Father with mutated mtDNA- why isn't his offspring at risk?

Father with mutated mtDNA- why isn't his offspring at risk?

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Mothers transmit their mitochondria (and therefore mtDNA) to their offspring and fathers don't. Lets assume that father had a mutation of the gene that encodes mtDNA, would then be his offspring at risk? Why?

I also found the following statement: "The current genetic advice is that fathers with mtDNA mutations are at no risk of transmitting the defect to their offspring."

How can that be true? Is it because of gene silencing?

Thank you in advance!

… would then be his offspring at risk? Why?

No. Generally speaking, fathers do not pass on their mtDNA (Mitochondrial DNA).

Why? Because the mitochondria present in oocytes (egg cell) is the mother's, as every oocyte directly inherits the mother's mitochondria when they are made in the reproductive organs. The mitochondria that the sperm from the father carry to the egg do not enter the egg cell or are destroyed in the process.

It's also worth mentioning that, in general, mtDNA does NOT reside in the nucleus of cells, but in the mitochondria itself. It is not condensed during cell division, it is not spliced during Meiosis II, and it does not undergo recombination with another cell's mtDNA. Instead, when a cell divides, each cell takes about half of the mitochondria present in the cell and maintains them. That way only the mitochondria present in the cell before division will be inherited by the daughter cells, and thus only the maternal mitochondria present in oocytes (egg cells) before sperm instigate cell division will be inherited by any offspring.

TL;DR: Ubiquitin.

Occasional occurrence of paternal inheritance of mtDNA has been suggested in mammals including humans. Clearly, spermatozoa have mitochondria; they make the energy needed for motility. Paternal mitochondrial DNA (mtDNA) does enter oocytes. It is a persisting fallacy that only maternal mtDNA is present in humans because only oocyte mitochondria are present in the product of conception.

This has been known for some time. According to an article in the Proceedings of the National Academy of Sciences, Nov. 1996, under Evolution:

In vertebrates, inheritance of mitochondria is thought to be predominantly maternal, and mitochondrial DNA analysis has become a standard taxonomic tool. In accordance with the prevailing view of strict maternal inheritance, many sources assert that during fertilization, the sperm tail, with its mitochondria, gets excluded from the embryo. This is incorrect. In the majority of mammals - including humans - the midpiece mitochondria can be identified in the embryo even though their ultimate fate is unknown. The "missing mitochondria" story seems to have survived - and proliferated - unchallenged in a time of contention between hypotheses of human origins, because it supports the "African Eve" model of recent radiation of Homo sapiens out of Africa.[1]

So, what happens to paternal mtDNA if it is indeed present in embryonic cells? Paternal mitochondria are targeted and destroyed.

While some confusion may still persist in popular science, research data clearly document that the paternal sperm-borne mitochondria of most mammalian species enter the ooplasm at fertilization and are specifically targeted for degradation by the resident ubiquitin system. Ubiquitin is a proteolytic chaperone that forms covalently linked polyubiquitin chains on the targeted proteinaceous substrates… Prohibitin, the major protein of the inner mitochondrial membrane, appears to be ubiquitinated in the sperm mitochondria.[2]

A finding of a patient with severe exercise intolerance in whom the mutated mtDNA in muscle was shown to be paternally inherited challenged the concept of strict maternal inheritance of mtDNA (the mtDNA harboring the mutation was paternal in origin and accounted for 90 percent of the patient's muscle mtDNA.)[3]

Paternal mtDNA inheritance may have gone unrecognized in cases of mitochondrial disease with no clear maternal pattern of inheritance because mitochondrial haplotypes are rarely investigated in diagnostic analyses.

However, a small study of 12 patients with mitochondrial myopathy failed to show Paternal mtDNA.[4]

It is too simplistic to say paternal inheritance of mtDNA does not occur. It has been shown in mice and other mammals.

The mitochondrial DNA of 172 sheep from 48 families were typed by using PCR-RFLP, direct amplification of the repeated sequence domain and sequencing analysis. The mitochondrial DNA from three lambs in two half-sib families were found to show paternal inheritance. Our findings provide direct evidence of paternal inheritance of mitochondria DNA in sheep. A total of 12 highly polymorphic microsatellite markers, which mapped on different chromosomes, were employed to type the sheep population to confirm family relationships. Possible mechanisms of paternal inheritance are discussed.[4]

We should not believe everything we read without more investigation.

[1] Misconceptions about mitochondria and mammalian fertilization: Implications for theories on human evolution
[2] Degradation of paternal mitochondria after fertilization: implications for heteroplasmy, assisted reproductive technologies and mtDNA inheritance
[3] Paternal Inheritance of Mitochondrial DNA
[4] No evidence for paternal inheritance of mtDNA in patients with sporadic mtDNA mutations
[5] Further evidence for paternal inheritance of mitochondrial DNA in the sheep (Ovis aries)

Mitochondrial DNA and the significance of the maternal line

A mightier power and stronger Man from his throne has hurled
For the hand that rocks the cradle Is the hand that rules the world.

[1865 W. R. Wallace in J. K. Hoyt Cyclopedia of Practical Quotations (1896) 402]

You can't prevent it it's the nature of the sex.
The hand that rocks the cradle rocks the world, in a volcanic sense.

[A 1916 ‘Saki’ Toys of Peace (1919) 158]

As the old adage goes: ‘The hand that rocks the cradle rules the world.’ Off and on I have given this old adage almost 20 years of thought. I first discussed the importance of this concept and its applicability to our breeding hens with Bob Kinney back in 1992. However as early as 1971 I was fascinated by this quote. I first encountered it in the "Review of Reviews" in reference to the "British Empire" and the role played by women in shaping the minds of their sons. These boys who would grow up to be military men, officers, scientist, innovators, financiers, lawyers and judges and seamen were nurtured by their mothers who in turn passed on to them a world view, a way of looking at and holding their vision of the world. This was not unique to Britain but was in fact common to all mothers in all nations. How men would come to see the world and their role in it was in fact filtered through and passed on to them by the female of the species. This truly fascinated me for contrary to all that "they" , "The press" and "feminists’" would have us unwittingly believe power really was the special prerogative of the allegedly weaker sex. That (1971) was the year that I experienced a paradigm shift in the way I viewed the world and the "true power" that females have and can wield. In essence "women" unlike men are "Co Creative" but our generation has so bamboozled women as to have them willing give up their true power as unique "creative beings" in the name of alleged equality. Without the female of the species all would cease to be! Access to the cradle is true power (and that is why all governments everywhere seek to usurp the role of the female (mother) by enticing all women into the workplace thus allowing their government bureaucrats access to the children) because "the hand that rocks the cradle rules the world."

As breeders of racing pigeons how or why is this even remotely applicable? The vast majority of pigeon fanciers, pigeon breeders worldwide are men. As breeders of livestock we believe that a Sire in horse breeding or a Bull in the breeding of cattle or a "ram" in the breeding of sheep or a "Cock" in the breeding of pigeons is of intrinsically greater value than the females of that same species. In fact most breeders never really give any real thought or credit to the hens. Our current mindset clearly rewards the owners of a stock cock from a financial point of view, this is strictly business, but in the sense of one wishing to create a line, or a dynasty, or a strain nothing could be further from the truth. Here is the rationality that is used to confirm the greater importance or value of the Sire. A Stallion, or Bull or Ram or Cock can service many hundreds of mares, or cows, or ewes or hens during their lifetime while the female horse or cow or ewe may only have less than a dozen or so children and the hen pigeon can have many more but nowhere near the numbers of a Cock especially one on the Bull system. On the face of it, it certainly seems to make sense, or does it? Financially it seems to make sense and after all everyone knows that males of any species are stronger, faster, more productive, and more important right?

