Introduction

Genetics is the study of inheritance and variation in both individuals and populations and has its origins in man’s curiosity about reproduction and inheritance, including inquisitiveness about both normal and abnormal developments – for example, why do certain diseases ‘run in families’, whilst others do not?

Virtually all pregnant women will want to know if their baby is within the spectrum of that which is regarded as ‘normal’, and advances in genetics can both help to answer this question and have other great practical benefits in the field of human reproduction: for example, the probability that a child will suffer from a particular genetic disease can be calculated, allowing parents to make informed choices in planning their families; it may be possible, in a few cases, to replace or supplement defective genes so that the diseases they cause can be cured (‘gene therapy’); the potential of stem cells is also on the horizon. Hence, it is important that practitioners in this area are aware of both fundamental principles and relevant applications of genetics. There are many ethical questions associated with genetics and it is also important that these are fully addressed.

Genes, chromosomes and dna

A gene is typically defined as a unit of inheritance. Genes are found on chromosomes, which are long, thread-like structures in the nucleus of the cell; each chromosome is made up of one DNA (deoxyribonucleic acid) molecule with many different proteins associated with it. Many genes are arranged throughout its length in a fixed manner, one after the other (Fig. 26.1).

Figure 26.1 Diagrammatic representation of the human X-chromosome showing some of the inherited characteristics carried.

DNA is the major single component of each chromosome and it acts as an information store: all the information necessary for the structure, function, reproduction and development of an organism is stored in a stable and coded form.

The DNA molecule is a long, thin molecule and consists of two strands wound around each other to form a double helix (Fig. 26.2): it is like a ladder in which the two uprights, whilst still remaining joined together by the rungs, are twisted round each other to form two interweaving spirals. In the DNA molecule, the ‘uprights’ are made of alternating sugar residues and phosphate groups (’sugar–phosphate backbones’) and the ‘rungs’ are composed of organic bases, each rung consisting of two bases. There are four different bases: two purine bases – adenine (A) and guanine (G); and two pyrimidine bases – cytosine (C) and thymine (T). Each ‘rung’ is made up of a pair of bases, one purine and one pyrimidine, and the pairing arrangements in these ‘rungs’ are very specific:

Figure 26.2 Diagram of a DNA double helix, including the process of replication.

The information stored in DNA needs to be decoded and used to make cellular and organismal components (a process known as ‘gene expression’); most commonly, the stored information in DNA is used to direct the production of proteins. There are thousands of different proteins in the body (for example, collagen in tendons, haemoglobin in red blood cells), each with its own specific metabolic role to play. Any protein is made up of amino acids joined together in a chain. Each protein has its own specific amino acid sequence determining its function.

The encoding of information on a DNA molecule is achieved by specifying the precise order (sequence) of the bases along the molecule’s length. Information is stored in the form of three-base units (codons). Each codon specifies a particular amino acid in a protein. Hence, the sequence of bases in a DNA molecule directly determines the sequence of amino acids in a protein and thus the function of that protein. (Another definition of a gene is, ‘that part of a DNA molecule which contains the series of codons necessary to encode a particular protein’.)

The information stored in DNA is decoded using two processes: transcription and translation. In transcription (which takes place in the nucleus), part of the DNA molecule is used as a template to produce a molecule of messenger RNA (mRNA) and this mRNA then undergoes translation (on the ribosomes in the cytoplasm of the cell) to produce the protein specified ultimately by the DNA (Fig. 26.3).

Figure 26.3 Processes involved in the expression of a gene.

Ribonucleic acid (RNA) is the other kind of nucleic acid found in the cell. Unlike DNA, it is single-stranded and it also contains the pyrimidine base uracil (U) instead of thymine. There are three different forms of RNA found in the cell, and all of these are involved in the decoding of information from DNA. These forms are: mRNA; rRNA (ribosomal RNA – a major component of the ribosome) and tRNA (transfer RNA – crucial in translation as an ‘adaptor’ molecule between mRNA and protein).

The human genome

The entire genetic complement of a cell or organism is referred to as its genome. Within the nucleus of all nucleated human cells (apart from the gametes – sex cells – ova and spermatozoa), there are 46 chromosomes: thus, the human genome comprises 46 chromosomes. These chromosomes are arranged in 23 (homologous) pairs, and within each of these pairs, one member is derived from the father, the other from the mother. One of these pairs is the sex chromosomes: in the female, this pair consists of two X chromosomes; in the male, it consists of one X and one Y chromosome. The remaining pairs are collectively known as autosomes and the chromosomes in this group are numbered by length, No. 1 being the longest and No. 22 the shortest (see Fig. 26.7).

Each chromosome carries a specific and particular set of genes and thus each individual carries two copies of any one gene, one copy derived from each parent. Any gene has different forms (or alleles). Classically, a gene has two different alleles. Different alleles produce differences in the appearance (or phenotype) of the individual. For example, the colour of the iris in the eye is controlled by a single gene which has two alleles – one allele causes the iris to be pale (blue or grey), the other allele causes it to be dark (brown, green or black).

With respect to any one gene, therefore, an individual can have two copies of one allele, two copies of the other allele (arrangements known as homozygous) or one copy of each (heterozygous). (Thus, for the hypothetical gene A with two alleles – A and a – the combinations AA, aa and Aa are possible.) Clearly, an individual who is homozygous for one allele would have the phenotype associated with that particular allele, but what of heterozygous individuals? In this case, one allele typically ‘overrides’ the other, an effect described as dominance of one allele over the other allele (which is known as the recessive allele).

