Traditional inheritance views the nucleus as the central repository of genetic information and meiosis as the principal determinant of the segregation of traits in families. However, the existence of another genome, the mitochondrial genome, in all cells introduces another twist of biology leading to nontraditional inheritance.
Mitochondria are organelles that provide much of the energy cells use for the work they do. Most biologists now believe that these structures evolved from microorganisms that established symbiotic relationships with the ancestors of animal cells very early in the history of life on this planet. Selection for metabolic advantages gained through symbiosis explains how it has come to be that mitochondria contain their own DNA that codes for 13 of their proteins along with ribosomal and transfer RNA that specifically help express mitochondrial series.
As with any form of DNA, mitochondrial DNA (mtDNA) sequences are susceptible to mutation In fact, there is evidence that mitochondrial sequences may mutate at rates 3 to 5 times greater than nuclear sequences. The consequences of mitochondrial mutations, however, may be very different from those that occur in nuclear DNA. First, each cell contains about 100,000 mitochondria, each of which has 2 to 10 copies of its genome. The effect a mutation in mtDNA will have on a cell's function will therefore depend on the number of mutant organelles in a cell compared to the number of normal, or "wild type", present. In this respect, each cell is analogous to an organism in which somatic mutation can produce mosaicism (see above). Here the mixture of genotypes is termed heteroplasmy.
When cells divide, their mitochondria independently replicate and then distribute randomly into daughter cells. This leads to variable phenotypes within and among tissues ranging from non-viable cells (hence death of tissue), to energy generation dysfunction, to subthreshold changes (i.e. "silent" mutations) that do not affect overall cell function. What this means is that mitochondrial mutations may be variable in their clinical presentation, depending on their timing and prevalence.
The human mitochondrial genome, which contains 16,569 nucleotide pairs, has been completely mapped and sequenced. Interestingly, it uses a slightly different genetic code (sequence of nucleotide bases that specifies an amino acid) than that used by nuclear genes. Several mutations, both single base changes (or point mutations) and structural changes (deletions) have been described which produce clinical disorders.
A number of specific disorders have been described where mitochondrial mutations are either inherited or occur early enough in development to dominate most cells. These disorders characteristically affect muscle and nervous tissue, particularly the optic tracks. Among these conditions are Leber's Hereditary Optic Neuropathv (LHON), which usually presents with onset of symptoms after puberty; Kearns-Sayre syndrome and chronic progressive external ophthalmoplegia (CPEO), which both result in paralysis of external, but not internal, eye muscles; myoclonic epilepsy with ragged red fibers (MERRF), which presents at various ages; and mitochondrial myopathy, encephalopathy, lactic acidosis with stroke-like episodes (MELAS), which evolves during infancy.
Mitochondria are passed from generation to generation only through maternal egg cells where they are abundant. Those present in sperm are concentrated in the tail and do not contribute to the compliment of the fertilized zygote. Molecular genetic tracking of polymorphic or variable regions through families and even across the millenia of human evolution confirm maternal inheritance of mitochondrial DNA.
Maternal inheritance looks very much like mendelian autosomal dominant inheritance with two important exceptions. First, all maternal offspring are usually affected. Even in highly penetrant dominant disorders only 50% of offspring are expected to be affected. Secondly, mitochondrially-inherited traits are never passed through a male. Males are as likely to be affected as females, but their offspring are not at risk.
Although mitochondrial inheritance looks easy to identify in a pedigree like the one in Figure 3, it must be remembered that phenotypic variability is a hallmark for these disorders, especially in cases where there is heteroplasmy. Therefore, a family history where some individuals present with strokes, others with muscle weakness, and still others with psychiatric or ophthalmologic complaints might not be immediately recognizable as one expressing a single mitochondrial mutation. This is an important point because while the human mitochondrial genome has been sequenced, a complete spectrum of its viable mutations is far from assembled.
With frequencies approaching 1:50,000 LHON and other mitochondrial disorders would appear to be rare. It is likely, however, that since mitochondrial mutations are frequent, there are many new phenotypes yet to be discovered. In aggregate, clinically significant mutations may be eventually shown to be common. Indeed, it has been proposed that accumulating mitochondrial mutations contribute significantly to aging.
A final point about mitochondrial inheritance that needs to be stressed is that most of the proteins contributing to mitochondrial structure and function are encoded by nuclear genes and their mutations therefore segregate as mendelian traits. Thus, a clear distinction needs to be kept between mitochondrial disorders, most of which are inherited as recessive traits, and mitochondrial inheritance, which is concerned only with those mutations occurring in mitochondrial DNA. Disorders of mitochondrial function inherited by either classical mendelian or mitochondrial inheritance may have overlapping features.
Referance:
