16 Jan Variations in Humans Related to Both Nuclear and Mitochondrial DNA
MedicalResearch.com Interview with:
Arslan Zaidi PhD
University of Pennsylvania and
Kateryna Makova, Ph.D.
Francis R. and Helen M. Pentz Professor
Director, Center for Medical Genomics
Department of Biology
Penn State University
University Park, PA 16802
MedicalResearch.com: What is the background for this study?
Response: Mitochondria are organelles that are involved in vital functions in eukaryotic cells, e.g., energy production. Even though they carry their own DNA (mitochondrial DNA, or mtDNA), most of the proteins required for mitochondrial function are encoded by the nuclear genome. Thus, mitochondrial and nuclear proteins must work together in a coordinated manner for proper mitochondrial function. These interactions can sometimes be disrupted leading to phenotypic consequences in inter-species and inter-population laboratory crosses of model organisms when the ancestry of the mitochondrial genome is very different from the nuclear genome.
While human populations are genetically not very different from each other, it has been suggested that recent admixture between geographically distant populations might also have phenotypic consequences in humans. We investigated whether there is evidence for this in six different recently admixed populations from the Americas.
MedicalResearch.com: What are the main findings?
Response: The nuclear genome of an individual from these populations, because it is inherited from the mother and the father, can be a mixture of African, European, and Native American ancestry while the mtDNA can only be of one of the three ancestry types because it is inherited maternally.
We first tested whether the degree of discordance, or difference in ancestry, between the nuclear and mitochondrial genomes is associated with mtDNA copy number. We chose mtDNA copy number because it was the only available phenotype in the dataset and because it is known to be associated with many health-related traits. We found that as the nuclear genome becomes increasingly dissimilar in ancestry from the mtDNA, the number of mtDNA molecules within a cell decreases.
Next, we tested whether there is an enrichment for a specific type of ancestry (African, European, or Native American) at nuclear-encoded mitochondrial genes in admixed populations. This could tell us whether natural selection has favored certain combinations of mito-nuclear interactions in these populations since the onset of admixture because they may have been important for human health. We found a statistically significant enrichment for Native American ancestry in Puerto Ricans (who have a prevalence of Native American mtDNA) and for African ancestry in African Americans (who have a prevalence of African mtDNA) at nuclear-encoded mitochondrial genes. This suggests that selection may have favored matching nuclear and mitochondrial ancestries in admixed populations. However, we found no such enrichment in the other populations studied. These results might be due to variation in competing selection pressures across populations.
MedicalResearch.com: What should readers take away from your report?
Response: Mito-nuclear interactions are likely important factors in contributing to phenotypic variation in humans. Such interactions should be studied further.
MedicalResearch.com: What recommendations do you have for future research as a result of this work?
Response: While we know that mito-nuclear interactions are important for mitochondrial function, we do not know to what extent they contribute to disease risk variation in human populations. In order to answer this, we recommend that genome-wide association studies (GWAS) be carried out in which the interaction between the ancestry of nuclear genes and mitochondrial ancestry are tested against various health-related phenotypes.
MedicalResearch.com: Is there anything else you would like to add?
Response: We would like to stress that our results, while encouraging, are based on data from cell lines cultured in the laboratory. Until this effect can be replicated with data from humans directly, it is unclear to what extent mito-nuclear interactions contribute to phenotypic variation in the general population. We also would like to highlight that this result does not imply that admixture is detrimental to health.
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