I will not argue the point. In the current financial and breeding model the male is definitely considered of much greater value from a monetary point of view. The male (of most species) is usually larger, more powerful and in terms of generating offspring definitely more productive but I definitely and adamantly draw the line at the assumption that males are more important. I have come to believe the very opposite that females are more important even the most important element in any breeding operation of any kind. The long term success of any serious breeding program lies squarely upon the shoulders of the females of the line and not one in ten thousand breeders have yet fully understood this fact.


In humans, mitochondrial DNA (mtDNA) forms closed circular molecules that contain 16,569 [2] [3] DNA base pairs, [4] 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. [4] Each human cell contains approximately 100 mitochondria, giving a total number of mtDNA molecules per human cell of approximately 500. [4]

Because mitochondrial diseases (diseases due to malfunction of mitochondria) 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 (depending on the species). 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 (increases or decreases) 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 (among other high-energy and metabolism-dependent 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 (in terms of mtDNA),
  • the number of affected mitochondria varies from cell (in this case, the fertilized oocyte) 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 (depending on how the twins divide from each other and how many mutant mitochondria happen to be on each side of the division). In a few cases, some mitochondria or a mitochondrion from the sperm cell enters the oocyte but paternal mitochondria are actively decomposed.

Genes in the human mitochondrial genome are as follows.

Electron transport chain, and humanin Edit

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 (made out of RNA):

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


The following genes encode rRNAs:

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


The following genes encode tRNAs:

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

Location of genes Edit

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, [5] [6] which was found to be related to the relative G+T nucleotide content of the strand. [7] 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. [8] [7] In humans, the light strand of mtDNA carries 28 genes and the heavy strand of mtDNA carries only 9 genes. [7] [9] 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 [1] [2] .

The genetic code is, for the most part, universal, with few exceptions: [10] mitochondrial genetics includes some of these. For most organisms the "stop codons" are "UAA", "UAG", and "UGA". In vertebrate mitochondria "AGA" and "AGG" are also stop codons, but not "UGA", which codes for tryptophan instead. "AUA" codes for isoleucine in most organisms but for methionine in vertebrate mitochondrial mRNA.

There are many other variations among the codes used by other mitochondrial m/tRNA, which happened not to be harmful to their organisms, and which can be used as a tool (along with other mutations among the mtDNA/RNA of different species) to determine relative proximity of common ancestry of related species. (The more related two species are, the more mtDNA/RNA mutations will be the same in their mitochondrial genome).

Using these techniques, it is estimated that the first mitochondria arose around 1.5 billion years ago. A generally accepted hypothesis is that mitochondria originated as an aerobic prokaryote in a symbiotic relationship within an anaerobic eukaryote.

Mitochondrial replication is controlled by nuclear genes and is specifically suited to make as many mitochondria as that particular cell needs at the time.

Mitochondrial transcription in humans is initiated from three promoters, H1, H2, and L (heavy strand 1, heavy strand 2, and light strand promoters). The H2 promoter transcribes almost the entire heavy strand and the L promoter transcribes the entire light strand. The H1 promoter causes the transcription of the two mitochondrial rRNA molecules. [11]

When transcription takes place on the heavy strand a polycistronic transcript is created. The light strand produces either small transcripts, which can be used as primers, or one long transcript. The production of primers occurs by processing of light strand transcripts with the Mitochondrial RNase MRP (Mitochondrial RNA Processing). The requirement of transcription to produce primers links the process of transcription to mtDNA replication. Full length transcripts are cut into functional tRNA, rRNA, and mRNA molecules. [ citation needed ]

The process of transcription initiation in mitochondria involves three types of proteins: the mitochondrial RNA polymerase (POLRMT), mitochondrial transcription factor A (TFAM), and mitochondrial transcription factors B1 and B2 (TFB1M, TFB2M). POLRMT, TFAM, and TFB1M or TFB2M assemble at the mitochondrial promoters and begin transcription. The actual molecular events that are involved in initiation are unknown, but these factors make up the basal transcription machinery and have been shown to function in vitro. [ citation needed ]

Mitochondrial translation is still not very well understood. In vitro translations have still not been successful, probably due to the difficulty of isolating sufficient mt mRNA, functional mt rRNA, and possibly because of the complicated changes that the mRNA undergoes before it is translated. [ citation needed ]

Mitochondrial DNA polymerase Edit

The Mitochondrial DNA Polymerase (Pol gamma, encoded by the POLG gene) is used in the copying of mtDNA during replication. Because the two (heavy and light) strands on the circular mtDNA molecule have different origins of replication, it replicates in a D-loop mode. One strand begins to replicate first, displacing the other strand. This continues until replication reaches the origin of replication on the other strand, at which point the other strand begins replicating in the opposite direction. This results in two new mtDNA molecules. Each mitochondrion has several copies of the mtDNA molecule and the number of mtDNA molecules is a limiting factor in mitochondrial fission. After the mitochondrion has enough mtDNA, membrane area, and membrane proteins, it can undergo fission (very similar to that which bacteria use) to become two mitochondria. Evidence suggests that mitochondria can also undergo fusion and exchange (in a form of crossover) genetic material among each other. Mitochondria sometimes form large matrices in which fusion, fission, and protein exchanges are constantly occurring. mtDNA shared among mitochondria (despite the fact that they can undergo fusion). [ citation needed ]

Damage and transcription error Edit

Mitochondrial DNA is susceptible to damage from free oxygen radicals from mistakes that occur during the production of ATP through the electron transport chain. These mistakes can be caused by genetic disorders, cancer, and temperature variations. These radicals can damage mtDNA molecules or change them, making it hard for mitochondrial polymerase to replicate them. Both cases can lead to deletions, rearrangements, and other mutations. Recent evidence has suggested that mitochondria have enzymes that proofread mtDNA and fix mutations that may occur due to free radicals. It is believed that a DNA recombinase found in mammalian cells is also involved in a repairing recombination process. Deletions and mutations due to free radicals have been associated with the aging process. It is believed that radicals cause mutations which lead to mutant proteins, which in turn led to more radicals. This process takes many years and is associated with some aging processes involved in oxygen-dependent tissues such as brain, heart, muscle, and kidney. Auto-enhancing processes such as these are possible causes of degenerative diseases including Parkinson's, Alzheimer's, and coronary artery disease. [ citation needed ]

Chromosomally mediated mtDNA replication errors Edit

Because mitochondrial growth and fission are mediated by the nuclear DNA, mutations in nuclear DNA can have a wide array of effects on mtDNA replication. Despite the fact that the loci for some of these mutations have been found on human chromosomes, specific genes and proteins involved have not yet been isolated. Mitochondria need a certain protein to undergo fission. If this protein (generated by the nucleus) is not present, the mitochondria grow but they do not divide. This leads to giant, inefficient mitochondria. Mistakes in chromosomal genes or their products can also affect mitochondrial replication more directly by inhibiting mitochondrial polymerase and can even cause mutations in the mtDNA directly and indirectly. Indirect mutations are most often caused by radicals created by defective proteins made from nuclear DNA. [ citation needed ]

Contribution of mitochondrial versus nuclear genome Edit

In total, the mitochondrion hosts about 3000 different types of proteins, but only about 13 of them are coded on the mitochondrial DNA. Most of the 3000 types of proteins are involved in a variety of processes other than ATP production, such as porphyrin synthesis. Only about 3% of them code for ATP production proteins. This means most of the genetic information coding for the protein makeup of mitochondria is in chromosomal DNA and is involved in processes other than ATP synthesis. This increases the chances that a mutation that will affect a mitochondrion will occur in chromosomal DNA, which is inherited in a Mendelian pattern. Another result is that a chromosomal mutation will affect a specific tissue due to its specific needs, whether those may be high energy requirements or a need for the catabolism or anabolism of a specific neurotransmitter or nucleic acid. Because several copies of the mitochondrial genome are carried by each mitochondrion (2–10 in humans), mitochondrial mutations can be inherited maternally by mtDNA mutations which are present in mitochondria inside the oocyte before fertilization, or (as stated above) through mutations in the chromosomes. [ citation needed ]

