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X-inactivation profile reveals extensive variability in X-linked gene expression in females


In female mammals, most genes on one X chromosome are silenced as a result of X-chromosome inactivation1,2. However, some genes escape X-inactivation and are expressed from both the active and inactive X chromosome. Such genes are potential contributors to sexually dimorphic traits, to phenotypic variability among females heterozygous for X-linked conditions, and to clinical abnormalities in patients with abnormal X chromosomes3. Here, we present a comprehensive X-inactivation profile of the human X chromosome, representing an estimated 95% of assayable genes in fibroblast-based test systems4,5. In total, about 15% of X-linked genes escape inactivation to some degree, and the proportion of genes escaping inactivation differs dramatically between different regions of the X chromosome, reflecting the evolutionary history of the sex chromosomes. An additional 10% of X-linked genes show variable patterns of inactivation and are expressed to different extents from some inactive X chromosomes. This suggests a remarkable and previously unsuspected degree of expression heterogeneity among females.

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Figure 1: Q-SNaPshot assay of allelic expression for three X-linked genes.
Figure 2: X-inactivation as a measure of allelic expression in non-randomly inactivated primary fibroblasts.
Figure 3: X-inactivation profile of the human X chromosome.
Figure 4: Xi expression data in primary fibroblasts and Xi hybrids correlate with location on X.


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We thank M. Ross for sharing information before publication and gratefully acknowledge technical assistance from G. Nickel, K. Trevarthen, J. Dunn, A. Cottle and M. Moon. This work was supported in part by a National Institutes of Health research grant to H.F.W. and L.C.

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Correspondence to Laura Carrel.

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Supplementary information

Supplementary Figure S1

Y homology influences Xi expression. (DOC 23 kb)

Supplementary Figure S2

Xi expression data correlate with repetitive element composition. (DOC 23 kb)

Supplementary Figure S3

Gene organization and sequence composition of 500 kb regions on the X; repetitive elements cannot fully explain Xi expression patterns. (PDF 107 kb)

Supplementary Figure S4

Distribution of transcripts with CpG islands. (DOC 23 kb)

Supplementary Figure S5

Levels of relative Xa and Xi expression. (DOC 63 kb)

Supplementary Figure S6

RT-PCR assays of gene expression from the Xi chromosome. (DOC 357 kb)

Supplementary Table S1

Genes assayed by quantitative analysis of expressed polymorphisms in panel of non-randomly inactivated primary fibroblasts. (XLS 40 kb)

Supplementary Table S2

X-linked genes analyzed in this study. (XLS 16 kb)

Supplementary Table S3

Genes analysed in Xi hybrids. (XLS 476 kb)

Supplementary Table S4

Comparison of X inactivation patterns as measured in primary fibroblasts and in Xi hybrids. (XLS 16 kb)

Supplementary Note S1

Notes as to why some reported genes were not fully analysed. (DOC 23 kb)

Supplementary Note S2

Although the RT-PCR assay utilized is not strictly quantitative, substantial effort was made to ensure that Xi hybrids scored positive did have significant levels of expression. (DOC 20 kb)

Supplementary Note S3

The S3/S4 boundary has been assigned to a 2.5 Mb region within Xp22.2-Xp22.31. (DOC 19 kb)

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Carrel, L., Willard, H. X-inactivation profile reveals extensive variability in X-linked gene expression in females. Nature 434, 400–404 (2005).

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