Inheritance, Extranuclear

Less than a decade after the rediscovery of Mendel's laws describing the inheritance of genes in the nucleus, hereditary traits were discovered that obey a different set of laws. The genes involved in this non-Mendelian pattern of inheritance reside outside the nucleus, in the cytoplasm of the cell. Specifically, they were found to reside in mitochondria , chloroplasts , or intracellular symbiotic bacteria. Those genes play important roles in the cell. Mutations in extranuclear genes are responsible for some hereditary diseases in humans and other organisms, are used in plant breeding, and are used to study population genetics and evolution.

Genes in Mitochondria and Chloroplasts

The cytoplasm of most eukaryotic cells contain organelles called mitochondria, where energy is extracted from food molecules and stored in ATP (adenosine triphosphate) for later use throughout the cell. Virtually all of the oxygen we use is consumed by our mitochondria.

Mitochondria contain their own DNA molecules (mitochondrial DNA, or mtDNA). These molecules carry a few dozen genes that are essential for energy metabolism. For example, the cob gene carries the instructions for making a protein, cytochrome b, which is an important component of the electron transport system in mitochondria. All the other proteins and RNAs encoded by mtDNA genes are also used in energy metabolism. However, many other key proteins for energy metabolism are encoded by nuclear genes. These are synthesized elsewhere in the cell and imported into the mitochondria. In fact, while the mtDNA genes are absolutely essential for the aerobic production of energy, the majority of all mitochondrial components derive from nuclear genes.

In addition to mitochondria, the cells of plants and algae also contain organelles called chloroplasts, in which photosynthesis takes place. Like the mitochondria, chloroplasts contain DNA molecules (chloroplast DNA, or cpDNA). The cpDNA molecules have genes that encode some of the proteins needed for photosynthesis. Also like the mitochondria, the majority of components needed for photosynthesis are made outside the chloroplast, using information from nuclear genes.

Endosymbiotic Origin of Mitochondria and Chloroplasts

Mitochondria and chloroplasts are self-replicating organelles: They can arise only by division of preexisting mitochondria or chloroplasts. DNA molecules are replicated and divided up among the daughter organelles after division. As a result, organelle genes show hereditary continuity from cell to cell and from parent to offspring, as do the genes in the nucleus. In fact, the ancestry of mtDNA and cpDNA can be traced back to intracellular symbionts (termed "endosymbionts").

Early in evolutionary history, an ancestor of the eukaryotes ingested an ancestor of the aerobic α-proteobacteria. This bacterium avoided digestion and became a permanent resident of the host cell, dividing within it and providing it with energy from aerobic metabolism. Gradually, over millions of years, the endosymbionts transferred most of their genes to the host nucleus, becoming completely dependent on the host cells. The host cells, in turn, came to depend on the symbiont for aerobic energy production.

Much later, an ancestor of the modern green algae and plants ingested a cyanobacterium capable of photosynthesis. Gradually this endosymbiont also lost most of its genes to the nucleus and became dependent on the host cell, while providing the host with energy from photosynthesis. The resulting organelles are self-replicating, like the original symbiont.

Because mitochondria and chloroplasts originated as endosymbiotic bacteria, their genomes differ from the nuclear genome in several important ways. First, all of the organelle genes are located on a single, circular DNA molecule. Second, the genes are virtually contiguous, with little or no intergenic DNA. Third, the gene coding sequences are continuous. In other words, there are no (noncoding) introns separating gene-coding sequences. Also, each organelle has many copies of the DNA molecule, and each cell usually has more than one organelle.

Plant cells commonly have from two to several hundred chloroplasts, while animal cells often have hundreds of mitochondria. As a result, each cell has hundreds or thousands of mtDNA or cpDNA molecules, and hence of each mitochondrial or chloroplast gene. In effect, each cell contains a small population of organelle genes. This is in contrast to the nucleus where, with few exceptions, there are only two copies of each chromosome and gene (or one copy in haploid cells).

Non-Mendelian Inheritance of Organelle Genes

The inheritance of genes in chloroplasts and mitochondria differs from that of nuclear genes in several ways. For instance, organelle genes are characterized by uniparental inheritance. During sexual reproduction, the nuclear genes are inherited from both parents (biparental inheritance). In contrast, the organelle genes are often inherited from only one parent. In animals, this is usually the female parent (maternal inheritance). Mitochondrial genes are inherited maternally because the egg is much larger than the sperm and contains tens of thousands of mtDNA molecules, while the sperm contains only a hundred or so mtDNA molecules. As a result, paternal genes are greatly outnumbered by the maternal genes and can be lost during random replication or other chance events. In addition, in some animals the mitochondrial or mtDNA molecules in the sperm are singled out for degradation in the egg.

