Paternally biased X inactivation in mouse neonatal brain.

Abstract

X inactivation in female eutherian mammals has long been considered to occur at random in embryonic and postnatal tissues. Methods for scoring allele-specific differential expression with a high degree of accuracy have recently motivated a quantitative reassessment of the randomness of X inactivation. After RNA-seq data revealed what appeared to be a chromosome-wide bias toward under-expression of paternal alleles in mouse tissue, we applied pyrosequencing to mouse brain cDNA samples from reciprocal cross F1 progeny of divergent strains and found a small but consistent and highly statistically significant excess tendency to under-express the paternal X chromosome. The bias toward paternal X inactivation is reminiscent of marsupials (and extraembryonic tissues in eutherians), suggesting that there may be retained an evolutionarily conserved epigenetic mark driving the bias. Allelic bias in expression is also influenced by the sampling effect of X inactivation and by cis-acting regulatory variation (eQTL), and for each gene we quantify the contributions of these effects in two different mouse strain combinations while controlling for variability in Xce alleles. In addition, we propose an efficient method to identify and confirm genes that escape X inactivation in normal mice by directly comparing the allele-specific expression ratio profile of multiple X-linked genes in multiple individuals.