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Mapping the Constrained Coding Regions in the Human Genome to Their Corresponding Proteins
Marcia A Hasenahuer1, Alba Sanchis-Juan2, Roman A Laskowski3
1European Molecular Biology Laboratory - European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SD, UK; Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK; Institute of Structural and Molecular Biology, University College London, London WC1E 6BT, UK.
Journal of Molecular Biology
|November 21, 2022
Summary
Constrained Coding Regions (CCRs) reveal segments of the human genome under evolutionary pressure. These regions, depleted of variants in healthy populations, highlight crucial functional elements beyond simple conservation.
Area of Science:
- Genomics
- Molecular Biology
- Evolutionary Biology
Background:
- Constrained Coding Regions (CCRs) are identified from large-scale human DNA sequencing data (gnomAD).
- CCRs represent genomic segments depleted of protein-altering variants, indicating evolutionary constraint.
- Understanding CCRs aids in interpreting the functional significance of genetic variation.
Purpose of the Study:
- To map human CCRs to protein structures and analyze their distribution.
- To investigate the co-occurrence of CCRs with various protein functional features.
- To compare intra-species constraints (CCRs) with inter-species conservation for variant analysis.
Main Methods:
- Utilized DNA sequencing data from the Genome Aggregation Database (gnomAD).
- Mapped genomic CCR coordinates to corresponding protein positions.
- Integrated CCR data with public protein annotation databases.
Main Results:
- Functional amino acids (DNA/RNA binding, protein contacts, catalytic sites) are highly constrained.
- Linear motifs, disorder-order transitions, and liquid-liquid phase separating (LLPS) regions show strong association with constraint.
- CCRs show weak correlation with inter-species conservation, suggesting complementary information.
Conclusions:
- CCRs highlight functionally important protein regions beyond conserved residues.
- Intra-species constraint analysis using CCRs provides complementary insights to inter-species conservation.
- CCRs offer a valuable tool for interpreting the impact of protein variants.
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