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

Area of Science:

• Genetics
• Molecular Biology
• Human Physiology

Background:

• Ribosomes are essential cellular machinery, with ribosomal RNAs (rRNAs) encoded by multi-copy ribosomal DNA (rDNA).
• rDNA exhibits significant variation in copy number and sequence (SNVs, INDELs) within species.
• The association between germline rDNA sequence variation and human phenotypic traits remains largely unexplored.

Purpose of the Study:

• To investigate the association between germline sequence variation in human rDNA and phenotypic traits.
• To identify specific rDNA variants linked to human complex traits using large-scale genomic data.

Main Methods:

• Utilized UK Biobank whole genome sequencing data.
• Derived and validated a high-confidence list of rDNA-associated single nucleotide variants (SNVs) and insertions/deletions (INDELs).
• Performed association analyses between identified rDNA variants and various human traits, controlling for rDNA copy number.

Main Results:

• Identified specific rDNA variants significantly associated with multiple human traits.
• Observed an enrichment of variants within the Expansion Segment 15L region of the 28S rRNA associated with body size traits.
• These associations remained significant even after accounting for total rDNA copy number.

Conclusions:

• Germline sequence variation in rDNA is a significant, yet overlooked, source of genetic variation influencing human complex traits.
• Specific rDNA sequence variants, particularly in the 28S rRNA, are associated with traits like body size.
• This study pioneers large-scale association analysis of rDNA sequence variation with human phenotypes.