Presentation Edit

Mitochondrial diseases range in severity from asymptomatic to fatal, and are most commonly due to inherited rather than acquired mutations of mitochondrial DNA. A given mitochondrial mutation can cause various diseases depending on the severity of the problem in the mitochondria and the tissue the affected mitochondria are in. Conversely, several different mutations may present themselves as the same disease. This almost patient-specific characterization of mitochondrial diseases (see Personalized medicine) makes them very hard to accurately recognize, diagnose and trace. Some diseases are observable at or even before birth (many causing death) while others do not show themselves until late adulthood (late-onset disorders). This is because the number of mutant versus wildtype mitochondria varies between cells and tissues, and is continuously changing. Because cells have multiple mitochondria, different mitochondria in the same cell can have different variations of the mtDNA. This condition is referred to as heteroplasmy. When a certain tissue reaches a certain ratio of mutant versus wildtype mitochondria, a disease will present itself. The ratio varies from person to person and tissue to tissue (depending on its specific energy, oxygen, and metabolism requirements, and the effects of the specific mutation). Mitochondrial diseases are very numerous and different. Apart from diseases caused by abnormalities in mitochondrial DNA, many diseases are suspected to be associated in part by mitochondrial dysfunctions, such as diabetes mellitus, [12] forms of cancer [13] and cardiovascular disease, lactic acidosis, [14] specific forms of myopathy, [15] osteoporosis, [16] Alzheimer's disease, [17] Parkinsons's disease, [18] stroke, [19] male infertility [20] and which are also believed to play a role in the aging process. [21]

Human mtDNA can also be used to help identify individuals. [22] Forensic laboratories occasionally use mtDNA comparison to identify human remains, and especially to identify older unidentified skeletal remains. Although unlike nuclear DNA, mtDNA is not specific to one individual, it can be used in combination with other evidence (anthropological evidence, circumstantial evidence, and the like) to establish identification. mtDNA is also used to exclude possible matches between missing persons and unidentified remains. [23] Many researchers believe that mtDNA is better suited to identification of older skeletal remains than nuclear DNA because the greater number of copies of mtDNA per cell increases the chance of obtaining a useful sample, and because a match with a living relative is possible even if numerous maternal generations separate the two.

Examples Edit

American outlaw Jesse James's remains were identified using a comparison between mtDNA extracted from his remains and the mtDNA of the son of the female-line great-granddaughter of his sister. [24]

Similarly, the remains of Alexandra Feodorovna (Alix of Hesse), last Empress of Russia, and her children were identified by comparison of their mitochondrial DNA with that of Prince Philip, Duke of Edinburgh, whose maternal grandmother was Alexandra's sister Victoria of Hesse. [25]

Similarly to identify Emperor Nicholas II remains his mitochondrial DNA was compared with that of James Carnegie, 3rd Duke of Fife, whose maternal great-grandmother Alexandra of Denmark (Queen Alexandra) was sister of Nicholas II mother Dagmar of Denmark (Empress Maria Feodorovna). [25] [26]

Inheritance Inheritance

Mitochondrial genetic disorder can be inherited in a variety of manners depending on the type of condition and the location of the disease-causing change ( mutation ). Those caused by mutations in mitochondrial DNA are transmitted by maternal inheritance. [1] [3] Only egg cells (not sperm cells) contribute mitochondria to the next generation, so only females can pass on mitochondrial mutations to their children. Conditions resulting from mutations in mitochondrial DNA can appear in every generation of a family and can affect both males and females. In some cases, the condition results from a new ( de novo ) mutation in a mitochondrial gene and occurs in a person with no history of the condition in the family.

Mitochondrial genetic disorders caused by mutations in nuclear DNA may follow an autosomal dominant , autosomal recessive , or X-linked pattern of inheritance. [1] [3] In autosomal dominant conditions, one mutated copy of the responsible gene in each cell is enough to cause signs or symptoms of the condition. In some cases, an affected person inherits the mutation from an affected parent. Other cases may result from new mutations in the gene. These cases occur in people with no history of the disorder in their family. A person with an autosomal dominant condition has a 50% chance with each pregnancy of passing along the altered gene to his or her child.

When a condition is inherited in an autosomal recessive manner, a person must have a change in both copies of the responsible gene in each cell. The parents of an affected person usually each carry one mutated copy of the gene and are referred to as carriers . Carriers typically do not show signs or symptoms of the condition. When two carriers of an autosomal recessive condition have children, each child has a 25% (1 in 4) risk to have the condition, a 50% (1 in 2) risk to be a carrier like each of the parents, and a 25% chance to not have the condition and not be a carrier.

A condition is considered X-linked if the mutated gene that causes the condition is located on the X chromosome , one of the two sex chromosomes (the Y chromosome is the other sex chromosome ). Women have two X chromosomes and men have an X and a Y chromosome. X-linked conditions can be X-linked dominant or X-linked recessive . The inheritance is X-linked dominant if one copy of the altered gene in each cell is sufficient to cause the condition. Women with an X-linked dominant condition have a 50% chance of passing the condition on to a son or a daughter with each pregnancy. Men with an X-linked dominant condition will pass the condition on to all of their daughters and none of their sons. The inheritance is X-linked recessive if a gene on the X chromosome causes the condition in men with one gene mutation (they have only one X chromosome) and in females with two gene mutations (they have two X chromosomes). A woman with an X-linked condition will pass the mutation on to all of her sons and daughters. This means that all of her sons will have the condition and all of her daughters will be carriers. A man with an X-linked recessive condition will pass the mutation to all of his daughters (carriers) and none of his sons.

Most Helpful Guys

genetics is a weird thing.
basically, we all have a crap ton of genetic information in us. And the more distant someone is from us genetically, the more diverse our children's genes will be.
This is good and bad. More diversity means more genes for bad things can get in. It also means more genes for good things.
Most bad things come from recessive genes. This means that the gene for the condition has to come from both sides. it also means genes that would other wise short out problems have to be missing.
When incest happens, there is less gene diversity. Nothing new is added. Good genetic traits are passed on strongly this way, but sadly, so are bad traits. And because both parents have the same recessive traits, the chance of bad things happening gets bigger.
In the general population, you might have a 1% chance of some birth defect. Because even people not related to you will have the same recessive genes. Hook up with a cousin, it might go 2-4%, because they have much the same as you, but some different. Hook up with a brother or sister, and you're at 10% your higher. Less diversity, more chances for defective genes to become pronounced.
Occasional incest can be mostly harmless. If the family has particularly good genes, it can even result in very healthy, otherwise blessed, kids. But regular or constant incest, or even just 2 or 3 generations, multiply the chance for problems by a lot.

Now, this is NOT just a human problem. Several animal species suffer from "genetic bottlenecks," because the population was so small at some point that every living member now is related because they got their numbers back from a small group. This is the case of Cheetahs. If you've ever heard of pure bread dogs or cats not being as smart, living shorter lives, and having more health problems, this is why. They are very inbred to get desired traits, but health problems come from that.

So why do some animals deal with it better? Because weak or sick animals die. So the animals that live to keep breeding are the strongest and healthiest. Like I said, not all incest produces sick offspring, and if there are good traits, they are passed on too. So the animals that are not worse off for being products of incest, or even the few who are better off for it, continue to breed. And the animals that suffer from their breeding die off, and don't pass on their damaged genes.

Its not only with humans, happens with any animal.

DNA is a code of letters. AATGGCAT, whatever

Those letters represent information, genes. Genes are expressed by RNA. A protein called RNA polymerase comes along and reads the DNA and turns the genetic information into proteins by combining different amino acids. A protein contains many amino acids.

