goloco: a web application to create genome scale information from surprisingly small experiments.

Background: Functional genomics aims to decipher gene function by observing cellular changes when specific genes are disrupted using CRISPR technology. However, these experiments are limited by scalability, as comprehensive CRISPR screens require extensive resources, involving millions of cells and thousands of sgRNAs, making large-scale studies challenging. We propose a novel approach with "CRISPR lossy compression" to reduce the complexity of CRISPR screens by focusing on key genetic nodes that can infer genome-wide phenotypes.

Incorporating mutational heterogeneity to identify genes that are enriched for synonymous mutations in cancer.

Background: Synonymous mutations, which change the DNA sequence but not the encoded protein sequence, can affect protein structure and function, mRNA maturation, and mRNA half-lives. The possibility that synonymous mutations might be enriched in cancer has been explored in several recent studies. However, none of these studies control for all three types of mutational heterogeneity (patient, histology, and gene) that are known to affect the accurate identification of non-synonymous cancer-associated genes.

How soluble misfolded proteins bypass chaperones at the molecular level.

Subpopulations of soluble, misfolded proteins can bypass chaperones within cells. The extent of this phenomenon and how it happens at the molecular level are unknown. Through a meta-analysis of the experimental literature we find that in all quantitative protein refolding studies there is always a subpopulation of soluble but misfolded protein that does not fold in the presence of one or more chaperones, and can take days or longer to do so.

Functional genomic analysis of adult and pediatric brain tumor isolates.

Background: Adult and pediatric tumors display stark differences in their mutation spectra and chromosome alterations. Here, we attempted to identify common and unique gene dependencies and their associated biomarkers among adult and pediatric tumor isolates using functional genetic lethal screens and computational modeling.

Methods: We performed CRISRP-Cas9 lethality screens in two adult glioblastoma (GBM) tumor isolates and five pediatric brain tumor isolates representing atypical teratoid rhabdoid tumors (ATRT), diffuse intrinsic pontine glioma, GBM, and medulloblastoma.

A pan-CRISPR analysis of mammalian cell specificity identifies ultra-compact sgRNA subsets for genome-scale experiments.

A genetic knockout can be lethal to one human cell type while increasing growth rate in another. This context specificity confounds genetic analysis and prevents reproducible genome engineering. Genome-wide CRISPR compendia across most common human cell lines offer the largest opportunity to understand the biology of cell specificity.