Skip to main content
Premium Trial:

Request an Annual Quote

Science Papers Present Approach to Evaluate Causal Variants, Prime Editing Method

Massively parallel reporter assays (MPRAs) represent an effective means of overcoming the challenge that linkage disequilibrium (LD) can have on identifying causal variants in genetic association studies, according to a new report in this week's Science. Genome-wide association studies are an important tool to assess the effect of individual genetic variants on phenotypes, but LD remains a challenge to identifying a single causal variant among multiple correlated variants. Statistical and functional fine-mapping approaches have been developed to identify credible sets of variants that contain the causal variant, but these approaches are often unable to distinguish between proximal or highly linked variants and lack systematic prior information on the number of causal variants underlying association signals. Aiming to overcome the LD hurdle, researchers from Stanford University applied an MPRA to functionally evaluate genetic variants in high, local LD for independent cis-expression quantitative trait loci. The study, they write, demonstrates that "MPRAs provide a scalable platform with which to separate and map the regulatory activities of expression- and complex trait-associated natural genetic variants," while highlighting the limitations of existing approaches to variant interpretation and computational fine mapping. GenomeWeb has more on this, here.

A novel prime editing approach with therapeutic potential for liver disorders is described in Science Translational Medicine this week. Unlike standard CRISPR gene editing, prime editing only nicks one strand of DNA. And because it involves the direct writing of new genetic information, it is extremely versatile. Yet the large size of prime editors hampers their delivery in vivo. In an effort to fit a prime editor into commonly used gene editing vectors, a group led by University of Zurich scientists created a reduced-size SpCas9 prime editor lacking its RNaseH domain. They show that this smaller prime editor, designed to correct the mutation causing phenylketonuria, can be loaded into an adenoviral vector and systemically administrated to a mouse model of the disease, lowering blood levels of phenylalanine. The scientists note that the treatment triggered immune responses, but that additional work could allow the technology to be used clinically for phenylketonuria and other genetic diseases of the liver.

Filed under