy.
    [Show full text]
  • Escape from X Chromosome Inactivation and the Female Predominance in Autoimmune Diseases
    International Journal of Molecular Sciences Review Escape from X Chromosome Inactivation and the Female Predominance in Autoimmune Diseases Ali Youness 1,†, Charles-Henry Miquel 1,2,† and Jean-Charles Guéry 1,* 1 Infinity-Toulouse Institute for Infectious and Inflammatory Diseases, University of Toulouse, INSERM, CNRS, UPS, 31300 Toulouse, France; [email protected] (A.Y.); [email protected] (C.-H.M.) 2 Arthritis R&D, 92200 Neuilly-Sur-Seine, France * Correspondence: [email protected]; Tel.: +33-5-62-74-83-78; Fax: +33-5-62-74-45-58 † These authors contributed equally to this work. Abstract: Women represent 80% of people affected by autoimmune diseases. Although, many studies have demonstrated a role for sex hormone receptor signaling, particularly estrogens, in the direct regulation of innate and adaptive components of the immune system, recent data suggest that female sex hormones are not the only cause of the female predisposition to autoimmunity. Besides sex steroid hormones, growing evidence points towards the role of X-linked genetic factors. In female mammals, one of the two X chromosomes is randomly inactivated during embryonic development, resulting in a cellular mosaicism, where about one-half of the cells in a given tissue express either the maternal X chromosome or the paternal one. X chromosome inactivation (XCI) is however not complete and 15 to 23% of genes from the inactive X chromosome (Xi) escape XCI, thereby contributing to the emergence of a female-specific heterogeneous population of cells with bi-allelic expression of some X-linked genes. Although the direct contribution of this genetic mechanism in the female susceptibility to autoimmunity still remains to be established, the cellular mosaicism resulting from XCI escape is likely to create a unique functional plasticity within female immune cells.
    [Show full text]
  • A Slippery Boundary
    COMMENTARY A slippery boundary Andrew G. Clark* Molecular Biology and Genetics, 107 Biotech Building, Cornell University, Ithaca, NY 14853 he Y chromosome has provided ing Y chromosome indicate greater sim- used to freely recombine between the X one of the greatest challenges in ilarity than any comparison between the and Y, but later the PAB moved to the finalizing complete mammalian X and Y chromosomes. As one moves right, leaving all of amelogenin in the genome sequences in part be- rightwards in Fig. 1, the genealogy nonrecombining region where it is to- Tcause of its unusual relationship with day. To date the time of movement of changes, such that some X- and Y- the X chromosome. Part of the Y chro- linked genes are closest neighbors on the pseudoautosomal boundary, Iwase mosome, known as the pseudoautosomal the tree. In this region, the divergence et al. (1) make use of the X vs. Y diver- region, must pair with the complemen- between the X and Y chromosomes gence, and arrive at an estimate of 27–70 tary region on the X chromosome and drops from Ϸ30% to Ϸ10%, and this million years ago. This is after the mam- undergo recombination, so that the re- drop occurs at a transposable element malian radiation, implying that there sulting crossovers stabilize the sex chro- insertion into the second intron of may have been more than one change in mosomes for proper separation during amelogenin. Because of this relatively the pseudoautosomal boundary. Consis- meiosis. The Y chromosome also bears lower X–Y divergence, Iwase et al.
    [Show full text]
  • A Short Pseudoautosomal Region in Laboratory Mice
    Downloaded from genome.cshlp.org on September 29, 2021 - Published by Cold Spring Harbor Laboratory Press Letter A Short Pseudoautosomal Region in Laboratory Mice Jo Perry, Steve Palmer, Anastasia Gabriel, and Alan Ashworth1 The Breakthrough Toby Robins Breast Cancer Research Centre, Institute of Cancer Research, London SW3 6JB, UK The pseudoautosomal region (PAR) of mammalian sex chromosomes is a small region of sequence identity that is the site of an obligatory pairing and recombination event between the X and Y chromosomes during male meiosis. During female meiosis, X chromosomes can pair and recombine along their entire length; recombination in the PAR is therefore ∼10× greater in male meiosis compared with female meiosis. A consequence of the presence of the PAR in two copies in males and females is that genes in the region escape the process of X-inactivation. Although the structure and gene content of the human PAR at Xq/Yq is well understood, the mouse PAR, which appears to be of independent evolutionary origin, is poorly characterized. Here we describe a yeast artificial chromosome (YAC) contig covering the distal part of the mouse X chromosome, which we have used to define the pseudoautosomal boundary, that is, the point of divergence of X-specific and X-Y–identical sequences. In addition, we have investigated the size of the mouse PAR by integrating a unique restriction endonuclease recognition site just proximal to the pseudoautosomal boundary by homologous recombination. Restriction digestion of this modified DNA and pulsed field gel electrophoresis reveal that the PAR in these cells is ∼700 kb. Thus, the mouse PAR, although small in size, has retained essential sex chromosome pairing functions despite its rapid rate of evolution.
