Functional characterization of archaic-specific variants in mitonuclear genes: insights from comparative analysis in S. cerevisiae

Author:

Aneli Serena1ORCID,Ceccatelli Berti Camilla23,Gilea Alexandru Ionut23,Birolo Giovanni4,Mutti Giacomo56,Pavesi Angelo23,Baruffini Enrico23,Goffrini Paola23ORCID,Capelli Cristian237

Affiliation:

1. Department of Public Health Sciences and Pediatrics, University of Turin , C.so Galileo Galilei 22, Turin 10126 , Italy

2. Department of Chemistry , Life Sciences and Environmental Sustainability, , Parco Area delle Scienze 11/a, Parma 43124 , Italy

3. University of Parma , Life Sciences and Environmental Sustainability, , Parco Area delle Scienze 11/a, Parma 43124 , Italy

4. Department of Medical Sciences, University of Turin , Via Santena 5, Turin 10126 , Italy

5. Barcelona Supercomputing Centre (BSC-CNS) , Department of Life Sciences, Plaça Eusebi Güell, 1-3, Barcelona 08034 , Spain

6. Institute for Research in Biomedicine (IRB Barcelona), Department of Mechanisms of Disease, The Barcelona Institute of Science and Technology , Baldiri Reixac, 10, Barcelona 08028 , Spain

7. Department of Biology, University of Oxford , 11a Mansfield Rd, Oxford OX1 3SZ , United Kingdom

Abstract

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.

Publisher

Oxford University Press (OUP)

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