Everything you do in life, everything you are, every move you make, is a protein to protein interaction.

When your body can't make a certain protein it requires complications occur which lead to a disease that often can't be treated. How does the protein get messed up? By a mutation. How does a mutation occur? A mutation occurs when there's an error in the genetic material, the DNA code. Thats what a mutation is! It can result in a different or a non function protein which in turn will mess up your life. Now you may ask where does inbreeding fit into the picture?

We have to talk about a bit about genes. Genes have 2 loci. When 2 parents have sex and make a baby, the baby inherits 1 set of genes from each parent. 1 loci might be damaged, there's a probability but at least half of the genetic material is healthy. When relatives breed there is a high probability that their offspring will have 2 of the same set of genes. This is called a homozygous genes.

When there's 1 good and 1 bad gene, protein can still be produced and your body can function but when you get 2 bad genes you will have some sort of a disease.


Prevalence of some single-gene disorders [ citation needed ]
Disorder prevalence (approximate)
Autosomal dominant
Familial hypercholesterolemia 1 in 500 [10]
Polycystic kidney disease 1 in 750 [11]
Neurofibromatosis type I 1 in 2,500 [12]
Hereditary spherocytosis 1 in 5,000
Marfan syndrome 1 in 4,000 [13]
Huntington's disease 1 in 15,000 [14]
Autosomal recessive
Sickle cell anaemia 1 in 625 [15]
Cystic fibrosis 1 in 2,000
Tay–Sachs disease 1 in 3,000
Phenylketonuria 1 in 12,000
Mucopolysaccharidoses 1 in 25,000
Lysosomal acid lipase deficiency 1 in 40,000
Glycogen storage diseases 1 in 50,000
Galactosemia 1 in 57,000
Duchenne muscular dystrophy 1 in 5,000
Hemophilia 1 in 10,000
Values are for liveborn infants

A single-gene disorder (or monogenic disorder) is the result of a single mutated gene. Single-gene disorders can be passed on to subsequent generations in several ways. Genomic imprinting and uniparental disomy, however, may affect inheritance patterns. The divisions between recessive and dominant types are not "hard and fast", although the divisions between autosomal and X-linked types are (since the latter types are distinguished purely based on the chromosomal location of the gene). For example, the common form of dwarfism, achondroplasia, is typically considered a dominant disorder, but children with two genes for achondroplasia have a severe and usually lethal skeletal disorder, one that achondroplasics could be considered carriers for. Sickle-cell anemia is also considered a recessive condition, but heterozygous carriers have increased resistance to malaria in early childhood, which could be described as a related dominant condition. [16] When a couple where one partner or both are sufferers or carriers of a single-gene disorder wish to have a child, they can do so through in vitro fertilization, which enables preimplantation genetic diagnosis to occur to check whether the embryo has the genetic disorder. [17]

Most congenital metabolic disorders known as inborn errors of metabolism result from single-gene defects. Many such single-gene defects can decrease the fitness of affected people and are therefore present in the population in lower frequencies compared to what would be expected based on simple probabilistic calculations. [18]

Autosomal dominant Edit

Only one mutated copy of the gene will be necessary for a person to be affected by an autosomal dominant disorder. Each affected person usually has one affected parent. [19] : 57 The chance a child will inherit the mutated gene is 50%. Autosomal dominant conditions sometimes have reduced penetrance, which means although only one mutated copy is needed, not all individuals who inherit that mutation go on to develop the disease. Examples of this type of disorder are Huntington's disease, [19] : 58 neurofibromatosis type 1, neurofibromatosis type 2, Marfan syndrome, hereditary nonpolyposis colorectal cancer, hereditary multiple exostoses (a highly penetrant autosomal dominant disorder), tuberous sclerosis, Von Willebrand disease, and acute intermittent porphyria. Birth defects are also called congenital anomalies.

Autosomal recessive Edit

Two copies of the gene must be mutated for a person to be affected by an autosomal recessive disorder. An affected person usually has unaffected parents who each carry a single copy of the mutated gene and are referred to as genetic carriers. Each parent with a defective gene normally do not have symptoms. [20] Two unaffected people who each carry one copy of the mutated gene have a 25% risk with each pregnancy of having a child affected by the disorder. Examples of this type of disorder are albinism, medium-chain acyl-CoA dehydrogenase deficiency, cystic fibrosis, sickle cell disease, Tay–Sachs disease, Niemann–Pick disease, spinal muscular atrophy, and Roberts syndrome. Certain other phenotypes, such as wet versus dry earwax, are also determined in an autosomal recessive fashion. [21] [22] Some autosomal recessive disorders are common because, in the past, carrying one of the faulty genes led to a slight protection against an infectious disease or toxin such as tuberculosis or malaria. [23] Such disorders include cystic fibrosis, [24] sickle cell disease, [25] phenylketonuria [26] and thalassaemia. [27]

X-linked dominant Edit

X-linked dominant disorders are caused by mutations in genes on the X chromosome. Only a few disorders have this inheritance pattern, with a prime example being X-linked hypophosphatemic rickets. Males and females are both affected in these disorders, with males typically being more severely affected than females. Some X-linked dominant conditions, such as Rett syndrome, incontinentia pigmenti type 2, and Aicardi syndrome, are usually fatal in males either in utero or shortly after birth, and are therefore predominantly seen in females. Exceptions to this finding are extremely rare cases in which boys with Klinefelter syndrome (44+xxy) also inherit an X-linked dominant condition and exhibit symptoms more similar to those of a female in terms of disease severity. The chance of passing on an X-linked dominant disorder differs between men and women. The sons of a man with an X-linked dominant disorder will all be unaffected (since they receive their father's Y chromosome), but his daughters will all inherit the condition. A woman with an X-linked dominant disorder has a 50% chance of having an affected fetus with each pregnancy, although in cases such as incontinentia pigmenti, only female offspring are generally viable.

X-linked recessive Edit

X-linked recessive conditions are also caused by mutations in genes on the X chromosome. Males are much more frequently affected than females, because they only have the one X chromosome necessary for the condition to present. The chance of passing on the disorder differs between men and women. The sons of a man with an X-linked recessive disorder will not be affected (since they receive their father's Y chromosome), but his daughters will be carriers of one copy of the mutated gene. A woman who is a carrier of an X-linked recessive disorder (X R X r ) has a 50% chance of having sons who are affected and a 50% chance of having daughters who are carriers of one copy of the mutated gene. X-linked recessive conditions include the serious diseases hemophilia A, Duchenne muscular dystrophy, and Lesch–Nyhan syndrome, as well as common and less serious conditions such as male pattern baldness and red–green color blindness. X-linked recessive conditions can sometimes manifest in females due to skewed X-inactivation or monosomy X (Turner syndrome).

Y-linked Edit

Y-linked disorders are caused by mutations on the Y chromosome. These conditions may only be transmitted from the heterogametic sex (e.g. male humans) to offspring of the same sex. More simply, this means that Y-linked disorders in humans can only be passed from men to their sons females can never be affected because they do not possess Y-allosomes.

Y-linked disorders are exceedingly rare but the most well-known examples typically cause infertility. Reproduction in such conditions is only possible through the circumvention of infertility by medical intervention.

Mitochondrial Edit

This type of inheritance, also known as maternal inheritance, is the rarest and applies to the 13 genes encoded by mitochondrial DNA. Because only egg cells contribute mitochondria to the developing embryo, only mothers (who are affected) can pass on mitochondrial DNA conditions to their children. An example of this type of disorder is Leber's hereditary optic neuropathy.

