Genes

Each human starts off as just one cell at the time of fertilisation. This cell contains two sets of genes, one set from the mother and one from the father. Genes are strings of chemicals found inside the cells within our body which contain the coded information for building proteins. Proteins are the crucial building blocks which enable the body to grow, develop and function.

For ease of storage and access, genes are packaged up into 46 protein parcels called chromosomes. When a cell divides, the genes are copied so that every new cell possesses the full complement of genetic material. Genes are made of a chemical called DNA (deoxyribonucleic acid), with each cell holding two metres of DNA.

Humans have approximately 35,000 genes stretched out along their DNA. Each gene acts as a recipe for the production of a protein and together they make up the blueprint for each individual. Different genes are read at different times, in different cells in response to the requirements of the body.

DNA

DNA (deoxyribonucleic acid) is the chemical responsible for preserving, copying and transmitting information within cells and from generation to generation. In humans, the DNA molecule consists of two ribbon-like strands that wrap around each other. The molecule resembles a twisted ladder and is often described as a double helix.

The double helix is made up of repeating units called nucleotides, each of which is a single building block of DNA. Nucleotides are composed of one sugar-phosphate molecule (the linear strands or outer rails of the ladder) and one base. Two nucleotide strands are joined by weak chemical bonds between the two bases, forming base pairs. A base pair is a rung or step on the ladder of the DNA. The bases are called A (for adenine), C (for cytosine), T (for thymine) and G (for guanine).

The bases always pair up in the following way:

• A and T
• C and G.

The precise sequence and combination of these pairs on the DNA ladder is the code by which genes function.

An example single strand of DNA looks like this: ATGCTCGAATAAATGTGAATTTGA. Each three-letter sequence of bases, e.g. ATG CTC GAA TAA ATG TGA ATT TGA, codes for a particular amino acid. These three-letter sequences make up genes. A single gene may be many thousand bases (letters) long. When it is read by the cell's molecular machinery, a protein is made up out of the amino acids coded for by the gene. Proteins are required for the structure, function, and regulation of the body's cells, tissues, and organs. There are approximately three billion base pairs (6 billion bases) of DNA in most human cells. This complete set of genes is called a genome. With the exception of identical twins, the sequence of the bases is different for everyone, making each person unique.

Chromosomes

DNA is contained in tightly coiled packets called chromosomes which are found in the cell nucleus. Chromosomes consist of a long strand of the double helix of DNA packaged with proteins and other molecules. Each chromosome has a centromere which plays an important role during cell division, and also divides the chromosome into a short arm and a long arm. Scientists can differentiate between chromosomes based on their size, the relative lengths of their arms, distinctive staining patterns and other characteristics.

Humans have two types of chromosomes: sex chromosomes and autosomes. Two sex chromosomes determine the sex of an individual; they are the X chromosome and the Y chromosome. Females have two X chromosomes and males have one X and one Y (although there are genetic conditions in which this varies). The autosomes comprise the other 22 chromosomes. The longest of the autosomes is referred to as chromosome 1, the next largest as chromosome 2, and so on.

Each cell nucleus contains two copies of each autosome (44 chromosomes), plus two sex chromosomes (either two Xs or an X and a Y) making a total of 46. With few exceptions, the chromosomes and genes found within any two cells of the body are identical. The body’s 46 chromosomes contain an estimated 35,000 genes.

Each chromosome pair is made up of one chromosome from the mother and one from the father. Because chromosomes come in pairs, the genes carried on them  also come in pairs. So each cell carries two copies of almost every one of the individual's genes, one copy on each of the paired chromosomes, which means there are usually two separate sets of instructions for that gene's function. The only exception to this is the sex chromosomes, where in males the two chromosomes are different from one another and so there is only one copy of some genes.

Although most of the cells in the human body contain 46 chromosomes inside the nucleus, there is one important exception: the gametes (sex cells). Sperm and ova are created by a special kind of cell division called meiosis. This separates partner chromosomes so that sperm and ova contain just one copy of each chromosome, i.e. 23 in total. Halving the number of chromosomes ensures that when sperm and egg join, the original number of 46 chromosomes is restored.

