Autosomal dominant inheritance

There are total 22 pairs of autosomes in humans. The non-sex chromosomes are known as autosomes. The anomalies associated with the autosomes are known as autosomal anomalies or autosomal abnormalities. The mutations in the genes present on these autosomes decide the inheritance of a particular disease. An autosome consists of a mutant gene in autosomal disorders. The mutant gene expresses the disorder even though present in a single dose. Autosomal diseases involve the presence of a mutant gene on one of the chromosomes in a pair. Consider a mating between a normal individual and an affected individual. The normal individual has a normal genotype. The affected individual has a mutant gene. Hence, 50% of the progeny will express the dominant mutant gene. The remaining 50% of progeny will be normal. The individuals showing a dominant mutant gene are known as heterozygotes. Consider another case of mating between both the affected parents. 25% of the offspring will show both the mutant genes. Hence, they are known as severely affected individuals. 50% of the progeny will show one mutant gene. Hence, they are known as affected individuals. The remaining 25% of individuals show a normal genotype.

Following are the characteristics of an autosomal dominant inheritance:

1.     Both the sexes equally get affected with the autosomal dominant traits.

2.    The genes or the traits get transmitted in four possible ways such as male to male, male to female, female to female and female to male types of transmissions. 

3.    Follows no skipping of generations

4.    Mostly seen in all the generations

5.    In most of the cases, the proband has at least one affected parent

6.    New autosomal dominant mutations occur newly in a generation due to some error in the gametogenesis in the parent. The child having new mutations passes on the traits to the next generations

7.   Those having the abnormal genes on the autosomes only pass on the trait to the next generation

8.  Those having normal genes and exhibiting normal phenotype do not pass on the trait

9.  The proportion of the normal and the affected individuals in a population is almost the same.

10.  An autosomal dominant gene mostly affects one part of the body. However, it may also lead to a disorder where many parts of the body get affected. One mutated gene can affect many phenotypes. A phenomenon in which one gene produces many phenotypes is known as pleiotropy. Hence, the autosomal dominant gene may exhibit pleiotropy.

11. The expression of the autosomal dominant gene varies from person to person. The phenotype also varies.

12. Sometimes a heterozygous individual does not show or express the dominant phenotype. Such a condition is known as penetrance. It occurs due to the influence of the genes at other loci.

Image: Autosomal dominant inheritance

Following are the examples of autosomal dominant disorders

Huntington’s chorea:

It involves a complete penetrance. Such a type of autosomal dominant disorder leads to nerve cell death and affects the central nervous system. It is a movement disorder mainly known to affect a person in the middle age. Hence, this type of movement is known as chorea. The mutated gene is present on the short of the 4^th chromosome. The gene shows the presence of an abnormally large CAG nucleotide repeat at 5’ end. A series of CAG repeats result in the production of glutamine chains. A glutamine chain is also known as a polyglutamine tract. This gene encodes Huntington protein. The altered form of Huntingtin protein is known as mutant Huntingtin. It increases the rate of neuronal cell death.  Huntington’s chorea affects 1 in 15,000 individuals. It leads to the breakdown of the nerve cells in the brain. Hence, such individuals experience a diminished ability to walk, speak, and carry out other activities. Involuntary movements in the face, muscles, hands, and legs occur in this condition. Jerks are very common in them. The intellectual ability also starts diminishing.

Familial hypercholesterolemia:

Familial hypercholesterolemia majorly involves heterozygous individuals and rarely involves homozygotes. Such a type of autosomal dominant disorder leads to high serum cholesterol level. Mutation in the LDL receptor gene leads to the disease. As the word suggests familial hypercholesterolemia, the defective gene gets inherited. The mutated gene responsible for the disease is present on chromosome number 19. An important clinical feature of familial hypercholesterolemia involves the progression of atherosclerosis. Cholesterol gets deposited in the arterial walls. Hence, it results in narrowing of the lumen. Three main types of cholesterols include LDL, HDL, and VLDL. LDL or low-density lipoprotein is known as bad cholesterol. HDL or high-density lipoprotein is also known as good cholesterol. Due to the defective LDL receptor, the patients suffering from familial hypercholesterolemia always show an increased level of blood cholesterol. The LDL cholesterol does not get eliminated from the blood. Xenthomata or the subcutaneous deposition of lipid occurs in familial hypercholesterolemia. Such individuals have an increased risk of myocardial infarction or heart attack. This type of autosomal dominant disorder affects 1 in 500 individuals.

