Mitochondrial DNA and Human Ancestry

Mitochondria are important organelles for generating energy in the cells. They have a unique genome. In some species, the mitochondrial DNA is linear. Whereas in some species it is circular. The endosymbiont theory revealed that the mitochondria and chloroplasts originated as prokaryotes. Later on, they invaded the eukaryotic cells to establish a symbiotic relationship. Mitochondria are involved in cellular respiration which is a process of oxidization of food molecules. Mainly, the oxidization of glucose gives rise to carbon dioxide and water. The energy released in this process is known as ATP (Adenosine Triphosphate). Thus, mitochondria are also known as energy powerhouses. Till now we only knew the genes present in the nucleus. We have studied the structure and expression of the nuclear genes. Years later the discovery of the nuclear genes, the scientists found that there was something else beyond the Mendelian pattern of inheritance. Mitochondria also controlled a few traits. The genes present in the cytoplasmic organelles such as mitochondria and chloroplast are known as extra-nuclear genes. They are alternatively known as Non-Mendelian genes because they do not follow Mendelian inheritance pattern.

Image 1: Mitochondrion and its DNA

The Mitochondrial Genome:

The origin of the mitochondrial DNA is of bacterial or prokaryotic origin. Thus, it shows similar replication and gene expression features. A wide structural variation persists in the eukaryotic mitochondrial genome. The complete sequences of mitochondrial DNA are now known to us. The structure of the mitochondrial genome is highly conserved in the mammals. Though mitochondria have their separate genomes, they are not completely self-operative. In some cases, they may also require nuclear gene products for carrying out their specific functions. The copy number of the mitochondrial genome in the oocytes is extremely high. Fertilization is a process in which the sperm and the egg fuse with each other. During this process, the mitochondria present in the sperm do not get transferred to the oocyte. Thus, the zygote contains the mitochondria of the oocyte. Thus it follows a maternal pattern of inheritance.

Description of mitochondrial DNA:

The mitochondrial DNA is double-stranded, supercoiled and circular. The mitochondrial DNA is also known as mtDNA. It codes for 37 genes in humans, and 35 genes in S. cerevisiae. The mitochondrial DNA consist of 16.6 kilobases nucleotide base pairs. The GC content of mtDNA differs from that of the nuclear DNA. Many genes in the mitochondria encode for the enzymes involved in the oxidative phosphorylation. Extranuclear processes require many such enzymes. For some of the processes, the nuclear genes may not be sufficient to encode proteins or enzymes. Thus, mitochondrial genes play a crucial role in synthesizing enzymes that catalyze reactions for generation of energy.

An abnormality in the mitochondrial genes may lead to mitochondrial disorders. The mitochondrial DNA does not associate with the histone proteins. There is very little extragenic or repetitive DNA in the mitochondrial genome. The human mitochondrial genome is small and compact. The genes are very close to each other with a very little space between them. In yeast, the mitochondrial genome consists of widely spaced genes. Mitochondrial genomes are studied using metagenomics.

Just like the nuclear DNA, the mitochondrial DNA also undergoes a semi-conservative type of replication. Mitochondrial DNA also requires DNA polymerases to carry out the process of replication. These enzymes are known as mitochondrial DNA polymerases. The mtDNA replication occurs throughout the cell cycle. Unlike nuclear DNA replication, the mtDNA is not S-phase specific. The displacement loop or D-loop model is studied. The two mtDNA strands show different densities. The bases are spaced unequally on the strands. The unequal spacing or distribution of bases creates heavy and light strands. Letter ‘H’ is used to denote the heavy strand. Letter ‘L’ is used to denote the light strand of the mitochondrial DNA. The mtDNA is supercoiled up to a hundred coils. The uncoiling takes place during the initiation of replication. The synthesis of H strand starts at the origin of replication. Formation of a ‘D’ shaped loop takes place. The loop expands further to synthesize a new light strand. Synthesis of the light strand starts at the second replication origin. Thus, mitochondrial DNA follows a continuous type of replication for both the strands. After completion of the replication, the supercoiling of the two circular mtDNAs occurs. The heavy and light strands consist of mitochondrial protein-coding genes.

