Somatic coding mutations in human induced pluripotent stem cells

Defined transcription factors can induce epigenetic reprogramming of adult mammalian cells into induced pluripotent stem cells. Although DNA factors are integrated during some reprogramming methods, it is unknown whether the genome remains unchanged at the single nucleotide level. Here we show that 22 human induced pluripotent stem (hiPS) cell lines reprogrammed using five different methods each contained an average of five protein-coding point mutations in the regions sampled (an estimated six protein-coding point mutations per exome). The majority of these mutations were non-synonymous, nonsense or splice variants, and were enriched in genes mutated or having causative effects in cancers. At least half of these reprogramming-associated mutations pre-existed in fibroblast progenitors at low frequencies, whereas the rest occurred during or after reprogramming. Thus, hiPS cells acquire genetic modifications in addition to epigenetic modifications. Extensive genetic screening should become a standard procedure to ensure hiPS cell safety before clinical use

Shared heritability and functional enrichment across six solid cancers

Correction: Nature Communications 10 (2019): art. 4386 DOI: 10.1038/s41467-019-12095-8Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (r(g) = 0.57, p = 4.6 x 10(-8)), breast and ovarian cancer (r(g) = 0.24, p = 7 x 10(-5)), breast and lung cancer (r(g) = 0.18, p = 1.5 x 10(-6)) and breast and colorectal cancer (r(g) = 0.15, p = 1.1 x 10(-4)). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.Peer reviewe

A global experiment on motivating social distancing during the COVID-19 pandemic

Finding communication strategies that effectively motivate social distancing continues to be a global public health priority during the COVID-19 pandemic. This cross-country, preregistered experiment (n = 25,718 from 89 countries) tested hypotheses concerning generalizable positive and negative outcomes of social distancing messages that promoted personal agency and reflective choices (i.e., an autonomy-supportive message) or were restrictive and shaming (i.e., a controlling message) compared with no message at all. Results partially supported experimental hypotheses in that the controlling message increased controlled motivation (a poorly internalized form of motivation relying on shame, guilt, and fear of social consequences) relative to no message. On the other hand, the autonomy-supportive message lowered feelings of defiance compared with the controlling message, but the controlling message did not differ from receiving no message at all. Unexpectedly, messages did not influence autonomous motivation (a highly internalized form of motivation relying on one’s core values) or behavioral intentions. Results supported hypothesized associations between people’s existing autonomous and controlled motivations and self-reported behavioral intentions to engage in social distancing. Controlled motivation was associated with more defiance and less long-term behavioral intention to engage in social distancing, whereas autonomous motivation was associated with less defiance and more short- and long-term intentions to social distance. Overall, this work highlights the potential harm of using shaming and pressuring language in public health communication, with implications for the current and future global health challenges

Shared heritability and functional enrichment across six solid cancers

Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (r(g) = 0.57, p = 4.6 x 10(-8)), breast and ovarian cancer (r(g) = 0.24, p = 7 x 10(-5)), breast and lung cancer (r(g) = 0.18, p = 1.5 x 10(-6)) and breast and colorectal cancer (r(g) = 0.15, p = 1.1 x 10(-4)). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis

Post-transcriptional regulation by the pluripotency associated RNA-binding protein LIN28