Neurofibromatosis:

It shows complete penetrance and variable expression. The mutated gene is present on the 17^th chromosome. The gene encodes for neurofibromin protein. It is known as a tumor suppressor gene. A mutated tumor suppressor gene enhances the cancer cell growth. Loss of both the alleles leads to tumor development. Neurofibromatosis leads to pea-sized benign tumors on the skin. Apart from tumors, epilepsy also manifests. 1 in 3000 people suffers from neurofibromatosis.

Here are some more examples of Autosomal dominant disorders:

Examples of autosomal dominant disorders	Gene mutations
Myotonic dystrophy	An abnormal gene on the 19th chromosome with a large CTG repeats 3’ end.
Achondroplasia	An abnormal gene is present on the short arm of the 4th chromosome.
Polycystic kidney disease	Abnormal PKD1 gene on chromosome 16 and PKD2 gene on chromosome 4.
Congenital cataract	PITX3 gene mutation
Polydactyly	A mutated GLI 3 gene on the 7th chromosome

 Table: Autosomal dominant disorders and related gene mutations

Codominance:

Both the traits get expressed fully in the heterozygous state. Example of codominance involves ABO blood groups. Presence of both A and B alleles leads to codominance.

References:
[1] Medical genetics, G.P. Pal
[2] Human Genetics, 3/e, Gangane
[3] Vogel and Motulsky's Human Genetics: Problems and Approaches, Friedrich Vogel, Gunter Vogel, Arno G. Motulsky
[4] Biology for the IB Diploma: Standard and Higher Level, Andrew Allott
[5] Principles of Medical Genetics, Thomas D. Gelehrter,

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Dominance relationships

 A single allele becomes totally dominant over the other allele in the case of complete dominance. The phenotype of the heterozygote appears similar to the phenotype of the homozygous dominant. On the other hand, complete recessiveness requires two recessive alleles, meaning the recessive allele gets expressed only in the homozygotes. Hence, these two extremities get classified under a range of dominance relationships. Main topics covered under the dominance relationships include complete dominance, incomplete dominance, codominance, and the molecular explanations related to the same.

Complete dominance:

One allele has a powerful effect of masking the activity of the other allele. It is known as complete dominance. One allele dominates the other allele thereby masking its expression. The allele getting masked is known as a recessive allele. Hence, the phenotype of the heterozygote shows similarity with the phenotype of the dominant homozygote. Let us consider the example of complete dominance. Seed shape in peas helps in determining the dominant alleles present in the pea plant. Round peas have R allele, the dominant one. The wrinkled peas have r allele, the recessive one. Hence, the combination of alleles includes RR (having round peas), rr (wrinkled peas), and Rr (Round peas).

Incomplete dominance:

Incomplete dominance, also known as partial dominance, occurs when one allele lacks complete dominance over the other allele. It usually becomes partially dominant. Since there is an incomplete dominance, the heterozygote expresses a phenotype intermediate to that of the homozygotes having either of the alleles. Let us consider an example of incomplete dominance in chickens. The plumage or feather colors of the chickens vary. It is due to incomplete dominance. Consider a cross between the true breeding black strain and a true breeding white strain. The true breeding black strain is a homozygote and consists of C^BC^B alleles. The true breeding white strain is also a homozygote showing C^WC^W alleles. A cross between both of them gives rise to an F1 generation of birds having bluish-grey plumage. They are also known as Andalusian blues. They show a genotype of C^BC^W. The letter C symbolizes the color of the plumage and the letters W and B symbolize white and black colors respectively. Consider another cross between Andalusians. In this case, both the Andalusian blues have C^BC^W genotype. The F2 generation now shows 1:2:1 phenotypic ratio. The progeny involves one black, one white, and two Andalusian blue fowls.

Let us consider one more example of incomplete dominance. The Palomino horse has a golden yellowish brown body color with a white mane and a tale. Interbreeding of the Palominos gives rise to the progeny with a phenotypic ratio of 1:2:1. The F2 generation consists of two palominos, one cremellos, and one light chestnut.

