Parental allele-specific genome architecture and transcription during the cell cycle

A normal human somatic cell inherits two haploid genomes. Individual chromosomes of each pair have distinct parental origins and parental alleles are known to unequally contribute to cellular function. We integrated chromosome conformation (form) and gene transcription (function) analyses to dissect the dynamics of the maternal and paternal genomes in lymphoblastoid cells during the cell cycle. We found a distinct set of homologous alleles with very different activity often located close to boundaries of euchromatin and heterochromatin domains. We also identified a set of allele-biased topologically associating domains (TADs) that were small sized and had higher gene density. Thousands of genes show allelically biased expression (ABE) with false discovery rate < 0.05, and 98% of them have no allelic switching during G1, S, and G2/M phases. A subset of ABE genes are preferentially localized near TAD boundaries, enriched with chromatin organization transcription factor binding sites, and contained higher number of sequence variants in CCCTC-binding factor sites. Our results extend previous findings of sequence variation as a basis for unequal functional parental genomes. Investigation of haplotype-resolved form-function dynamics may further our understanding of phenotypic traits, genetic diseases, vulnerability to complex disorders, and the development of cancers.