Lionizing lyonization 50 years on

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Fifty years ago, and building upon earlier observations bySusumo Ohno and colleagues (Ohno et al. 1959), MaryLyon proposed the random inactivation of one female Xchromosome early in embryogenesis to account for themottled phenotype of female mice heterozygous forspeciWc coat colour gene mutations.“It is here suggested that this mosaic phenotype is dueto the inactivation of one or other X-chromosomeearly in embryonic development. If this is true,pigment cells descended from cells in which thechromosome carrying the mutant gene was inacti-vated will give rise to a normal-coloured patch andthose in which the chromosome carrying the normalgene was inactivated will give rise to a mutant-coloured patch” (Lyon 1961).A key element of Lyon’s hypothesis was the randomnature of X-inactivation (subsequently also given theeponym, ‘lyonization’), aVecting either the maternally orthe paternally inherited X chromosome. Thus, all femalemammals are eVectively mosaics for two distinct cell lines,with either the maternal or the paternal X chromosomebeing inactivated. The relative proportion of the two celllines (the X-inactivation pattern) in any given individualmay, however, be skewed, resulting in an X-inactivationpattern where >80% of the cells exhibit preferential inacti-vation of one or other X chromosome. Unfavourable skew-ing can be important in clinical practice, e.g. in cases ofclinically aVected female carriers of a speciWc X-linkedcondition where the X chromosome carrying the mutantallele is predominantly the active X chromosome (Orstavik2009).In principle, X-inactivation ensures dosage equalitybetween males and females in terms of the number of trans-criptionally active X-linked genes. However, it is nowknown that a subset of X-linked genes escape silencing byX-inactivation and these genes continue to be expressedfrom both X chromosomes. It is also now known that theprocess of X-inactivation involves a number of diVerentmechanisms including DNA methylation, RNA-mediatedgene silencing, and changes in chromatin modiWcation/organization. It is controlled by a speci Wc region on the longarm of the X chromosome (Xq13.2) termed the X-inactivationcentre. Within this X-inactivation centre are a number ofgenes (including