High male: female ratio of germ-line mutations: An alternative explanation for postulated gestational lethality in males in X-linked dominant disorders

G. H. Thomas

Research output: Contribution to journalArticle

Abstract

In this paper I suggest that a vastly higher rate of de novo mutations in males than in females would explain some, if not most, X-linked dominant disorders associated with a low incidence of affected males. It is the inclusion of the impact of a high ratio of male:female de novo germ-line mutations that makes this model new and unique. Specifically, it is concluded that, if an X-linked disorder results in a dominant phenotype with a significant reproductive disadvantage (genetic lethality), affected females will, in virtually all cases, arise from de novo germ-line mutations inherited from their fathers rather than from their mothers. Under this hypothesis, the absence of affected males is explained by the simple fact that sons do not inherit their X chromosome (normal or abnormal) from their fathers. Because females who are heterozygous for a dominant disorder will be clinically affected and will, in most cases, either be infertile or lack reproductive opportunities, the mutant gene will not be transmitted by them to the next generation (i.e., it will be a genetic lethal). This, not gestational lethality in males, may explain the absence of affected males in most, if not all, of the 13 known X-linked dominant diseases characterized by high ratios of affected female to male individuals. Evidence suggesting that this mechanism could explain the findings in the Rett syndrome is reviewed in detail.

Original languageEnglish (US)
Pages (from-to)1364-1368
Number of pages5
JournalAmerican Journal of Human Genetics
Volume58
Issue number6
StatePublished - 1996

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Germ-Line Mutation
Fathers
Rett Syndrome
X Chromosome
Nuclear Family
Mothers
Phenotype
Mutation
Incidence
Genes

ASJC Scopus subject areas

  • Genetics

Cite this

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abstract = "In this paper I suggest that a vastly higher rate of de novo mutations in males than in females would explain some, if not most, X-linked dominant disorders associated with a low incidence of affected males. It is the inclusion of the impact of a high ratio of male:female de novo germ-line mutations that makes this model new and unique. Specifically, it is concluded that, if an X-linked disorder results in a dominant phenotype with a significant reproductive disadvantage (genetic lethality), affected females will, in virtually all cases, arise from de novo germ-line mutations inherited from their fathers rather than from their mothers. Under this hypothesis, the absence of affected males is explained by the simple fact that sons do not inherit their X chromosome (normal or abnormal) from their fathers. Because females who are heterozygous for a dominant disorder will be clinically affected and will, in most cases, either be infertile or lack reproductive opportunities, the mutant gene will not be transmitted by them to the next generation (i.e., it will be a genetic lethal). This, not gestational lethality in males, may explain the absence of affected males in most, if not all, of the 13 known X-linked dominant diseases characterized by high ratios of affected female to male individuals. Evidence suggesting that this mechanism could explain the findings in the Rett syndrome is reviewed in detail.",
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