If one parent (Parent 1 in the example in Fig. 28.1a) is heterozygous for an abnormal gene (A) and the other parent is homozygous for the normal gene (N), the possible combinations in the offspring are shown in the square in this figure.

On a statistical basis, half the offspring will be heterozygous (AN) for gene A, like Parent 1. None will be homozygous for the abnormal gene (AA).

If both parents are heterozygous (AN; Fig. 28.1b), a quarter of the offspring will be homozygous (AA) and half will be heterozygous (AN).

If one parent is homozygous (AA) and the other normal (NN), all the offspring will be heterozygous.

The metabolic consequences of an abnormal gene depend on the effectiveness of that gene compared with the normal one.

Some abnormal genes are carried only on the sex (almost always the X) chromosomes.

Occasionally there may be several alleles governing the same characteristic. In such cases, different pair combinations may produce different disease patterns, for example some of the haemoglobinopathies, or the variant may be detectable only by biochemical testing, such as, for example, some of the plasma protein variants.

In rare cases, spontaneous new mutations may occur and may produce dominant disorders in unaffected families. The terms ‘dominant’ and ‘recessive’ are relative. A dominant gene may fail to manifest itself (incomplete penetrance) and may therefore appear to skip a generation. A gene may vary in its degree of expression, and therefore in the degree of abnormality that it produces. A recessive gene, which produces disease only in homozygotes (AA), may be detectable by laboratory tests in clinically unaffected heterozygotes.

Chromosomes consist of both protein and DNA; chromosomal DNA contains an average of 100-200 million bases. DNA is a nucleoside polymer arranged in two strands as a double helix. There are four bases in DNA, namely adenine (A), cytosine (C), guanine (G) and thymine (T). These nucleotides consist of ester-linked phosphate residues at the 5′-hydroxyl residue of a deoxyribose molecule that itself is linked to a purine or pyrimidine base by its 1′-hydroxyl group. Each of the DNA strands has polarity, namely 5′ and 3′ ends with the two opposite-running strands in opposite directions (anti-parallel).

The two DNA strands are complementary, so that C on one strand bonds by hydrogen bonds with G on another strand and A pairs with T. These bases are always numbered from the 5′ to the 3′, with letters indicating the nucleotide bases. Genetic material can copy itself (replication) during the S phase of the cell cycle. DNA polymerase needs a pre-existing DNA template and moves along the two strands and adds the appropriate nucleotides, following the base pairing rules, to the growing chain. Two new double strands of DNA are formed, identical to the original double strand and the strands are anti-parallel. DNA polymerase always moves from 3′ to 5′ along the template strand, i.e. the reverse of the newly forming strand. Variable number tandem repeats (VNTR) are short and repetitive repeats distributed throughout the genome and that are grouped near telomeres.

Transcription is the process whereby the polypeptide or protein-coding instructions from the genes are transcribed indirectly through mRNA; the latter moves from the nucleus to the cellular cytoplasm, serving as the template for protein synthesis. Translation is the process whereby the ribosomal system then translates the codons into an amino acid chain that will constitute the polypeptide or protein molecule for which it codes. A gene is a unique sequence of nucleotides that codes for
a particular protein or peptide and can be represented by one or more alleles. The genetic code is thus a series of codons that instruct which amino acids are needed to synthesize specific polypeptides or proteins.

Deoxyribonucleic acid can easily be prepared from very small amounts of biological samples, often blood. This essentially involves three steps: leucocyte lysis, chloroform/phenol extraction to remove contamination by proteins, followed by proteinase and RNAase treatment to remove remaining protein and RNA contamination.

Samples of DNA after digestion are separated by electrophoresis due to its strong negative charge at neutral pH and, by running the DNA through agarose gels, it can be separated into discrete DNA molecules of 100-10 000 base pairs. Smaller DNA pieces can be separated by polyacrylamide gels, which are a tighter molecular sieve than agarose. DNA probes can be a piece of DNA of variable length that can be inserted into the DNA of a plasmid. These circular pieces of double-stranded DNA can be artificially introduced into bacteria and incorporated into their DNA by a process called transformation. By adding divalent cations the bacteria are made permeable to DNA and a selectable marker such as antibiotic resistance is then inserted, and only those bacteria containing this will grow in media containing the antibiotic. The probes can be labelled to locate them in DNA experiments, using either radiolabelled phosphorus-32 or, for example, non-radiolabelled horseradish peroxidase-enhanced chemiluminescence or digoxigenin.