Image: Incomplete dominance

Codominance:

The phenotype of the heterozygote resembles that of both the homozygotes in codominance. Codominance and Incomplete dominance are related to one another. Codominance is a form of modified dominance relationship. Example of codominance involves ABO blood groups. A glycoprotein known as the H antigen occurs on the surfaces of the blood cells. Three main alleles control the chemical modification of the glycoprotein. Two out of three alleles are codominant. They are known as IA and IB respectively. These alleles are dominant over the recessive “i” allele. Both IA and IB code for different enzymes. The one coded by IA adds an N-acetylgalactosamine to the H antigen. The one encoded by IB adds galactose. The recessive i allele does not modify anything.

In the ABO system of blood groups, there are four main phenotypes such as O, A, B, and AB. Individuals with A blood group express antigen A. Individuals with B blood groups express B antigen. Individuals with AB blood group express both the antigens. The individuals with O blood groups express none of the antigens. Out of the four types, the AB blood group individuals produce A and B antigens. Hence, it is an example of codominance.  Another example of codominance involves MN blood group system. Let us consider another example of codominance. Sickle cell anemia is a type of hemoglobinopathy. Three molecular types of hemoglobin include HbA/HbA, HbA/HbS, and HbS/HbS.

Molecular explanation

Both the homozygote phenotype so gets expressed in a heterozygote since it has both the alleles. It is a general explanation of codominance. However, incomplete dominance results in the expression of only one allele out of the two in a heterozygote. Hence, a homozygote consists of two doses of the gene product. Here we talk about haplosufficiency. Heterozygote showing normal dominance requires only half of the homozygous allele for expression of the phenotype. Dominance occurs due to the presence of a non-functional allele. Meaning, one allele loses its functions such as expressing a protein product or skips the process of transcription. It also occurs due to mutation altering the DNA sequence. Hence, the organism having a non-functional allele will show a particular phenotype. Example, albinism is an autosomal recessive disorder occurring due to the inefficient synthesis of the pigment melanin in the skin and the hair. Hence, such individuals show whitish-pink skin coloration. Let us consider the interaction between the alleles that make an allele recessive. The single allele produces a product or a phenotype identical to that of the homozygote (haplosufficiency). Hence, the functional allele becomes dominant to the non-functional one. In the case of an albino gene locus, the heterozygous individuals produce sufficient melanin in the skin. Hence, they exhibit normal pigmentation in the skin.

Consider another interaction involving haploinsufficiency. The phenotype expressed by the functional allele involves less severity when compared with that of a non-functional homozygote. Rarely may it also produce an insufficient gene product as compared to that of a non-functional homozygote. Sometimes, the non-functional allele may also produce defective protein products interfering with the normal protein functioning.

Dominant negative mutations mostly arise in the somatic cells. These mutations are harmful to the body. They provide scope for the mutant cells to proliferate and expand. Most of the dominant negative mutations a cancer cell or a mutant cell resistant to the natural cell death process known as apoptosis. Hence, the damaged DNA in these cells does not get repaired. Example, dominant negative mutations occur in the tumor suppressor gene such as p53. The p53 mutations occur in different types of cancer cells such as cells present in the breast, prostate, and the brain.

References:
[1] Principles Of Genetics 7/E, By Tamarin
[2]  Essential Genetics: A Genomics Perspective, Hartl, Elizabeth W. Jones

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Multiple Alleles

Some of the genes also show the presence of multiple alleles. These alleles constitute a series of alleles. Hence, they are known as multiple allelic series. Multiple allelism is an existence of several known alleles of a gene. The concept gets clearer when we look into the examples.

ABO blood groups:                                                                                

A scientist known as Karl Landsteiner worked on the human blood groups. He set an example of the existence of multiple alleles of a gene in human ABO blood groups. The four blood group types in an ABO system include O, A, B, and AB blood groups. The ABO blood group alleles get denoted as I^A, I^B, and i giving rise to their respective phenotypes. O blood group individuals are homozygotes for the recessive allele i. Since I^A and I^B are dominant to the recessive I, those individuals homozygous for i allele get O blood group. Hence, we write their genotype as i/i. The individuals with A blood group either have I^A/I^A genotype or I^A/i genotype. Similarly, the individuals with B blood group either have I^B/I^B genotype or I^B/i genotype. The heterozygous I^A/I^B individuals have AB blood group.

