Transmission‐ratio distortion of X chromosomes among male offspring of females with skewed X‐inactivation

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Abstract
We have begun a search for heritable variation in X‐chromosome inactivation pattern in normal females to determine whether there is a genetic effect on the imprinting of X‐chromosome inactivation in humans. We have performed a quantitative analysis of X‐chromosome inactivation in lymphocytes from mothers in normal, three‐generation families. Eight mothers and 12 grandmothers exhibited evidence of highly skewed patterns of X‐chromosome inactivation. We observed that the male offspring of females with skewed X‐inactivation patterns were three times more likely to inherit alleles at loci that were located on the inactive X chromosome (Xi) than the active X chromosome (Xa). The region of the X chromosome for which this phenomenon was observed extends from XP11 to ‐Xq22. We have also examined X‐chromosome inactivation patterns in 21 unaffected mothers of male bilateral sporadic retinoblastoma patients. Six of these mothers had skewed patterns of X‐chromosome inactivation. In contrast to the tendency for male offspring of skewed mothers from nondisease families to inherit alleles from the inactive X chromosome, five of the six affected males inherited the androgen receptor alleles from the active X chromosome of their mother.

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