A first-generation X-inactivation profile of the human X chromosome

In females, most genes on the X chromosome are generally assumed to be tran scriptionally silenced on the inactive X as a result of X inactivation. How ever, particularly in humans, an increasing number of genes are known to "e scape" X inactivation and are expressed from both the active (Xa) and inact ive (Xi)X chromosomes; such genes reflect different molecular and epigeneti c responses X inactivation and are candidates for phenotypes associated wit h X aneuploidy. To identify genes that escape X inactivation and to generat e a first-generation X-inactivation profile of the X, we have evaluated the expression of 224 X-linked genes and expressed sequence tags by reverse-tr anscription-PCR analysis of a panel of multiple independent mouse/human som atic cell hybrids containing a normal human Xi but no Xa, The resulting sur vey yields an initial X-inactivation profile that is estimated to represent approximate to 10% of all X-linked transcripts. Of the 224 transcripts tes ted here, 34 (three of which are pseudoautosomal) were expressed in as many as nine Xi hybrids and thus appear to escape inactivation, The genes that escape inactivation are distributed nonrandomly along the X; 31 of 34 such transcripts map to Xp, implying that the two arms of the X are epigenetical ly and/or evolutionarily distinct and suggesting that generic: imbalance of Xp may be more severe clinically than imbalance of Xq. A complete X-inacti vation profile will provide information relevant to clinical genetics and g enetic counseling and should yield insight into the genomic and epigenetic organization of the X chromosome.