It is important to stress that the vast majority of mitochondrial diseases (particularly when symptoms develop in early life) are actually caused by a nuclear gene defect, as the mitochondria are mostly developed by non-mitochondrial DNA. These diseases most often follow autosomal recessive inheritance. [28]

Genetic disorders may also be complex, multifactorial, or polygenic, meaning they are likely associated with the effects of multiple genes in combination with lifestyles and environmental factors. Multifactorial disorders include heart disease and diabetes. Although complex disorders often cluster in families, they do not have a clear-cut pattern of inheritance. This makes it difficult to determine a person's risk of inheriting or passing on these disorders. Complex disorders are also difficult to study and treat because the specific factors that cause most of these disorders have not yet been identified. Studies that aim to identify the cause of complex disorders can use several methodological approaches to determine genotype–phenotype associations. One method, the genotype-first approach, starts by identifying genetic variants within patients and then determining the associated clinical manifestations. This is opposed to the more traditional phenotype-first approach, and may identify causal factors that have previously been obscured by clinical heterogeneity, penetrance, and expressivity.

On a pedigree, polygenic diseases do tend to "run in families", but the inheritance does not fit simple patterns as with Mendelian diseases. This does not mean that the genes cannot eventually be located and studied. There is also a strong environmental component to many of them (e.g., blood pressure). Other factors include:

A chromosomal disorder is a missing, extra, or irregular portion of chromosomal DNA. It can be from an atypical number of chromosomes or a structural abnormality in one or more chromosomes. An example of these disorders is trisomy 21 (Down syndrome), in which there is an extra copy of chromosome 21.

Due to the wide range of genetic disorders that are known, diagnosis is widely varied and dependent of the disorder. Most genetic disorders are diagnosed pre-birth, at birth, or during early childhood however some, such as Huntington's disease, can escape detection until the patient is well into adulthood.

The basic aspects of a genetic disorder rests on the inheritance of genetic material. With an in depth family history, it is possible to anticipate possible disorders in children which direct medical professionals to specific tests depending on the disorder and allow parents the chance to prepare for potential lifestyle changes, anticipate the possibility of stillbirth, or contemplate termination. [29] Prenatal diagnosis can detect the presence of characteristic abnormalities in fetal development through ultrasound, or detect the presence of characteristic substances via invasive procedures which involve inserting probes or needles into the uterus such as in amniocentesis. [30]

Not all genetic disorders directly result in death however, there are no known cures for genetic disorders. Many genetic disorders affect stages of development, such as Down syndrome, while others result in purely physical symptoms such as muscular dystrophy. Other disorders, such as Huntington's disease, show no signs until adulthood. During the active time of a genetic disorder, patients mostly rely on maintaining or slowing the degradation of quality of life and maintain patient autonomy. This includes physical therapy, pain management, and may include a selection of alternative medicine programs.

The treatment of genetic disorders is an ongoing battle, with over 1,800 gene therapy clinical trials having been completed, are ongoing, or have been approved worldwide. [31] Despite this, most treatment options revolve around treating the symptoms of the disorders in an attempt to improve patient quality of life.

Gene therapy refers to a form of treatment where a healthy gene is introduced to a patient. This should alleviate the defect caused by a faulty gene or slow the progression of the disease. A major obstacle has been the delivery of genes to the appropriate cell, tissue, and organ affected by the disorder. Researchers have investigated how they can introduce a gene into the potentially trillions of cells which carry the defective copy. Finding an answer to this has been a roadblock between understanding the genetic disorder and correcting the genetic disorder. [32]

Around 1 in 50 people are affected by a known single-gene disorder, while around 1 in 263 are affected by a chromosomal disorder. [7] Around 65% of people have some kind of health problem as a result of congenital genetic mutations. [7] Due to the significantly large number of genetic disorders, approximately 1 in 21 people are affected by a genetic disorder classified as "rare" (usually defined as affecting less than 1 in 2,000 people). Most genetic disorders are rare in themselves. [5] [8] There are well over 6,000 known genetic disorders, [4] and new genetic disorders are constantly being described in medical literature. [5]

The earliest known genetic condition in a hominid was in the fossil species Paranthropus robustus, with over a third of individuals displaying amelogenesis imperfecta. [33]

Basics of Genetic Inheritance- Genotype and Phenotype

To understand the exact science of genetic inheritance, we must first appreciate some basic genetic vocabulary and concepts.

We’ll start with the terms genotype and phenotype, discuss their relationship and look at why we choose to study them.


A genotype is the genetic constitution of an organism. It may refer to an entire organism or, in principle, a cell or other unit of selection.

Scientists can apply the word genotype to bacteria, plants, animals and cyanobacteria.

The same gene can be present in different forms in similar organisms, these are known as alleles.

A genotype is the combination of alleles present in an organism- regardless of the question if we can see it in the physical appearance of the body.


A phenotype is an observable and/or a measurable characteristic of an organism.

A phenotype results from the interaction between an organism’s genotype and the environment, including culture or situations in which they find themselves.

The phenotype of an organism describes how it expresses its traits. If two contrasting alleles are present in the organism, the characteristic that expresses itself is known as the phenotype.

How Does Genetic Information Pass From One Generation To Another?

Genetic information, including genes and DNA, controls the development, maintenance, and reproduction of organisms.

Understanding heredity for humans and other organisms can help you understand basic biology principles and can help you make decisions regarding your life based on your genes.

But how do they pass from one generation to another?

In the simplest sense, parents pass genetic information from one generation to another through the units of inheritance (genes), which are made of DNA.

Most of the chemical information or DNA is in chromosomes, which are thread-like structures within a cell nucleus. A human cell has 46 chromosomes.

Each chromosome contains thousands of genes. The gene on each chromosome produces a protein that makes it function properly. It regulates almost every aspect of an organism.

Each individual is unique and has different genetic material. The process of sexual reproduction gives the offspring this new genetic material, which allows for the creation of something entirely new.

Organisms repeat this process with slight variations until a group all shares similar characteristics–this is known as ‘evolution.’

Genetic Inheritance Through Sexual and Asexual Reproduction

Organisms reproduce and create new organisms with a similar genotype. The process in which two individuals produce organisms is sexual reproduction, through the union of two gametes.

Asexual reproduction occurs when there is no union of gametes, but still they make a copy of the organism. So, let’s look at the difference between the offspring formed due to sexual and asexual reproduction.

Sexual Reproduction

In humans, sexual reproduction involves combining genetic material through fertilization, which is the fusion of female gamete (egg) and male gamete (sperm).

Gametes are haploid cells, which means they have only one set of 23 chromosomes. Genetic inheritance begins when a sperm cell containing one chromosome from each pair fuses with an egg cell containing one chromosome from each one.

The resulting zygote contains twenty-three chromosomes (one from each pair), including a combination of maternal, paternal, and recombinant DNA.

Therefore, when the two sex cells combine, their two single sets become a new diploid cell, which has 46 chromosomes- 23 pairs of chromosomes.

The transmission of an individual’s genetic information through generations is divided into two primary classes: sex-linked and autosomal.

There are twenty-three chromosomes in the human body, which contain genetic information. The sex-linked chromosome, when combined with the other, decides the sex of the newborn.

The remaining 22 chromosomes control the transmission of genetic information in non-sex-linked genes like eye color, skin color, nose shape, etc.

This process is based on the twenty-two pairs of non-sex-linked chromosomes, which are labelled as autosomes.

Autosomal Inheritance

In human genetics, autosomal inheritance is the independent inheritance of a physical characteristic, not linked to a sex chromosome.

The offspring receives two alleles (a form of a gene), one from either parent, to form a genotype.

However, only one of the two characteristics, received from the mother and the father, can be expressed in the baby. So, depending on the information, we are faced with one of four situations:

Dominant genes

Human beings possess two sets of genes, one inherited from their mother and the other from their father.

A dominant trait is when only one of the two recipes is expressed, be it the mother’s or the father’s, with one dominating over the other. A capital letter represents the dominating genes.

For example: Let’s suppose that the information from a mother is “tall” and from the father is “short“.

