Information on human genetics


Individuals inherit a unique pattern of DNA sequences. Much of the variation in DNA occurs in non-coding regions and is of no direct relevance to development and function. Other variants occur within genes leading to a different protein product. If a particular variation results in sufficient impairment of protein function to bring about a deleterious effect, a genetic disease may result. We can only recognise diseases in which the genetic abnormality has been sufficiently mild' to permit early development; other genetic abnormalities may impair such vital processes that embryogenesis cannot proceed. The genotype of individuals refers to their genetic make-up, i.e. the sequence of their genes. The phenotype describes any aspect of structure, development or pathophysiology in an individual. Diseases may result from purely genetic, purely environmental factors or, more frequently , a combination of the two .


These terms cause much confusion in the medical literature, as they can be defined in more than one way . Each refers to the different forms of a gene (alleles) which can be present in a population. The term mutation has been used to describe any permanent variation between template and daughter sequence in DNA polymerisation. The strict definition of a "polymorphism 1s that at least 1% of the population must have a different allele from the usual form. However, in the study of numan disease, the same terms are used to distinguish two types of DNA variation, and have slightly different connotations. By convention, a mutation is recognised as a disease-causing DNA variation, whereas sequence changes which do not result in a disease state are referred to as polymorphisms, even if they occur in less than 1% of individuals.


A disease-causing mutation is a variation in DNA sequence which alters the protein product in such a way as to contribute to a disease process. In the simplest sense, these mutations may be divided into two subgroups (see Fig. 1.31). and may result from the deletion of all or part of a gene, or a specific alteration of the genetic code. As a result, the encoded protein may be unable to function sufficiently due to lack of intrinsic activity or inefficient cellular processing and transport mechanisms. Sometimes, the mutated protein may have a novel effect which means the normal copy is unable to function normally, the so-called dominant-negative effect. Alternatively, a mutation may result in less RNA being available for translation into protein, either due to promoter region mutations reducing gene transcription, or to mutations in introns altering RNA stability.


Small DNA sequence changes may be functionally silent if they:

  • are located in non-coding DNA (which constitutes the majority of the genome)
  • do not alter the amino acid inserted in a given protein (for example, there are six serine codon
  • s)
  • result in a novel amino acid which is able to perform the same function as the original, even if the two are distinguishable (e.g. polymorphisms at the ABO blood group and major histocompatibility loci).

Site of mutated gene and inheritance pattern

Dominant and recessive traits

The manner in which a mutated gene behaves is determined in the first instance by its chromosomal site. As alluded to in the section on cancer, the critical question is whether there is a second 'normal' copy of the gene which can compensate for the abnormal. This varies between genes according to their function and position; for example, there is no second copy of X or Y chromosome genes in men. The essential features of inheritance, the patterns of inheritance and the terminology used in describing family pedigrees. It shows the processes involving a single gene in a monogenic trait. However, the same principles of genotype inheritance, if not phenotypic manifestations, apply to genes involved in polygenic and multifactorial traits where the effects of more than one gene are required to generate disease.

It should be remembered that there is always the first mutation in a particular family. If this is in a somatic cell in an individual, it will be passed on to a proportion of the tissues (generating a mosaic), but not to the offspring. If, however, the mutation arises in a germ-line cell which will generate sperm or oocytes, then the offspring of that individual may be affected even though no grandparent had the mutated gene.

Variations in the effects of mutations between different individuals and throughout successive generations Penetrance

Individuals who inherit a particular mutation rarely demonstrate identical consequences, since they may not have the other genetic or environmental predisposition to unmask the full effect of the mutation in question. The mutation is said to be fully penetrant if all individuals who inherit the abnormality display a result (an altered phenotype). If additional environmental factors are needed, the gene may display late-onset penetrance, or may even be nonpenetrant, if the individual is never exposed to sufficient additional factors .

Epigenetics and imprinting

These are processes which alter the effect of a gene according to whether it lies on one or other of a chromosomal pair, and may result in a mutated gene resulting in different effects according to whether it was inherited from the mother or the father .

One example is the mechanism which inactivates one of the two X chromosomes in female cells to prevent the cell from having twice as much protein product of an X-linked gene as male cells. The X-inactivation centre recognises if more than one X chromosome is present, and after 15 days of embryogenesis, in each cell of the embryo, one of the X chromosomes is randomly selected to be condensed and inactivated. During subsequent cell divisions, X-chromosomes replicated from the inactivated chromosome are also inactivated. Both X chromosomes are active only in the female germ cells.