Organelle genes are inherited maternally in most plants. In some conifers, mitochondrial genes are inherited maternally, whereas chloroplast genes are inherited paternally. In other conifers, both organelle genomes are inherited paternally. Some other plants (for example, the geranium) and some fungi and protists show a mixed pattern of inheritance. In these organisms, some offspring from a mating inherit organelle genes from only one parent, some only from the other, and some from both parents.

Another way in which extranuclear inheritance differs from nuclear genes is that organelles show vegetative segregation. During the mitotic divisions that produce an adult eukaryote from a single cell, each daughter cell receives one copy of each preexisting nuclear chromosome and gene. The result is that if a cell is heterozygous (has two different versions or alleles of a gene in the nucleus), all of the daughter cells are also heterozygous.

In contrast, different alleles of organelle genes segregate from each other during mitosis. For example, a plant egg with a mixture of normal green and mutant white chloroplasts develops into a plant with a mixture of cells, some of which will contain all green chloroplasts, whereas others will contain all white chloroplasts. This process is called vegetative segregation because it was first discovered in plants, where green and mutant white chloroplasts were observed to segregate during vegetative growth. However, it is now known to occur in all eukaryotes.

Vegetative segregation is the result of two remarkable features of organelle genes. One is random replication. Recall that an organelle contains many copies of its DNA molecule. When mtDNA or cpDNA molecules are replicated before cell division, individual molecules are randomly selected for replication until the total number of molecules has doubled. Consequently, some molecules, and some alleles, are replicated more than others.

The other feature is random partitioning. When an organelle divides, the mtDNA or cpDNA molecules are partitioned (divided up) randomly between the daughter organelles. The result is that heteroplasmic mitochondria or chloroplasts produce homoplasmic daughter organelles with a certain probability in each generation. (An organelle is said to be heteroplasmic if it contains two or more forms of a particular gene. If all the gene copies are identical, it is homoplasmic.) Moreover, when a cell divides, the organelles are partitioned randomly between the two daughter cells, so that a heteroplasmic cell can produce homoplasmic daughters. Over a large number of cell divisions, random replication and random partitioning result in the complete replacement of heteroplasmic cells by homoplasmic cells.

Plasmids

Bacteria often carry small circular DNA molecules called plasmids. These molecules sometimes carry genes that have important properties; for example, some plasmid genes make the host cell resistant to antibiotics, with important consequences for human health. Plasmids are widely used in genetics labs in the process of cloning genes. Like organelle DNA in eukaryotes, plasmid molecules are replicated independently of the cell chromosome, and one cell can contain many copies. Plasmid DNA molecules are replicated randomly and partitioned randomly to daughter cells, just like organelle genes. As a result, a cell with two different genotypes of plasmids may produce daughter cells with only one or the other. This process, analogous to vegetative segregation, is called plasmid incompatibility.

Genes in Intracellular Symbionts

Many eukaryotes harbor intracellular symbiotic bacteria as well as organelles. These are usually inherited from only one parent and may have significant effects on their host. Many insects have endosymbionts that are inherited only through the female germ line . Well-studied examples are bacteria of the genus Buchnera in aphids. Since they took up residence in insect cells, Buchnera have lost a number of genes, just like the early ancestors of mitochondria and chloroplasts. Protists also harbor hereditary symbiotic bacteria. An example is a bacterium called kappa, found in Paramecium. Kappa makes a toxin that is secreted by its host and kills other Paramecium cells that do not contain kappa.

The Practical Importance of Extranuclear Genes

Mutations of mitochondrial genes have been found to cause a number of hereditary diseases in humans. Many of these mutations lead to defects in muscles, including the heart, and the nervous system. Because mitochondrial genes are found in nearly all eukaryotes, they are often used to trace the evolutionary history of organisms, including humans. Chloroplast genes are used for evolutionary studies in plants and algae. When organelle genes are inherited from only one parent, they can be used to trace the ancestry of individuals within a species without the complications caused by recombination between maternal and paternal genes.

Mitochondrial genes can also be used to trace the female ancestor of humans, while Y-chromosome genes can be used to trace male ancestors. In this way, differences between males and females in migration or patterns of reproduction can be detected. In addition, mitochondrial genes are used in studies of animal behavior to identify the parents of animals and birds and determine their social structure. Since the organelle genome is so highly simplified, mtDNA or cpDNA can be retrieved and analyzed from ancient or poorly preserved samples in which there would be no chance of retrieving a nuclear marker.

see also Cell, Eukaryotic; Mitochondrial Diseases; Mitochondrial Genome; Molecular Anthropology; Plasmid; Prion.

C. William Birky,Jr.