Image 2: Mitochondrial inheritance

Investigation of the genetic relationships:

Mitochondria exclusively follow maternal inheritance. It means that they are inherited only from the female gamete, the oocyte. Thus, the oocyte is the major contributor of the cytoplasm. The mitochondrial DNA analysis can be used to assess the genetic variability of a given population. The diseases caused due to maternal inheritance get detected using information related to mitochondrial DNA mutations. Finding the ancestors and relatives of an individual may be easier.

The story of the Tsar and Tsarina:

The Bolsheviks executed the Tsar and his family in the eighteenth century. However, one of the Tsar’s three daughters, Princess Anastasia managed to escape from the execution. After many years, a woman claimed herself as Anastasia. She lived in the United States for many years as Anna Anderson. The Tsar’s family members’ mtDNA samples were used to study their relationships. Thus mtDNA analysis helped to reveal the true relationships in the Romanovs.

Human ancestry linked to mtDNA studies:

Various studies revealed that genetic recombination is uncommon in the mitochondrial DNA. Thus it is similar to the Y chromosome. The mtDNA is a good genetic marker for tracing the human ancestry. Human mitochondrial DNA undergoes evolutionary changes in the sequences at an approximately constant rate. The statistical figures suggest one change per mitochondrial lineage every three thousand to four thousand years. Analyzing mitochondrial DNA from human bones provides a good number of lineal history evidence. Just as the Y chromosome is inherited only through the father, the mitochondrial DNA is inherited only through the mother. Thus mitochondrial DNA exhibits itself as a family album with pictures of the members. It helps to identify the degree of kinship and the familial origin.

Various studies report a pre-historic migration of human population into North America. The first mtDNA study revealed that Native Americans descended from the Asian ancestors many years ago. They found four distinct mitochondrial haplogroups. Another study revealed the African origin of the modern human population. You might know the story of an African woman (called as Mitochondrial Eve), who lived many lakhs of years ago. She passed on her mitochondrial DNA to future generations. Similarly, the man who passes on the Y chromosome was known as Y chromosome- Adam. Hence, human origin is a topic of debate.

The sequences from the bones of the Neandertal-human were analyzed. PCR analysis was used to obtain DNA sequences from the bone specimens. The relationships between the Neandertals and modern humans were studied using phylogenetic trees. Molecular information such as mtDNA sequences and immunological data were studied. Thus, mitochondrial DNA provided a crucial role in tracing the human ancestry and origin.

References:

[1] Medical genetics, G.P. Pal

[2] Mitochondrial DNA- Wikipedia

[3] Genomics of Chloroplasts and Mitochondria, Ralph Bock, Volker Knoop

[4] Introduction to Genomics, Arthur Lesk
[5] Biomolecular Archaeology: An Introduction, T. A. Brown, Keri Brown

© Copyright, 2018  All Rights Reserved

X-linked dominant inheritance

This type of inheritance indicates the presence of a dominant gene on the X chromosome. Only one copy of the mutated gene is enough to express the trait. Hence, an individual with one X chromosome with a mutated gene expresses the phenotype fully. Unlike X-linked recessive traits, X-linked dominant traits do not necessarily affect males. It equally affects both the sexes. The gene is dominant. Hence, it expresses in the heterozygous females as well as males. Following are the characteristics of the X-linked dominant inheritance:

·        All the fathers pass on the trait to all the daughters since it follows an X-linked dominant pattern.

·        Sons get affected if the only mother or both the parents get affected with the gene mutation.

·              Affected son always has an affected mother.

·           Females show a higher prevalence of X-linked dominant disorder since they consist of two copies of the X chromosome.

·           The carrier mothers themselves get affected with the disorder.  They pass it on to their progeny. 50% of the progeny will get the disorder whereas 50% of the progeny remain unaffected.

·        A carrier father will also suffer from the disease apart from transmitting it to the next generation. 100% of his daughters will have the disorder. None of his sons will get affected.

