Institute for Personalized and Translational Medicine, Adelson School of Medicine, Ariel University, Ariel 4070000, Israel.
Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263.
Proc Natl Acad Sci U S A. 2024 Nov 5;121(45):e2313581121. doi: 10.1073/pnas.2313581121. Epub 2024 Oct 28.
Approximately half of mammalian genomes are occupied by retrotransposons, highly repetitive interspersed genetic elements expanded through the mechanism of reverse transcription. The evolution of this "retrobiome" involved a series of explosive amplifications, presumably associated with high mutation rates, interspersed with periods of silencing. A by-product of retrotransposon activity is the formation of processed pseudogenes (PPGs)-intron-less, promoter-less DNA copies of messenger RNA (mRNA). We examined the proportion of PPGs with varying degrees of deviation from their ancestor mRNAs as an indicator of the intensity of retrotranspositions at different times in the past. Our analysis revealed a high proportion of "young'' (recently acquired) PPGs in the DNA of mice and rats, indicating significant retrobiome activity during the recent evolution of these species. The ongoing process of new PPG entries in mouse germ line DNA was confirmed by identifying diversity in PPG content within the single strain of mice, C57BL/6. In contrast, the highly abundant PPGs of the naked mole rat (NMR) exhibited substantial deviation from their mRNAs, with a near-complete lack of PPGs without mutations, indicative of the silencing of the retrobiome in the most recent evolutionary past, preceded by a period of high activity. This distinctive feature of the NMR genome was confirmed through the analysis of a broad range of mammalian species. The peculiar evolutionary dynamics of PPGs in the NMR, an organism with exceptional longevity and resistance to cancer, may reflect the role played by the retrobiome in aging and cancer.
大约一半的哺乳动物基因组被逆转录转座子占据，这些高度重复的分散遗传元件是通过逆转录机制扩增的。这个“返祖生物群”的进化涉及一系列爆发性扩增，推测与高突变率有关，期间穿插着沉默期。逆转录转座子活动的一个副产品是形成加工假基因（PPG）——无内含子、无启动子的信使 RNA（mRNA）的 DNA 拷贝。我们检查了与祖先 mRNA 存在不同程度偏差的 PPG 的比例，作为过去不同时间逆转座强度的指标。我们的分析表明，在老鼠和老鼠的 DNA 中存在大量“年轻”（最近获得的）PPG，表明在这些物种的最近进化过程中，返祖生物群活动非常活跃。通过鉴定 C57BL/6 这一单一老鼠品系中 PPG 含量的多样性，证实了老鼠种系 DNA 中不断有新的 PPG 进入的过程。相比之下，裸鼹鼠（NMR）中高度丰富的 PPG 与其 mRNA 存在显著偏差，几乎完全缺乏没有突变的 PPG，表明在最近的进化过程中，返祖生物群被沉默，之前是一段高度活跃的时期。这一独特特征通过对广泛的哺乳动物物种的分析得到了证实。NMR 中 PPG 的特殊进化动态，这种具有异常长寿和抗癌能力的生物体，可能反映了返祖生物群在衰老和癌症中的作用。
