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Cited by 154Genetic and Clinical Aspects of Sex Determination and Chromosomal AbnormalitiesSexual Differentiation and DisordersSex and Gender in Healthcare

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A primer on the use of mouse models for identifying direct sex chromosome effects that cause sex differences in non-gonadal tissues

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Burgoyne, Paul S., Arnold, Arthur P.·2016·Biology of Sex Differences
DOI 10.1186/s13293-016-0115-5PMC PMC5154145
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Abstract

In animals with heteromorphic sex chromosomes, all sex differences originate from the sex chromosomes, which are the only factors that are consistently different in male and female zygotes. In mammals, the imbalance in Y gene expression, specifically the presence vs. absence of Sry , initiates the differentiation of testes in males, setting up lifelong sex differences in the level of gonadal hormones, which in turn cause many sex differences in the phenotype of non-gonadal tissues. The inherent imbalance in the expression of X and Y genes, or in the epigenetic impact of X and Y chromosomes, also has the potential to contribute directly to the sexual differentiation of non-gonadal cells. Here, we review the research strategies to identify the X and Y genes or chromosomal regions that cause direct, sexually differentiating effects on non-gonadal cells. Some mouse models are useful for separating the effects of sex chromosomes from those of gonadal hormones. Once direct “sex chromosome effects” are detected in these models, further studies are required to narrow down the list of candidate X and/or Y genes and then to identify the sexually differentiating genes themselves. Logical approaches to the search for these genes are reviewed here.

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Figures

Fig. 1 Major parts of the mouse X and Y chromosomes. Top: The 170-Mb X chromosome is divided into the pseudoautosomal region (PAR), containing the Sts gene and a few others, and the non-PAR region (NPX). The 89-Mb Y chromosome comprises the PAR and non-PAR Y (NPY). The Sry gene is on the Y chromosome short arm. Bottom: XX progeny inherit X chromosomes from the mother (Xm) and father (Xp). The XX mouse is a mosaic of cells expressing one of the parental X chromosomes. Green shows the patches of tissues in which Xp is active, and lavender shows the patches in which Xm is active. The XY mouse inherits the Xm and expresses only that X chromosome in all tissues. CEN centromere
Fig. 1 Major parts of the mouse X and Y chromosomes. Top: The 170-Mb X chromosome is divided into the pseudoautosomal region (PAR), containing the Sts gene and a few others, and the non-PAR region (NPX). The 89-Mb Y chromosome comprises the PAR and non-PAR Y (NPY). The Sry gene is on the Y chromosome short arm. Bottom: XX progeny inherit X chromosomes from the mother (Xm) and father (Xp). The XX mouse is a mosaic of cells expressing one of the parental X chromosomes. Green shows the patches of tissues in which Xp is active, and lavender shows the patches in which Xm is active. The XY mouse inherits the Xm and expresses only that X chromosome in all tissues. CEN centromereCC BY · PubMed Central
Fig. 2 Possible outcomes of experiments using the four core genotypes to assess the effects of sex chromosome complement (XX vs. XYˉ) and gonadal sex (males M vs. females F) on a dependent variable (DV)
Fig. 2 Possible outcomes of experiments using the four core genotypes to assess the effects of sex chromosome complement (XX vs. XYˉ) and gonadal sex (males M vs. females F) on a dependent variable (DV)CC BY · PubMed Central
Fig. 3 Sex chromosome structure diagrams related to Cross A (XY* model [70]). Sections of the sex chromosomes have been deleted to allow expansion of other regions for illustration. For the WT sex chromosomes, the PAR is illustrated in three sections†, one of which contains Sts. The minute + subregion of the NPX (<1% of the total NPX), adjacent to the PAR, is shown as a bracketed region within the entire NPX for the X and XXY* chromosomes, and in yellow for the Y* and Y*X chromosomes. The Y* chromosome has an X centromere and the plus (+) region of NPX adjacent to a unique duplicated PAR that nevertheless lacks Sts (ΔPAR). The X centromere (X CEN) is the functional centromere, whereas the Y centromere is inactive (Y CEN). The Y* chromosome undergoes abnormal recombination with the X chromosome to produce (1) the long XY* chromosome that is an end-to-end fusion of NPX and NPY with the ΔPAR lacking Sts and (2) the minute Y*X chromosome with a normal PAR and the plus (+) region of NPX. The gene map for the Y*X illustrates the approximate positions of genes transcribed from the forward strand (black rectangles) or reverse strand (lines), with the centromere (orange) and the plus (+) region of NPX (yellow) color coded. In effect, Y*X is an X chromosome with a massive NPX deletion running from a region thought to be just proximal to Msl3 and ending within the Sstx/Spin2 multi-copy cluster adjacent to the telomeric X centromere [22, 72, 118–120]. The dividing line between NPX+ and the rest of NPX is not known precisely but is on the centromeric side of Msl3 [72]. This figure updates and corrects earlier versions [50, 121]. † The PAR sections A–C were originally defined by mapping using the XY* model [71]: A, the terminal section of Mid1/Fxy (including the last three exons) that lies within the PAR [122]; B, the region that contains the multi-copy locus DXYHgu1 [123]; and C, the region containing Sts [124]. It is now known that Erdr1 is located in the PAR just distal to Mid1 and is retained in Y* and XY*—thus, it maps to the PAR region B [125]. On the other hand, Asmt is absent in Y* and XY*—thus, it maps to the PAR region C [126]. Sts is thought to be distal to Asmt, but this has not been confirmed
Fig. 3 Sex chromosome structure diagrams related to Cross A (XY* model [70]). Sections of the sex chromosomes have been deleted to allow expansion of other regions for illustration. For the WT sex chromosomes, the PAR is illustrated in three sections†, one of which contains Sts. The minute + subregion of the NPX (<1% of the total NPX), adjacent to the PAR, is shown as a bracketed region within the entire NPX for the X and XXY* chromosomes, and in yellow for the Y* and Y*X chromosomes. The Y* chromosome has an X centromere and the plus (+) region of NPX adjacent to a unique duplicated PAR that nevertheless lacks Sts (ΔPAR). The X centromere (X CEN) is the functional centromere, whereas the Y centromere is inactive (Y CEN). The Y* chromosome undergoes abnormal recombination with the X chromosome to produce (1) the long XY* chromosome that is an end-to-end fusion of NPX and NPY with the ΔPAR lacking Sts and (2) the minute Y*X chromosome with a normal PAR and the plus (+) region of NPX. The gene map for the Y*X illustrates the approximate positions of genes transcribed from the forward strand (black rectangles) or reverse strand (lines), with the centromere (orange) and the plus (+) region of NPX (yellow) color coded. In effect, Y*X is an X chromosome with a massive NPX deletion running from a region thought to be just proximal to Msl3 and ending within the Sstx/Spin2 multi-copy cluster adjacent to the telomeric X centromere [22, 72, 118–120]. The dividing line between NPX+ and the rest of NPX is not known precisely but is on the centromeric side of Msl3 [72]. This figure updates and corrects earlier versions [50, 121]. † The PAR sections A–C were originally defined by mapping using the XY* model [71]: A, the terminal section of Mid1/Fxy (including the last three exons) that lies within the PAR [122]; B, the region that contains the multi-copy locus DXYHgu1 [123]; and C, the region containing Sts [124]. It is now known that Erdr1 is located in the PAR just distal to Mid1 and is retained in Y* and XY*—thus, it maps to the PAR region B [125]. On the other hand, Asmt is absent in Y* and XY*—thus, it maps to the PAR region C [126]. Sts is thought to be distal to Asmt, but this has not been confirmedCC BY · PubMed Central
Fig. 4 Logic tree for genetic dissection of direct sex chromosome effects
Fig. 4 Logic tree for genetic dissection of direct sex chromosome effectsCC BY · PubMed Central