·        Consider a case wherein both the parents are carriers. 100% of the daughters will have the disorders. 50% of the sons will have the disorder. The remaining 50% of the sons will be normal.

Image 1: X-linked dominant inheritance (Unaffected father and affected mother)

                          Image 2: X-linked dominant inheritance (Affected father and unaffected mother)

Following are the examples of X-linked dominant disorders:

Fragile X syndrome:

It is a genetic disorder causing intellectual disability in the children. They have a narrow face, large testis, high arched palate, and difficulty in speaking. Fragile X children are hyperactive. Most of them do not show any physical symptoms before puberty. Sinusitis also occurs among them. They also have anxiety and attention deficit disorder.  It occurs due to a mutation in the FMR1 gene. It leads to an increased CGG trinucleotide repeats in the 5’ untranslated region. Unaffected individuals have 20-30 repeats of the CGG trinucleotide. Chromosome Xq27.3 gets methylated. Affected individuals have more than 40 repeats. A constricted region on the X chromosome appears like a fragile site under a microscope. This type of X-linked dominant condition exhibit variable expressivity and reduced penetrance. The FMR1 gene encodes a protein known as FMRP protein. The protein gets involved in synapses and also regulates the production of some other proteins. Abnormally large CGG repeat leads to silencing of FMR1 gene. Loss of FMRP disrupts the functioning of the nervous system.  

Rett syndrome:

It is a brain disorder caused due to gene mutations present on the X chromosome. It predominantly affects females. It affects language, coordination, and movements. It affects 1 in 10,000 females between the age of 5 to 18. Such children lose the conscious control of their hands. They also have diminished growth. They lose their ability to walk due to an increased muscle weakness and joint contracture. The infants suffer from poor sucking ability and hypotonia. A gene known as MECP2 is present on the X chromosome. It gets mutated and leads to this condition. It occurs exclusively in girls. Chances of Rett syndrome in boys are quite a few. However, the boys having MECP2 mutation die after birth.

X-linked hypophosphatemia:

It is also known as X-linked vitamin D rickets. It follows X-linked dominant inheritance. A typical feature of X-linked dominant inheritance is bow-leggedness. The symptoms include bone pain, skeletal abnormalities, osteoarthritis, hearing loss, and dental problems.  A gene present on the X chromosome known as PHEX gene gets mutated. The PHEX gene regulates the production of a protein known as PHEX protein. The PHEX protein, in turn, regulates another protein known as fibroblast growth factor 23. Parents having a mutated gene pass it on to the next generation. Excessive synthesis of FGF23 reduces the phosphate absorption capacity of the kidneys, leading to hypophosphatemia. The kidneys do not handle vitamin D properly. X-linked hypophosphatemia leads to vitamin D deficiency.

Alport syndrome:

It leads to glomerulonephritis, kidney disease, and hearing loss. It is an X-linked dominant disorder and involves many gene mutations. Mainly, the genes present on the X chromosome get mutated and hence, get passed on from one generation to another. The mode of inheritance of Alport’s syndrome depends on the X chromosome consisting of mutated genes. It either gets inherited from the mother or the father. Certain genes including the COL4A3, COL4A4, and COL4A5 play an important role in the biosynthesis of collagen. Mutations in any of these genes alter its production. Typically, the collagen associated with the glomerulus gets affected. The type IV collagen is important in the basement membrane in the kidneys, lung alveoli, inner ear, and eye. Majority of the mutations occur in COLA5 gene leading to Alport syndrome. In case of more than one gene mutation on the same autosome, it becomes an autosomal recessive disorder.

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

© Copyright, 2018 All Rights Reserved.

X-linked recessive inheritance

The recessive mutant allele is present on the X chromosome. Some of the genes present on the X chromosome functionally resemble the genes present on the autosomes. The recessive traits manifest only in a homozygous state or in a double dose. A mutation of a gene present on the X chromosome expresses the phenotype in males. These males show hemizygosity for the gene mutation since they have only one X chromosome. The females show homozygosity for the gene mutation. Since the females have two X chromosomes, they have a copy of the gene mutation on each X chromosome. Carriers have only one copy of the mutant gene. Hence, they do not express the phenotype. A carrier female transmits the gene to the next generation. An affected male transmits the mutant gene to all his daughters who become carriers in the future.

