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The Human Genome

Approximately one in 1,000 letters of code varies between each human, meaning that we are 99.9% the same as each other.

Our bodies have many different types of cells such as those found in our heart, brain, lungs, skin, muscles, kidneys and eyes. With the exception of red blood cells, they each have a control centre called the nucleus. This is where important genetic material called DNA is stored.

About two metres of DNA are packaged into every nucleus of every cell. DNA is short for deoxyribonucleic acid and it holds the instructions that tell our bodies how to grow, develop and function. Instructions within the DNA are written out as a code made up of four different chemicals (called nucleotides or bases) but are more commonly represented by the letters – A, T, C and G. The human genetic code (genome) has three billion letters in total.

Different patterns of A, T, C and G codes for the set of instructions that tell your cells how to make a specific protein. Proteins are used by the cell to perform certain functions, for example, they build bones, enable muscles to move, control digestion, keep your heart beating and power the visual cycle in the retina.

Each section of DNA that ‘encodes’ a protein is called a gene. It is thought that we have about 20,000 – 25,000 genes in our cells arranged on a number of thread-like structures called chromosomes. Almost all cells in a human have 23 pairs of chromosomes.

As you have ten to 100 trillion cells, this equals hundreds of kilometres of DNA in your body!

 

Genetic Conditions

Changes in genes or chromosomes are called mutations. You could think of a mutation as a spelling mistake or a series of words changed in a sentence. Mutations are very common and we all carry a number of them. The effect of a mutation can be good or bad, or it may have no effect at all. Sometimes changes cause little differences, like hair colour. Other changes in genes can cause health problems.

For example, there are over 4,000 genetic diseases in humans that are caused by variation in one or more of the genes found in the human genome. Genetic disorders, involving a mistake in just a single gene, are called Mendelian disorders.

A misspelling (mutation) in the gene can result in a protein not being made properly. 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 including inherited retinal degenerations (IRDs). As of January 2019, over 271 genes have been linked to inherited retinal degenerations (IRDs).

Watch this video of Dr Sally Ann Lynch, a consultant in genetics who introduces and explains clinical genetics.

 

Mitochondrial Genetics and Mitochondrial Disease

Between the nucleus and membrane of the cell is an area called the cell cytoplasm. This contains many other parts of the cell machinery including structures (or organelles) called ‘mitochondria’. Mitochondria are responsible for making the energy that is needed for your cells to function. Because of this, mitochondria are called the ‘power houses’ of the cell. Hundreds of mitochondria can be found in each cell.

Mitochondria are also unique and special because they have their own DNA or genome. The DNA found in your mitochondrial is much smaller than that found in the nucleus of your cell. For example, mitochondria have 16,600 letters of code compared to the three billion letters of code found in the nucleus. 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.

 

Inheritance Patterns

We inherit our chromosomes from our parents, 23 from our mother and 23 from our father. This means that half of our DNA comes from our mother and half from our father. Therefore we have two sets of 23 chromosomes or 23 ‘pairs’. The male determining chromosome is the Y chromosome. Males have an X and a Y chromosome and females have two X chromosomes.

Scientists have discovered that many retinal degenerative conditions are hereditary, which means they can be passed from one generation to another. There are many different ways with which a genetic condition such as a retinal degeneration may be inherited. Sometimes it only takes one faulty copy of a gene to result in sight loss (dominant inheritance), whereas in other cases two faulty copies of a gene must be present for symptoms to develop (recessive inheritance). In some cases a gene may not completely control a particular trait, but may contribute towards it. In this case, a combination of genes and environment may result in the development of a genetic condition.

 

Autosomal dominant inheritance

Autosomal dominant inheritance occurs when just one copy of a damaged gene is enough to cause an individual to be affected by the condition. The mutation can lead to development of the condition even when the second copy of the gene is normal. Such conditions can present in two different ways. An affected person can have an affected parent, with the disorder tending to occur in every generation of an affected family. In other cases, the damaged gene which gives rise to the condition may be a ‘de novo’ mutation, described as variants in the gene that occur for the first time in an individual, without any prior family history. These variations are believed to occur when chromosome pairs are split to form reproductive cells.

Both males and females can be affected, however some may be affected so mildly that they may not even be aware that they have signs of the disease. In rare cases, someone with a dominant mutation may not show any signs of the condition. In autosomal dominant inheritance, each affected individual has a 50% chance with each pregnancy of having a child affected by the condition.
Examples of autosomal dominant conditions include mutations in the RPE65 gene or Rhodopsin gene associated with Retinitis pigmentosa (RP).

