The GENCODE exome: sequencing the complete human exome.

Area of Science:

• Genomics
• Human Genetics
• Molecular Biology

Background:

• Exome sequencing is vital for identifying rare variants linked to human diseases.
• Current exome capture reagents primarily target the Consensus Coding Sequence (CCDS) database.
• This approach may miss disease-associated variants in unannotated or less-studied regions.

Purpose of the Study:

• To design and evaluate an extended set of targets for comprehensive human exome capture.
• To improve the identification of rare and low-frequency variants associated with disease traits.
• To include previously inaccessible disease genes in exome sequencing studies.

Main Methods:

• Utilized GENCODE consortium annotations to define an extended exome target set.
• Compared the coverage of the new GENCODE set with existing CCDS-based sets.
• Performed sequence capture experiments using the developed GENCODE exome set.
• Analyzed SNP variant identification rates between the GENCODE and CCDS-based approaches.

Main Results:

• The GENCODE exome set covers an additional 5594 genes and 10.3 Mb compared to CCDS-based sets.
• The extended set includes 43 ion channel and 70 protein kinase genes.
• Sequence capture experiments demonstrated good performance of the GENCODE exome set.
• Identified over 5000 (24%) more SNP variants using the GENCODE exome target compared to CCDS-based sequencing.

Conclusions:

• The GENCODE exome set provides significantly broader coverage for human exome sequencing.
• This expanded target set enhances the discovery of disease-associated variants, including those in important gene families.
• The developed method offers a more comprehensive approach to identifying genetic factors in human diseases.