On other chromosomes, shorter stretches of DNA may be inactivated according to whether the chromosomal region was inherited from the individual's mother or father. The section of DNA is usually inactivated by the addition of a methyl group to cytosine on both DNA strands of the chromosome. Following DNA replication, the newly synthesised daughter strand is also methylated, hence all DNA derived from the methylated template will be 'imprinted'. Imprinted DNA leads to a modification of the chromatin scaffold, restricting the transcriptional activity of the imprinted gene. If an imprinted gene carries a mutation, then the manifestation of any resultant disease will vary according to which parent transmitted the mutation. For example, a critical region on chromosome 15 contains several genes in which only the paternal allele is transcriptionally active. Mutations in one or more of these genes are likely to contribute to the Prader-Willi syndrome, which results from a lack of a normal paternal contribution to the chromosome 15 region.

Trinucleotide repeats and genetic anticipation

An unusual genetic phenomenon was observed in a number of inherited neurological diseases, and was described as genetic anticipation, since the disease demonstrated increasing severity (as shown by earlier age of onset, or disease severity) during transmission through the generations. The mutation in these cases was shown to reside in a stretch of repetitive DNA sequence, altered not in sequence but in the number of repeat units present. Repeat sequences occur throughout the human genome and are key tools in gene mapping . Variation in their length may cause disease if they alter the sequence of the mature peptide—for example, by expansion of the [CAG] codon for glutamine, or if repeats (triplet and non-triplet) expand in non-coding regions, disturbing mRNA stability or DNA replication. The basis of the anticipation phenomenon is that the replication machinery tends to increase the number of repeats in offspring, with alleles inherited from a father expanding further.


The basis of population genetics follows from simple statistical principles. If only two forms of an autosomal gene are possible, say the red and yellow circles , then all individuals will have either identical alleles and be homozygous (YY or RR), or two different alleles in a heterozygote (Y and R). Heterozygotes will be twice as common as homozygotes, since if a yellow- and red-sided coin were to be tossed twice, there would be twice as many chances of getting a heterozygote (Y then R, or R then Y) as a homozygote. This would be true, no matter how heavily the coin were 'weighted'. In population genetics terms, the coin is weighted by how common the particular allele is in the population. This is best understood by considering the Hardy-Weinberg equilibrium, in this case describing the situation if the yellow normal allele is found on 99% of chromosomes (gene frequency p = 0.99), and the red mutant allele on 1% (gene frequency q = 0.01).

A disease gene is virtually always less common in the population than the normal gene, so heterozygotes are more common than homozygotes. For example, as approximately 1 in 25 of the Caucasian population carries a mutant gene for cystic fibrosis, the gene frequency q is 0.04, hetero

Distribution of ABO blood groups as an illustration of a three-allele system
Phenotype Genotype Frequency Combined frequency
Group O OO 0.72 0.72 =0.49
Group A
  • AA
  • AO
  • OA
  • 0.22
  • 0.2 x 0.7
  • 0.7 x 0.2
0.22 + 2(0.2 x 0.7) = 0.32
Group B
  • BB
  • BO
  • OB
  • 0.12
  • 0.1 x 0.7
  • 0.7 x 0.1
0.12 + 2(0.1 x 0.7) = 0.15
Group AB
  • AB
  • BA
  • 0.1 x 0.2
  • 0.2 x 0.1
2(0.1 x 0.2) = 0.04
All groups =1

zygote carriers will occur at a frequency of 8% (from 2 x 0.04 x [1 -0.04]), and homozygotes who have the disease, at a frequency of 0.16% (0.04)2.

If there are three alleles, a three-sided dice tossed twice analogy is more appropriate, but the same principles apply: 1 = p2 + q2 +r2 + 2(pq) + 2(pr) + 2(qr). An example of such a system is the ABO group, which is more complicated since blood group O is recessive to A and B, although it is the most common gene. If the gene frequencies are 0.7 (p, group O), 0.2 (q, group A) and 0.1 (r, group B), the incidences of particular blood groups in the population .

Selection pressures and heterozygote advantage

Since polymorphisms do not result in major functional consequences, there are virtually no controls on the spread of a particular allele throughout the population. In contrast, the disease produced by a mutant gene may prevent the affected individual from reproducing and transmitting the gene. Thus dominant disease genes can only persist in the population if the disease phenotype is mild during the reproductive period of an individual, or by virtue of new mutations. In contrast, recessive genes can persist in the population, no matter how severe the phenotype in homozygotes, by virtue of the pool of normal carriers. Furthermore, there may be instances in which it is advantageous to have one copy of a recessive disease gene, so-called heterozygous advantage. The best-known example of this is the protection sickle-cell heterozygotes have against malaria, accounting for the high incidence of the mutated genes in malaria-endemic, but not malaria-free areas.