    [Show full text]
  • The Humanx Chromosome
    Proc. Nati. Acad. Sci. USA Vol. 87, pp. 3680-3684, May 1990 Genetics Long-range restriction map of the terminal part of the short arm of the human X chromosome (sex reversals/X-recessive chondrodysplasia punctata/Kalmaun syndrome) CHRISTINE PETIT, JACQUELINE LEVILLIERS, AND JEAN WEISSENBACH Unitd de Recombinaison et Expression G6ndtique, Institut National de la Santd et de la Recherche Mddicale U163, Centre National de la Recherche Scientifique UA 271, Institut Pasteur, 25 Rue du Dr Roux, 75724 Paris Cedex 15, France Communicated by Jean Dausset, February 27, 1990 ABSTRACT The terminal part of the short arm of the tion (MR) are all localized distal to the X-linked ichtyosis human X chromosome has been mapped by pulsed-field gel (XLI) locus (13-16) (STS locus), Kallmann syndrome (KAL) electrophoresis (PFGE). The map, representing the distal locus maps proximal to STS (17). two-thirds ofXp22.3 spans a total of 10,000 kilobases (kb) from Finally, a genetic map expansion has been observed in Xpter to the DXS143 locus. A comparison with linkage data telomeric regions of human chromosomes (18-20). While in indicates that 1 centimorgan (cM) in this region corresponds to male meiosis the genetic map expansion in the pseudoauto- about 600 kb. CpG islands were essentially concentrated in the somal region is dramatic (21-24), in female meiosis no such 1500 kb immediately proximal to the pseudoautosomal bound- expansion has been observed (21, 24). However, map ex- ary. Several loci, including the gene encoding steroid sulfatase pansions in more subtelomeric parts of Xp22.3 cannot be (STS) and the loci for the X-linked recessive form of chondro- excluded, and the occurrence of a recombination hot spot dysplasia punctata (CDPX) and for Kallmann syndrome (KAL) within locus DXS278 from Xp22.3 has been proposed (10).
    [Show full text]
  • Natural Selection on Human Y Chromosomes
    Title:Natural selection on human Y chromosomes Authors:Chuan-Chao Wang1, Li Jin1, 2, 3, Hui Li1,* Affiliations: 1. State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai 200433, China 2. CAS-MPG Partner Institute for Computational Biology, SIBS, CAS, Shanghai, China 3. Institute of Health Sciences, China Medical City, Taizhou, Jiangsu, China * Correspondence to: [email protected] Abstract The paternally inherited Y chromosome has been widely used in population genetic studies to understand relationships among human populations. Our interpretation of Y chromosomal evidence about population history and genetics has rested on the assumption that all the Y chromosomal markers in the male-specific region (MSY) are selectively neutral. However, the very low diversity of Y chromosome has drawn a long debate about whether natural selection has affected this chromosome or not. In recent several years, the progress in Y chromosome sequencing has helped to address this dispute. Purifying selection has been detected in the X-degenerate genes of human Y chromosomes and positive selection might also have an influence in the evolution of testis-related genes in the ampliconic regions. Those new findings remind us to take the effect of natural selection into account when we use Y chromosome in population genetic studies. Keywords Y chromosome; purifying selection; demographic history Introduction In the field of anthropology, the uniparentally inherited Y chromosome has long been used to trace the paternal lineage of the populations and to understand differences in migration and population genetics between males and females, with additional advantages of small effective population size, low mutation rate, sufficient markers, and population-specific haplotype distribution (Jobling and Tyler-Smith, 1995; Jin and Su, 2000; Underhill et al., 2000).
    [Show full text]
  • Ensuring Meiotic DNA Break Formation in the Mouse Pseudoautosomal Region
    bioRxiv preprint doi: https://doi.org/10.1101/536136; this version posted January 31, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. Acquaviva et al., 30 Jan, 2019 – bioRxiv preprint v1 Ensuring meiotic DNA break formation in the mouse pseudoautosomal region Laurent Acquaviva1*, Michiel Boekhout1†, Mehmet E. Karasu1,2, Kevin Brick3, Florencia Pratto3, Megan van Overbeek1‡, Liisa Kauppi1§, R. Daniel Camerini-Otero3, Maria Jasin2,4* and Scott Keeney1,2,5* 1 Molecular Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. 2 Louis V. Gerstner, Jr., Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY, USA. 3 Genetics & Biochemistry Branch, NIDDK, NIH, Bethesda, MD, USA. 4 Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. 5 Howard Hughes Medical Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. * Correspondence to [email protected], [email protected] or [email protected] Current addresses: †UMC Utrecht, Oncode Insitute, Utrecht University, Utrecht, Netherlands; ‡Caribou Biosciences, Inc., Berkeley, CA, USA; §Faculty of Medicine, University of Helsinki, Helsinki, Finland. Sex chromosomes in males share only a diminutive homologous Results segment, the pseudoautosomal region (PAR), wherein meiotic double-strand breaks (DSBs), pairing, and crossing over must occur A distinctive PAR ultrastructure rich in pro-DSB factors for correct segregation. How cells ensure PAR recombination is We applied a cytogenetic approach to investigate the mouse PAR unknown.