The field of stem cell biology is moving forward at an unprecedented rate in part due to the discovery that adult somatic cells can be reprogrammed to a pluripotent stem cell like state. The factors first used in reprogramming were transcription factors such as OCT4, SOX2 and NANOG, and the RNA-binding protein LIN28. Like transcription factors, RNA-binding proteins (RBPs) control vast networks of gene targets to direct pathways in the cell; however, for RBPs this is accomplished through post-transcriptional binding to RNA transcripts. Only recently has it been possible to survey the transcripome-wide RNA binding interactions of a protein, through isolation of endogenous RBP-RNA complexes paired with high-throughput sequencing technologies. Using cross-linking followed by immunoprecipitation of protein-RNA complexes and sequencing of isolated transcripts (CLIP-seq) we have identified LIN28 binding sites throughout the human transcriptome. The resolution of our data enabled us to define characteristic LIN28 mRNA interactions at GGAGA rich motifs within unpaired regions of hairpin loops. This binding pattern mimics interactions described for LIN28 binding within let-7 family microRNA precursors. The ability to consider LIN28 targets on a global scale enabled the identification of RNA processing factors, in particular splicing factors, as prevalent functions encoded by LIN28 bound RNAs. This information helped to accurately predict which of the thousands of LIN28 targets would be functionally regulated. We found evidence that LIN28 increases the protein production of splicing factors resulting in massive rearrangement of RNA transcripts through downstream splicing changes. Subsequent transcriptome-wide studies of LIN28 have confirmed these findings despite differences in the pool of direct targets defined by individual reports. Taken together, we understand that LIN28 can bind to a wide network of transcripts, influencing development through these direct RNA interactions and via downstream effects. Combinatorial approaches in the study of LIN28 using changes in RNA- levels, protein production, strength of CLIP-seq binding, and ontological classification of gene targets have extracted meaningful information about mechanisms of LIN28 regulation. We expect that application of similar methods will enable studies of additional RBPs. For example, in the study of other stem cell enriched proteins like the IGFII-mRNA binding proteins (IG2BP or IMP). Furthermore, the overlap of other regulatory networks hold promise of highlighting novel hubs of regulation that may be exploited in reprogramming or directed differentiation. The next step is to use these connections to explain how genetic changes within an individual can affect RBP function and result in disease. We can apply in vitro modeling of development using directed differentiation to iteratively test how the connection of LIN28 to its target transcripts impacts its role in development and diseas

Enhanced CLIP Uncovers IMP Protein-RNA Targets in Human Pluripotent Stem Cells Important for Cell Adhesion and Survival

Human pluripotent stem cells (hPSCs) require precise control of post-transcriptional RNA networks to maintain proliferation and survival. Using enhanced UV crosslinking and immunoprecipitation (eCLIP), we identify RNA targets of the IMP/IGF2BP family of RNA-binding proteins in hPSCs. At the broad region and binding site levels, IMP1 and IMP2 show reproducible binding to a large and overlapping set of 3′ UTR-enriched targets. RNA Bind-N-seq applied to recombinant full-length IMP1 and IMP2 reveals CA-rich motifs that are enriched in eCLIP-defined binding sites. We observe that IMP1 loss in hPSCs recapitulates IMP1 phenotypes, including a reduction in cell adhesion and increase in cell death. For cell adhesion, we find IMP1 maintains levels of integrin mRNA specifically regulating RNA stability of ITGB5 in hPSCs. Additionally, we show that IMP1 can be linked to hPSC survival via direct target BCL2. Thus, transcriptome-wide binding profiles identify hPSC targets modulating well-characterized IMP1 roles

Grb 051022: Physical parameters and extinction of a prototype dark burst

GRB 051022 was undetected to deep limits in early optical observations, but precise astrometry from radio and X-rays showed that it most likely originated in a galaxy at z approximate to 0.8. We report radio, optical, near-infrared, and X-ray observations of GRB 051022. Using the available X-ray and radio data, we model the afterglow and calculate its energetics, finding it to be an order of magnitude lower than that of the prompt emission. The broadband modeling also allows us to precisely define various other physical parameters and the minimum required amount of extinction to explain the absence of an optical afterglow. Our observations suggest a high extinction, at least 2.3 mag in the infrared (J) and at least 5.4 mag in the optical (U) in the host-galaxy rest frame. Such high extinctions are unusual for GRBs and likely indicate a geometry where our line of sight to the burst passes through a dusty region in the host that is not directly colocated with the burst itself

The major genetic determinants of HIV-1 control affect HLA class I peptide presentation.

Infectious and inflammatory diseases have repeatedly shown strong genetic associations within the major histocompatibility complex (MHC); however, the basis for these associations remains elusive. To define host genetic effects on the outcome of a chronic viral infection, we performed genome-wide association analysis in a multiethnic cohort of HIV-1 controllers and progressors, and we analyzed the effects of individual amino acids within the classical human leukocyte antigen (HLA) proteins. We identified >300 genome-wide significant single-nucleotide polymorphisms (SNPs) within the MHC and none elsewhere. Specific amino acids in the HLA-B peptide binding groove, as well as an independent HLA-C effect, explain the SNP associations and reconcile both protective and risk HLA alleles. These results implicate the nature of the HLA-viral peptide interaction as the major factor modulating durable control of HIV infection