MRC National Institute for Medical Research, London
Science for Health
Gender differences in aneuploidy explained
03 May 2011
A genetic basis for the difference in the male and female rates of aneuploidy has been discovered by scientists at NIMR. The research is published in Current Biology.
It has long been known that women transmit more gametes with the wrong number of chromosomes (aneuploid) than do males. Although most of the resulting aneuploid conceptions miscarry in early pregnancy some are viable, for example Down syndrome.
During mammalian meiosis, cells with unpaired (univalent) chromosomes at the first meiotic division (MI) trigger a ’spindle assembly checkpoint’ (SAC) that is designed to allow time for all pairs of chromosomes to attach correctly to the spindle; an essential prerequisite to the balanced segregation of the two chromosome sets. In males, cells that trigger this checkpoint are efficiently eliminated by programmed cell death (apoptosis).
Paul Burgoyne’s Group in NIMR’s Division of Stem Cell Biology and Developmental Genetics seeks to define the functions of Y encoded genes in spermatogenesis. In an earlier study in which they produced males with no Y chromosome, a single X chromosome, and just two Y genes (Sry and Eif2s3y) they noted that the expected elimination of MI spermatocytes did not occur in response to the univalent X. They and their colleagues have now shown that this is because another Y gene, Zfy2 (encoding a putative transcription factor) is required for the efficient apoptotic elimination at MI.
The authors argue that the efficient apoptotic elimination of cells with univalents during male meiosis, but not in female meiosis, helps to explain the female bias in chromosomal errors originating at the first meiotic division.
We have previously suggested that the gender difference in the transmission of aneuploidy may be due to the absence in females of an apoptotic response to the short MI SAC mediated delay, rather than to a less efficient MI SAC response. The importance of the present study is that it provides a genetic basis for the gender difference in mice by identifying a Y-encoded gene, Zfy2, as being necessary for the efficient male-specific apoptotic response.
Paul Burgoyne
Click image to view at full-size
In XSxra O males (right) nearly all MI spermatocytes are eliminated by apoptosis (green fluorescent cells). In XO, Sry,Eif2s3y double transgenic males (left), apoptosis is markedly reduced and most spermatocytes complete the first meiotic division. In XO, Sry,Eif2s3y,Zfy2 triple transgenic males (middle), apoptotic elimination is restored to a level similar to XSxra O males. The bottom panels show a high magnification of the top panels.
Original article
The Y-encoded gene Zfy2 acts to remove cells with unpaired chromosomes at the first meiotic metaphase in male mice
Nadège Vernet, Shantha K. Mahadevaiah, Obah A. Ojarikre, Guy Longepied, Haydn M.Prosser, Allan Bradley, Michael J. Mitchell, and Paul S. Burgoyne (2011)
Current Biology, Epub ahead of print. Publisher abstract
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