    [Show full text]
  • Y Chromosome
    Y chromosome Description The Y chromosome is one of the two sex chromosomes in humans (the other is the X chromosome). The sex chromosomes form one of the 23 pairs of human chromosomes in each cell. The Y chromosome spans more than 59 million building blocks of DNA ( base pairs) and represents almost 2 percent of the total DNA in cells. Each person normally has one pair of sex chromosomes in each cell. The Y chromosome is present in males, who have one X and one Y chromosome, while females have two X chromosomes. Identifying genes on each chromosome is an active area of genetic research. Because researchers use different approaches to predict the number of genes on each chromosome, the estimated number of genes varies. The Y chromosome likely contains 50 to 60 genes that provide instructions for making proteins. Because only males have the Y chromosome, the genes on this chromosome tend to be involved in male sex determination and development. Sex is determined by the SRY gene, which is responsible for the development of a fetus into a male. Other genes on the Y chromosome are important for enabling men to father biological children (male fertility). Many genes are unique to the Y chromosome, but genes in areas known as pseudoautosomal regions are present on both sex chromosomes. As a result, men and women each have two functional copies of these genes. Many genes in the pseudoautosomal regions are essential for normal development. Health Conditions Related to Chromosomal Changes The following chromosomal conditions are associated with changes in the structure or number of copies of y chromosome.
    [Show full text]
  • The Human Pseudoautosomal Regions: a Review for Genetic Epidemiologists
    European Journal of Human Genetics (2008) 16, 771–779 & 2008 Nature Publishing Group All rights reserved 1018-4813/08 $30.00 www.nature.com/ejhg REVIEW The human pseudoautosomal regions: a review for genetic epidemiologists Antonia Flaquer1, Gudrun A Rappold2, Thomas F Wienker1 and Christine Fischer*,2 1Institute for Medical Biometry, Informatics, and Epidemiology, University of Bonn, Bonn, Germany; 2Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany Two intervals of sequence identity at the tips of X and Y chromosomes, the human pseudoautosomal regions PAR1 and PAR2, have drawn interest from researchers in human genetics, cytogenetics, and evolutionary biology. However, they have been widely ignored in linkage and association studies. The pseudoautosomal regions (PARs) pair and recombine during meiosis like autosomes, but the recombination activity in PAR1 is extremely different between sexes. In men, it exhibits the highest recombination frequencies of the genome. Conflicting genetic maps of this region have been estimated by using three-generation pedigrees, sperm typing, and by using haplotypes from single nucleotide polymorphisms. Male genetic map lengths in the literature vary, and linkage disequilibrium has not been analyzed in detail. We review existing tools like genetic and physical maps, linkage disequilibrium methods, linkage and association analysis, implemented statistical methods, and their suitability for PARs. For multipoint linkage analysis, sex specificity must be indicated twice, first using sex-specific maps, and second by considering the sex-specific pseudoautosomal inheritance pattern. Currently, microsatellite panels and single nucleotide polymorphism chips do not contain sufficient numbers of markers in PAR1 and PAR2. The number of markers in PAR1, needed in indirect association studies, should be much larger than for autosomal regions alike in size, since linkage disequilibrium is very low.
    [Show full text]
  • X Chromosome Dosage Compensation and Gene Expression in the Sheep Kaleigh Flock [email protected]
    University of Connecticut OpenCommons@UConn Master's Theses University of Connecticut Graduate School 8-29-2017 X Chromosome Dosage Compensation and Gene Expression in the Sheep Kaleigh Flock [email protected] Recommended Citation Flock, Kaleigh, "X Chromosome Dosage Compensation and Gene Expression in the Sheep" (2017). Master's Theses. 1144. https://opencommons.uconn.edu/gs_theses/1144 This work is brought to you for free and open access by the University of Connecticut Graduate School at OpenCommons@UConn. It has been accepted for inclusion in Master's Theses by an authorized administrator of OpenCommons@UConn. For more information, please contact [email protected]. X Chromosome Dosage Compensation and Gene Expression in the Sheep Kaleigh Flock B.S., University of Connecticut, 2014 A Thesis Submitted in Partial Fulfillment of the Requirements for the Degree of Masters of Science at the University of Connecticut 2017 i Copyright by Kaleigh Flock 2017 ii APPROVAL PAGE Masters of Science Thesis X Chromosome Dosage Compensation and Gene Expression in the Sheep Presented by Kaleigh Flock, B.S. Major Advisor___________________________________________________ Dr. Xiuchun (Cindy) Tian Associate Advisor_________________________________________________ Dr. David Magee Associate Advisor_________________________________________________ Dr. Sarah A. Reed Associate Advisor_________________________________________________ Dr. John Malone University of Connecticut 2017 iii Dedication This thesis is dedicated to my major advisor Dr. Xiuchun (Cindy) Tian, my lab mates Mingyuan Zhang and Ellie Duan, and my mother and father. This thesis would not be possible without your hard work, unwavering support, and guidance. Dr. Tian, I am so thankful for the opportunity to pursue a Master’s degree in your lab. The knowledge and technical skills that I have gained are invaluable and have opened many doors in my career as a scientist and future veterinarian.
    [Show full text]