3.1 Mendel & Genetics.

Human genetics, or more specifically the inheritance of biological characteristics from previous generations, follows the laws established by Gregor Mendel in the 19th century. Most people know a little about Mendel's work, that his research studies involved the breeding of pea plants, and that he was a monk. But the real science behind Mendel's work was that he established that the inheritance of certain characteristics can be predicted mathematically when sexual reproduction is involved. These patterns apply equally to peas and people.

Mendel's genetics or Mendelian genetics as it is commonly called, involves a set of principles.

1. Inherited characteristics are determined by units of biological information (genes).Each gene may have different forms called alleles.

2. Each individual has a pair of alleles for each gene (one from mum, one from dad).

3. When eggs and sperm are made using meiotic division, each pair of alleles separates so that each egg or sperm has only one allele. When reproduction occurs (fertilization of egg by sperm) the pair of alleles is restored.

4. It is different genes which control the different biological characteristics of an organism and the alleles of these genes will re assort into new combinations independently of each other.

So, when a new human is formed from the fertilization of an egg, the characteristics it inherits are determined by which alleles have been passed from its parents. We must also understand that any biological characteristic (called the phenotype) is dependent on the combination of alleles passed from each parent (the genotype).

Children may inherit identical alleles from their parent and these children are then said to be homozygous for that allele. Or, they may inherit different alleles from their parents in which case they are said to be heterozygous. Knowing whether a person is homozygous or heterozygous for a certain allele will give big clues to the way in which the biological characteristic will manifest itself.

To give a clinical example, a person will inherit cystic fibrosis from its parents only if they are homozygous for a mutated allele of the CFTR gene. However they will not inherit cystic fibrosis if they have a heterozygous genotype.

But what dictates which allele is actually chosen by the body to produce the CFTR protein? Well that is decided by another property of alleles, namely their dominance or recessivity. A dominant allele is one which is always chosen when in a pair with other alleles, whilst a recessive allele is one which is only chosen if the other allele in the pair is identical (i.e. the person is homozygous for the recessive allele). In the cystic fibrosis example above, the mutated and abnormal form of the CFTR gene is a recessive allele.

The consequence of understanding homozygous and heterozygous alleles and the concept of dominance, is that we can make very good predictions about the biological characteristics of a person according to the alleles they have inherited. This is the basis for attributing risk of inheriting certain genetic diseases as well as the rationale of genetic screening to determine which alleles a certain individual possesses.

The fourth principle highlighted above, basically means that we will inherit a range of characteristics from our parents, but not necessarily in the proportions dictated by sexual reproduction (50% from mum, 50% from dad). It actually means that we could inherit a large proportion from one side of the family, because the alleles of genes assort themselves independently.This is the explanation for the differences in characteristics that may occur even in brothers and sisters from the same parents.


Mendels laws

Basic Principles of Genetics

3.2 Chromosomal Changes.

The pairs of human chromosomes from number 1 to number 23 each carry a proportion of the total number of genes required to build and maintain a human body. All this information, the entire repertoire of genes is referred to as the genome. It is estimated that the human genome contains in the region of 25,000 individual genes.

Therefore any changes to either the number or structure of a human chromosome is likely to involve many hundreds of genes. A little known fact is that approximately 80% of all human conceptions fail to go to full term. The majority of losses are thought to be due to conceptions that result in the collection of faults in chromosome structure or number which are incompatible with successful development or life maintenance.

3.2.1 Changes to Chromosomal Structure.

The first type of structural change is seen when a translocation event occurs. A translocation is where parts of chromosomes are exchanged between two or more chromosomes during cell division. Two major types of translocation are recognized, namely reciprocal and Robertsonian translocations. Both types of abnormality have the potential to produce humans with essentially normal characteristics, but the likelihood is that the offspring of affected individuals may have a chromosomal imbalance.

Reciprocal translocation means that there is a reciprocal exchange of material between chromosomes, whilst Robertsonian translocations are known as centric fusions as they involve the fusion of chromosomes near the centromere. Robertsonian translocations, normally affecting 14,15,21 and 22 actually involve a loss of genetic material, but are termed "balanced" because the genes lost have little bearing on the new individual. All the affected chromosomes have extremely short arms and the material lost is largely confined to genes for ribosomal RNA.

