Polymorphic X-Chromosome Inactivation of the Human TIMP1 Gene

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Polymorphic X-Chromosome Inactivation of the Human TIMP1 Gene Catherine L. Anderson, Carolyn J. Brown The American Journal of Human Genetics Volume 65, Issue 3, Pages 699-708 (September 1999) DOI: 10.1086/302556 Copyright © 1999 The American Society of Human Genetics Terms and Conditions

Figure 1 Expression analysis of genes in Xp11.23. A, Schematic map of genes flanking TIMP1. ZNF41 is present in a YAC spanning the region represented by the arrow; however, the unbroken portion of the arrow represents the most likely area for ZNF41, since an overlapping YAC that was negative for ZNF41 was shown to be deleted in this region (Brandau et al. 1998). B, Products from amplification of cDNA derived from the hybrids, listed with human-specific primers for the genes shown. Hybrids retaining the active X chomosome (Xa) or inactive X chromosome (Xi) are denoted as follows (numbers denote lanes): 1 = A23-1aC15; 2 = tHM-34-2A41B; 3 = t11-4Aaz5; 4 = t48-1a-1Daz4a; 5 = tHM-34-2A-3az1a; 6 = t75-2maz34-1a; 7 = t86-B1maz1b-3a; 8 = CHO-01416-07. The American Journal of Human Genetics 1999 65, 699-708DOI: (10.1086/302556) Copyright © 1999 The American Society of Human Genetics Terms and Conditions

Figure 2 TIMP1 polymorphism assay and results. A, Schematic outline of the TIMP1 polymorphism assay. Oligonucleotide primers were designed and optimized to provide allele-specific amplification. We analyzed females with extreme skewing of X inactivation so that the same X chromosome would be active in all cells. DNA was first tested to find heterozygous females. In these informative females, cDNA was then amplified. The resulting products differ, in size, between DNA and cDNA, since the primers span a small intron. In this diagram, the active X chromosome is shown to have the C allele, and the inactive X chromosome has the T allele. If only the C allele was amplified in cDNA, there was no TIMP1 expression from the inactive X chromosome. If both the C and T alleles were seen in cDNA, TIMP1 was expressed from both X chromosomes. B, Specificity of the allele-specific primers, as demonstrated by the amplification of only one allele in the homozygous samples (end lanes). When these DNA samples were mixed in the various proportions as listed, 10% of one allele could be detected in the presence of the other allele. C, Results for females with extreme skewing of X inactivation, demonstrated by other assays (numbers denote gels): 1 = female homozygous for C (GM07023); 2 = female homozygous for T (AG); 3 = heterozygous female, TIMP1 inactivated (09); 4 = heterozygous female, TIMP1 expressed from both X chromosomes (07); 5 = heterozygous female, TIMP1 inactivated (GM07059); 6 = heterozygous female, TIMP1 expressed from both X chromosomes. L = lymphoblast (HSC593); F = fibroblast (60). D, Confirmation of X-inactivation patterns (>90% skewing), for panels 4 and 6. For female 07 (gel 4), androgen-receptor methylation assay is shown. Both alleles are seen in uncut DNA. After digestion with the methylation-sensitive enzyme HpaII, amplification of the bottom allele is essentially eliminated, demonstrating that it is unmethylated—and therefore active—in the majority of the cells. For female HSC593 (L) and 60 (F) (gel 6), the results of XIST allele-specific PCR amplification are shown. Both alleles are present in DNA, but only one allele is amplified in cDNA, showing that the same X chromosome is inactive in all cells. The American Journal of Human Genetics 1999 65, 699-708DOI: (10.1086/302556) Copyright © 1999 The American Society of Human Genetics Terms and Conditions