Biology subjects

McCole, R. B.

Publications and source records attributed to McCole, R. B..

4 recordsLinked to original sources

bioRxiv2018

The genome-wide, multi-layered architecture of chromosome pairing in early Drosophila embryos

Genome organization involves cis and trans chromosomal interactions, both implicated in gene regulation, development, and disease. Here, we focused on trans interactions in Drosophila, where homologous chromosomes are paired in somatic cells from embryogenesis through adulthood. We first addressed the long-standing question of whether pairing extends genome-wide and, to this end, developed a haplotype-resolved Hi-C approach that uses a new strategy to minimize homolog misassignment and thus robustly distinguish trans-homolog from cis contacts. This approach revealed striking genome-wide pairing in Drosophila embryos. Moreover, we discovered pairing to be surprisingly structured, with trans-homolog domains and interaction peaks, many coinciding with the positions of analogous cis features. We also found a significant correlation between pairing and the chromatin accessibility mediated by the pioneer factor Zelda. Our findings reveal a complex, highly structured organization underlying homolog pairing, first discovered more than a century ago.\n\nOne Sentence SummaryA robust approach for haplotype-resolved Hi-C reveals highly-structured homolog pairing in early stage Drosophila embryos.

genetics↗

bioRxiv2018

Highly Structured Homolog Pairing Reflects Functional Organization of the Drosophila Genome

Trans-homolog interactions encompass potent regulatory functions, which have been studied extensively in Drosophila, where homologs are paired in somatic cells and pairing-dependent gene regulation, or transvection, is well-documented. Nevertheless, the structure of pairing and whether its functional impact is genome-wide have eluded analysis. Accordingly, we generated a diploid cell line from divergent parents and applied haplotype-resolved Hi-C, discovering that homologs pair relatively precisely genome-wide in addition to establishing trans-homolog domains and compartments. We also elucidated the structure of pairing with unprecedented detail, documenting significant variation across the genome. In particular, we characterized two forms: tight pairing, consisting of contiguous small domains, and loose pairing, consisting of single larger domains. Strikingly, active genomic regions (A-type compartments, active chromatin, expressed genes) correlated with tight pairing, suggesting that pairing has a functional role genome-wide. Finally, using RNAi and haplotype-resolved Hi-C, we show that disruption of pairing-promoting factors results in global changes in pairing.\n\nOne Sentence SummaryHaplotype-resolved Hi-C reveals structures of homolog pairing and global implications for gene activity in hybrid PnM cells.

genetics↗

bioRxiv2018

Walking along chromosomes with super-resolution imaging, contact maps, and integrative modeling

Chromosome structure is thought to be crucial for proper functioning of the nucleus. Here, we present a method for visualizing chromosomal DNA at super-resolution and then integrating Hi-C data to produce three-dimensional models of chromosome organization. We begin by applying Oligopaint probes and the single-molecule localization microscopy methods of OligoSTORM and OligoDNA-PAINT to image 8 megabases of human chromosome 19, discovering that chromosomal regions contributing to compartments can form distinct structures. Intriguingly, our data also suggest that homologous maternal and paternal regions may be differentially organized. Finally, we integrate imaging data with Hi-C and restraint-based modeling using a method called integrative modeling of genomic regions (IMGR) to increase the genomic resolution of our traces to 10 kb.\n\nOne Sentence SummarySuper-resolution genome tracing, contact maps, and integrative modeling enable 10 kb resolution glimpses of chromosome folding.

genetics↗

bioRxiv2017

Structural disruption of genomic regions containing ultraconserved elements is associated with neurodevelopmental phenotypes

The development of the human brain and nervous system can be affected by genetic or environmental factors. Here we focus on characterizing the genetic perturbations that accompany and may contribute to neurodevelopmental phenotypes. Specifically, we examine two types of structural variants, namely, copy number variation and balanced chromosome rearrangements, discovered in subjects with neurodevelopmental disorders and related phenotypes. We find that a feature uniting these types of genetic aberrations is a proximity to ultraconserved elements (UCEs), which are sequences that are perfectly conserved between the reference genomes of distantly related species. In particular, while UCEs are generally depleted from copy number variant regions in healthy individuals, they are, on the whole, enriched in genomic regions disrupted by copy number variants or breakpoints of balanced rearrangements in affected individuals. Additionally, while genes associated with neurodevelopmental disorders are enriched in UCEs, this does not account for the excess of UCEs either in copy number variants or close to the breakpoints of balanced rearrangements in affected individuals. Indeed, our data are consistent with some manifestations of neurodevelopmental disorders resulting from a disruption of genome integrity in the vicinity of UCEs.

genomics↗