Chromosomes may also suffer deletions during division and development. Deletions are a loss of material from the generation of two breaks in the chromosome followed by a fault in the repair mechanisms employed by the cell. Obviously the effect of the deletion is dependent on the amount of genetic information lost and the significance (dominance or recessivity) of the missing genes.

When a chromosome breaks in two places, there is always a chance of the two broken ends fusing together, this is known as ring chromosome formation. A chromosome may also break and the resulting fragment may then fuse to a similar region on another chromosome of the same structure. This fusion results in what is called a duplication event.

3.2.2 Changes to Chromosomal Number (aneuploidy).

The term aneuploidy refers to any change to the normal number of 46 chromosomes. Another term is also used when their are multiples of the normal number, this term is polyploidy. Aneuploidies can involve both autosomes and sex chromosomes.In cases of where an individual has inherited only one of a chromosome pair, this is known as monosomy, whilst the inheritance of three copies of a chromosome is termed a trisomy. It has been estimated that at least a quarter of conceptions may involve a chromosomal disorder, but loss occurring mainly in the first trimester of pregnancy reduces the proportion at birth to below 1%.The loss or gain of a chromosome means that there can be a significant accompanying loss or gain of genetic information. However there are a number of conditions that result in live births as well as conditions for which their may be a normal life span.

The most well known aneuploidy is probably a trisomy of chromosome 21, which accounts for 96% of those individuals with the condition Down syndrome. The karyotype of these individuals is written as 47,XX,+21 or 47,XY,+21 (the 47 indicates an extra chromosome, XX or XY indicates male or female and +21 indicates the number of the extra chromosome).

Other trisomies include Edward syndrome, trisomy 18 and Patau syndrome, Trisomy 13.

Aneuploidy with regard to the sex chromosomes involves both X and Y forms.

Individuals with Klinefelter syndrome are males who have a karyotype which indicates the inheritance of extra X chromosomes (47, XXY; 48 XXXY; 49, XXXY etc). Whilst those with Turner syndrome are females with a missing X chromosome (45, X).

Males with an extra Y chromosome have XYY syndrome (47,XYY) whilst females with an extra X chromosome have Triple X syndrome.

Aneuploidies are all thought to be the result of the failure of chromosome conjugation in the first division of meiosis or non-dysjuntion, premature disjunction or delayed separation in the second meiotic division. Non dysjunction of chromosomes can also occur in mitotic division and results in individuals with two different cell lines from the same fertilised egg. These persons are known as mosaic individuals.




3.3 Autosomal Dominant Inheritance.

Autosomal dominant inheritance is the term used to describe the inheritance of a characteristic imparted by an allele which dominates over the normally occurring allele. The term autosomal refers to genes carried on the non sex chromosomes (everything except X and Y).

A number of genetic diseases are caused by the inheritance of a dominant allele from a parent. Huntington disease, neurofibromatosis, FAP (familial adenomatous polyposis) and familial hypercholesterolaemia all follow a pattern of autosomal dominant inheritance. These diseases may be apparent at birth, but many only manifest themselves in later life. The pathology is determined by the dominating effect of a faulty gene over the normal genetic background.For some conditions, the inheritance of the dominant allele may predispose the person to a particular future disease.

A parent affected or predisposed to a condition arising from the inheritance of a dominant faulty allele, will pass on either the faulty or normal allele during sexual reproduction, and therefore there are a number of possible outcomes from the resulting pregnancy. These possible outcomes can be seen in figure 3.3, below.

In this figure we see a mother whose chromosome pairs contain the normal allele "d", she will provide the eggs for the next generation and these will contain the normal allele. However, the father carries a faulty dominant gene "D" and the probability that he will pass this on to the next generation in his sperm is 1 in 2 or 50%. As a result of sexual reproduction between these parents, there are four possible outcomes. Two of the four outcomes will produce babies who inherit two copies of the normal allele "d", whilst the other two possible outcomes are babies who have inherited a copy of the dominant faulty gene "D" from their father. Therefore there is a 2 in 4 or 50% chance that children of these parents will be unaffected by the faulty allele and a 2 in 4 or 50% chance that children of these parents will be affected by the faulty allele. In reality, we are saying that for every pregnancy that arises from these two parents, there is a 50% chance of a baby with the inherited faulty allele.

