Telomeres are evolutionarily conserved nucleoprotein caps at the physical ends of eukaryotic chromosomes that ensure genome stability and regulate cellular lifespan. In humans, telomere length is likely under strong stabilizing natural selection, since accelerated shortening of telomere tracts can cause early onset of age-related diseases, while overly long telomeres are linked to cancer. Despite this evolutionary constraint, substantial heritable genetic variation in mean telomere length (set point) exists in yeast, mice, humans and plants. Family and twin studies revealed that up to 80% of human telomere length variation between individuals at birth is determined genetically. However, the causal genetic factors remain largely elusive. Here we employ quantitative trait locus (QTL) mapping, computational candidate gene screens and transgenic manipulations to identify genes that control telomere length set point in the model plant Arabidopsis thaliana. We detected several QTL, the largest of which explained 47% of observed telomere length variation in a multi-parent mapping population. To search for candidate genes, we employed a system genetics approach that combined nucleotide sequence and gene expression polymorphism surveys with T-DNA mutation knock-out and quantitative complementation comparative analyses. Our analysis uncovered NOP2A, a ribosomal RNA methyltransferase with major roles in cellular proliferation. We found that nop2a loss-of-function mutants established a stable and shorter set point than the wild type. Genetic analysis of the NOP2A gene network implicated rRNA processing and ribosome biogenesis RPL5A and RPL5B genes as additional important regulators of telomere length. These findings establish NOP2A and RPL5 genes as novel regulators of telomere length set point in plants and directly connect telomere biology, ribosome biogenesis and cell proliferation pathways.
Coauthors: Liliia Nigmatullina – Kazan Federal University;John Lovell – HudsonAlpha Institute for Biotechnology;Inna Agabekian – Kazan Federal University;Lia Valeeva – Kazan Federal University;Thomas Juenger – University of Texas at Austin;Dorothy Shippen – Texas A&M University