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Biology subjects

Brody, L.

Publications and source records attributed to Brody, L..

3 recordsLinked to original sources

A genetic perspective on the recent demographic history of Ireland and Britain

BackgroundWhile subtle yet discrete clusters of genetic identity across Ireland and Britain have been identified, their demographic history is unclear. MethodsUsing genotype data from 6,574 individuals with associated regional Irish or British ancestry, we identified Irish-like and British-like genetic communities using network community detection. We segregated Identity-by-Descent (IBD) and Runs-of-Homozygosity (ROH) segments by length and approximated their corresponding time periods. Through this, we inferred the regional Irish and British demographic histories in these time periods by (1) estimating genetic relatedness between communities, (2) estimating changes in effective population sizes, (3) inferring recent migration rates across Ireland and Britain, and (4) estimating changing affinities to regional European populations. For a subset of the Irish communities, we determined the enrichment/depletion of surnames within the genetic communities. ResultsThrough patterns of IBD-sharing and ROH, we find evidence of recent population bottlenecks in the Orcadian, Manx and Welsh communities. While the structure in Ireland is subtler, the communities share relatively more IBD segments that are shorter in length, and the genetic differences between the Irish communities are more subtle on average, when compared to the British communities. Regional effective population size trajectories indicate a similar demographic history throughout the island of Ireland. Further, we observe a stable migration corridor between north-east Ireland and south-west Scotland while there is a recent migration barrier between South-Eastern Ireland and Western Ireland. We observed an enrichment of Anglo-Norman and English surnames in the Wexford community while within the West Ulster-Argyll community, we saw an enrichment of Gallowglass and Scottish surnames. ConclusionsUsing well-annotated Irish and British reference genotypes, we observed temporal changes in genetic affinities within and between genetic communities in Ireland and Britain. In addition, using effective population size estimates and levels of haplotype-sharing, we detected varying degrees of genetic isolation in some Irish and British genetic communities across time. Using these new insights into the regional demographic history of Ireland and Britain across different time periods, we hope to understand the driving forces of rare allele frequencies and disease risk association within these populations.

genetics↗

Chromatin accessibility changes at intergenic regions associates with ovarian cancer drug resistance

We have investigated how genomic distribution of chromatin accessibilities alter during acquisition of resistance to carboplatin-based chemotherapy using matched ovarian cell lines from high grade serous ovarian cancer (HGSOC) patients before and after becoming clinically resistant to platinum-based chemotherapy. Resistant lines show altered chromatin accessibility at intergenic regions, but less so at gene promoters. Super-enhancers, as defined by clusters of cis-regulatory elements, at these intergenic regions show chromatin changes that are associated with altered expression of linked genes, with enrichment for genes involved in the Fanconi anemia/BRCA DNA damage response pathway. Further, genome-wide distribution of platinum adducts associates with the chromatin changes observed and distinguish sensitive from resistant lines. In the resistant line, we observe fewer adducts around gene promoters and more adducts at intergenic regions. Thus, chromatin changes at intergenic regulators of gene expression are associated with in vivo derived drug resistance and Pt-adduct distribution in patient-derived HGSOC drug resistance models.

cancer biology↗

Genome assembly and gene expression in the American black bear provides new insights into the renal response to hibernation.

The prevalence of chronic kidney disease (CKD) is rising worldwide and 10-15% of the global population currently suffers from CKD and its complications. Given the increasing prevalence of CKD there is an urgent need to find novel treatment options. The American black bear (Ursus americanus) copes with months of lowered kidney function and metabolism during hibernation without the devastating effects on metabolism and other consequences observed in humans. In a biomimetic approach to better understand kidney adaptations and physiology in hibernating black bears, we established a high-quality genome assembly. Subsequent RNA-Seq analysis of kidneys comparing gene expression profiles in black bears entering (late fall) and emerging (early spring) from hibernation identified 169 protein-coding genes that were differentially expressed. Of these, 101 genes were downregulated and 68 genes were upregulated after hibernation. Fold changes ranged from 1.8-fold downregulation (RTN4RL2) to 2.4-fold upregulation (CISH). Most notable was the upregulation of cytokine suppression genes (SOCS2, CISH, and SERPINC1) and the lack of increased expression of cytokines and genes involved in inflammation. The identification of these differences in gene expression in the black bear kidney may provide new insights in the prevention and treatment of CKD.

genomics↗