Submitted to: Journal of Biological Chemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/19/2003
Publication Date: 12/19/2003
Citation: Kovtun, I.V., Welch, G.R., Guthrie, H.D., Hafner, K.L., Mcmurray, C.T. 2004. Cag repeat lengths in x- and y-bearing sperm indicate that gender bias during transmission of huntington's disease gene is determined in the embryo. Journal of Biological Chemistry. Vol. 279, No. 10, Issue of March 5, pp. 9389-9391.
Interpretive Summary: The size of the CAG tract at the Huntington's disease (HD) locus upon transmission depends on the gender of the parent. However, the basis for the parent-of-origin effect is unknown. To test whether expansion and contraction in HD are "imprinted" in the germ cells, we isolated the X- and Y-bearing sperm of HD transgenic mice. Here we show that CAG repeat distributions in the X- and Y-bearing spermatozoa of founding fathers do not differ. These data show that gender-dependent changes in CAG repeat length arise in the embryo. These results point to a new kind of imprinting in that depends on signals in the embryo and may influence far-reaching implications with respect to the interpretation of genetic data.
Technical Abstract: Huntington's Disease (HD) is a progressive neurodegenerative disorder in which the underlying mutation is a CAG expansion encoding a polyglutamine tract. It has been documented that alterations in length of the CAG repeat after transmission are distinctly dependent on the gender of the transmitting parent. Large changes in repeat number are always associated with paternal transmission in HD. Males predominantly expand the repeat while females predominantly contract the repeat. This has raised the issue of whether the gender dependence of expansion in HD is 'imprinted' in the germ cells of the parent or arises from the differences in the postzygotic stages. To distinguish between the two possibilities, we evaluated whether CAG repeat size differed in the X- and Y-bearing sperm of the founding father. Sperm from founding fathers were separated into distinct X- and Y-bearing populations by FACS analysis and the CAG repeat size in each population was evaluated. The purity of sorted cells was confirmed by FISH. We found no difference in CAG repeat distribution among the two sorted populations. We conclude that the gender dependence of CAG expansion in HD mice occurs postzygotically in the early embryo. Since the gender of the embryo is determined by the presence of X,X or X,Y chromosomes, our data support a model in which X- and Y-encoded factors contribute to the expansion.