Characteristics:

1.     The X-linked recessive inheritance predominantly affects males since they consist of a single X chromosome with the affected or a mutated gene.

2.     A homozygous female is rare in this case (mutant allele occurs mostly in the double dose).

3.     Mostly, the unaffected carrier females transmit the mutant gene to their sons.

Consider a mating between a normal male and a carrier female. 25% of the females exhibit a normal phenotype, 25% of the males exhibit a normal phenotype, 25% of the females become carriers, and remaining 25% of the males exhibit a normal phenotype. Consider another mating example between the affected male and a normal female. In this case, an affected male will never transmit the disorder. 50% of the females will become carriers whereas 50% of the males will exhibit a normal phenotype.

 Image 1: X-linked recessive inheritance (Affected father and unaffected mother)

                        Image 2: X-linked recessive inheritance (Unaffected father and carrier mother)

Disorders associated with X-linked recessive inheritance:

Duchenne muscular dystrophy (DMD):

It severely affects the muscles. This type of dystrophinopathy is predominant in males. DMD involves severe muscular weakness and wasting. An affected person shows an awkward structure of the shoulders and arms while walking. They have very weak belly muscles. These weak muscles lead to the sticking of the belly, thereby affecting the sitting position of the person. Individuals with DMD have weak thighs, weak muscles in the front leg, foot drop and bent knees. Children with DMD may walk on toes due to tight heel cord (contracture). The calf muscles get replaced by fat and the connective tissues. Most of them use a wheelchair since they show difficulty in walking. A gene known as DMD gene gets mutated. The DMD gene encodes a protein known as dystrophin. Different kinds of DMD gene mutations exist. They lead to a wide range of dystrophinopathies. The protein dystrophin mainly gets synthesized in the heart and the skeletal muscles. However, neurons also synthesize this protein in small amounts. Inheritance of DMD follows an X-linked recessive pattern of inheritance. Improper synthesis of dystrophin protein due to DMD gene mutation affects the muscles and the bones of the individual. In DMD, the dystrophin is almost not there. Hence, muscle cells become a deficit of this essential protein. Muscle cells start becoming weak and hence, they die. Patients with DMD also experience heart problems.

Mainly the X chromosome consists of the DMD gene. Hence, a mutated DMD gene mainly passes through the X chromosome. Males have only one X chromosome. Females have two X chromosomes. Each X chromosome has a single copy of the DMD gene. Males receive their X chromosome from the mother and Y chromosome from the father. Hence, the mutated gene passes on from the mother. Since females have two X chromosomes, so they get the disorder if both the X chromosomes have a mutated gene. If one X chromosome has a mutated gene, the females become carriers of DMD gene mutation. A man with DMD will pass on the trait to all his daughters. Since sons inherit Y chromosome, the father may not pass the trait to the son. Sometimes de novo mutations also occur in the family.

Hemophilia:

It belongs to a category of bleeding disorders. It lowers the body’s natural process of blood clotting. Individuals with hemophilia bleed for a very long time. Bleeding in these individuals not necessarily involve an accident or an injury. It may also happen spontaneously. Individuals suffering from hemophilia have blood in their urine and the stools. Their gums always bleed. They also have deep bruises, frequent nosebleeds, and joint pains.

There are two main types of hemophilia. Hemophilia A (classic hemophilia) results in factor VIII protein deficiency thereby affecting 1 in 4000 individuals. Hemophilia B (Christmas disease) arises due to factor IX protein deficiency and affects 1 in 20,000 individuals. Hemophilia occurs commonly in males than in females.

Genetics:

Hemophilia A arises due to changes in a gene known as F8 gene. A normal F8 gene provides instructions in making coagulation factor VIII protein. Hemophilia B arises due to changes in the F9 gene. It encodes coagulation factor IX. Both the proteins work together in the blood clotting process. A blood clot majorly plays a role in protecting the body from excessive blood loss. Without the factor VIII and factor IX proteins, the blood clotting process becomes inefficient.

