High-throughput assays to assess variant effects on disease

Area of Science:

• Genetics
• Molecular Biology
• Genomics

Background:

• Interpreting rare genetic variants for human health is challenging due to limited clinical data.
• Deep mutational scanning (DMS) offers a way to study genetic variants not found in clinical reports, aiding rare disease diagnostics.
• Functional assays specific to disease mechanisms are currently a bottleneck for maximizing DMS potential.

Purpose of the Study:

• To explore high-throughput functional methodologies for examining broad disease mechanisms.
• To integrate disease-relevant assays into the deep mutational scanning (DMS) framework.
• To identify methods that do not require robotics or automation, focusing on molecular tools for detectable signals.

Main Methods:

• Focus on functional assays that transform biological mechanisms into detectable signals (e.g., cell survival, fluorescence, drug resistance).
• Exploration of methodologies suitable for high-throughput screening without extensive automation.
• Development of molecular tools for unbiased variant investigation.

Main Results:

• Identification of suitable high-throughput functional assays for DMS.
• Demonstration of methods to link biological mechanisms to measurable outputs.
• Bridging the gap between disease-specific assays and the DMS framework.

Conclusions:

• Deep mutational scanning (DMS) can be enhanced by integrating novel, high-throughput functional assays.
• This approach improves the study of rare genetic variants and their link to human diseases.
• The developed methodologies facilitate broader application of DMS in genetic research and diagnostics.