Human mitochondrial genetics

Human mitochondrial genetics is the study of the genetics of human mitochondrial DNA. The human mitochondrial genome is the entirety of hereditary information contained in human mitochondria. Mitochondria are small structures in cells that generate energy for the cell to use, and are hence referred to as the "powerhouses" of the cell.
Mitochondrial DNA is not transmitted through nuclear DNA. In humans, as in most multicellular organisms, mitochondrial DNA is inherited only from the mother's ovum. There are theories, however, that paternal mtDNA transmission in humans can occur under certain circumstances.
Mitochondrial inheritance is therefore non-Mendelian, as Mendelian inheritance presumes that half the genetic material of a fertilized egg derives from each parent.
This allowed the creation of mitochondrial DNA haplogroups to study population genetics.
Eighty percent of mitochondrial DNA codes for mitochondrial RNA, and therefore most mitochondrial DNA mutations lead to functional problems, which may be manifested as muscle disorders.
Because they provide 30 molecules of ATP per glucose molecule in contrast to the 2 ATP molecules produced by glycolysis, mitochondria are essential to all higher organisms for sustaining life. The mitochondrial diseases are genetic disorders carried in mitochondrial DNA, or nuclear DNA coding for mitochondrial components. Slight problems with any one of the numerous enzymes used by the mitochondria can be devastating to the cell, and in turn, to the organism.

Quantity

In humans, mitochondrial DNA forms closed circular molecules that contain 16,569 DNA base pairs, with each such molecule normally containing a full set of the mitochondrial genes. Each human mitochondrion contains, on average, approximately 5 such mtDNA molecules, with the quantity ranging between 1 and 15. Each human cell contains approximately 100 mitochondria, giving a total number of mtDNA molecules per human cell of approximately 500. The amount of mitochondria per cell also varies by cell type, with some examples being:

Erythrocytes: 0 mitochondria per cell.
Lymphocytes: 3 mitochondria per cell.
Egg cell: Mature metaphase II egg cells can contain 100,000 mitochondria, and 50,000–1,500,000 copies of the mitochondrial genome.
Inheritance patterns

Because mitochondrial diseases can be inherited both maternally and through chromosomal inheritance, the way in which they are passed on from generation to generation can vary greatly depending on the disease. Mitochondrial genetic mutations that occur in the nuclear DNA can occur in any of the chromosomes. Mutations inherited through the chromosomes can be autosomal dominant or recessive and can also be sex-linked dominant or recessive. Chromosomal inheritance follows normal Mendelian laws, despite the fact that the phenotype of the disease may be masked.
Because of the complex ways in which mitochondrial and nuclear DNA "communicate" and interact, even seemingly simple inheritance is hard to diagnose. A mutation in chromosomal DNA may change a protein that regulates the production of another certain protein in the mitochondria or the cytoplasm; this may lead to slight, if any, noticeable symptoms. On the other hand, some devastating mtDNA mutations are easy to diagnose because of their widespread damage to muscular, neural, and/or hepatic tissues and because they are present in the mother and all the offspring.
The number of affected mtDNA molecules inherited by a specific offspring can vary greatly because

the mitochondria within the fertilized oocyte is what the new life will have to begin with,
the number of affected mitochondria varies from cell to cell depending both on the number it inherited from its mother cell and environmental factors which may favor mutant or wildtype mitochondrial DNA,
the number of mtDNA molecules in the mitochondria varies from around two to ten.

It is possible, even in twin births, for one baby to receive more than half mutant mtDNA molecules while the other twin may receive only a tiny fraction of mutant mtDNA molecules with respect to wildtype. In a few cases, some mitochondria or a mitochondrion from the sperm cell enters the oocyte but paternal mitochondria are actively decomposed.

Genes

Genes in the human mitochondrial genome are as follows.

