Protein-coding repeat polymorphisms strongly shape diverse human phenotypes

Area of Science:

• Genetics
• Human Biology
• Bioinformatics

Background:

• Many human proteins feature domains with variable sizes or copy numbers due to variable numbers of tandem repeats (VNTRs) in protein-coding exons.
• The phenotypic impact of VNTRs remains largely unexplored due to challenges in accurately measuring these repetitive genetic elements.

Purpose of the Study:

• To develop novel computational methods for estimating VNTR lengths from whole-exome sequencing (WES) data.
• To impute VNTR alleles into single-nucleotide polymorphism (SNP) haplotypes for large-scale genetic association studies.
• To investigate the associations between common VNTRs and a wide range of human phenotypes.

Main Methods:

• Development of algorithms to infer VNTR lengths directly from WES data.
• Implementation of imputation techniques to integrate VNTR data with existing SNP haplotype information.
• Genome-wide association study (GWAS) analysis of 118 protein-altering VNTRs across 786 phenotypes in the UK Biobank cohort (n=415,280).

Main Results:

• Identification of strong associations between common VNTRs and numerous human phenotypes, including height, hair morphology, and various health biomarkers.
• Discovery of some of the most significant associations reported to date for common genetic variants with human traits.
• Demonstration that incorporating large-effect VNTRs improves the fine-mapping of associations to specific protein-coding mutations within genes.

Conclusions:

• VNTRs represent a significant, yet previously underappreciated, source of genetic variation influencing human phenotypes.
• The developed methods enable the systematic study of VNTRs, unlocking insights into their role in human health and disease.
• These findings highlight the importance of considering highly polymorphic structural variants in molecular and phenotypic analyses.