Most of the DNA in our chromosomes actually lies outside our genes. The function of this surplus DNA, sometimes known as 'junk DNA', is not yet known. It could be 'dead genes' - old inactive DNA, including DNA inserted during viral infections that has been automatically copied and passed down from generation to generation.
This junk DNA (which is being mapped by the Human Genome Project together with the gene DNA) varies much more between individuals than our genes do. So it is a very reliable way of tracing family relationships and identifying people. There may be as many as a million differences in the DNA sequences of two unrelated people.

Just about every one of the billions of cells that make up the body carries an identical copy of an individual’s unique genetic recipe. Although all cells have the same basic design, cells are specialised to perform particular roles within the body. Cells only produce the proteins appropriate to their function. For example, skin cells produce lots of keratin but not haemoglobin.

Genes can be turned on or off like light switches. When a gene is in the 'on' position a protein can be made. But when the gene is in the 'off' position, no protein is made. Cells are different from one another because they have different combinations of genetic switches turned on. This genetic switching is what enables a single fertilised cell to develop into a complex human being.

When a male sperm fuses with a female ovum a fertilised egg is formed. This is the first cell of a new life. It contains a mixture of genes from the mother and the father. All the genetic information necessary for the subsequent development of the embryo is contained in the DNA of that single cell. The single cell divides again and again, by a process known as mitosis, eventually forming billions of cells, each with a set of genes identical to those in the fertilised egg. While this is happening, a precise and ordered sequence of genetic switching takes place.

As the cells divide and grow, specific combinations of genes are turned on or off. The combination of genes turned on in one cell affects which genes are turned on in neighbouring cells, so that as the embryo continues to grow, cells become specialised and organised into the different tissues and organs of the body.

Cell division

Each chromosome within the body (except the chromosomes within cells that develop into sperm or ova) is created by making a copy of a previously existing chromosome. This occurs during the process called mitosis during which cells divide for growth or repair. Before each division, the cell makes an identical copy of each chromosome, and during mitosis each of the two new cells receives a complete set of 46 chromosomes.

Each new cell has the same set of chromosomes and the same genetic information as the ‘parent’ cell. This explains why almost every cell in your body has the same genetic information.

A slightly different process takes place during the production of ova and sperm cells. When an ovum and a sperm unite at fertilisation, their nuclei unite to form the nucleus of a human zygote. If the sperm and egg carried 46 chromosomes, like the rest of the body's cells, then the zygote would have 92 chromosomes, which would be incompatible with life. To prevent this, a special type of cell division, called meiosis, takes place.

The process of meiosis begins with a single cell containing 46 chromosomes and results in four reproductive cells (sperm or eggs), each of which carries 23 chromosomes. An important feature of these four cells is that the combination of genes they carry on their 23 chromosomes is a unique mix of the genes present in the original single cell.

Individuals resemble their parents because half of the instructions or genes came from the father and half from the mother. Similarly, brother and sisters also receive half of their genetic instructions from each parent, but the set that each receives is different. That is why siblings may resemble each other but are not identical. Identical twins receive exactly the same combination of genes and chromosomes.

Mutations

A mutation or polymorphism is a change in the sequence of bases in the DNA of a gene or an alteration in the chromosomes. Polymorphisms are common differences in the sequence of DNA, occurring in at least 1% of the population. Mutations are less common differences, occurring in less than 1% of the population.

A mutation in one place may be a polymorphism in another. For example, the base change that causes sickle cell anaemia is defined as a mutation in Caucasian populations because it occurs in less than 1% of the population. In parts of Africa where it is found in 25% of the population, it is defined as a polymorphism.

Most DNA variation is neutral (not beneficial or harmful), but harmful sequence changes sometimes do occur. Changes within genes can result in proteins that do not work normally or do not work at all. Some of these changes can contribute to disease or affect how someone responds to a drug.

