Lyon-hypothesis

All females are technically mosaic for the genes of their X chromosomes due to inactivation of one or the other X chromosomes early in development, a phenomenon termed the Lyon hypothesis or lyonization. 

Lyon hypothesis Idea proposed by Mary Lyon that mammalian females inactivate one or the other X-chromosome during early embryogenesis. This deactivated chromosome forms the Barr body. ... 

The answer is a. (Murray, pp 812-828. Scriver, pp 3-45. Sack, pp 97-158. Wilson, pp 23—39.) Females have two alleles for each locus on the X chromosome because of their 46,XX karyotype. One normal allele is by definition sufficient for normal function in X-linked recessive disorders, so that females with one abnormal allele are carriers instead of affected individuals. Only when the companion normal allele is disrupted or missing does the abnormal allele cause disease. The Lyon hypothesis predicts that X inactivation is early, irreversible, and random, but some females inactivate only the X chromosome carrying the normal allele. X autosome translocations may disrupt an X chromosome locus and cause disease because the translocated autosome must remain active to avert embryonic death nonrandom inactivation of the normal X chromosome thus ablates expression of its normal allele. Females with Turner s syndrome, like males with 46,XY karyotypes, have only one X chromosome and can be affected with X-linked recessive diseases. Conversely, females with triple X or trisomy X syndrome have three alleles at each X chromosome locus and are not affected with X-linked recessive disorders. Since choices c, d, and e each require two genetic changes, they are less common than choice a. 

According to the Lyon hypothesis (L9), one X-chromosome in each cell is randomly inactivated in an early stage of embryonic development. As a result one half of the cells of a carrier of this enzyme deficiency should have normal amounts of the enzyme and the other should possess the amount that the individual with the defect has. Half of the cells of a mother of a Lesch-Nyhan patient should have no HPRT and half should have the normal amount the carriers of defects that result in 10% enzyme activity in the effected male offspring should have half of their cells normal and half with 10% of the enzyme. In addition, one would expect that the average value of the enzyme in a sample of red cells drawn from heterozygotes should have contained 50% normal activity in the case of the carrier of Lesch-Nyhan syndrome and the appropriate proportion in the carrier of a partial defect. 

The goal of loading tests is to unmask a functional defect where there is residual activity. In heterozygotic females with OTC deficiency (x-chromo-somal) it can only be used to confirm, but never to exclude a carrier status because of mosaicism (Lyon hypothesis) which might be strongly skewed towards the wild type and thus overlap normal values. 

SEEGMILLER, J.E. (1967K Lyon hypothesis and X-linked disease. Lancet 2 305-306. 

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