An individual cannot be both tall and short. We could say that we have a dominant trait because the individual will need only one-out-of-two chromosomes for producing the result. Since tallness is the dominant gene, the offspring will be tall.

Recessive genes

A recessive trait or character is displayed when the individual gene codes but is not expressed in the offspring’s physical appearance.

They are in recess, which means they are hidden. The other trait in the gene codes dominates over these traits.

These traits can only express themselves when an identical allele is present. They are represented by a small letter.

For example: Let’s suppose the father has black hair, and the mother has red hair.

The offspring gets chromosomes of both black and red hair. However, since red hair is recessive compared to black hair, the baby will express black hair.

The red hair will be hidden in the gene codes. It’ll only express itself if two red-hair alleles are present. Now, observe the diagram below.

Note that the green color of the pod is a dominant trait compared to the yellow color of the pod.

Co-Dominant genes

In biology, a codominant expression of two alleles from one or both parents is referred to as co-dominant inheritance.

Co-dominant inheritance occurs when both alleles are expressed at the same time. It is a relationship between two versions of a gene where individuals receive one version of a gene, called an allele, from each parent. In codominance, neither allele is recessive, and the phenotypes of both alleles are expressed.

For example: The phenotype caused by the ABO blood group system. In this example, both alleles (the B allele and the A allele) are expressed. So if an individual inherits allele A from their mother and allele B from their father, the individual has blood group AB. This is because A and B alleles are codominant, and neither are recessive.

If A or B were to combine with an O allele (a recessive gene), the offspring would have A or B blood type. The O would be hidden in the genotype.

Intermediate Genes

In genetics, an intermediate trait occurs when both recipes are expressed at the same time. So, the resulting character or trait is an intermediate expression of both because neither dominates over the other.

Think about it like a pie. There are two recipes. The first recipe has 1 cup of flour and 1 cup of sugar, while the second recipe has 2 cups of flour and 1/4 cup of sugar.

When we mix both recipes, we get a pie with an intermediate value between the two recipes- 3/2 cups of flour and 5/8 cups of sugar. The same concept applies to genes in biology.

For example: If we cross-bred white flowers with red flowers, the descendants will have pink flowers. The pink flowers result from mixing up both pigments. Like so:

Sex-Linked Inheritance

The sex of offspring, like eye color, is determined by the twenty-third pair. The individuals that procreate choose the genetic makeup of the offspring.

Genetics is a complex process in which mothers and fathers pass on chromosomes to the child. When this happens, the characteristic of gender occurs and can be female (XX) or male (XY).

The X chromosome has a gene essential to female development, while the Y chromosome is present in males only.

Therefore, a female will result if an egg gets fertilized by an X chromosome (XX), while a male will occur if a sperm contributes an X or a Y chromosome during fertilization.

Asexual Reproduction

Asexual reproduction involves one parent. Therefore, there is no fusion of gamete or exchange of chromosomes. So, the offspring is an identical copy of the parent.

It inherits all the characteristics, favourable or unfavourable. Since there is less scope for variation, the survival probability of an asexually reproducing organism is lower than a sexually reproducing one.

This is because sexual reproduction creates a completely unique organism, and leaves a range for variation.

The earth is changing constantly. Carbon dioxide levels are increasing, and as a result, so are heat levels.

If it wants to survive, an organism needs to build up resistance via variation. However, biochemical processes are not always reliable.

So, when an organism reproduces, certain favourable traits pass on- which then accumulate because of the process of evolution.

For example, imagine bacteria living in a pond. The pond is gradually getting warmer because of global warming.

So, imagine that due to a fault in the biochemical aspect of reproduction, the offspring builds up a little heat resistance. Thus, the heat resistance will consistently increase throughout the generations.

Thus, this line of bacteria will survive global warming, whereas other asexually reproducing organisms will die. That’s how important genetics is!

We Are Not Just Our DNA: The Ethical Dangers of Three-Parent Embryos

The FDA is currently debating whether to approve testing of three procedures designed to enable women with a mitochondrial disease to produce healthy children.

Mitochondria are small structures within cells that supply the energy required for life. They are unusual in that they have their own DNA that produces some of the molecules required for energy metabolism. And when this mitochondrial DNA (mtDNA) has a mutation, medical conditions affecting energy production can result. A curiosity of mammalian biology is that all the mitochondria an individual has are inherited from the mother. So, if the mother carries a mutation in her mtDNA, her children will have the same mutation.

Proponents of conducting human experiments to generate “three-parent embryos” cast this procedure as a beneficent therapeutic approach to treat women with mitochondrial disease and allow them to bear healthy children. In reality, it is a macabre form of eugenic cloning, in which a human being with a medical condition is killed and his or her parts are used to create a new human being with an improved biological state.

Maternal Spindle Transfer

The procedures under consideration by the FDA fall into three general classes. The first, known as “Maternal Spindle Transfer,” would use an egg from the mother with the mitochondrial disease and a donor egg from a woman with healthy mitochondria. The nucleus of the donor’s egg would be replaced by the nucleus of the mother’s egg. This would create a “hybrid” egg, with the nuclear DNA from the mother and the cytoplasmic elements (including healthy mitochondria) from the donor. This hybrid egg would then be fertilized by the father’s sperm to create a “three-parent” human embryo: DNA from mother, DNA from father, and non-nuclear components of the egg (including mtDNA) from the donor.

Maternal Spindle Transfer is a risky experiment with an uncertain outcome. If either the mother’s nucleus or the donor’s egg is damaged, the resulting embryo may develop abnormally or die. Yet Maternal Spindle Transfer is essentially a manipulation of human cells, not human beings. Consequently, it is the least ethically problematic of the three proposals.

By contrast, the two other procedures under consideration (“Pro-Nuclear Transfer” and “Embryo Cell Nuclear Transfer”) involve the direct destruction of at least one embryo and the subsequent use of its parts to create a new, cloned embryo with superior biology. Given that human life begins at the moment of sperm-egg fusion, these procedures are both forms of eugenic cloning conducted at a very early stage of the human life span.

In Pro-Nuclear Transfer, a single-cell embryo is created using sperm and egg from the mother and father. This embryo has mutated mitochondria from the mother. At the same time, a second embryo is created using a donor egg with healthy mitochondria. These one-cell human embryos or zygotes are clearly human beings at the earliest stage of the natural lifespan. The “pro-nuclei” (nuclei derived from the sperm and egg) are removed from both embryos—killing them both. Then a new embryo is produced by transferring the pronuclei from the afflicted embryo to the healthy cytoplasm of the “host” embryo. This is a form of destructive human cloning i.e. the nuclear DNA of one human being is used to create a genetic copy or “clone” of that individual by transfer to egg-derived cytoplasm from a donor, killing the original embryo and the donor in the process (see “Serious Ethical Concerns” below).

In this procedure, as in Maternal Spindle Transfer, there is risk of damaging the transferred nucleus or the “host” embryo, causing development of the resulting, cloned embryo to be abnormal. In addition, two embryos are created and then destroyed in the process of producing the third, cloned embryo. Finally, this procedure involves the intentional creation of a “defective” human being who is then destroyed so that a part of the body (the nucleus) can be used to clone a new human being, who is viewed as biologically superior. It is eugenic cloning.

Embryo Cell Nuclear Transfer

Embryo Cell Nuclear Transfer is similar to Pro-Nuclear Transfer, except that only one embryo is produced from the sperm and egg of the parents. This embryo is allowed to develop for a day or two before a nucleus from one of its cells is used to produce a new, cloned embryo by transferring it to a donor egg cell with healthy mitochondria that has had its own nucleus removed. The original embryo with the mitochondrial disease is then destroyed.

In this case, as in the two procedures above, there is a significant risk of damaging the egg cell or the transferred nucleus, resulting in abnormal or failed development of the resulting cloned embryo. And Embryo Cell Nuclear Transfer is also a form of eugenic cloning where a “defective” human being is destroyed to obtain desirable parts (in this case, a nuclear genome derived from both parents) to construct a superior human being.