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Metadata

Authors
Burgoyne, P. S., & Arnold, A. P.
Affiliations
  • National Institute for Medical Research (GB)
  • University of California, Los Angeles (US)
Corresponding author
Arnold, Arthur P.
ORCID
Venue
Biology of Sex Differences
Publisher
Springer Science and Business Media LLC
Published
2016-12
Volume
7
Issue
1
Pages
68-68
ISSN
2042-6410 (ISSN-L)
DOI
10.1186/s13293-016-0115-5
PMC
PMC5154145
OpenAlex
W2563939294
Cited by
154
References
144
Citations by year
2026: 17 · 2025: 11 · 2024: 34 · 2023: 14 · 2022: 23 · 2021: 17 · 2020: 14 · 2019: 7 · 2018: 9 · 2017: 8
FWCI
1.07
Type
journal article
Language
en
Open access
Licence
Locations
  • Biology of Sex Differences (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Figshare (submittedVersion, cc-by)
  • The Francis Crick Institute (cc-by)
Funders
  • UK Medical Research Council (U117532009)
  • NIMH (MH59268)
  • National Institute on Deafness and Other Communication Disorders (DC000217)
  • National Institute of Neurological Disorders and Stroke (NS045966, NS043196,)
  • NIDDK (DK083561)
  • National Institute of Child Health and Human Development (HD076125)
  • National Heart, Lung, and Blood Institute (HL119886, HL131182)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Sexual Differentiation and Disorders
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Sex and Gender in Healthcare
Keywords
sex differences, mouse model, SRY, Y chromosome, X chromosome, gonadal hormones, sexual differentiation, candidate gene identification, sex chromosome inactivation

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