Although not being a geneticist let alone aware of modern genetics, Charles Darwin stated in ‘The Origin of Species’ (1859, chapter 2): “No one supposes that all the individuals of the same species are cast in the very same mould. These individual differences are highly important for us, as they afford materials for natural selection to accumulate”. Indeed, this view is supported at the modern genomic era, by analysis of genetic variation in many life forms, which reveals signatures of evolutionary processes, such as genetic drift or natural selection.


The genetic material does not only passively respond to evolutionary changes. Rather, it is the interplay between genes and environment that underlies the differential response of organisms to continuously changing environments, disease susceptibility differences among people and even the emergence of new species. However, evolutionary processes are largely unpredictable and are governed by both random and non-random forces. The plot thickens when one adds to the interplay of genes and environment the functional and genetic interactions between genes, and the differences in mutation rates among DNA sequence in evolutionary time scales. Varying levels of the interplay of gene-gene-environment underlie the operation of most cellular activities. However there is a unique organelle within each of all animal cells that out compete all others both at the level of genetic variability between individuals. This organelle is the mitochondrion, the major provider of cellular energy and a central player in metabolism and cell death. This is the only component within the cytoplasm of animal cells that has its own genetic material, a strictly maternally inherited genome (the mtDNA).


Unlike the genes in our nucleus, the mtDNA resides in multiple copies per cell thus adding another layer to the genetic variation in humans and other organisms: the intracellular variation and the epistatic, physical and regulatory interaction between the mtDNA and the cell nucleus.


Current research


In our lab we investigated the genetic and evolutionary principles that govern mitochondrial genetic variation between individuals and within cells in health and disease conditions. We also are interested in the genetic, physical and regulatory interactions between the mitochondria and the cell nucleus.


Several lines of research guide our thinking:  


1. Investigate the functional potential and phenotypic consequences of subtle genetic alterations in mitochondrial factors encoded both by the mtDNA and the nuclear genome.


2. Investigating co-evolution between mitochondrial protein-coding genes and its implication on the entire subunit interactions scheme within the oxidative phosphorylation (OXPHOS) system: OXPHOS complex I as a model.


3. Analysing the effects of natural selection on the population genetic mtDNA variation within cells and individuals: human and non-human species.


4. Investigating the complexity of mtDNA transcriptional regulation: exploring all regulatory factors involved, their mtDNA binding sites and the possible functional co-evolution between the factors and their mtDNA recognition sites.


5. Investigating the genetic, mechanistic and evolutionary principles underlying genetic variation among mitochondria within the cell – heteroplasmy.

Prof. Dan Mishmar  E-mail: