Mendel Was Developed 4 Hypotheses

Inheritance patterns

Mendel was developed 4 hypotheses:

1. There are alternative forms of genes (discrete portions or sequences of the DNA molecule in chromosomes), the units that determine heritable traits.We now call alternative forms of genes alleles. 2. For each inherited trait, an organism has 2 genes (alleles), one from each parent. These genes may be both the same allele, or they may be different alleles 3. A sperm or an egg carries only one allele for each inherited trait, because allele pairs separate (segregate) from each other during the formation of the gametes 4. When the 2 genes of a pair are different alleles, one is fully expressed and the other has no noticeable effect on the organism's appearance These are called the dominant allele and recessive allele respectively

Our genes, located on our chromosomes in our cells, provide the information for the growth, development and function of our bodies. When the information in a gene is changed, there is a different message sent to the cells. A change to the genetic code that causes the gene not to work properly is called a mutation: the gene is described as faulty.

Inheritance patterns in families of conditions due to faulty(mutation) genes The inheritance pattern depends on whether the • Faulty gene is located on one of the chromosomes numbered 1-22 called an autosome or on the X chromosome which is one of the sex chromosomes. • Change to the genetic code that makes the gene faulty is ‘recessive’ or ‘dominant’ . The most common patterns of inheritance: • Autosomal recessive • Autosomal dominant • X-linked recessive • X-linked dominant

a) Autosomal Dominant Inheritance

Genes are the blueprints for making the substances, called proteins, our bodies need to develop and work properly. Most genes come in pairs, one of which is inherited from the mother and the other from the father. A mutation is a change in a gene that prevents it from working properly. Mutations in genes are inherited from our biological parents in specific ways. One of the basic patterns of inheritance of mutations is called autosomal dominant inheritance.

Autosomal dominant inheritance means that the gene carrying a mutation is located on one of the autosomes (chromosome pairs 1 through 22). This means that males and females are equally likely to inherit the mutation.

1 "Dominant" means that having a mutation in just one of the two copies of a particular gene is all it takes for a person to have a trait, such as an increased risk of developing cancer. When a parent has a dominant gene mutation, there is a 50 percent chance that any child he/she has will also inherit the mutation.

The other 50 percent have not inherited the mutation. These four combinations are possible every time a pregnancy occurs between these two individuals. The gender of the children (whether they are sons or daughters) does not matter. The chance is 50/50 for each pregnancy.

An important characteristic of dominant gene mutations is that they can have variable expression. This means that some people have milder or more severe symptoms than others. In addition, which systems of the body the mutation affects can vary as can the age at which the disease starts, even in the same family. In some cases, they can have reduced penetrance. This means that sometimes a person can have a dominant mutation but not show any signs of disease. The concept of reduced penetrance is particularly important in the case of autosomal dominant cancer susceptibility genes. If a person has inherited a cancer susceptibility gene, it does not mean he or she will automatically develop cancer. It simply means that the person has inherited a mutation in a gene that gives him or her a higher chance to develop cancer than the general population - someone without the mutation.

Most families know that there is a dominant trait or disorder in their family, because it is passed from parent to child and can be seen in many generations. When a cancer susceptibility gene mutation is inherited in an autosomal dominant manner, it means that the mutation can be inherited from the mother, or the father, who may or may not have ever had any type of cancer.

2 However, with autosomal dominant inheritance, if a parent does not have the gene mutation associated with cancer risk in the family, he or she cannot pass it on to his or her children.

b) Autosomal Recessive Inheritance

Genes are the blueprints for making the substances, called proteins, our bodies need to develop and work properly. Most genes come in pairs, one of which is inherited from the mother and the other from the father. A mutation is a change in a gene that prevents it from working properly. Mutations in genes are inherited from our biological parents in specific ways. One of the basic patterns of inheritance of our genes is called autosomal recessive inheritance.

Autosomal – this means the disease affects both males and females equally Recessive – this means both parents must be a carrier for a child to be at risk although the parents themselves (the carriers) are not affected by the disease Inheritance – this means the process of genetic transmission of characteristics (in this case the gene which causes Tay-Sachs) from parents to offspring. Autosomal recessive inheritance means that the gene carrying the mutation is located on one of the autosomes (chromosome pairs 1 through 22). This means that males and females are equally affected. "Recessive" means that both copies of the gene must have a mutation in order for a person to have the trait. One copy of the mutation is inherited from the mother, and one from the father. A person who has only one recessive gene mutation is said to be a "carrier" for the trait or disease, but he or she does not have any health problems from carrying this one mutation. Most people do not know they carry a recessive gene mutation for a disease until they have a child with the disease. Once parents have had a child with a recessive disease, there is a one out of four, or 25 percent chance, with each subsequent pregnancy, for another child to be born with the same disorder. This means that there is a three out of four, or 75 percent chance, for another child to not have the disease.

3 The birth of a child with a recessive condition is often a total surprise to a family, since in most cases, there is no previous family history of the condition. Many autosomal recessive conditions occur this way. It is estimated that all people carry some recessive genes that cause genetic diseases or conditions. It is only when a person has a child with a partner that carries the same recessive gene mutation, that there is a chance of having a child with a recessive disorder. Mutations in certain genes have occurred over time in different parts of the world.

a) X-linked Recessive: Red-Green Color Blindness, Hemophilia A

Genes are inherited from our biological parents in specific ways. One of the basic patterns of inheritance of our genes is called X-linked recessive inheritance.

In genetics, the term "recessive gene" refers to an allele that causes a phenotype (visible or detectable characteristic) that is only seen in a homozygous genotype (an organism that has two copies of the same allele) and never in a heterozygous genotype. Every person has two copies of every gene on autosomal chromosomes, one from mother and one from father. If a genetic trait is recessive, a person needs to inherit two copies of the gene for the trait to be expressed. Thus, both parents have to be carriers of a recessive trait in order for a child to express that trait.

X-linked inheritance means that the gene causing the trait or the disorder is located on the X chromosome. Remember, females have two X chromosomes, while males have one X and one Y. Genes on the X chromosome can be recessive or dominant, and their expression in females and males is not the same because the genes on the Y chromosome do not exactly pair up with the genes on the X chromosome.

X-linked recessive genes are expressed in females only if there are two copies of the gene (one on each X chromosome). However, for males, there only needs to be one copy of an X-linked

4 recessive gene in order for the trait or disorder to be expressed. For example, a woman can carry a recessive gene on one of the X chromosomes unknowingly, and pass it on to a son, who will express the trait:

There is a 50 percent chance that daughters carry the gene and can pass it to the next generation. There is a 50 percent chance that a daughter will not carry the gene and, therefore, cannot pass it on. There is a 50 percent chance that sons do not have the gene and will be healthy. However, there is a 50 percent chance that a son will have inherited the gene and will express the trait or disorder.

Examples of X-linked recessive conditions include red-green color blindness and hemophilia A:

. Red-green color blindness. Red-green color blindness simply means that a person cannot distinguish shades of red and green (usually blue-green). Their visual acuity (ability to see) is normal. There are no serious complications; however, affected individuals may not be considered for certain occupations involving transportation or the Armed Forces where color recognition is required. Males are affected 16 times more often than females, because the gene is located on the X chromosome. Hemophilia A. Hemophilia A is a disorder where the blood cannot clot properly due to a deficiency of a clotting factor called Factor VIII. This results in abnormally heavy bleeding that will not stop, even from a small cut. People with hemophilia A bruise easily and can have internal bleeding into their joints and muscles. The occurrence of hemophilia A (Factor VIII deficiency) and hemophilia B (Factor IX deficiency) combined is one in 10,000 live male births, with hemophilia A accounting for 80 percent of all cases. Treatment is available by infusion of Factor VIII (blood transfusion). Female carriers of the gene may show some mild signs of Factor VIII deficiency such as bruising easily or taking longer than usual to stop bleeding when cut. However, not all female carriers present these symptoms. One third of all cases are thought to be new mutations in the family (not inherited from the mother). Another examples such as muscular dystrophy and fragile X syndrome.

5 b) X-linked dominant inheritance . Sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome. As an inheritance pattern, it is less common than the X-linked recessive type. In medicine, X-linked dominant inheritance indicates that a gene responsible for a genetic disorder is located on the X chromosome, and only one copy of the allele is sufficient to cause the disorder when inherited from a parent who has the disorder.

. X-linked dominant traits do not necessarily affect males more than females (unlike X- linked recessive traits). The exact pattern of inheritance varies, depending on whether the father or the mother has the trait of interest. All daughters of an affected father will also be affected but none of his sons will be affected (unless the mother is also affected). In addition, the mother of an affected son is also affected (but not necessarily the other way round).

Males are normally hemizygous for the X chromosome, having only one copy. As a result, X- linked dominant disorders usually show higher expressivity in males than females.

a) When the mother is an affected X-linked dominant faulty gene carrier, in every pregnancy, there is  1 chance in 2, or 50% chance, that both her sons and daughters will inherit the faulty gene copy from her and be affected by the condition.  1 chance in 2, or 50% that her children (both sons and daughters) will inherit the working copy of the gene from her (‘d’) and not be affected by the condition. This pattern of inheritance is superficially similar to that of autosomal dominant inheritance

6 b) When the father is affected by a condition due to an X-linked dominant faulty gene the unaffected mother will only give working copies of the gene to her children but the father will pass his X chromosome to his daughters. This means that in every pregnancy: None of his sons can inherit the faulty gene since the son only inherits from his father the Y chromosome that does not have the faulty gene copy. They will inherit the working copy from their mother. None of his sons will have the condition. All of his daughters will inherit from their mother the working gene copy and the faulty gene copy from him. All of his daughters will have the condition

Mitochondrial Inheritance: Leber's Optic Atrophy

The normal 46 chromosomes in our body are contained in the center of our cells, which is called the nucleus. Mitochondria are structures in the cytoplasm of the cell, located outside of the nucleus in the cytoplasm, that make energy for the cell. Mitochondria also contain their own genes that are separate from the ones in the nucleus.

Unlike nuclear genes, which are inherited from both parents, mitochondrial genes are inherited only from the mother. If there is a mutation in a mitochondrial gene, it is passed from a mother to all of her children; sons will not pass it on, but daughters will pass it on to all of their children,

7 and so on. The first human disease that was associated with a mutation in mitochondrial DNA is called Leber's Hereditary Optic Neuropathy, or LHON.

What is Leber's hereditary optic neuropathy (LHON)?

LHON causes a painless loss of central vision due to the death of optic nerve cells. It leads to blindness in young adult life, typically between 12 and 30 years of age, and both eyes are affected at the same time. Males are approximately four times more likely to be affected than females. Males will not pass the gene to any of their children, but females with the mutation will pass it to all of their children, regardless of whether they are sons or daughters. LHON is also a multifactorial disease; both alcohol and tobacco use are important environmental factors associated with increased risk of blindness in carriers of the mutation.

Some of the estimated 20,000 genes in the human genome are located in small compartments in the cell called the mitochondria, rather than on chromosomes in the cell’s nucleus. Some cells contain many hundreds of mitochondria • The genes found within the mitochondria contain the information that codes for the production of many of the important enzymes that drive the biochemical reactions to produce the body’s source of energy: a chemical called ATP (adenosine triphosphate). The cells in the body, especially in organs such as the brain, heart, muscle, kidneys and liver, cannot function normally unless they are receiving a constant supply of energy • Faulty mitochondrial genes can result in absence of these enzymes, or enzymes that are impaired and do not work properly. This leads to a reduction in the supply of ATP, and may result in problems with the body’s functions • The pattern of inheritance of conditions due to faulty mitochondrial genes is often called maternal inheritance. This is because a child inherits the great majority of their mitochondria from their mother through the egg • Usually a mother will have a mixture of mitochondria containing the working gene copy and others containing the faulty gene.

For a condition to develop, the number of mitochondria with the faulty gene must be above a critical level

Another place in the cell where DNA is found is in very small compartments called mitochondria (plural) or mitochondrion (singular), that are found randomly scattered in the cytoplasm of the cell outside the nucleus. The cells in the body, especially in organs such as the brain, heart, muscle, kidneys and liver, cannot function normally unless they are receiving a constant supply of energy. The cell’s energy source is a chemical called ATP (adenosine triphosphate) that is used by the body to drive the various reactions essential for the body to function, grow and develop. A number of biochemical reactions that occur in an ordered sequence within the mitochondria are responsible for this process of ATP production. These reactions are under the control of special proteins called enzymes. The genes found within the mitochondria contain the information that codes for the production of some of these important enzymes.

8 Inheritance of faulty mitochondrial genes (maternal inheritance). The number of mitochondria in every cell of a person’s body varies from a few, to hundreds. • All of these mitochondria, and therefore the DNA within the mitochondria, descend from the small number of mitochondria present in the original egg cell at the time of that person’s conception • The sperm contributes very few mitochondria to the baby An individual’s mitochondria are generally only inherited from his or her mother. A change (mutation) in one of the mitochondrial genes that makes it faulty, can therefore be passed by the mother to a child in her egg cells. • This pattern of inheritance is therefore often referred to as maternal inheritance. The egg cell contains many mitochondria, each having on average one to several copies of the mitochondrial genes. If a particular gene in every mitochondrion in an egg cell is faulty and is therefore sending the incorrect instructions, the disruption to energy production would be so severe that the early embryo would probably not survive. The fact that a person survives to birth and is affected with a mitochondrial condition means that they must have inherited two types of mitochondria from his or her mother: some containing the working copy of the gene, and some containing the faulty gene.