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Nature Papers Examine Residual Protein Expression Following CRISPR Knockout, Polygenic Score Predicts Depression Risk

While CRISPR-Cas9 is commonly used to generate genetic knockouts via the introduction of frameshift mutations, residual protein expression may hinder this application of the gene-editing technology, according to a new study in Nature Methods. A team led by scientists from the European Molecular Biology Laboratory used RNA sequencing and triple-stage mass spectrometry to characterize 193 genetically verified deletions targeting 136 distinct genes generated by CRISPR-induced frameshifts in HAP1 cells. They find residual protein expression for about one third of the quantified targets at levels ranging from low to original, as well as the partial preservation of protein function for three truncated targets. The findings, they write, point to "an important potential limitation of the CRISPR technology for biological research, as well as therapeutic applications," and highlights the need for systematic characterization of residual protein expression or function in CRISPR-Cas9-generated knockout lines. 

A recently developed polygenic risk score for depression has proven effective for identifying individuals at risk for the condition when under stress. In a study appearing in Nature Human Behavior, University of Michigan researchers applied the major depressive disorder polygenic risk score (MDD-PRS), which was derived from the most recent Psychiatric Genomics Consortium–UK Biobank–23andMe genome-wide association study, to around 5,200 training physicians. They found that the score could predict depression under training stress, that it was more strongly associated with depression under stress than at baseline, and that known risk factors accounted for substantially less of the association between score and depression when under stress than at baseline. Further, individuals with extremely low MDD-PRS scores were found to be particularly resilient to depression under stress, suggesting that the behavioral and biological responses to stress of people with low MDD-PRS could be used to identify strategies to prevent depression and inform the incorporation of precision medicine into psychiatry, the study's authors write.