Meiotic nondisjunction in the mouse: methodology for genetic testing and comparison with other methods

Since trisomies produce adverse effects relatively late in development or even postnatally, they are an important component of the array of genetic damages that might be caused by environmental agents. Whole-chromosome aneuploidy (as opposed to breakage-derived aneuploidy) might come about secondarily from crossover depression, or could follow damage to the meiotic spindle or to kinetochores. For simplicity, the event—by whichever of the mechanisms—is referred to as meiotic nondisjunction (ND). A genetic method has been devised which is based on the facts that ND involving the sex chromosomes produces mostly viable mice, and that such exceptional animals can be externally recognized by the use of appropriate markers. The method is compared with the following other ND indicators: univalent and/or chiasma frequencies at M I; number of dyads at M II; extra sex chromosomes in spermatids; karyotypes in cleavage, morula, or blastocyst metaphases; and chromosome constitution of mid-gestation embryos. Some of the cytological endpoints are found to be unreliable. Various biological variables (germ-cell stage, sex, age) are examined with a view toward maximizing the chances for detecting induced nondisjunction. While experimental evidence on this question is equivocal, a consideration of the probable ND mechanisms suggests that the early spermatocyte (in stages including the premeiotic S phase) may be a favorable test object. The numerical sex-chromosome anomaly (NSA) method is useful not only in the study of ND but also in detecting breakage-derived chromosome losses induced in females, where the dominant lethal test is not easily applicable.