Every cell in your body has a complete set of instructions about how to make your cells and their components, and to direct how these interact. This set of instructions is your genome. Your genome is quite similar to everyone else's genome, which is why we all turn out to be human beings. You could think of your genome as a recipe book that carries all of the instructions to make a human being.
The human genome consists of 46 chromosomes.
Your genome is made of a chemical called deoxyribonucleic acid or DNA. All living organisms have DNA packaged into their cells. In animals DNA is tightly packaged into bundles, wrapped around a scaffold of protein. If we look at DNA under a microscope, we can sometimes see these bundles of protein and DNA, called chromosomes.
The amount of DNA and the number of chromosomes in an organism's cells depends on the species it comes from. Humans have 46 chromosomes, actually 23 pairs of chromosomes, one chromosome of each pair coming from the mother and the other chromosome from the father. If you are thinking about the genome as a recipe book you could see the chromosomes as chapters in the book.
DNA's code is written in only four 'letters', called A, C, G and T. The meaning of this code lies in the sequence of the letters A, C, G and T in the same way that the meaning of a word lays in the sequence of alphabet letters. Your cells read the DNA sequence one recipe at a time, each contained within a functional region of DNA, called a gene. These genes usually code for a protein. In our cells, proteins are the workforce; they get everything done. Proteins break down our food to release energy. Proteins organise the transport of useful chemicals between cells. Often, these useful chemicals are themselves proteins.
As well as doing things, proteins are the building blocks for most of your body. In the same way that a wall is made mostly of bricks, your body is made mostly of protein.
Less than 2% of the genome codes for protein. The rest of the DNA is made up of the same letters as coding DNA but it doesn't have the same meaning. We are not sure what all of this non-coding DNA is for. We know that some of it controls when genes are switched on or off and others are important for the structure of chromosomes. However we are still finding out what much of this DNA does.
Between generations or over a lifetime genomes change. These changes are called mutations. Mutations are happening in your cells all the time. They can happen spontaneously and at random. You can also inherit from your parents mutations that arose many generations ago. This is why diseases can run in families.
If a mutation happens in a part of the DNA that does not code for a protein or regulate when a gene is switched on or off, the chances are that the mutation will have no health consequences for the individual. However, some mutations can be detected because they alter the structure of a protein or the amount of protein produced. These relatively few mutations can directly affect the ability of the protein to carry out its normal job.
However, some mutations can be detected because they lead to a change in the coding parts of a gene and result in a change to the protein structure or amount of protein produced. These relatively few mutations directly affect the ability of the protein to carry out its job or change the way the protein does its job.
Mutations come in many different shapes and sizes: a single letter may be changed, a whole segment of DNA sequence may be flipped over and reverse itself, or huge sections of the genome could be duplicated or deleted. A few of these changes can be seen under a high-powered microscope but most require techniques (such as Microarray or Exome sequencing) that can compare the sequence or activity of specific DNA segments.
Single letter changes are also called point mutations.
This is where a single letter in the DNA sequence is changed. This is equivalent to a spelling error in a word of our genome recipe book. This is detectable by exome sequencing.
An additional copy of chromosome 21 causes Down's syndrome.
Small or large sections of DNA can be duplicated or deleted in different individuals. These duplications or deletions can have a dramatic effect on the health of an individual. For example people with Down's syndrome have an additional copy of chromosome 21 causing a condition with significant physical differences and learning difficulties. This is equivalent to a word, paragraph or even a whole chapter of our genome recipe book being repeated or deleted; an additional copy of a chromosome is called a trisomy. This is detectable by microarray or when the repetition or deletion is larger by standard karyotyping.
Small or large sections of DNA can be can be reversed (an inversion) or swapped between different chromosomes (a translocation). For example, some forms of the blood disorder haemophilia are caused by short segments of the Factor VIII gene being inverted or reversed inside the gene. This is equivalent to a paragraph or pages of our genome recipe book being removed and pasted back in the wrong way (an inversion) or removed and pasted in a different chapter (a translocation). This is detectable by standard karyotyping.
Mutations in DNA and their implications in human diseases have been known about for many years. However, recent studies looking at the entire genome are rapidly increasing our understanding of the different types of genetic variant that cause genetic conditions.
Although most of the time these forms of mutation have no visible impact on an individual's health, in some people they have been found to be the cause of birth defects or genetic disorders.
The technology we will be using in the PAGE study is called sequencing. This involves reading the exact order of letters - As, Cs, Gs and Ts - along a piece of DNA. This is the most detailed genetic test possible. It allows us to read the entire genome 'recipe book' from start to end, or to dip in and out and read selected chapters of particular importance.
Using sequencing, we are able to detect extra or missing words and spelling mistakes. This technology means that we should be able to find any changes to the DNA that might have caused structural anomalies in prenatal ultrasound screening. However, interpreting this information is very complicated as there is no appropriate reference to turn to, like a dictionary.
Every individual has a unique DNA sequence and there are lots of tiny genetic differences between all of us, some common and some rare. This makes finding the genetic differences which cause a particular disorder much more challenging.
One of the ways that we can start to make sense of whether the changes are important and are causing problems or not is to record results anonymously in an international database. This way clinicians and scientists around the world can start to build up a picture of what are the likely important differences in DNA and start to form this 'DNA dictionary'.