85. Cell-type-specific genotypic interpretation in the human breast

Aly Abdelkareem

Axel Hauduc

Axel Hauduc is a Ph.D. candidate in the Hirst Lab at the University of British Columbia, Canada. Axel grew up in the Seattle area and attended the University of California, Berkeley for his bachelor’s degree in Molecular & Cell Biology (Neurobiology emphasis) and French. While at Cal, Axel was a research intern at the Gladstone Institutes at the University of California, San Francisco, and the Allen Institute for Brain Science in Seattle, working mainly in neurobiology and mouse models of Alzheimer’s disease. After graduation, Axel was drawn to genomics for its potential to transform the huge influxes of genetic data generated each day into deeper understanding of biology and potential therapies. Axel enrolled in the Genome Science and Technology program at UBC’s Michael Smith Laboratories in September 2019 and joined the Hirst Lab in January 2020. At the Hirst Lab, Axel’s research focuses on interpreting cell-type-specific epigenetic datasets and characterizing the interactions between various epigenetic marks and genetic variants in human breast tissue.


Axel Hauduc, Annaick Carles, Misha Bilenky, Edmund Su, Martin Hirst

UBC, Vancouver, BC, CA

Understanding the interplay between genetic and epigenetic states is fundamental to the study of development and mechanisms of disease. Most studies that have explored this interplay have leveraged population-scale genotype surveys to associate genetic polymorphisms with epigenetic states in whole blood or other heterogenous tissue types. However, epigenetic states are cell-type specific, raising the possibly of cell-type-specific genetic/epigenetic relationships that could drive specific functional states and disease predisposition. To address this question, I analyzed enriched regions for six histone modifications across four functionally distinct human breast cell types from eight phenotypically normal women to identify genetic variants that influence cell-type-specific epigenetic states. I define the incidence by cell-type and histone mark of these interactions across breast cell types, terming them cis histone binary trait loci, or cis-hBTLs, and prioritize them through interrogation of matched gene expression datasets. Variants were prioritized based on altered expression of associated genes and these were found to be enriched in genes and long noncoding RNAs implicated in breast carcinogenesis. A subset of these variants was then validated in epithelial breast cell lines. My analysis thus suggests that genotype is variably interpreted across functionally distinct breast cell subtypes and that this variation may have implications for understanding genetic influences on breast cancer initiation and progression.