Focus on your locus with a massively parallel reporter assay

Area of Science:

• Genomics
• Neuroscience
• Molecular Biology

Background:

• Genome-wide association and whole genome sequencing studies identify numerous genetic variants associated with neurodevelopmental disorders.
• Causal variants within large noncoding haplotype blocks and the functional impact of rare noncoding variants remain challenging to determine without experimental validation.

Purpose of the Study:

• To review and discuss the application of Massively Parallel Reporter Assays (MPRAs) for the functional validation of genetic variants implicated in neurodevelopmental disorders.
• To explore various MPRA designs and their potential for future research in this field.

Main Methods:

• Massively Parallel Reporter Assays (MPRAs) enable simultaneous functional validation of thousands of regulatory elements.
• MPRAs utilize high-throughput sequencing and barcode technology to assess gene regulatory effects of genetic variants.
• Adaptations of MPRA measure cis- and trans-regulatory effects and posttranscriptional processes.

Main Results:

• MPRAs can screen thousands of sequences in a single experiment, significantly narrowing down potential causal genetic variants.
• This technique provides functional insights into the molecular effects of genetic variants associated with neurodevelopmental disorders.

Conclusions:

• MPRAs are a powerful tool for experimentally validating genetic variants linked to neurodevelopmental disorders, despite limitations like the lack of genomic context modeling.
• Future applications of MPRA include studying gene-by-environment interactions and pharmacogenetics in the context of neurodevelopmental disorders.