Abstract
Mitochondrial DNA (mtDNA) variants have been traditionally used as markers to trace ancient population migrations. Although experiments relying on model organisms and cytoplasmic hybrids, as well as disease association studies, have served to underline the functionality of certain mtDNA SNPs, only little is known of the regulatory impact of ancient mtDNA variants, especially in terms of gene expression. By analyzing RNA-seq data of 454 lymphoblast cell lines from the 1000 Genomes Project, we found that mtDNA variants defining the most common African genetic background, the L haplogroup, exhibit a distinct overall mtDNA gene expression pattern, which was independent of mtDNA copy numbers. Secondly, intra-population analysis revealed subtle, yet significant, expression differences in four tRNA genes. Strikingly, the more prominent African mtDNA gene expression pattern best correlated with the expression of nuclear DNA-encoded RNA-binding proteins, and with SNPs within the mitochondrial RNA-binding proteins PTCD1 and MRPS7. Our results thus support the concept of an ancient regulatory transition of mtDNA-encoded genes as humans left Africa to populate the rest of the world.
Highlights
Genetic variants in the nuclear and mitochondrial genomes have been traditionally used to trace the ancient global migration paths of different human populations [1, 2]
Mitochondrial DNA variants have been traditionally used as neutral markers to trace ancient population migrations
We show for the first time that the ancient migration of humans out of Africa correlated with differences in mitochondrial gene expression patterns, and could be explained by the activity of certain RNA-binding proteins
Summary
Genetic variants in the nuclear and mitochondrial genomes have been traditionally used to trace the ancient global migration paths of different human populations [1, 2]. Unlike the nuclear genome (nDNA), most (~93%) of the human mtDNA contains intron-less genes, with the majority of known gene regulatory elements being mapped within the major mtDNA non-coding control region, the D-loop These transcriptional regulatory elements include the heavy strand and light strand promoters, as well as the three conserved sequence blocks (CSBs I-III). We and others have shown that additional nDNA-encoded transcription factors, such as MEF2D, the estrogen receptor, c-Jun and Jun-D are imported into mitochondria, where they bind the mtDNA within the coding region outside the D-loop to regulate transcription [17,18,19,20] These findings suggest that mtDNA transcriptional regulation is more complex than once thought and imply that the quest for genetic variants that affect the regulation of mitochondrial gene expression should not be limited to non-coding mtDNA sequences
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