Electron transport chain, and humanin

It was originally incorrectly believed that the mitochondrial genome contained only 13 protein-coding genes, all of them encoding proteins of the electron transport chain. However, in 2001, a 14th biologically active protein called humanin was discovered, and was found to be encoded by the mitochondrial gene MT-RNR2 which also encodes part of the mitochondrial ribosome :

Complex number	Category	Genes	Positions in the mitogenome	Strand
I	NADH dehydrogenase	-	-	-
I	NADH dehydrogenase	MT-ND1	3,307–4,262	H
I	NADH dehydrogenase	MT-ND2	4,470–5,511	H
I	NADH dehydrogenase	MT-ND3	10,059–10,404	H
I	NADH dehydrogenase	MT-ND4L	10,470–10,766	H
I	NADH dehydrogenase	MT-ND4	10,760–12,137	H
I	NADH dehydrogenase	MT-ND5	12,337–14,148	H
I	NADH dehydrogenase	MT-ND6	14,149–14,673	L
III	Coenzyme Q - cytochrome c reductase / Cytochrome b	MT-CYB	14,747–15,887	H
IV	Cytochrome c oxidase	MT-CO1	5,904–7,445	H
IV	Cytochrome c oxidase	MT-CO2	7,586–8,269	H
IV	Cytochrome c oxidase	MT-CO3	9,207–9,990	H
V	ATP synthase	MT-ATP6	8,527–9,207	H
V	ATP synthase	MT-ATP8	8,366–8,572	H
—	Humanin	MT-RNR2	—	—

Unlike the other proteins, humanin does not remain in the mitochondria, and interacts with the rest of the cell and cellular receptors. Humanin can protect brain cells by inhibiting apoptosis. Despite its name, versions of humanin also exist in other animals, such as rattin in rats.

rRNA

The following genes encode rRNAs:

Subunit	rRNA	Genes	Positions in the mitogenome	Strand
Small	12S	MT-RNR1	648–1,601	H
Large	16S	MT-RNR2	1,671–3,229	H

tRNA

The following genes encode tRNAs:

Amino Acid	3-Letter	1-Letter	MT DNA	Positions	Strand
Alanine	Ala	A	MT-TA	5,587–5,655	L
Arginine	Arg	R	MT-TR	10,405–10,469	H
Asparagine	Asn	N	MT-TN	5,657–5,729	L
Aspartic acid	Asp	D	MT-TD	7,518–7,585	H
Cysteine	Cys	C	MT-TC	5,761–5,826	L
Glutamic acid	Glu	E	MT-TE	14,674–14,742	L
Glutamine	Gln	Q	MT-TQ	4,329–4,400	L
Glycine	Gly	G	MT-TG	9,991–10,058	H
Histidine	His	H	MT-TH	12,138–12,206	H
Isoleucine	Ile	I	MT-TI	4,263–4,331	H
Leucine	Leu	L	MT-TL1	3,230–3,304	H
Leucine	Leu	L	MT-TL2	12,266–12,336	H
Lysine	Lys	K	MT-TK	8,295–8,364	H
Methionine	Met	M	MT-TM	4,402–4,469	H
Phenylalanine	Phe	F	MT-TF	577–647	H
Proline	Pro	P	MT-TP	15,956–16,023	L
Serine	Ser	S	MT-TS1	7,446–7,514	L
Serine	Ser	S	MT-TS2	12,207–12,265	H
Threonine	Thr	T	MT-TT	15,888–15,953	H
Tryptophan	Trp	W	MT-TW	5,512–5,579	H
Tyrosine	Tyr	Y	MT-TY	5,826–5,891	L
Valine	Val	V	MT-TV	1,602–1,670	H

Location of genes

Mitochondrial DNA traditionally had the two strands of DNA designated the heavy and the light strand, due to their buoyant densities during separation in cesium chloride gradients, which was found to be related to the relative G+T nucleotide content of the strand. However, confusion of labeling of this strands is widespread, and appears to originate with an identification of the majority coding strand as the heavy in one influential article in 1999. In humans, the light strand of mtDNA carries 28 genes and the heavy strand of mtDNA carries only 9 genes. Eight of the 9 genes on the heavy strand code for mitochondrial tRNA molecules. Human mtDNA consists of 16,569 nucleotide pairs. The entire molecule is regulated by only one regulatory region which contains the origins of replication of both heavy and light strands. The entire human mitochondrial DNA molecule has been mapped.