Mutations may be passed down from parent to child (in the sperm or ova), may occur around the time of conception or may be acquired during a person's lifetime. Mutations can also arise spontaneously during normal cell functions, such as when a cell divides, or in response to environmental factors such as toxins, radiation, hormones and diet.

The body has a system of finely tuned repair enzymes that find and repair most DNA errors. But as the body changes in response to age, illness and other factors, these repair systems may become less efficient. Uncorrected mutations can accumulate, resulting in diseases such as cancer.

Genetic tests may be offered to people in various situations. One of the most common is when a couple know they might have a child with a serious genetic disorder. This may be due to a family history of a disease, or they already have a child with a disease. By examining the genes of the two parents, genetic testing can be used to assess the actual risk of any future child inheriting the disorder. If a pregnancy does occur, the couple may then wish to have prenatal diagnosis to analyse the foetus' own genes. This may be able to tell them, to a high degree of certainty (although not absolutely 100%), whether the foetus actually has the abnormal genes. If it does, one option they may wish to consider is to terminate the pregnancy.

Pregnant women in the UK are offered various screening tests for Down’s syndrome (not all are available on the NHS). These tests measure levels of certain chemicals in the mother's blood (the Double, Triple or Quadruple test) or measure the depth of the pad of fat on the baby's neck (the Nuchal test) to estimate the risk of Down's Syndrome. If the risk is high, the mother may be offered further tests. These include an amniocentesis which tests the cells in the fluid around the foetus for the chromosomal abnormality that causes Down's syndrome or CVS (chorionic villus sampling) which looks at a tiny sample of cells from the placenta.

Other rare abnormalities may also occasionally be picked up through routine antenatal screening. However it would be an enormous task to screen for every possible genetic disorder. Also, most genetic conditions cannot be detected by routine screening because doctors do not yet know precisely which gene they are looking for as it has not yet been identified. Some conditions could be due to one or more mistakes in different pieces of the DNA code, so a very specialised genetic search would be required to rule out all possible abnormalities.

A pregnant mother may be referred for special screening if:

• she already has a child with an inherited genetic condition
• there is or may be a genetic condition in her or her partner's family
• she or her partner belong to an ethnic community in which a particular condition is more common. Such conditions include thalassaemia (Cypriot, Pakistani and Indian communities), sickle cell anaemia (Afro-Caribbean communities), Tay-Sachs disease (certain Jewish communities).

The characteristics of a child are not always midway between those of their parents. Sometimes a characteristic in a parent will disappear in their children, only to reappear in their grandchildren. It is not just a simple matter of genetic mixing. For example, although tall fathers and short mothers generally produce children who grow up to be an average height, parents of average height can produce children who grow up to be tall or short.

Two major factors explain this:

• during the process of reproduction, parents' genes are shuffled and dealt out in new combinations which, by interacting with each other, decide all the in-born characteristics that make up an individual
• every aspect of a human being is a combination of nature (genes) and nurture (the environment, e.g. diet, exposure to chemicals and infections). These environmental factors can cause considerable variation among people who are related.

Despite physical differences between humans, we are surprisingly alike at the DNA level. The DNA of most people is 99.9% identical. Only about 3 million base pairs are responsible for the differences between us, which is only 0.1% of our DNA. Yet these DNA base sequence variations influence most of our physical differences and many of our other characteristics also.

Sequence variations occur in genes, and the resulting different forms of the same gene are called alleles. The most common form of an allele is called its ‘wild type’. No matter how many forms (or alleles) that a gene has, each person inherits only two – one from the mother and one from the father. People can have two identical or two different alleles for a particular gene.

Genotype (the pair of alleles a person has at a specific location in the genome) affects phenotype (the observable effect of the allele, such as eye colour or how a person reacts to a drug). Gene variants (alleles) may change the gene so that it codes for a protein that works just as well or better than the protein coded for by the wild type. However, variant alleles can also change a protein so that it no longer works as well or does not work at all.

