Human Genetics – A Brief Insight
Each human individual is composed of approximately ten to one hundred trillion cells. Each one of these cells has a control centre called a nucleus where vital information is stored. The nucleus enables the correct components of the cell to be formed so that the cell can function efficiently. Our genetic material, called deoxyribonucleic acid (DNA), is found in the nucleus of the cell. In humans, the DNA is divided among the chromosomes in the nucleus. Almost all cells in a human have 23 pairs of chromosomes. It is only the cells involved in reproduction, that is, ova and sperm, that have a single set of chromosomes – egg and sperm cells simply have 23 chromosomes. In this way when an egg is fertilised, the correct number of 23 pairs of chromosomes is reconstituted.
The chromosome material is made of DNA, and this DNA is wound around proteins called histone proteins. The DNA found in human chromosomes contains the genetic code that enables cells to function properly. The human genetic code has three billion letters (akin to a book with a million pages). These letters are called nucleotides or bases; the whole code is termed the human genome. Approximately one in 1,000 letters of code varies between each human, which means that we are 99.9% the same as each other. Although the human genome comprises three billion letters of code found in 23 pairs of chromosome in each cell, this vital material is highly compacted and tightly packaged into the nucleus. Indeed there are about two meters of DNA packaged extremely tightly into every nucleus of every cell. As each person has ten to one hundred trillion cells, they have hundreds of thousands of kilometres of DNA in their body.
What does the genetic code / your genome do?
The genome codes for the key components that enable each of your ten to one hundred trillion cells to survive and to function properly. Major building blocks in your cells are the various proteins the cells contain. The genetic code has sections within it (involving approximately 2% of the total genetic code) that are dedicated to supplying the information that will allow the correct proteins with the correct sequence to be generated in cells. Each section of DNA that encodes a protein is given the term “gene”. Humans have approximately 20,000-25,000 genes, found in the DNA of the 23 pairs of chromosomes in the nucleus. The letters of code in the DNA are translated into a language of proteins, so that the sequence that the protein has is directly related to the sequence that the section of DNA or gene has.
So what about genetic disorders?
Given that the DNA code is directly related to protein sequences, it is therefore not surprising that when the DNA code has a mistake or a mutation in it, if this occurs in a region of the genetic code that is dedicated to making a protein, then an incorrect protein with a mistake in it will be generated. If this protein in turn has a vital function in the cell, the cell may not function properly and indeed may possibly die. This is the basis of many genetic disorders. There are over 3,000 genetic diseases in humans that are caused by a mutation in one of the 20,000 - 25,000 genes found in the human genome. These disorders, involving a mistake in just a single gene, are called Mendelian disorders.
So what is the relevance of this to patients and human health?
We are now in the era of “genomics” and what is termed the era of “big data” where it is possible to obtain the DNA sequence of someone’s genome quite rapidly and generate large amounts of data. The genomics revolution enables scientists to begin to understand which genes are causative of which disorders. In essence, this means that one can begin to decipher for a given patient what may be the underlying genetic cause of their disorder. Next generation sequencing (NGS) technologies can be used to rapidly sequence parts of a patient’s genome. This enables scientists and clinicians to develop therapies that are directed towards the primary cause of a disorder – this is termed rational drug design where, for example, genetic information is used to develop innovative therapies that are targeted to correcting the precise problem and hence notably may represent more effective treatments.
For example for a patient who does not have a normal copy of a gene (a copy without a mutation), delivering a normal gene represents a logical solution for many genetic disorders. There are to date approximately 1,900 gene therapy trials in humans reported; encouragingly, some of these therapies in trial have provided real benefit to patients (www.clinicaltrials.gov).
Mitochondrial disorders and the mitochondrial genome
While the DNA found in 23 pairs of chromosomes in the nucleus of human cells represents the majority of DNA present in every cell of an individual’s body, there is one notable exception. Surrounding the nucleus is what is termed the cell cytoplasm. The cell cytoplasm is enclosed from other cells by the cell membrane. Much of the machinery of the cell is found in the cell cytoplasm. A really vital part of this cellular machinery is found in structures termed ‘mitochondria’. These are structures (or organelles) that are central to generating the energy that enables a cell to function. This energy is in the form of ATP and is essential for the many functions that any cell undertakes – the mitochondria are called the ‘power houses’ of the cell. The mitochondria in the cell cytoplasm have their own DNA or genome. The mitochondrial DNA genome is much smaller than the DNA genome in the nucleus, just approximately 16,600 letters of code versus three billion. In each cell there are hundreds of mitochondria, and in each mitochondria there are between two to ten copies of the mitochondrial DNA genome. It turns out that mistakes or mutations in the code of the mitochondrial genome can also give rise to disorders – these are called mitochondrial disorders. One such mitochondrial disorder is Leber hereditary optic neuropathy (LHON) which causes significant visual loss and for which a number of gene therapies are under development. See page 48 for more information on mitochondrial disorders.
There are so many questions that are still to be answered; however, the technologies that allow scientists to address such questions are improving rapidly. Undoubtedly there are exciting times ahead with significant scientific discoveries and the development of effective therapies within our grasp; such advances should improve the quality of life for patients with both genetic and acquired disorders.
Prof Jane Farrar, Trinity College Dublin.