HUMAN SEX CHROMOSOME ABNORMALITIES IN RELATION TO DNA REPLICATION AND HETEROCHROMATINIZATION.

Striking differences are demonstrable in the morphological and functional state of the two X-chromosomes in somatic cells of the female of a variety of mammalian species. Recent studies'-10 have led to the concept that in somatic cells one of the two X-chromosomes, which may be of either maternal or paternal origin, undergoes a change of state which first becomes manifest during early ontogeny. The transformation is characterized by (1) delayed replication of DNA during the regular synthetic period of interphase,4' 5 (2) a potential for precocious condensation during prophase and formation of a prominent heteropycnotic body during interphase, Barr's sex chromatin,1-3 and (3) suppression or modification of the action of genes6-'0 on these parts of the X-chromosome. The other X-chromosome of females and the single X in somatic cells of males complete replication along with the majority of the complement, are isopycnotic, and genetically active. Based on the time of appearance of sex chromatin in the human embryo and the heteropycnotic behavior of X-chromosomes in sex-chromosome abnormalities in man, Grumbach and Morishima3 proposed that the change of state, heterochromatinization, is induced in a large part of one of the two X-chromosomes of each cell during an early embryonic stage, the "fixed differentiation hypothesis." The transformation once established is then transmitted to all descendants of that particular chromosome in succeeding somatic cell generations. 'yon,7 on the basis of mosaicism in the expression of X-linked factors in female mice, proposed a similar hypothesis which involves the genetic inactivation of the heterochromatinized X-chromosome. Heterochromatin as originally defined by Heitz" is characterized by permanent heteropycnosis (highly condensed state) and relative genetic inactivity. It has often been assumed to represent a different kind of chromatin from the regular euchromatin, a special type of DNA, perhaps nonspecific in its action. On the other hand, others have proposed that heterochromatin and euchromatin represent alternative states of the chromosome related to function over the cell cycle or during morphogenesis.'2 However, the interesting feature of the mammalian X-chromosome system is that here we have a clear indication that this heterochromatin, at least, is not a special type of genetic material, but represents an induced state, a type of genetic control which we suggest may operate at many loci in autosomes as