Retrotransposition events shape the evolution of the ataxin-3 gene family in primates

Evolutionary studies of disease-associated genes provide crucial insights into pathological mechanisms and potential therapeutic targets. Polyglutamine spinocerebellar ataxias (SCAs) are human neurodegenerative diseases caused by toxic expanded CAG repeats. Studies on SCA1 have shown that a paralog of the causing-gene can partially rescue protein function and alleviate the neuropathology. The most common SCA, Machado-Joseph disease (MJD/SCA3), caused by mutated ataxin-3 gene (ATXN3), has no treatment currently available. Its paralog ataxin-3 like (ATXN3L) remains largely unexplored. Here, we identify three new retrotransposition events of ATXN3: ATXN3L0 in Euarchontoglires, ATXN3L2 in Simiformes, and ATXN3L3 in Cercopithecidae, in addition to ATXN3L (herein called ATXN3L1) originated in Haplorrhini. ATXN3 and ATXN3L1 are both under purifying selection throughout primate evolution, maintaining about 70% of amino acid identity. Also, the high conservation of ATXN3L1 Josephin domain hints at functional redundancy with the parental disease-associated ATXN3. ATXN3L2 presents a remarkable nucleotide similarity to ATXN3 (79%) in an interrupted reading frame, which may produce a regulatory RNA. Conversely, ATXN3L0 is likely a non-functional retrocopy and ATXN3L3 is absent in humans with no relevance for the disease. The comparison of (CAG)n interruption patterns of the different paralogs in several primates elucidates the process leading to the currently observed pure long tracts in human ATXN3, responsible for disease when expanded. This study intends to pioneer the identification of new paralogs of SCA-associated genes and the use of phylogenetic analyses to explore their potential role for targeted therapies.