Non-Canonical and Sexually Dimorphic X Dosage Compensation States in the Mouse and Human Germline

Abstract

SummarySomatic X dosage compensation requires two mechanisms: X inactivation balances X gene output between males (XY) and females (XX), while X upregulation, hypothesized by Ohno and documented in vivo, balances X gene with autosomal gene output. Whether X dosage compensation occurs in germ cells is unclear. We show that mouse and human germ cells exhibit non-canonical X dosage states that differ from the soma and between the sexes. Prior to genome-wide reprogramming, X upregulation is present, consistent with Ohno's hypothesis. Subsequently, however, it is erased. In females, erasure follows loss of X inactivation, causing X dosage excess. Conversely, in males, erasure leads to permanent X dosage decompensation. Sex chromosomally abnormal models exhibit a “sex-reversed” X dosage state: XX males, like XX females, develop X dosage excess, while XO females, like XY males, develop X dosage decompensation. Thus, germline X dosage compensation states are determined by X chromosome number, not phenotypic sex. These unexpected differences in X dosage compensation states between germline and soma offer unique perspectives on sex chromosome infertility.

Mammalian X Chromosome Dosage Compensation: Perspectives From the Germ Line

“…Using this approach, studies have concluded that the X:A ratio is close to 0.5, and therefore that XCU does not take place in eutherians . Conversely, when assaying XCU in reproductive tissues, including reproduction‐related genes increases the X:A ratio above 1, because tissue‐specific genes are expressed at higher levels . Only when lower and upper thresholds of expression are imposed does the presence of XCU, that is X:A ratios of 1, become apparent .…”

“…Conversely, when assaying XCU in reproductive tissues, including reproduction‐related genes increases the X:A ratio above 1, because tissue‐specific genes are expressed at higher levels . Only when lower and upper thresholds of expression are imposed does the presence of XCU, that is X:A ratios of 1, become apparent . It is noteworthy that in the single metatherian in which XCU has been examined, the opossum Monodelphis domestica , somatic X:A ratios approximate 1, even when these expression limits are not imposed .…”

“…Because the X chromosome contains a preponderance of genes expressed only in reproductive tissues, it is tempting to attribute the infertility phenotype to an imbalance in the dosage of these genes. However new work has shown that X housekeeping genes exhibit unusual dosage compensation states during germ cell development, making them alternative candidates for sex chromosome − related infertility …”

New Advances in Human X Chromosome Status from a Developmental and Stem Cell Biology

“…This eroded state has significant implications for the clinical safety of such cultured cells. In one study, spurious reactivation of immune gene clusters on the Xi was implicated in the pathogenesis of systemic lupus erythematosus (42), while in another study, primordial germ cell specification was shown to rely on specific X:Autosome gene dosage ratios (10). Overall, current research indicates that correct X chromosome regulation is an essential component of many types of healthy cells, and that dysregulation of the X chromosome status can lead to pathology or failure in a wide variety of cellular contexts.…”

“…In humans, this process likely occurs around embryonic days 7–9 (7, 8). Studies from the mouse show that this is a biologically critical process, and that even changes in gene expression(9) or gene load during this time can have strong effects on embryo viability(10, 11). …”