Important things to note:
A “genome” is all the genetic material that makes a living organism; genetic material is made up of DNA, comprising four chemical bases A, T, C, G. A “gene” is a string of A, T, C, Gs with a distinct function; each gene makes a protein and proteins form the building blocks of cells. The human genome is made up of 3 billion chemical bases arranged into 30,000 genes separated from each other by long stretches of DNA that doesn’t make protein. We inherit two copies of each gene, one inherited from our mother and one from our father.
We all carry changes in our genetic material called mutations; for example, a normal gene, AATTCCGG, can be mutated into AAATCCGG (the first T has changed into A). Most mutations are harmless but some disrupt the function of genes (e.g. they can alter the protein made by the affected gene). Our close relatives share most of our mutations with us, while distant relatives do not.
Discovering disease genes
Most of the mutated genes identified as causing a disease are found in rare families with lots of affected close relatives. This suggests that the same causative mutation is in each affected family member but missing in those unaffected by the disease. Studying these families has the great advantage of reducing the number of genetic changes that could be causing the disease because each family member will carry similar mutations; the needle is in a smaller haystack. In contrast, there are many different mutations in the general population, making it very difficult to identify the causative mutation by studying whole populations; the haystack is huge!
To identify disease genes, the genome is “mapped” to discover regions shared in affected but not in unaffected family members. This is done by identifying distinct motifs or signatures in the sequence of DNA (e.g. AT repeats, ATATATAT) in known regions of the genome; if these motifs are shared among affected individuals then genes within this region are more likely to carry the causative mutation.
Once a region has been identified the genes within that region can be read (by DNA sequencing), revealing any mutations. If a mutation is found only in affected family members, it is likely that the mutated gene is important in causing the disease.
The difficulty of subtle genetic effects
The procedure for identifying disease genes just described is powerful when the mutation has a large genetic effect; there is a direct link between the mutation and the disease. However, in complex diseases, such as Parkinson’s, mutations are likely to have an indirect link to the disease and exert a more subtle genetic effect (regions containing mutations are likely to be missed when mapping). For example, it is possible that Parkinson’s disease is caused by lots of mutated genes, each with a small effect, coming together and exerting a cumulative effect. This complex inheritance is very difficult to untangle; there are many different haystacks to search. One way to identify multiple genetic factors is to sequence every gene of affected individuals. This identifies lots of mutations but most will not be responsible for the disease. A laborious process of validation in cells will have to take place to identify causative mutations.
Understanding the effect of mutations
It is not enough to just identify a disease causing mutation. Further work is needed to understand what effect the mutation is having on the normal function of the gene. Is it abolishing the function of the protein made by the affected gene or just diminishing it? It is also possible for mutations to make the protein hyperactive or take on a new function altogether. To understand how the altered gene function is causing a disease the context of the cell must be considered; does the protein normally interact with other proteins and is this disrupted by the mutation? Does the protein switch on a particular function of the cell and is this missing in people with mutations? Mutations do not happen in isolation; they occur in and potentially affect the complex functions of the cell. If genetic diseases are to be understood and tackled by new medication, it is crucial to understand what the mutation is doing to the normal function of the cell.
Genes identified in Parkinson’s
Genetic diseases come in two different varieties, dominant and recessive, depending on whether one or two copies of a gene need to carry a mutation to cause a disease. Dominant disease occurs when only one copy of a gene is mutated. In contrast, a recessive mutation needs to be present in both copies of a gene to cause a recessive disease.
Progress has been made in identifying both dominant and recessive mutations that cause Parkinson’s disease:
α-synuclein – dominant mutations cause inappropriate clumping of α-synuclein protein into Lewy bodies, a common feature of nerve cells in the brain affected by Parkinson’s
LRRK2 – dominant mutations cause LRRK2 protein, which normally interacts and carefully switches on other proteins, to activate proteins inappropriately.
Parkin – recessive mutations disrupt the control Parkin protein exerts on the levels of particular proteins in the cell
DJ1 – recessive mutations make mitochondria (energy producers of the cell) less able to cope with oxidative stress (a natural effect of energy production), leading to cell death and loss of nerve cells in the brain
PINK1 – recessive mutations affecting PINK1 protein, like LRRK2, cause inappropriate activation of other proteins
All of the genetic causes of Parkinson’s somehow (this is currently unknown) cause the death of dopamine producing nerve cells in the substantia nigra.