The Universe of Genetic Testing

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The Basics

The total of an individual's genetic information is called their genome. The genome consists of structures called chromosomes that are composed of very long double strands of DNA. Each human cell contains 23 pairs of chromosomes. One of each pair is inherited from an individual's mother and the other of each pair is inherited from an individual's father. Twenty-two of the 23 pairs of chromosomes are called autosomes; the other pair are the X and Y chromosomes that determine a person’s sex and are therefore termed the sex chromosomes. Normal males have one X and one Y chromosome while normal females have two X chromosomes.

Chromosomes are located in the part of the cell called the nucleus. The long, double strand of DNA (sometimes called “nuclear DNA”) contained in each chromosome is organised into many subunits of genetic information, the most important of which are referred to as genes. Genes are made up of nucleotides which are composed of phosphates, a sugar, and a nitrogen-containing base. There are four kinds of bases in DNA; adenine, guanine, thymine, and cytosine. It is the difference in the order (or sequence) of these bases on each strand of DNA that leads to the uniqueness of each person’s genetic makeup. The sequence of bases in each gene is used to produce messenger RNA that is, in turn, translated into proteins and the other components of our bodies. There are an estimated 22,000 genes in the human genome and expression of these genes controls the development and maintenance of the individuals we each become.

There is also a tiny bit of DNA that is not located in the nucleus of the cell but in the mitochondria that are located in the cytoplasm of every cell. Mitochrondria are the energy providers for cells and contain their own circular piece of DNA. This DNA is called “extra-nuclear DNA”, or more simply “mitochrondrial DNA,” and the mitochondrial genes, in collaboration with nuclear genes, make the proteins that are needed for the mitochrondria to function properly.

A person’s genotype is their genetic identity, the specific combination of genes that they have in their cells. Observable traits or characteristics, such as hair colour or height, are considered a person’s phenotype. Phenotype is the physical expression of the genotype. People’s phenotypes are different because their genotypes are different. Although human genotypes are alike in many ways, small differences make us unique beings in both genetic makeup and appearance. These differences are called polymorphisms. Genetic polymorphisms in both nuclear DNA and mitochrondrial DNA help to identify us as individuals. Sometimes, but not always, these differences in our genotype are related to disease or to the inability to metabolise or break down drugs normally. These kinds of polymorphisms are called genetic variations, or mutations, and they are either inherited or they can occur spontaneously. Some of these genetic variations occurred over time in an attempt by our bodies to protect us from disease. These variations will be discussed under the specific “Conditions and Diseases” that have a genetic component, such as cystic fibrosis. Sometimes only one nucleotide in a gene is different, and this is referred to as a “single-nucleotide polymorphism.” On other occasions, the number of copies of a particular stretch of DNA can vary leading to the term “copy number variation”. This will be explained in greater detail in the section on “ Clinical Genetic Testing". It is important to remember that not all genetic variations, or mutations, are harmful or lead to disease.

Patterns of Inheritance
There are several ways in which an individual’s polymorphisms or mutations are inherited. These are called “patterns of inheritance” and result in the transmission of a polymorphism or mutation from one generation to the next.

One pattern is referred to as autosomal dominant because a single variant or mutated gene on one chromosome “dominates” the normal copy on the other chromosome so that a certain trait or disease appears. The variant or mutation may be inherited from either an individual's mother or father. Individuals with an autosomal dominant trait or disease have a 50-50 chance of passing the same variation or mutation on to their children. Examples of autosomal traits are brown eyes or the ability to roll one’s tongue; examples of autosomal dominant diseases are Familial Hypercholesterolemia or Huntington disease.

An unusual concept of dominant genes is referred to as codominance, in which the genes on both chromosomes are expressed together. An example of this is the blood type AB, in which the A antigen protein and the B antigen protein are both located on an individual’s red blood cells.

A second pattern of inheritance is termed autosomal recessive because it requires the inheritance of two genetic variant or mutated copies of the same gene for the trait to appear or the disease to develop. One copy is inherited from an individual's mother and the second copy is inherited from an individual's father. If the individual inherits only one of the variant or mutated genes, he or she will not develop the disease but instead will be an unaffected “carrier”, like his or her parent, and can in turn pass the variant or mutant gene on to his or her children. An example of an autosomal recessive trait would be blue eyes; examples of autosomal recessive diseases include cystic fibrosis, sickle cell anaemia, and haemochromatosis.

There are also patterns of inheritance in which the variant gene is on either the X or Y sex chromosome, and these are referred to as sex-linked patterns of inheritance. With X-linked recessive diseases, a female carries the abnormal gene on one of her two X chromosomes, but because she possesses one normal copy of the gene, she is not normally affected. However, since males have only one X chromosome, a single abnormal copy of the recessive gene on his X chromosome (inherited from his mother) is sufficient to cause the disease. Examples include Duchenne muscular dystrophy and haemophilia. If a disease is X-linked dominant, a single abnormal gene on the X chromosome can cause that disease to develop so that a female is affected and the condition is often lethal in males. This is a rare pattern of inheritance.

It is interesting to note that mitochondrial DNA (or “extra-nuclear DNA”) is inherited only from our mothers and the Y chromosome only from our fathers. This is referred to as a “maternal” or “paternal” mode of inheritance. However, there are a number of factors that can obscure or complicate inheritance patterns by affecting the way a gene is inherited or expressed.

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