Sex-specific chromosome instability in early human development

Abstract

The predominance of females segregating chromosome aberrations to their offspring has been explained mostly by selection disadvantage of unbalanced products of spermatogenesis. However, analysis of data from the literature supports the idea that somatic cells of early female embryos are similar to female germ cells in that they are prone to malsegregation. The goal of this study was to compare the sex ratio (male to female ratio) of carriers of presumably mitotic-occurring chromosome abnormalities to identify any sex biases. In examining the literature, we found a female prevalence in cases of mosaicism associated with uniparental disomy (UPD) (26 male individuals/conceptions and 45 female individuals/conceptions, sex ratio is 0.58, significantly different from 1.06 in newborn population, P = 0.0292). This predominance was highest at gestational age <16 week (8 male and 22 female conceptuses, sex ratio is 0.36, significantly different from expected figure of 1.28, P = 0.0025), which diminished at later stages of fetal development indicating potential correction of trisomies predominantly in females. There is a threefold prevalence of 46,XX/45,X mosaics over 46,XY/45,X mosaics in prenatally diagnosed cases, which also suggests a gender-specific postzygotic chromosome loss. The male prevalence in Prader-Willi syndrome with maternal UPD of chromosome 15 also can be explained by sex-specific trisomy correction, with predominant loss of a maternal chromosome causing biparental inheritance and therefore, complete correction of trisomy in females (without UPD). Finally, there is a female predominance in carriers of chromosome rearrangement with pericentromere break (mosaicism for Robertsonian translocation/isochromosome, centric fission, nonacrocentric isochromosome, and whole arm rearrangement), in both prenatal (21 males and 36 females, sex ratio is 0.58, P < 0.0184) and postnatal ill-defined cases (14 males and 35 females, sex ratio is 0.40, P = 0.001). Thus, the findings presented in this paper suggest that, in addition to reduction in male fertility, and to probable selection against abnormal cell line(s), there are two mechanisms that contribute to female preponderance among carriers of mosaicism: sex-specific chromosome loss and sex-specific centromere instability. The data obtained suggest that females may have gonadal mosaicism for aneuploidies and structural rearrangements more often than males. This may lead to the maternal origin bias in offspring with trisomies or structural rearrangements.