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Elazzabi, Nairuz

University of British Columbia

Clinical reports on monozygotic and dizygotic twins provided the initial evidence for the involvement of genetic factors in risk vulnerability for fetal alcohol spectrum disorder (FASD). Research with selectively bred and inbred rodents further clarified the role of both maternal and fetal genetics in the development of FASD, such that certain lines (e.g, C57BL/6) are extremely sensitive to the effects of ethanol while others (eg, DBA/2J) are quite resistant. This phenotypic variation between the inbred strains of laboratory mice is attributed to functional genomic variants and the complexity of genetic action underlying most quantitative traits. The identification of such candidate genetic factors that underlie vulnerability for FASD and alcohol teratogenesis is still at an early stage of discovery. Here, I utilized a prenatal alcohol exposure (PAE) mouse model to generate reciprocal F1 hybrids from the inbred strains C57BL/6 and DBA/2J to study allele-specific and allele-agnostic expression. Timed pregnancies were established to collect E9.5 F1 embryos and to dissect hindbrain tissue from these embryos. The E9.5 time point was chosen because it is developmentally equivalent to the first trimester of human pregnancy when both the human and the mouse embryos are known to be extremely sensitive to ethanol exposure. This model explored how allele-specific expression, due to parent-of-origin effect and strain-specific genetic variation, is influencing the phenotypic variation in response to ethanol seen in C57BL/6 and DBA/2J mouse strains. By using a multi-pronged approach (allele-specific and allelic agnostic RNA-seq analysis), this study: (1) captured genes that demonstrate gene x environment (GxE) interactions providing molecular insights into the phenotype of enhanced cell death in the hindbrain seen in the susceptible strain; (2) showed that there are cis-acting factors mediating GxE interactions; (3) showed that there is a strong C57BL/6 maternal effect on increasing susceptibility to ethanol exposure; and (4) showed that certain imprinted alleles, involved in fetal growth, are more sensitive to ethanol-induced expression changes than other alleles.

Text

2023-04-30

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/81465

Medical Genetics

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/