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Fig. 1 | Genome Medicine

Fig. 1

From: Environment-driven somatic mosaicism in brain disorders

Fig. 1

Environmental influence on retrotransposition and disease risk. a Environmental factors can increase the rate of retrotransposition by affecting cellular and molecular processes that act at different levels of the insertion cycle (thunderbolts represent environmental effects). (1) In the nucleus (dotted line represents the nuclear envelope), full-length long interspersed nuclear element (L1) retrotransposon elements are transcribed from an internal Pol II promoter. Environmental effects on transcription factor expression or binding, on DNA methylation of L1 elements, or on heterochromatin structure could increase the transcription of L1, introducing more substrate for potential retrotransposition. (2) L1 mRNA encodes two proteins: an RNA-binding protein (ORF1p) and a protein with endonuclease and reverse transcriptase domains (ORF2p). These proteins form a ribonucleoprotein (RNP) complex with L1 mRNA in cis-preference (that is, mRNA from the same L1 element), and this complex can be imported into the nucleus or sequestered into stress granules and degraded. Environmental factors may influence cellular defenses involved in the sequestration and degradation of L1 proteins, which could affect the amount of stable L1 RNP complexes available for import into the nucleus. (3) L1 RNP complexes are imported into the nucleus during cell division when the nuclear envelope is disrupted, or through an unknown import mechanism. Environmental effects on nuclear permeability or on the rate of cell division could increase the number of L1 RNP complexes imported into the nucleus, thus increasing availability of the machinery needed for retrotransposition. (4) Once inside the nucleus, L1 endonuclease nicks the genomic DNA at a TTAAA sequence and the L1 mRNA is inserted via target-primed reverse transcription (pink circle represents ORF2p reverse transcribing L1 mRNA). Environmental effects on DNA damage, DNA repair processes, or chromatin structure could affect the accessibility of the genomic DNA and its vulnerability to acquiring a new insertion. b Many neurological phenotypes, for example stress activity, are normally distributed, with extreme traits at the outer tails of the distribution predicting disease (top graph). The effect of high levels of somatic mutation on disease risk might be explained by models of additive or neutral risk. An extreme model would suggest that all somatic variation is associated with additive risk. In this case, the net result would be a shift in the mean of the respective phenotype (middle graph). Conversely, a more conservative model would posit that somatic events, much like germline mutations, have a largely neutral effect on the phenotype, with rare events having an equal chance of increasing or decreasing risk. In this case, an accumulation of normally distributed interacting effects would expand the variance of a distribution while keeping the mean constant (bottom graph). Environmental factors that accelerate the somatic mutation rate could ultimately expand the phenotypic diversity in an affected population beyond its natural state, potentially increasing disease risk in the population. If the phenotypic distribution were expanded or shifted, more individuals would exhibit extreme neurological traits at the outer tails of the distribution

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