Some alleles are dominant (or over-riding) and others are recessive (or beaten by more dominant genes). If an individual has two alleles that are the same they are said to be homozygous. Those with different alleles for the same gene are said to be heterozygous. The dominant allele is usually represented by a capital letter and the recessive allele by a lower case letter (e.g. A and a). The existence of different alleles for a gene is known as genetic variation. Genetic variation is responsible for much of the physical variety between all living things, including humans. The total variety of all the alleles of all the genes within a population of individuals is known as the 'gene pool'.

Patterns of inheritance

The most common patterns of inheritance are:

• autosomal dominant
• autosomal recessive
• X-linked recessive inheritance
• complex inheritance.

Autosomal dominant inheritance is caused by a mutation in a gene located on an autosomal chromosome. It occurs when one autosomal allele masks the expression of another. A dominant gene from just one parent will result in the phenotype from that parent showing, which may be eye or hair colour (see below) or it may be a serious condition such as Huntington’s disease.

For example, if you inherit an allele for black hair from each of your parents then your hair colour will be dark because the hair colour alleles your parents passed on to you were homozygous, or the same (i.e. both dark). But you could have two parents with black hair yet have red hair yourself. This would be because, despite each carrying one of the black hair alleles and having dark hair themselves, your parents both also carried the allele for red hair (inherited from their parents) and passed it on to you. The allele for black hair is dominant while red is recessive, so red did not come out in your parents. But the red allele came out in you because your hair colour alleles were both for red (homozygous) and there was no black to dominate.

Autosomal recessive inheritance is also caused by a mutation in a gene located on an autosome, but in this case, two copies of the recessive gene are needed for the trait to be expressed. Cystic fibrosis and diseases affecting metabolism (such as phenylketonuria/PKU) are autosomal recessive conditions.

X-linked recessive inheritance is caused by a gene on the X chromosome rather than on an autosome. Females have two X chromosomes, so they need to inherit two copies of the allele to express the trait; if they have just one copy, they are a carrier of the trait, but do not usually exhibit it (although they may have mild symptoms in some cases). Males are affected by X-linked recessive traits because they have only one X chromosome, so they need only one variant gene to express the trait. Haemophilia is an example of an X-linked recessive disease - it affects men most severely.

Complex inheritance involves the additive effect of many genes interacting with each other and with the environment. Common diseases such as heart disease, obesity, osteoarthritis and asthma are not inherited according to Mendel's patterns, but result from interplay of environmental factors (such as diet, exercise, smoking, and exposure to pollutants) with susceptibility genes.

• familial hypercholesterolaemia
• adult polycystic kidney disease
• achondroplasia
• Huntington’s disease
• neurofibromatosis
• cleft chin.

These conditions are mostly very rare, although polycystic kidney disease, for example, is the fourth most common cause of kidney failure in the UK.

Examples of genetic conditions with a recessive inheritance pattern include:

• cystic fibrosis
• albinism
• thalassaemia
• sickle cell anaemia.

Most recessive conditions occur in fewer than one in 10,000 births.

Sex-linked conditions include:

• fragile X syndrome (one of the most common genetic diseases and the single most common cause of learning disability; 1 in 2000 males are affected. Females may have some protection from the gene on their second X chromosome, so although 1 in 4000 are affected they tend to be more mildly affected)
• haemophilia A and B (women carry the conditions but do not suffer from them because they have a normal copy of the gene on their other X chromosome. Men with the gene have haemophilia)
• Duchenne muscular dystrophy
• colour-blindness
• hairy ears (only men get this facial characteristic as it is one of the few genes carried on the Y chromosome).

Chromosome disorders are due to abnormalities in the normal group of 46 chromosomes that are inherited from our parents. For example, individuals may have more or fewer chromosomes than normal, or there may be structural changes in them, where part of one chromosome may be lost or has attached to the end of another chromosome (a condition known as translocation). Some of the most common chromosomal disorders are a group known as the trisomies. A trisomy means a person has three copies of one of their chromosomes instead of two, e.g. in Down’s syndrome or Trisomy 21, there are 3 copies of chromosome number 21. Edward's Syndrome is Trisomy 18 and Patau's syndrome is Trisomy 13. There may also be 3 copies of the sex chromosomes, e.g. in Klinefelter’s syndrome.