The genes associated with hemophilia are present on the X chromosome. Males have one copy of X chromosome inherited from the mother. Hence, if the mother has a copy of a mutated gene on the X chromosomes, she becomes a carrier of the trait. Females have two X chromosomes. Hence, they either become carriers or express the trait fully.

Color blindness:

Color blindness (an X-linked recessive type of disorder) is responsible for lowering a person’s ability to see colors or differentiate color shades. These individuals face a problem in identifying colors and hence, get confused while performing tasks. Identifying traffic lights, selecting ripe fruits, and identifying next to similar colors becomes difficult for them. They become uncomfortable in bright environments. Such individuals have a problem in the development of the color sensing cones in the eye. Color blindness gets detected using the Ishihara test of determining various colors. There are many forms of color blindness such as red-green color blindness, blue-yellow color blindness, and total color blindness.

Genetics:

The X chromosomal genes such as OPN1LW, OPN1MW, and OPN1SW get mutated leading to color vision deficiency. A light-sensitive tissue consists of the color vision promoting proteins. It is present at the backside of the eye. The ophthalmic structures (consisting of rods and cones) transmit the signals from the eye to the brain. Rods provide vision in low light whereas cones provide vision in bright light. The above genes help in making opsins in the cones. Mutated genes result in color blindness or difficulty in visualizing specific spectrum of colors. 

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

© Copyright, 2018 All Rights Reserved.

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,

© Copyright, 2018 All Rights Reserved.

Study of Inheritance patterns in humans

Study of inheritance patterns plays an important role in understanding the features of genetic disorders. The traits or the characters get passed on from one generation to the next. This process is known as inheritance or heredity. With a combination of the father’s and mother’s genes, the zygote genetic material gets developed. Along with the healthy genes, there are chances of inheriting faulty or mutated genes or the carrier genes. Although there are no gene mutations, the incorrect chromosome segment exchange or chromosomal aberrations contribute to the risk of inheriting genetic disorders.

The inheritance of common traits follows either of the two patterns such as monogenic or polygenic inheritance. It is clear to study an inheritance pattern using a pedigree chart. The family history of the patient helps to collect the information of the inheritance pattern in a particular family and draw a pedigree chart. A pedigree is a sophisticated diagram showing the ancestral history of the patient and the relatives. The hereditary behavior of the genes depends on the type of the genetic material or a chromosome. There are two types of sex chromosomes such as X and Y chromosomes. X chromosomes are common in females. Y chromosomes are present in the males. The karyotype of a normal male is 46, XY. The karyotype of a normal female is 46, XX. Similarly, mitochondrial DNA follows maternal inheritance.  

Monogenic inheritance:

The monogenic or Mendelian inheritance determines the traits by a single gene. Hence, monogenic disorders are known as single gene disorders. There are two main kinds of monogenic disorders such as autosomal and sex-linked inheritance. Each of them follows the dominant or recessive pattern of inheritance.

Image 1: Autosomal dominant and autosomal recessive inheritance

1.     Autosomal dominant inheritance:

The phenotype gets expressed in those who have inherited only one copy of a particular gene mutation. The condition is heterozygous. It refers to a gene on one of the 22 pairs of autosomes (non-sex chromosomes). Thus, the disorder manifests only due to the presence of the affected gene in a single dose. Autosomal dominant inheritance affects both the sexes. The transmission of the affected gene follows male to male, female to female, male to female and female to male inheritance pattern. Almost every generation exhibits the trait. The traits do not skip between the generations. All the affected persons have at least one affected parent. Not all the offsprings suffer from the disorder. Some exhibit a normal phenotype or genotype. The marriage between the normal individuals prevents the mutant gene transmission to the next generation. Autosomal dominant cases equally exhibit the normal and affected individuals. Examples include Huntington’s disease, Myotonic dystrophies, and neurofibromatosis.

Autosomal recessive inheritance:

The gene or the mutant allele prevails in a double dose for expressing the trait. A heterozygous individual does not express the trait and is perfectly healthy.