 

Autosomal recessive inheritance

In autosomal recessive inheritance, on the other hand, a person develops the condition only when both copies of the gene are disrupted. That is, the gene from the mother and the gene from the father both have mutations and the affected person inherited one gene mutation from each parent.

Typically, only one generation is affected and both males and females can be affected. In this type of inheritance, people with only one functional copy of the gene still do not have the condition, but they are called ‘carriers’. When both parents are carriers, there is a 25% chance with each pregnancy that they child will have the condition.

Examples of autosomal recessive conditions include some forms of Retinitis pigmentosa (RP), Usher syndrome, Leber congenital amaurosis (LCA)and achromatopsia.

X-linked recessive inheritance

In X-linked recessive inheritance, the mutation is on the X chromosome. Males have an X and a Y chromosome and females have two X chromosomes. Because males have only one X chromosome, if they inherit a causative mutation on that chromosome, they will develop the condition. Females with one mutation and one regular copy of the gene may not show signs of disease or may only have mild symptoms, although due to the phenomenon of non-random X chromosome-inactivation, some female carriers may display symptoms.

In families, multiple generations of affected males are observed, connected through unaffected females. For example, an affected grandfather might have a daughter who is a carrier and she may then have a son who is affected. When a male is affected, all of his daughters will be carriers and none of his sons will be affected. When a female is a carrier, each daughter has a 50% chance of being a carrier and each son has a 50% chance of being affected.

Examples of X-linked recessive conditions include X-linked retinoschisis , Choroideremia , X-linked retinitis pigmentosa, and blue-cone monochromacy.

 

Mitochondrial inheritance

Mitochondrial inheritance, also known as maternal inheritance, applies to genes contained within mitochondrial DNA. Mitochondria are structures within each cell that convert molecules into energy. Because only egg cells and not sperm cells predominantly contribute mitochondria to a developing embryo, only females pass on mitochondrial mutations to their children. These conditions can affect both males and females and can appear in every generation of a family, but fathers do not pass down these conditions to their children. The severity of symptoms may vary from one affected individual to another; even within the same family due to a ‘dosage’ effect.

This is due to the fact that we have many mitochondria in each cell. In one individual, if only a small proportion of mitochondria in each cell have the mutation, symptoms will be mild. In another individual, if a higher proportion of mitochondria in each cell carry the mutation, symptoms will be more severe.

Examples of mitochondrial conditions include Leber hereditary optic neuropathy (LHON).

 

Uncertain inheritance

Very often, a person diagnosed with an inherited condition has no other family members with the disease. There are several possible reasons for only finding one person affected in the family.

The harmful change in the gene (mutation) giving rise to the condition may be a new event in that person. There is a chance that the mutation may be passed on to future generations and as such, would be regarded as an inherited condition, even if it had not been previously observed within the family.

In some cases, family members may have the gene associated with an inherited retinal degeneration, but do not develop the condition. In such cases, the gene is regarded as having a ‘reduced penetrance’, where the effect of the mutated gene is somehow changed and the condition doesn’t occur in some people.

In some instances, family members may have the gene mutation but show very few, if any symptoms. Such genes are regarded as having ‘variable expressivity’, where the severity of the effects of the gene mutation can vary from one family member to another. As such, the effects of the condition may not have been identified in previous generations of a family.

For autosomal recessive disease, carriers may have been present in the mother’s and father’s side of the family for several generations, but a child won’t develop a condition unless both parents are carriers and both pass on their affected genes to their child.

 

Genetic Counselling

One of the challenges facing someone with an inherited retinal degeneration (IRD) is the lack of a precise genetic diagnosis. However, the delivery of this important genetic information back to people requires time with trained professionals such as a genetic counsellor. These are health care professionals with specialist expertise in medical genetics and counselling.

They play a vital role in providing support and guidance to patients and their families around the inheritance pattern of disease and the likelihood of it recurring in other family members. They can also explain the next steps for a patient and their family in terms of continued clinical care or treatment options, if available. Fighting Blindness is funding the first ophthalmology-specific genetic counsellor in Ireland as part of the Target 5000 Programme. For more information, see the Target 5000 page

 

The Future of Genetics in 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 causing what diseases.

Importantly it also enables scientists and clinicians to develop therapies that are directed towards the primary cause of a disorder. There are to date approximately 4,000 gene therapy trials reported; encouragingly, some of these therapies in trial have provided a real benefit to patients. There are so many questions that are still to be answered; however, the technologies that allow scientists to address such questions are improving rapidly.