Serena Aneli, Camilla Ceccatelli Berti, Alexandru Ionut Gilea, Giovanni Birolo, Giacomo Mutti, Angelo Pavesi, Enrico Baruffini, Paola Goffrini, Cristian Capelli
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引用次数: 0
Abstract
Neanderthal and Denisovan hybridisation with modern humans has generated a non-random genomic distribution of introgressed regions, the result of drift and selection dynamics. Cross-species genomic incompatibility and more efficient removal of slightly deleterious archaic variants have been proposed as selection-based processes involved in the post-hybridisation purge of archaic introgressed regions. Both scenarios require the presence of functionally different alleles across Homo species onto which selection operated differently according to which populations hosted them, but only a few of these variants have been pinpointed so far. In order to identify functionally divergent archaic variants removed in humans, we focused on mitonuclear genes, which are underrepresented in the genomic landscape of archaic humans. We searched for non-synonymous, fixed, archaic-derived variants present in mitonuclear genes, rare or absent in human populations. We then compared the functional impact of archaic and human variants in the model organism Saccharomyces cerevisiae. Notably, a variant within the mitochondrial tyrosyl-tRNA synthetase 2 (YARS2) gene exhibited a significant decrease in respiratory activity and a substantial reduction of Cox2 levels, a proxy for mitochondrial protein biosynthesis, coupled with the accumulation of the YARS2 protein precursor and a lower amount of mature enzyme. Our work suggests that this variant is associated with mitochondrial functionality impairment, thus contributing to the purging of archaic introgression in YARS2. While different molecular mechanisms may have impacted other mitonuclear genes, our approach can be extended to the functional screening of mitonuclear genetic variants present across species and populations.
期刊介绍:
Human Molecular Genetics concentrates on full-length research papers covering a wide range of topics in all aspects of human molecular genetics. These include:
the molecular basis of human genetic disease
developmental genetics
cancer genetics
neurogenetics
chromosome and genome structure and function
therapy of genetic disease
stem cells in human genetic disease and therapy, including the application of iPS cells
genome-wide association studies
mouse and other models of human diseases
functional genomics
computational genomics
In addition, the journal also publishes research on other model systems for the analysis of genes, especially when there is an obvious relevance to human genetics.