Such an individual acts as a carrier and passes on the affected gene to the next generation. The trait prevails in the same generation between the siblings. However, it may be absent in the previous generations. Autosomal recessive inheritance equally affects both males and females. Mainly autosomes follow this kind of inheritance. The chances of manifesting the recessive disorder increase in the case of closely related parents. A pseudo-dominant inheritance results due to mating between an affected individual and a carrier. Thus the autosomal dominant inheritance affects 50% of the offspring. Examples of recessive inheritance include spinal muscular atrophy and cystic fibrosis.

Sex-linked inheritance:

Sex chromosomes mainly the X and Y chromosomes follow sex-linked inheritance pattern.

Image 2: X-linked inheritance pattern

X linked inheritance:

It occurs in the dominant or recessive form. A dominant mutation in the X chromosome is seen mostly in females. The male inheriting this condition does not survive as the gene is lethal. In an X linked dominant inheritance, mutant gene exists on the X chromosome. It gets expressed in the heterozygous females and males. It resembles an autosomal dominant inheritance because of the heterozygous pattern. However, there is a slight difference. The affected male transmits the traits to all the daughters and not to the sons. Hence, the trait distinguishes itself from the autosomal dominant trait. Vitamin-D resistant rickets, Xg blood groups, and hypophosphatemia are examples of X-linked dominant inheritance.

X-linked recessive inheritance involves the presence of a mutant gene. It leads to the expression of phenotype in males with the hemizygous condition (since males possess only one chromosome). In females, the expression of the phenotype occurs in homozygous individuals. Some of the genes present on the X chromosome resemble the genes on the autosomes. Examples include genes for color perception. The recessive traits express themselves only in a homozygous condition. A heterozygous female, though normal in the phenotype, becomes a carrier. She passes on the genes from the next generation. X-linked recessive inheritance dominates in males and affects less number of females. Mainly the unaffected carrier females pass on the traits to their sons. The affected male passes on the trait to all the daughters who will become carriers in future. The affected male does not transmit the trait to the sons since the affected genes are not present on the Y chromosome. Examples include DMD and hemophilia.

A very few cases involve Y linked inheritance. The H-Y histocompatibility antigen genes are present on a Y chromosome. There exist genes responsible for spermatogenesis. An affected individual transmits Y linked trait to all the sons and not to the daughters. Females never transmit the trait. Examples of Y linked inheritance include hairy ears.

Mitochondrial inheritance:

The mitochondrial DNA (mtDNA) follows maternal inheritance, meaning, it passes from the mother to the child. We all have our mother’s mitochondrial DNA. Since mitochondria constitute a part of the cytoplasm, this type of inheritance is also known as cytoplasmic inheritance. Mutations in mitochondrial DNA lead to cardiomyopathy, neuropathy, seizures, and encephalopathy.

 

Type of inheritance pattern	Study of familial disorders	Measures for prevention of the familial disorders
Autosomal dominant inheritance	Pedigree analysis Genetic testing Karyotyping	Prenatal diagnosis Genetic counseling
Autosomal recessive inheritance	Pedigree analysis Genetic testing Karyotyping	Genetic counseling Carrier detection Chromosome study Gene therapy (available for some cases)
Sex-linked inheritance	Pedigree analysis Karyotyping	Genetic counseling Adoption of the child or termination of the pregnancy may be adviced.
Mitochondrial inheritance	Shotgun testing Pedigree analysis A test involving 5-Mettetrahydrofolate in CSF	Genetic counseling Assisted reproduction technology

Table: Summary of different types of inheritance patterns and related familial disorders

Polygenic and Multifactorial inheritance:

Polygenic inheritance does not follow Mendelian inheritance pattern. A polygene involves a group of genes controlling a quantitative character. A polygenic character is a quantitatively variable phenotype. It depends on the interaction of numerous genes. Polygenic inheritance is also known as quantitative inheritance since it depends on cumulative gene action. Polygenic traits include intelligence, height, blood pressure, and eye color. Since many genes get involved, the inheritance pattern is known as multifactorial one.

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

© Copyright, 2018 All Rights Reserved.