In all three cases, a human being is produced using essential components from three parents: nuclear DNA from the two intended parents and egg cytoplasm from a donor.

Serious Ethical Concerns

Surprisingly, many people do not see an obvious problem with these proposals. A medical colleague of mine recently opined, “If you take the newly formed pronucleus and put it in a different ‘body’ (i.e., another woman’s egg), are you really destroying that embryo? The individual would still develop with almost all the same genetic traits, and would potentially survive longer if the therapy worked.”

Yet the view that transfer of an embryo’s nucleus is merely a “therapeutic” approach for treatment of disease is false. The embryo produced by this procedure is not just the original child of the parents, moved to a new cytoplasmic “environment.” This would only be true if a human being were nothing more than his or her DNA, which is clearly not the case. While our unique DNA clearly determines many aspects of our individual characteristics, we are also greatly influenced by the specific, non-genetic composition of the egg that produced us. As explained in detail in a paper available here, many aspects of embryonic development, and therefore many aspects of the unique individual we end up being, depend on non-genetic components derived from the cytoplasm of the egg.

The importance of non-genetic factors in determining the unique character of a human individual is very clearly illustrated by “maternal effect mutations.” These mutations have no effect on the development or function of the mother, but specifically disrupt development of embryos derived from her eggs. The embryo may not even have the “bad” gene (only half of the mother’s genome is passed on to any one child), but embryonic development can still be profoundly affected by the molecules present in the egg itself. Many key developmental factors work like this—in both positive and negative ways. Therefore, all three of the procedures described above would indeed generate “three-parent embryos,” whose unique traits and human identity would reflect the genetic contributions of both mother and father as well as the critical, non-genetic contributions made by the egg donor.

In addition to the obvious ethical issues raised by eugenic cloning and destructive experimentation on human embryos, these procedures raise two other serious concerns. All three are highly likely to be unsafe for the resulting children, even the ones that are not deliberately destroyed and are not damaged by the procedure itself. Mitochondrial heteroplasmy, or the persistence of some mitochondria from both the mother and the donor egg, is a significant risk to any children produced by these techniques. In general, heteroplasmy is not a good thing, and in this case, it could also cause reappearance of the disease in the offspring of any woman produced by the “three-parent” approach, due to mitochondrial “founder effects” in oogenesis. Even a few “bad” mitochondria can become the dominant type in any one egg, causing the mitochondrial disease to recur in any child produced from that egg.

Second, these procedures are forms of “germ-line engineering” that alter the genetic makeup of future generations in a permanent way. We know that in nature, mtDNA and nuclear DNA “co-evolve” to work with each other in an efficient manner. In some species, incompatibility between the mitochondrial and nuclear genome significantly compromises the health of the individual.

All of the proposed methods of “treating” mitochondrial disease introduce a permanent and unnatural mismatch between the nuclear and the mitochondrial genome that will be inherited by all subsequent generations. This constitutes unethical, destructive experimentation on humans, with no guarantee of outcome for either the “patient” (the cloned embryo produced) or any of the offspring of that patient. This is an unwarranted approach that puts future generations at grave risk of unforeseen consequences, in addition to the clearly foreseen destruction of a class of “defective” humans in the hope of manufacturing “superior” offspring.

Inherited Colour Vision Deficiency

Colour blindness is a common hereditary (inherited) condition which means it is usually passed down from your parents.

Red/green colour blindness is passed from mother to son on the 23rd chromosome, which is known as the sex chromosome because it also determines sex. Chromosomes are structures which contain genes – these contain the instructions for the development of cells, tissues and organs. If you are colour blind it means the instructions for the development of your cone cells are different to those for people who have ‘normal’ colour vision meaning one cone cell type might be missing, or less sensitive to light or it may be that the pathway from your cone cells to your brain has not developed in the usual way.

For the sake of simplicity we refer to a colour blind ‘gene’ but this is not strictly a true description.

The 23rd chromosome is made up of two parts – either two X chromosomes if you are female or an X and a Y chromosome if you are male. The ‘gene’ which causes (inherited, red and green types of) colour blindness is found only on the X chromosome. So, for a male to be colour blind the colour blindness ‘gene’ only has to appear on his X chromosome. For a female to be colour blind it must be present on both of her X chromosomes.

If a woman has only one colour blind ‘gene’ she is known as a ‘carrier’ but she won’t be colour blind. When she has a child she will give one of her X chromosomes to the child. If she gives the X chromosome with the colour blindness ‘gene’ to her son he will be colour blind, but if he receives the X chromosome which doesn’t carry the colour blindness ‘gene’, he won’t be colour blind.

A colour blind boy can’t receive a colour blind ‘gene’ from his father, even if his father is colour blind, because his father can only pass an X chromosome to his daughters.

A colour blind daughter therefore must have a father who is colour blind and a mother who is a carrier (who has also passed the colour blindness ‘gene’ to her daughter). If her father is not colour blind, a ‘carrier’ daughter won’t be colour blind. A daughter can become a carrier in one of two ways – she can acquire the ‘gene’ from a carrier mother or from a colour blind father.

This is why red/green colour blindness is far more common in men than women.

Blue/yellow colour blindness affects both men and women equally, because it is carried on a non-sex chromosome.

For the sake of the following explanation a normal X chromosome is shown as (X) whilst a colour blind carrying X chromosome is shown in bold ( X ).

The colour blind ‘gene’ is carried on one of the X chromosomes. Since men have only one X chromosome, if his X chromosome carries the colour blind ‘gene’ ( X ) he will be colour blind ( X Y). A woman can have either:-
(i) two normal X chromosomes, so that she will not be colour blind or be a carrier (XX),
(ii) or, one normal X and one colour blind carrying X chromosome, in which case she will be a carrier (X X ), or rarely
(iii) she will inherit a colour blind X from her father and a colour blind X from her mother and be colour blind herself ( X X ). She will pass on colour blindness to all of her sons if this is the case.

See the tables below to understand how people can become colour blind and how colour blindness is passed on to future generations.

Table 1
A colour blind man and a non-colour blind woman

Table 2
A non colour blind man and a colour blind carrier woman

Table 3
A colour blind man and a colour blind carrier woman

Table 4
A non colour blind man and a colour blind woman

Rare Disease Database

NORD gratefully acknowledges Peter W. Stacpoole, PhD, MD, Professor of Medicine, Biochemistry and Molecular Biology, College of Medicine, University of Florida, for assistance in the preparation of this report.

Synonyms of Congenital Lactic Acidosis

Subdivisions of Congenital Lactic Acidosis

General Discussion

Lactate is a chemical compound normally produced by all cells and plays important roles in several chemical processes in the body. Lactic acidosis occurs when lactate and other molecules, called protons, accumulate in bodily tissues and fluids faster than the body can remove them. Consequently, tissues and fluids may become acidic and impair the normal functioning of cells. Lactic acidosis can have many different causes and is often present in severely ill patients hospitalized in intensive care units. Congenital lactic acidosis is a rare form of lactic acidosis. The word “congenital” means that the underlying condition that increases risk of developing lactic acidosis is present at birth. In most cases, the cause of congenital lactic acidosis is due to a defect in an enzyme responsible for helping the body convert carbohydrates and fats into energy. Most of these enzymes are located in specialized structures within the cell called mitochondria. Therefore, most causes of congenital lactic acidosis are due to genetic mitochondrial enzyme deficiencies. These are either inherited from one or both parents or arise spontaneously in the developing embryo.

Signs & Symptoms

The enzyme deficiencies that give rise to congenital lactic acidosis can potentially affect many different organ systems of the body and, therefore, lead to a wide variety of symptoms and signs. Whereas some individuals may have persistently elevated levels of lactic acid in blood, cerebrospinal fluid and urine, other persons may have only occasional increases in lactic acid that are brought on by another illness, such as an infection, a seizure or an asthmatic attack.

