Mode of Inheritance of the Higher Degree of Megakaryocyte Polyploidization in C3H Mice. I. Evidence for a Role of Genomic Imprinting in Megakaryocyte Polyploidy Determination

Abstract

AbstractC3H mice have higher average ploidy megakaryocytes than all other mouse strains tested, but the mode of inheritance of this anomaly is unknown. Therefore, to clarify the genetics of high ploidy megakaryocytes in C3H mice, we measured megakaryocyte DNA content from both male and female offspring from F1, as well as backcross mat-ings. In all, offspring from seven different matings of mice were studied: (1) C57BL X C57BL (the first strain listed is the male parent in each case), (2) B6C3F1 (offspring from C57BL X C3H mating) X C57BL, (3) C57BL X B6C3F1, (4) C57BL X C3H, (5) C3H X B6C3F1, (6) B6C3F1 X C3H, and (7) C3H X C3H. The polyploid megakaryocyte DNA content distributions of the offspring from these matings show that C3H mice have higher percentages of high ploidy megakaryocytes than did all other mice. Also, male mice had significantly higher percentages of high ploidy (32N and 64N) megakaryocytes than did female mice for all matings, except backcross mating no. 6. The megakaryocyte DNA content for individual offspring of a given back-cross appeared to form a single, continuous distribution, rather than segregate into two distinct groups, suggesting that the higher megakaryocyte DNA content of C3H mice is caused by involvement of multiple allelles. This conclusion is further supported by our finding that the frequency of high ploidy megakaryocytes among offspring of the various matings was related to the proportion of C3H genotype contributed by the parents, ie, average megakaryocyte DNA content increased linearly(r2 = .88 for male mice and .84 for female mice, P < .0001) with increasing C3H gene dosage; the correlations for both male and female mice were essentially parallel (slope = 0.08 and 0.09, respectively). In addition, we found an effect of genomic imprinting on megakaryocyte DNA content in backcross offspring. The genetic imprinting was characterized by the female parent having a greater influence on the offspring’s megakaryocyte DNA> content than the male parent, ie, although the overall genetic makeup was the same, female offspring from backcross no. 6 (in which the female was C3H) had higher average megakaryocyte ploidy values than those from backcross no. 5 (in which the female was B6C3F1). The same phenomenon was observed when comparing the results from backcrosses no. 2 and 3, ie, male offspring from mating no. 3 (B6C3F1 female parent) had a higher average polyploid megakaryocyte DNA content than did male offspring from backcross no. 2 (C57BL female parent). Thus, we find that a number of factors influence megakaryocyte DNA content, including genomic imprinting and male sex hormones; however, we conclude that the higher megakaryocyte DNA content of C3H mice results from the interaction of multiple alleles that are additive. We hypothesize that a larger dosage of these genes in the C3H mouse is responsible for the higher DNA content of their megakaryocytes.