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. 2006 Aug;173(4):2103-10.
doi: 10.1534/genetics.105.054882. Epub 2006 Apr 2.

Genetic Control of X Chromosome Inactivation in Mice: Definition of the Xce Candidate Interval

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Free PMC article

Genetic Control of X Chromosome Inactivation in Mice: Definition of the Xce Candidate Interval

Lisa Helbling Chadwick et al. Genetics. .
Free PMC article

Abstract

In early mammalian development, one of the two X chromosomes is silenced in each female cell as a result of X chromosome inactivation, the mammalian dosage compensation mechanism. In the mouse epiblast, the choice of which chromosome is inactivated is essentially random, but can be biased by alleles at the X-linked X controlling element (Xce). Although this locus was first described nearly four decades ago, the identity and precise genomic localization of Xce remains elusive. Within the X inactivation center region of the X chromosome, previous linkage disequilibrium studies comparing strains of known Xce genotypes have suggested that Xce is physically distinct from Xist, although this has not yet been established by genetic mapping or progeny testing. In this report, we used quantitative trait locus (QTL) mapping strategies to define the minimal Xce candidate interval. Subsequent analysis of recombinant chromosomes allowed for the establishment of a maximum 1.85-Mb candidate region for the Xce locus. Finally, we use QTL approaches in an effort to identify additional modifiers of the X chromosome choice, as we have previously demonstrated that choice in Xce heterozygous females is significantly influenced by genetic variation present on autosomes (Chadwick and Willard 2005). We did not identify any autosomal loci with significant associations and thus show conclusively that Xce is the only major locus to influence X inactivation patterns in the crosses analyzed. This study provides a foundation for future analyses into the genetic control of X chromosome inactivation and defines a 1.85-Mb interval encompassing all the major elements of the Xce locus.

Figures

F<sc>igure</sc> 1.—
Figure 1.—
LOD curves from the B6CASTF2 Xce heterozygotes/Xce homozygotes whole-genome scan. LOD score is on the y-axis; chromosomes are on the x-axis. Genetic location of markers tested are indicated by tick marks on the x-axis. The genomewide level of significance as determined by permutation tests is LOD = 3.5. Significance was reached only on the X chromosome, indicating that Xce is the only major locus influencing X inactivation patterns in this cross.
F<sc>igure</sc> 2.—
Figure 2.—
X chromosome LOD curve from extended Xce heterozygote/Xce homozygote analysis (n = 655, from B6CAST and BALBCAST intercrosses and backcrosses). LOD scores are on the y-axis; genetic positions of markers tested (from MGD) are on the x-axis. The genetic locations of Pctk1, Idh3g, Xist/Tsix/Xite, DXMit41, and DXMit171 are indicated. The 1.5-LOD confidence interval is indicated by a short, solid horizontal line, intersected by a vertical line indicating the peak. This suggests that the Xce locus is located between DXMit41 and DXMit171.
F<sc>igure</sc> 3.—
Figure 3.—
Haplotype map of females with crossovers between DXMit41 and DXMit171. Heterozygous genotypes (B6/CAST or BALB/CAST) are indicated as shaded segments; homozygous genotypes (B6/B6 or BALB/BALB) are indicated as solid segments. Diagonal regions between markers indicate the location of crossover events. The locations of Xite, Tsix, and Xist are indicated. The genetic background and X inactivation pattern of each individual are also indicated. Animals with homozygous genotypes between SNP-846 and DXMit171 had Xce homozygous-like X inactivation patterns, suggesting that the proximal boundary of the Xce interval lay between DXMit168 and SNP-846. Conversely, animals with heterozygous genotypes between DXMit41 and SNP-843 had Xce heterozygous-like X inactivation patterns, suggesting that the distal boundary of the candidate interval lay between LeeSNPG-I and SNP-843. The B6CAST N4 backcross individual selected for further progeny testing (Figure 4) is indicated by an arrowhead.
F<sc>igure</sc> 4.—
Figure 4.—
Progeny testing to confirm the distal boundary of the Xce candidate region. A B6CAST N4 backcross female with a crossover between LeeSNPG-I and SNP-843 was crossed to a B6 male and the X inactivation patterns of the N5 progeny were determined. The predicted range of X inactivation patterns for Xce homozygotes (mean = 0.5, SD = 0.1, as suggested by Plenge et al. 2000) and Xce heterozygotes arising from this cross (mean = 0.29, SD = 0.13, from Chadwick and Willard 2005) are indicated. “Recombinant” animals do not carry the heterozygous haplotype of the parent in the DXMit41–DXMit171 candidate region; “nonrecombinant” animals have the same haplotype as the N4 parent. As expected, N5 females with the recombinant haplotype have X inactivation patterns that are generally consistent with an Xce homozygous genotype, while N5 females with the nonrecombinant haplotype have X inactivation patterns consistent with an Xce heterozygous genotype.
F<sc>igure</sc> 5.—
Figure 5.—
LOD curves from B6CASTF2 Xce heterozygote whole-genome scan. (Top) The LOD scores from the whole-genome analysis of B6CASTF2 Xce heterozygous adult samples. The genomewide significance level as determined by permutation tests is LOD = 3.5. (Bottom) The LOD scores of adults (solid lines) and embryos (dashed lines) for the five most significant chromosomes from the adult analysis. The location of Xiaf1 on chromosome 15 is indicated (Percec et al. 2002).

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