Heterologous Inferential Analysis (HIA) and Other Emerging Concepts: In Understanding Mitochondrial Variation In Pathogenesis: There is no More Low-Hanging Fruit

Methods Mol Biol. 2021:2277:203-245. doi: 10.1007/978-1-0716-1270-5_14.


Here we summarize our latest efforts to elucidate the role of mtDNA variants affecting the mitochondrial translation machinery, namely variants mapping to the mt-rRNA and mt-tRNA genes. Evidence is accumulating to suggest that the cellular response to interference with mitochondrial translation is different from that occurring as a result of mutations in genes encoding OXPHOS proteins. As a result, it appears safe to state that a complete view of mitochondrial disease will not be obtained until we understand the effect of mt-rRNA and mt-tRNA variants on mitochondrial protein synthesis. Despite the identification of a large number of potentially pathogenic variants in the mitochondrially encoded rRNA (mt-rRNA) genes, we lack direct methods to firmly establish their pathogenicity. In the absence of such methods, we have devised an indirect approach named heterologous inferential analysis (HIA ) that can be used to make predictions concerning the disruptive potential of a large subset of mt-rRNA variants. We have used HIA to explore the mutational landscape of 12S and 16S mt-rRNA genes. Our HIA studies include a thorough classification of all rare variants reported in the literature as well as others obtained from studies performed in collaboration with physicians. HIA has also been used with non-mammalian mt-rRNA genes to elucidate how mitotypes influence the interaction of the individual and the environment. Regarding mt-tRNA variations, rapidly growing evidence shows that the spectrum of mutations causing mitochondrial disease might differ between the different mitochondrial haplogroups seen in human populations.

Keywords: Heterologous inferential analysis; Mitochondrial RNA; Mitochondrial haplogroups; Mitochondrial pathogenesis; Mitochondrial translation; Mitotypes.

MeSH terms

  • Computational Biology / methods*
  • DNA, Mitochondrial / genetics*
  • Genomics / methods*
  • Humans
  • Mitochondrial Diseases / genetics*
  • Mutation
  • Protein Biosynthesis
  • RNA, Mitochondrial / genetics*
  • RNA, Ribosomal
  • RNA, Ribosomal, 16S
  • RNA, Transfer / genetics


  • DNA, Mitochondrial
  • RNA, Mitochondrial
  • RNA, Ribosomal
  • RNA, Ribosomal, 16S
  • RNA, ribosomal, 12S
  • RNA, Transfer