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Ribosomal DNA Copy Number Levels Linked to Kidney Function, Inflammation in UK Biobank

NEW YORK – New research suggests that an uptick in copy number of poorly studied repeat sequences from ribosomal DNA (rDNA) corresponds with blood cell composition and kidney function features.

"This is a type of genetic variation that has never really been considered before (and hence not much was known about it)," Vardhman Rakyan, a professor at Queen Mary University of London, explained in an email, noting that "rDNA is a critical region of the genome that ultimately is involved in protein production."

In a study published in Cell Genomics on Tuesday, Rakyan and his colleagues reasoned that whole-genome sequence data from the UK Biobank project could reveal repetitive sequence features missed with other genetic profiling approaches.

"Repetitive regions are difficult to analyze and hence are left out of genetic profiling platforms, such as microarrays," Rakyan explained. "However, the UK Biobank released whole genome sequences for half a million people, which means we can now look [at] such regions and ask if they mean anything for [a certain] phenotype or disease."

In particular, the team searched through available whole-genome sequencing data for roughly 490,505 UK Biobank participants to identify copy number variants of the multi-copy 47S ribosomal DNA, which is found at multiple sites in the genome and codes for the 18S, 5.8S, and 28S ribosomal RNAs behind protein-producing ribosomal components.

From there, the researchers brought in additional genetic and phenotypic data — ranging from genetic variation to blood protein and biomarker measurements — for White British participants to perform genome-wide association, phenome-wide association, and other analyses focused on the consequences of rDNA copy number variation.

Together, their results pointed to apparent ties between rDNA copy number and estimated glomerular filtration, a measure of kidney function, in the White, European-ancestry participants. While relatively low rDNA copy numbers coincided with increased kidney function, for example, they saw poorer-than-usual kidney function as rDNA copy numbers crept up.

Likewise, the representation of certain blood cell subtypes, particularly neutrophil immune cells, and the presence of related inflammation markers tended to increase alongside higher-than-usual copy numbers of the rDNA sequences considered.

"Our analyses support rDNA [copy number] variation being a genetic influence on hematological profiles and renal function in humans," the authors reported, noting that "further mechanistic investigation is limited by the lack of suitable methods for the controlled genetic manipulation of rDNA [copy number] in mammalian cells."

Although the investigators did not have sufficient samples sizes to do the same level of analyses in other populations, they noted that their initial analyses hinted at comparable patterns in non-European ancestry groups.

"Our next steps are to understand the mechanism and look at how rDNA copy number variation impacts other phenotypes," Rakyan explained. "Ultimately this will be very useful for improved genetic risk prediction, and possibly treatments that target the ribosome."