In some children (especially those with a severe enzyme defect), symptoms of congenital lactic acidosis develop within the first hours or days of life and may include loss of muscle tone (hypotonia), lethargy, vomiting and abnormally rapid breathing (tachypnea). Eventually, the condition may progress to cause developmental delay, mental retardation, motor abnormalities, behavioral issues, abnormalities of the face and head and, ultimately, multi-organ failure. In some individuals in whom the disease is due to a mutation in mitochondrial DNA, the complications of congenital lactic acidosis may not appear until adolescence or adulthood.


Most cases of congenital lactic acidosis are caused by one or more inherited mutations of genes within the DNA located within the nucleus (nDNA) or within the mitochondria (mtDNA) of cells. Genes carry the genetic instructions for cells. A mutation is a change in a gene located in nuclear or mitochondrial DNA that may cause disease. Mutations of nDNA, which occur in cellular chromosomes, can be inherited through different forms of transmission of the mutation, including autosomal recessive, autosomal dominant or X-linked recessive inheritance.

Mutations affecting the genes for mitochondria (mtDNA) are inherited from the mother. MtDNA that is found in sperm cells is typically lost during fertilization. As a result, all human mtDNA comes from the mother. An affected mother will pass on the mutation to all her children, but only her daughters will pass on the mutation to their children. Mitochondria, which are found by the hundreds or thousands in the cells of the body, particularly in muscle and nerve tissue, carry the blueprints for regulating energy production.

As cells divide, the number of normal mtDNA and mutated mtDNA are distributed in an unpredictable fashion among different tissues. Consequently, mutated mtDNA accumulates at different rates among different tissues in the same individual. Thus, family members who have the identical mutation in mtDNA may exhibit a variety of different symptoms and signs at different times and to varying degrees of severity.

Pyruvate dehydrogenase complex (PDC) deficiency is a genetic mitochondrial disease of carbohydrate metabolism that is due to a mutation in nDNA. It is generally considered to be the most common cause of biochemically proven cases of congenital lactic acidosis. PDC deficiency can be inherited as an autosomal recessive or X-linked recessive trait.

Genetic information is contained in two types of DNA: nuclear DNA (nDNA) is contained in the nucleus of a cell and is inherited from both biological parents. Mitochondrial DNA (mtDNA) is contained in the mitochondria of cells and is inherited exclusively from the child’s mother.

Genetic diseases, due to mutations (changes in genetic information) in the nDNA of a cell, are determined by two genes, one received from the father and one from the mother. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.

Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.

X-linked genetic disorders are conditions caused by an abnormal gene on the X chromosome and manifest mostly in males. Females that have an altered gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and only one carries the altered gene. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains an altered gene he will develop the disease.

Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son.

If a male with an X-linked disorder is able to reproduce, he will pass the altered gene to all of his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring.

Although genetic mitochondrial diseases are the commonest causes of congenital lactic acidosis, additional conditions that are present at birth can result in the disorder. These include biotin deficiency, bacterial infection in the bloodstream or body tissues (sepsis), certain types of glycogen storage disease, Reye syndrome, short-bowel syndrome, liver failure, a defect in the heart or blood vessels that leads to a deficiency in the amount of oxygen reaching the body’s tissues (hypoxia) and bacterial meningitis (which causes elevated lactic acid in cerebrospinal fluid).

Affected Populations

Congenital lactic acidosis affects males and females in equal numbers. The exact incidence of congenital lactic acidosis is unknown. One estimate places the incidence at 250-300 live births per 1,000 per year in the United States. However, it is likely that many cases go undiagnosed or misdiagnosed, making it difficult to determine the true frequency of congenital lactic acidosis in the general population.

Related Disorders


A diagnosis of congenital lactic acidosis is made based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Blood and cerebrospinal fluid tests can reveal certain findings associated with congenital lactic acidosis such as elevated levels of lactate. An enzyme deficiency may be diagnosed by tests conducted in white blood cells or in skin or muscle cells obtained by biopsy.

Standard Therapies

There is no proven treatment for any congenital lactic acidosis that is due to a genetic mitochondrial disease. Therefore, treatment is directed toward the specific symptoms and signs that are present in each individual. Vitamins and certain co-factors (for example, carnitine and coenzyme Q) are frequently administered to patients with congenital lactic acidosis, but there is no proof that such agents are effective, except in extremely rare cases of PDC deficiency that respond to high doses of thiamine.

For many years so-called “ketogenic” diets that are very high in fat and very low in carbohydrate have been used in patients with PDC deficiency, with beneficial effects reported in the scientific literature. However, the long-term safety and effectiveness of ketogenic diets have not been studied in a rigorous fashion.

Dichloroacetate (DCA) has been investigated as a potential therapy for individuals with congenital lactic acidosis. Various studies have shown the drug to be well-tolerated in children and to lead to a reduction in lactic acid levels in many patients with various causes of congenital lactic acidosis. However, the clinical benefit of chronic DCA treatment for any type of congenital lactic acidosis has not yet been demonstrated by controlled clinical trials. In addition, the drug has been shown to worsen or to cause reversible peripheral nerve damage in some individuals with congenital lactic acidosis, especially in older adolescents and adults. Recent studies, however, indicate that this potential side effect may be mitigated or prevented by careful dosing, based on a person’s particular genotype.

Additional therapies for individuals with congenital lactic acidosis are directed at specific complications, such as anti-seizure medications (anti-convulsants) for seizures. Genetic counseling may benefit affected individuals and their families, depending on the underlying cause of the congenital lactic acidosis.

Investigational Therapies

Information on current clinical trials is posted on the Internet at All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]

For information about clinical trials sponsored by private sources, contact:

For information about clinical trials conducted in Europe, contact:

Contact for additional information about congenital lactic acidosis:
Peter W. Stacpoole, PhD, MD
Professor of Medicine, Biochemistry and Molecular Biology
College of Medicine
P.O. Box 100226
University of Florida
Gainesville, FL 32610
Phone: 352-273-9599
Fax: 352-273-9013


Congenital Lactic Acidosis Resources

Supporting Organizations

    • 1A Whitley Close
    • Cheshire, CW10 0NQ United Kingdom
    • Phone: 160683719
    • P.O. Box 5801
    • Bethesda, MD 20824
    • Phone: (301) 496-5751
    • Toll-free: (800) 352-9424
    • Website:


    Clarke JTR, Ed. A Clinical Guide to Inherited Metabolic Disease. Cambridge, MA: Cambridge University Press 2006:213-214.

    Stacpoole PW. The Congenital Lactic Acidoses. NORD Guide to Rare Disorders. Philadelphia, PA: Lippincott Williams & Wilkins 2003:462-464.

    Menkes JH, Pine Jr JW, et al. Eds. Textbook of Child Neurology. 5th ed. Baltimore, MD: Williams & Wilkins 1995:853-856.

    Patel KP, O’Brien TW, Subramony SH, Shuster J, Stacpoole PW. The spectrum of pyruvate dehydrogenase complex deficiency: clinical, biochemical and genetic features in 371 patients. Mol Genet Metab. 2012105(1):34-43.

    Stacpoole PW, Gilbert LR, Neiberger R, et al. Evaluation of long-term treatment of children with congenital lactic acidosis with dichloroacetate. Pediatrics. 2008121:e1223-e1228.

    Stacpoole PW, Kerr DS, Barnes C, et al. Controlled clinical trial of dichloroacetate for treatment of congenital lactic acidosis in children. Pediatrics. 2006117:1519-1531.

    Gunnerson KJ. Lactic Acidosis.Medscape. Updated: Mar 06, 2017. Accessed March 5, 2018.

    Years Published

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