The cellular antigens get attached to the cell surface of the red blood cells. Here we talk about the antigen-antibody interactions. The antigens often get recognized as foreign molecules and trigger the immune response. The antibodies are the immune molecules that recognize and bind to the antigens for processing them further. An individual consists of a large number of cell surface antigens. Hence, the blood group matching plays a very important role, especially during the blood transfusion. Mismatched blood groups trigger serious immune response and also lead to the death of the individual. Hence, a careful blood group matching procedure gets conducted before the blood transfusions. The people with A blood group have A antigen on their cell surface. The people with B blood group have B antigen on their cell surface. The O blood group individuals have none of the above antigens on their cell surface. Only the AB blood group individuals have A and B antigens on their cell surface. Agglutination involves clumping of red blood cells due to the interactions between the antigen and the antibody. The procedure of finding a blood group of an individual is known as blood typing. The antibodies against the antigen A agglutinate only the red blood cells having A antigen on their cell surface. Similarly, the antibodies against the antigen B agglutinate or clump the cells having B antigen on their cell surface. The blood serum prepared from the individuals with A blood group consists of anti-B antibodies and no anti-A antibodies. The blood serum of the B blood group individuals consists of anti-A antibodies. The individuals with AB blood group neither have anti-A nor have anti-B antibodies in their blood serum. The blood serum of the individuals having O blood group consists of both anti-A and anti-B antibodies.

The blood of the A blood group individuals can be transfused only to the individuals having A or AB blood group. The blood of the B blood group individuals can be transfused only to the individuals having B or AB blood group. People with AB blood group produce both A and B antigens. Hence their blood gets transfused to the individuals having AB blood group. The blood of the people with O blood group gets transfused to all the individuals such as A, B, AB, and O groups. Hence, individuals with AB blood group are known as universal recipients. The individuals with O blood groups are known as universal donors.

An enzyme known as glycosyltransferase adds sugar groups to the polysaccharide which combines with the lipid molecules and forms glycolipids. This enzyme gets encoded by the ABO locus. The association of the glycolipids with the RBC membrane lead to the formation of blood group antigens. H antigen is the most common blood group antigen. In the A and B blood group individuals, the H antigen remains unconverted. In the IA/IB heterozygotes, the H antigen gets converted to A and B antigens. The homozygotes for O allele produce no enzymes for converting the H antigen glycolipid.

Image: Drosophila eye color

Drosophila eye color:

Consider a cross between a white-eyed female and a vermilion eyed-male in the Drosophila species. The F1 generation involved all the females having a red eye. Morgan proposed a concept that the white and the vermilion colors got specified by two different genes. The wild-type allele for the eye color involved brick red color. The presence of the wild-type allele in these females led to the expression of that allele leading to the brick-red eyes. Another cross involved eosin-eyed female and a white-eyed male. The F1 females had eosin eyes. The above crosses easily depict that the dominant allele is present on the X chromosome. Hence, the phenotypic trait is visible in the females. Sturtevant observed that the red color was dominant over the white and the eosin colors. Eosin was dominant over the white. Hence, a single gene consisted of both eosin and white mutant alleles. Hence, the white-eyed gene had multiple alleles. Then, both the scientists considered a cross between eosin eyed females and red-eyed males. All the F1 females were red-eyed. However, they were heterozygotes. Half of the male progeny had eosin eyes. The remaining half had white eyes. The eye color in the Drosophila depends on the amount of the pigment deposited in the eye cells of the fly. For example, the relative amount of the pigment in a wild-type red-eyed fly is 1.0000.

The gene products ranging from null mutants to wild-type alleles exist due to the level of the gene product. The overproduction of the gene product leads to the manifestation of the mutant phenotype. Hence, the number of alleles existing in a given gene decides the number of genotypes. The number of genotypes indicates n(n+1)/2, where n is the number of alleles in the gene.

A red clover plant consists of a gene known as the S gene. It shows the presence of multiple alleles involved in the prevention of the self-fertilization. The self-incompatibility alleles in the parent plant prevent pollen tube in the style. Hence, there are many such examples of multiple alleles. 

References:
[1] Advanced Biology, Michael Kent
[2] Schaum's Outline Of Genetics, Susan Elrod
[3] Principles Of Genetics, Tamarin

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