Regulation of Gene Action — Dosage Compensation 



485 



the number of Barr bodies. Consequently, 

 the genes for sex, particularly those located 

 in the Y, do not suppress Barr body forma- 

 tion in normal or abnormal males. 



According to the hypothesis under dis- 

 cussion, each excess X is rendered hyper- 

 coiled and functionally inactive. It is, how- 

 ever, still capable of being replicated dur- 

 ing interphase, although the replication is 

 delayed. - That no normal tissue in a fe- 

 male ever has 100 per cent of its nuclei 

 showing a Barr body may very well be 

 partly due to errors in cytological observa- 

 tion. It is also possible that some of the 

 cells that fail to show a Barr body are rep- 

 licating the X chromosome involved. As a 

 consequence of Barr body formation, males 

 and females — whether normal or abnormal 

 — apparently have similar numbers of func- 

 tional X chromosomal genes per diploid 

 number of autosomes. :; In other words, 

 basically males and females may not be very 

 different after all, at least at the functional 

 X chromosome level. 



The human X chromosome (Figure 10- 

 7, p. 139) contains a gene necessary for 

 production of the enzyme glucoses-phos- 

 phate dehydrogenase ( G-6-PD ) . One X 

 chromosomal mutant fails to produce this 

 enzyme. Males with the normal X there- 

 fore can and those with the mutant X can- 

 not make this enzyme. Since the Y chro- 

 mosome has no effect on the production of 

 this enzyme it carries no allele for this gene. 

 When individually tested, 4 red blood cor- 

 puscles of genetically pure, normal males 

 and females show the same amount of G- 

 6-PD activity. If both normal alleles op- 

 erated in the female as they did in the male, 

 we would expect the red blood corpuscles 



2 See M. M. Grumbach, A. Morishima, and J. H. 



Taylor (1963). 



-See M. F. Lyon (1962). 



4 See E. Beutler, M. Yeh, and V. F. Fairbanks 



(1962), and D. R. Davidson, H. M. Nitowsky, and 



B. Childs (1963). 



of a normal female to produce twice as 

 much enzyme as those of a normal male. 

 When the red blood cells of females hetero- 

 zygous for the X-linked mutant are studied, 

 however, some are found to be normal and 

 others deficient with respect to G-6-PD; 

 no corpuscles of intermediate activity are 

 found. These results prove that such hu- 

 man females are functional mosaics for 

 this locus. Some of their red blood cor- 

 puscles are derived from nucleated cells in 

 which the normal gene is nonfunctional, the 

 defective locus functional; others come from 

 cells in which the mutant gene is nonfunc- 

 tional, the normal locus functional. The al- 

 ready-mentioned results obtained with nor- 

 mal females support the general conclusion 

 that euploid females can express only one 

 allele of this locus in any cell, with some- 

 times the maternally-derived, sometimes the 

 paternally-derived locus being operational. 

 In support of this conclusion is the finding 

 that in human females not carrying the G- 

 6-PD mutant, otherwise diploid cells, either 

 X0, XX, XXXY, or XXXX, all produce 

 the same amount of G-6-PD. 



Since X-linked muscular dystrophy is due 

 to a rare mutant of an X-limited gene, usu- 

 ally only males have this disease. Muscular 

 dystrophy is closely associated with certain 

 enzymatic and histological abnormalities. 

 Studies of females known to be mutant het- 

 erozygotes and showing subclinical and clin- 

 ical muscular dystrophy "' reveal two popu- 

 lations of muscle fiber — one normal and the 

 other dystrophic, a result best attributed to 

 functional mosaicism, just as described for 

 the G-6-PD locus. The same kind of re- 

 sult is obtained for at least five other X- 

 linked genes. On the basis of these genetic 

 results and the cytological studies of Barr 

 bodies, we can conclude that a female nor- 

 mally has an appreciable portion of one X 

 chromosome inactivated in many diploid so- 



5 See C. M. Pearson, W. M. Fowler, and S. W. 

 Wright (1963). 



