The African Society of Human Genetics successfully launches global data science workshops.

To accelerate the impact of African genomics on human health, data science skills and awareness of Africa's rich genetic diversity must be strengthened globally. We describe the first African genomics data science workshop, implemented by the African Society of Human Genetics (AfSHG) and international partners, providing a framework for future workshops.

PTBP1 enforces ATR-CHK1 signaling determining the potency of CDC7 inhibitors.

CDC7 kinase is crucial for DNA replication initiation and fork processing. CDC7 inhibition mildly activates the ATR pathway, which further limits origin firing; however, to date the relationship between CDC7 and ATR remains controversial. We show that CDC7 and ATR inhibitors are either synergistic or antagonistic depending on the degree of inhibition of each individual kinase. We find that Polypyrimidine Tract Binding Protein 1 (PTBP1) is important for ATR activity in response to CDC7 inhibition and genotoxic agents. Compromised PTBP1 expression makes cells defective in RPA recruitment, genomically unstable, and resistant to CDC7 inhibitors. PTBP1 deficiency affects the expression and splicing of many genes indicating a multifactorial impact on drug response. We find that an exon skipping event in RAD51AP1 contributes to checkpoint deficiency in PTBP1-deficient cells. These results identify PTBP1 as a key factor in replication stress response and define how ATR activity modulates the activity of CDC7 inhibitors.

Controlling for background genetic effects using polygenic scores improves the power of genome-wide association studies.

Ongoing increases in the size of human genotype and phenotype collections offer the promise of improved understanding of the genetics of complex diseases. In addition to the biological insights that can be gained from the nature of the variants that contribute to the genetic component of complex trait variability, these data bring forward the prospect of predicting complex traits and the risk of complex genetic diseases from genotype data. Here we show that advances in phenotype prediction can be applied to improve the power of genome-wide association studies. We demonstrate a simple and efficient method to model genetic background effects using polygenic scores derived from SNPs that are not on the same chromosome as the target SNP. Using simulated and real data we found that this can result in a substantial increase in the number of variants passing genome-wide significance thresholds. This increase in power to detect trait-associated variants also translates into an increase in the accuracy with which the resulting polygenic score predicts the phenotype from genotype data. Our results suggest that advances in methods for phenotype prediction can be exploited to improve the control of background genetic effects, leading to more accurate GWAS results and further improvements in phenotype prediction.

ATR Restrains DNA Synthesis and Mitotic Catastrophe in Response to CDC7 Inhibition.

DNA replication initiates from multiple origins, and selective CDC7 kinase inhibitors (CDC7is) restrain cell proliferation by limiting origin firing. We have performed a CRISPR-Cas9 genome-wide screen to identify genes that, when lost, promote the proliferation of cells treated with sub-efficacious doses of a CDC7i. We have found that the loss of function of ETAA1, an ATR activator, and RIF1 reduce the sensitivity to CDC7is by allowing DNA synthesis to occur more efficiently, notably during late S phase. We show that partial CDC7 inhibition induces ATR mainly through ETAA1, and that if ATR is subsequently inhibited, origin firing is unleashed in a CDK- and CDC7-dependent manner. Cells are then driven into a premature and highly defective mitosis, a phenotype that can be recapitulated by ETAA1 and TOPBP1 co-depletion. This work defines how ATR mediates the effects of CDC7 inhibition, establishing the framework to understand how the origin firing checkpoint functions.