One outcome from the Human Genome Project is that it is now known that the human genome contains a total of some 20,000 genes (Klug et al 2009).

Cell division

There are two different types of cell division:

Figure 26.4 Mitosis.

Figure 26.5 Meiosis.

Mitosis occurs extensively during prenatal development to increase cell numbers, in the adult in tissues where cells are routinely lost (such as skin) and in some of the repair processes that occur following tissue damage. Meiosis only occurs during the production of gametes in the gonads. The reduction in chromosome number is essential if sexual reproduction is to take place without doubling the amount of genetic material in each generation. Note that some rearrangement of genetic material can occur during meiosis; this is an important part of the genetic variation that is an essential feature of sexual reproduction (Fig. 26.6).

Figure 26.6 Crossover of genetic material in meiosis.

Copying (replication) of DNA occurs during both mitosis and meiosis and it is very important that this occurs accurately, so that errors are not introduced into the DNA, with possible consequent changes in the structure and function of encoded proteins. One very important way in which this is ensured is by the ‘semi-conservative’ mechanism of DNA replication: a parental DNA molecule separates into its two component strands and each of these is then used as a template for the assembly of a new strand. The strict rules of base pairing (A always pairing with T, G with C) ensure that each new double-stranded molecule is an exact copy of the parent molecule (See Fig. 26.2; Russell 2006).

Chromosomal analysis and anomalies

The study of chromosomes is called cytogenetics. Chromosomes can be isolated from accessible adult tissues (such as lymphocytes from the blood) or from amniotic fluid or chorionic villi when information about the embryo/fetus is required. The process of examining the chromosomes is referred to as karyotyping and it can provide very valuable information about the genome of the cell (Fig. 26.7A,B).

Figure 26.7 A. A normal human male karyotype. B. A normal human female karyotype.

If there is an abnormal number of chromosomes present after fertilization (often due to abnormal events during meiosis), or if there is some alteration in structure, the pregnancy may result in miscarriage or an abnormal fetus. Generally, very major abnormalities (for example, involving whole or large pieces of chromosomes) are likely to have very serious effects. It has been shown that the majority of severe chromosomal abnormalities are not compatible with normal development. Embryos with such defects die at an early stage of development – for example, approximately 15% of pregnancies terminate in spontaneous abortion, with about 50% of these being chromosomally abnormal (Lockwood 2000).

Several different types of chromosomal abnormality are known:

The commonest chromosomal birth anomaly is Down syndrome, where there are 47 chromosomes instead of 46 (termed trisomy 21 – three copies of chromosome 21) (Fig. 26.8A). The incidence is 1.5 per 1000 live births and this figure rises with maternal age (Cummings 2003). There are only two other examples of trisomies that are consistent with life – trisomy 13 and trisomy 18 – and even in these cases, the defects are many and severe, and affected individuals typically survive for only a short time after birth (Fig. 26.8B,C).

Figure 26.8 A. Karyotype of a female patient with Down syndrome (trisomy 21). B. Karyotype of a male patient with Edward syndrome (trisomy 18). C. Karyotype of a female patient with Patau syndrome (trisomy 13).

Other common chromosomal anomalies occur among the sex chromosomes; for example, 1.3% of implanted conceptions may carry one X-chromosome without a Y or second X (monosomy X, Turner syndrome – the only viable human monosomy) (Fig. 26.9). Very few of these fetuses survive – about 0.4 per 1000 live-born girls. More common at birth are other anomalies such as XXX (0.65 per 1000 girls), XYY, and XXY or XXXY (1.5 per 1000 boys – Klinefelter syndrome; Cummings 2003) (Fig. 26.10). These sex chromosome anomalies, however, generally produce fewer ill effects than the autosomal anomalies, though these effects can still be serious for the affected individual.

Figure 26.9 Karyotype of a patient with Turner syndrome (monosomy X).

Figure 26.10 Karyotype of a patient with Klinefelter syndrome (XXY).

Modes of inheritance

Genetic characteristics (including genetically determined diseases) can be inherited in one of four principal ways:

Note that the usual patterns of dominance and recessiveness do not apply in the cases of genes carried on the sex chromosomes – see below.

Common types of genetic disease include:

Autosomal characteristics/diseases

Most human genetic diseases are due to mutations in autosomal genes, simply because there is much more genetic material in total in the 22 pairs of autosomes than in the single pair of sex chromosomes.

A homozygous person can only transmit one type of allele to any child they have, whilst a heterozygous person (‘carrier’) can transmit either of their two alleles to a child. Which allele a heterozygous parent transmits in any particular case is a random event, so there is a 1 in 2 (50%) chance of the child inheriting either allele. Thus, the following situations can arise:

• If both parents are homozygous for the same allele (dominant or recessive), then all their children will also inevitably be homozygous for that allele (Fig. 26.11).

• If one parent is homozygous for one allele and the other parent homozygous for the other allele, then all their children will inevitably be heterozygous (Fig. 26.12).

• If both parents are heterozygous, then there is a 1 in 4 (25%) chance of them producing a homozygous recessive child, a 1 in 4 (25%) chance of them producing a homozygous dominant child, and a 2 in 4 (50%) chance of them producing a heterozygous child. Note that in terms of phenotypes, the chance of producing a child of the dominant phenotype is 3 in 4 (75%) and of producing a child of the recessive phenotype is 1 in 4 (25%) (Fig. 26.13).

Figure 26.11 Inheritance pattern – two homozygous parents, each carrying the same allele.

Figure 26.12

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