RESUMO
Phenotypic differences between species are driven by changes in gene expression and, by extension, by modifications in the regulation of the transcriptome. Investigation of mammalian transcriptome divergence has been restricted to analysis of bulk gene expression levels and gene-internal splicing. Using allele-specific expression analysis in inter-strain hybrids of Mus musculus, we determined the contribution of multiple cellular regulatory systems to transcriptome divergence, including: alternative promoter usage, transcription start site selection, cassette exon usage, alternative last exon usage, and alternative polyadenylation site choice. Between mouse strains, a fifth of genes have variations in isoform usage that contribute to transcriptomic changes, half of which alter encoded amino acid sequence. Virtually all divergence in isoform usage altered the post-transcriptional regulatory instructions in gene UTRs. Furthermore, most genes with isoform differences between strains contain changes originating from multiple regulatory systems. This result indicates widespread cross-talk and coordination exists among different regulatory systems. Overall, isoform usage diverges in parallel with and independently to gene expression evolution, and the cis and trans regulatory contribution to each differs significantly.
Assuntos
Elementos Facilitadores Genéticos , Camundongos/genética , RNA Mensageiro/genética , Transcriptoma , Alelos , Processamento Alternativo , Animais , Quimera/genética , Evolução Molecular , Éxons , Feminino , Masculino , Camundongos/classificação , Fenótipo , Poliadenilação , Regiões Promotoras Genéticas , Sítio de Iniciação de TranscriçãoRESUMO
Gene expression levels are thought to diverge primarily via regulatory mutations in trans within species, and in cis between species. To test this hypothesis in mammals we used RNA-sequencing to measure gene expression divergence between C57BL/6J and CAST/EiJ mouse strains and allele-specific expression in their F1 progeny. We identified 535 genes with parent-of-origin specific expression patterns, although few of these showed full allelic silencing. This suggests that the number of imprinted genes in a typical mouse somatic tissue is relatively small. In the set of nonimprinted genes, 32% showed evidence of divergent expression between the two strains. Of these, 2% could be attributed purely to variants acting in trans, while 43% were attributable only to variants acting in cis. The genes with expression divergence driven by changes in trans showed significantly higher sequence constraint than genes where the divergence was explained by variants acting in cis. The remaining genes with divergent patterns of expression (55%) were regulated by a combination of variants acting in cis and variants acting in trans. Intriguingly, the changes in expression induced by the cis and trans variants were in opposite directions more frequently than expected by chance, implying that compensatory regulation to stabilize gene expression levels is widespread. We propose that expression levels of genes regulated by this mechanism are fine-tuned by cis variants that arise following regulatory changes in trans, suggesting that many cis variants are not the primary targets of natural selection.
Assuntos
Evolução Molecular , Regulação da Expressão Gênica , Camundongos Endogâmicos C57BL/genética , Camundongos Endogâmicos/genética , Alelos , Animais , Ritmo Circadiano/genética , Feminino , Impressão Genômica , Masculino , Camundongos , Modelos Moleculares , Fenótipo , Análise de Sequência de RNA/métodosRESUMO
Nuclear transcription factors have been detected in mammalian mitochondria and may directly regulate mitochondrial gene expression. Emerging genomics techniques may overcome outstanding challenges in this field.