Figure 3.3 Autosomal Dominant Inheritance : The faulty dominant allele is shown as "D", the normal allele is shown as "d".




Although this example shows a father affected by the disorder, the mother could also be affected whilst the father is normal. Autosomal dominant conditions usually affect both sexes equally.

So what happens if both parents carry the faulty dominant allele. Well, in this case both parents can contribute a faulty allele to the next generation.


Where both parents carry the faulty dominant allele, the chance of passing on any associated genetic condition is 75% in each possible pregnancy. This 75% chance is the same for all autosomal dominant disorders where both parents are heterozygous (carrying different forms of the gene).

Dominant faulty alleles may arise in an individual due to mutation in an egg cell or sperm cell or during the fertilization process. This type of mutation is known as a spontaneous mutation.



3.4 Autosomal Recessive Inheritance.

As you are now probably aware, there are two copies of each of every autosomal gene. People may carry autosomal recessive mutations that are capable of causing disease, but because their effects are masked by the presence of dominating "normal" genes, they cause no symptoms. These people may pass the mutated allele to their children, and are therefore known as "carriers" of the disease.

However if a person inherits two copies of the mutated recessive allele, they will become affected by the deleterious effects of the mutation, usually the consequences of a mutated allele is the loss of a biological function. One of the commonest conditions resulting from autosomal recessive inheritance is cystic fibrosis. In this conditions symptoms arise from the failure to move water across cell membranes in sufficient quantities.

Because symptoms are associated with the inheritance of two copies of the mutated allele, both parents have to be heterozygous carriers of the mutation.

Other autosomal recessive disorders include the nervous system disorder Tay-Sachs disease, Spinal muscular atrophy and Phenylketonuria.




3.5 Sex-Related Inheritance.

Men and women differ in the types of gametes they produce (eggs or sperm) and their physiology. These differences can influence inheritance. However, the majority of disorders that are called "sex linked" are caused by X chromosome linked recessivity in males. In these conditions the incidence is much higher in men than women, the mutant allele is never passed from father to son, the mutated allele is passed to all of a father's daughters (but they never express it) and a heterozygous carrier woman passes the allele to half of her sons, who express it, and half her sons who don't.

The best example of this type of disorder is Haemophilia A, a deficiency in blood clotting factor VIII which causes prolonged bleeding in untreated individuals. A single copy of the recessive allele will not affect any heterozygous individual who inherits it. Heterozygous females are normal. As a man receives his Y chromosome from his father and passes a copy to every son, he also receives an X chromosome from his mother and passes a copy to every daughter.

Dominant X-linked disorders are rare, but include conditions such as Hyperphosphataemia. In these conditions the condition occurs twice as frequently in females, an affected man passes the condition to every daughter, but never to a son. An affected woman passes the condition to every son and half her daughters.





3.6 Congenital Abnormalities.

The process of human development is an impressive biological feat. The transformation of a single cell at conception to a living organism consisting of trillions of cells arranged into tissues, organs and organ systems is almost miraculous. The process is made possible by a highly coordinated series of genetic events that lead to the construction of the human body.The process is nowhere near foolproof however, and it is estimated that over 75% of human conceptions fail to result in live birth. The term congenital means existing at birth and includes all birth defects regardless of how they are caused.

Only approximately 15% of congenital abnormalities have a recognized genetic basis, whilst approximately 10% have recognized environmental triggers such as the exposure to toxic chemicals and infections. An additional 25% of these abnormalities are thought to have a multifactorial basis. Up to 60% of birth defects are of unknown origin.

Birth defects can be classified into six main groups:

1. Syndromes - groups of abnormalities found together.

2. Malformations - resulting from errors in the initial formation of structures.

3. Disruptions - occurring as a result of destructive processes after an organ or tissue has formed.

4. Deformations - caused by mechanical forces out of the normal range.

5. Dysplasias - failure of cells to organize properly into tissues.

6. Sequence effects - result from the effect of an earlier abnormal event.



The genetic disorders described elsewhere on this site, all fit into the category of congenital abnormality. The other types are explained and analysed in other places.



3.7 Multifactorial & Polygenic Disorders.

3.8 Genetics of Common Diseases.