Germline sequence variation within the ribosomal DNA is associated with human complex traits.

Area of Science:

• Genetics
• Molecular Biology
• Human Phenotypes

Background:

• Ribosomal RNAs (rRNAs) are vital for protein synthesis, encoded by ribosomal DNA (rDNA).
• rDNA exhibits significant variation in copy number and sequence (SNVs, indels) within and between individuals.
• The association between germline rDNA sequence variation and human traits is largely unexplored.

Purpose of the Study:

• To identify and validate single-nucleotide variants (SNVs) and insertions/deletions (indels) in germline rDNA.
• To investigate the association of these rDNA variants with human phenotypes, independent of rDNA copy number.
• To explore the functional impact of rDNA variants on rRNA structure and ribosome function.

Main Methods:

• Utilized UK Biobank whole-genome sequencing data for variant identification.
• Stringently validated a list of rDNA-associated SNVs and indels.
• Performed association analyses between rDNA variants and human phenotypes, controlling for rDNA copy number.

Main Results:

• Identified a validated list of germline rDNA SNVs and indels.
• Demonstrated that specific rDNA variants associate with human phenotypes independently of rDNA copy number.
• Found that variants in the 28S expansion segment 15L are associated with body size traits.
• Predicted that variant combinations could alter rRNA secondary structure in actively translating ribosomes.

Conclusions:

• This is the first large-scale study linking germline rDNA sequence variation to human traits.
• Germline rDNA sequence variation represents a significant, yet overlooked, source of genetic influence on human phenotypes.
• Specific rDNA variants, particularly in the 28S rRNA, may impact traits like body size by altering rRNA structure.