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Understanding the impact of rare variants is essential to understanding human health. We analyze rare (MAF, Population-based association analyses of rare genetic variants with complex traits are limited by the availability of data from sufficiently large cohorts. Here, Cirulli et al. report gene-based collapsing analysis of exomes from 49,960 participants of the UK Biobank and 21,866 participants of the Healthy Nevada Project over a total of 4377 traits.

The highly transmissible B.1.1.7 variant of SARS-CoV-2, first identified in the United Kingdom, has gained a foothold across the world. Using S gene target failure (SGTF) and SARS-CoV-2 genomic sequencing, we investigated the prevalence and dynamics of this variant in the United States (U.S.), tracking it back to its early emergence. We found that while the fraction of B.1.1.7 varied by state, the variant increased at a logistic rate with a roughly weekly doubling rate and an increased transmission of 40-50%. We revealed several independent introductions of B.1.1.7 into the U.S. as early as late November 2020, with community transmission spreading it to most states within months. We show that the U.S. is on a similar trajectory as other countries where B.1.1.7 became dominant, requiring immediate and decisive action to minimize COVID-19 morbidity and mortality., Genomic epidemiology analyses explain the introduction and transmission of the B.1.1.7 variant of SARS-CoV-2 into the United States, with projections for it to soon be the dominant strain in the country.

Author(s): Washington, Nicole L; Gangavarapu, Karthik; Zeller, Mark; Bolze, Alexandre; Cirulli, Elizabeth T; Schiabor Barrett, Kelly M; Larsen, Brendan B; Anderson, Catelyn; White, Simon; Cassens, Tyler; Jacobs, Sharoni; Levan, Geraint; Nguyen, Jason; Ramirez, Jimmy M; Rivera-Garcia, Charlotte; Sandoval, Efren; Wang, Xueqing; Wong, David; Spencer, Emily; Robles-Sikisaka, Refugio; Kurzban, Ezra; Hughes, Laura D; Deng, Xianding; Wang, Candace; Servellita, Venice; Valentine, Holly; De Hoff, Peter; Seaver, Phoebe; Sathe, Shashank; Gietzen, Kimberly; Sickler, Brad; Antico, Jay; Hoon, Kelly; Liu, Jingtao; Harding, Aaron; Bakhtar, Omid; Basler, Tracy; Austin, Brett; Isaksson, Magnus; Febbo, Phil; Becker, David; Laurent, Marc; McDonald, Eric; Yeo, Gene W; Knight, Rob; Laurent, Louise C; de Feo, Eileen; Worobey, Michael; Chiu, Charles; Suchard, Marc A; Lu, James T; Lee, William; Andersen, Kristian G | Abstract: As of January of 2021, the highly transmissible B.1.1.7 variant of SARS-CoV-2, which was first identified in the United Kingdom (U.K.), has gained a strong foothold across the world. Because of the sudden and rapid rise of B.1.1.7, we investigated the prevalence and growth dynamics of this variant in the United States (U.S.), tracking it back to its early emergence and onward local transmission. We found that the RT-qPCR testing anomaly of S gene target failure (SGTF), first observed in the U.K., was a reliable proxy for B.1.1.7 detection. We sequenced 212 B.1.1.7 SARS-CoV-2 genomes collected from testing facilities in the U.S. from December 2020 to January 2021. We found that while the fraction of B.1.1.7 among SGTF samples varied by state, detection of the variant increased at a logistic rate similar to those observed elsewhere, with a doubling rate of a little over a week and an increased transmission rate of 35-45%. By performing time-aware Bayesian phylodynamic analyses, we revealed several independent introductions of B.1.1.7 into the U.S. as early as late November 2020, with onward community transmission enabling the variant to spread to at least 30 states as of January 2021. Our study shows that the U.S. is on a similar trajectory as other countries where B.1.1.7 rapidly became the dominant SARS-CoV-2 variant, requiring immediate and decisive action to minimize COVID-19 morbidity and mortality.

Induced pluripotent stem cells (iPSCs) show variable methylation patterns between lines, some of which reflect aberrant differences relative to embryonic stem cells (ESCs). To examine whether this aberrant methylation results from genetic variation or non-genetic mechanisms, we generated human iPSCs from monozygotic twins to investigate how genetic background, clone, and passage number contribute. We found that aberrantly methylated CpGs are enriched in regulatory regions associated with MYC protein motifs and affect gene expression. We classified differentially methylated CpGs as being associated with genetic and/or non-genetic factors (clone and passage), and we found that aberrant methylation preferentially occurs at CpGs associated with clone-specific effects. We further found that clone-specific effects play a strong role in recurrent aberrant methylation at specific CpG sites across different studies. Our results argue that a non-genetic biological mechanism underlies aberrant methylation in iPSCs and that it is likely based on a probabilistic process involving MYC that takes place during or shortly after reprogramming.

In this study, we used whole genome sequencing and gene expression profiling of 215 human induced pluripotent stem cell (iPSC) lines from different donors to identify genetic variants associated with RNA expression for 5,746 genes. We were able to predict causal variants for these expression quantitative trait loci (eQTLs) that disrupt transcription factor binding and validated a subset of them experimentally. We also identified copy number variant (CNV) eQTLs, including some that appear to affect gene expression by altering the copy number of intergenic regulatory regions. In addition, we were able to identify effects on gene expression of rare genic CNVs and regulatory single nucleotide variants, and found that reactivation of gene expression on the X chromosome depends on gene chromosomal position. Our work highlights the value of iPSCs for genetic association analyses and provides a unique resource for investigating the genetic regulation of gene expression in pluripotent cells.