Historically, humans unknowingly but successfully applied genetics to the breeding and domestication of animals and plants. However, the first systematic study of genetic interactions is associated with the breeding experiments of Gregor Mendel, an Austrian monk, in the 1860s. Mendel established inheritance patterns of certain traits in pea plants and demonstrated that application of statistics to inheritance could be very useful. Subsequently, more complex forms of inheritance have been identified.

Mendel correctly identified the concept of genes long before the structures of DNA and chromosomes were understood. He proposed that ‘particles of inheritance’ were transmitted from one generation to the next and defined a concept that he described as an allele. The term ‘allele’ is now used to describe a specific variant or alternative form of a particular gene occupying a given locus (position) on a chromosome.

The term ‘eugenics’ was coined by Francis Galton (a cousin of Charles Darwin) who advocated that application of Darwinian theories and selective breeding could improve the quality of entire populations, particularly with respect to talent and intelligence. In the late nineteenth century, eugenics societies formed in various parts of the world sought to promote such practices as marriage restriction, sterilization and custodial commitment of those thought to have unwanted characteristics and positively encouraging reproduction in those individuals perceived as the best and brightest. The popularity of the eugenics movement was already waning when infamous eugenics programmes of Nazi Germany were revealed at the end of World War II.

Darwin’s ‘survival of the fittest’ theory promoted the concept of natural selection and how environmental conditions determine survival and reproduction of organisms with particular traits. If environmental conditions do not vary much, these traits continue to be adaptive and become more common within the population.

Neo-Darwinism (or ‘modern evolutionary synthesis’) extends the scope of Darwin’s ideas of natural selection by including modern genetic knowledge about DNA and concepts such as speciation, kin selection and altruism. It advocates that survival of a species is not necessarily by the fittest but by those that are most likely to reproduce successfully. This is reflected in the work of William Hamilton, popularized by Richard Dawkins, who asserted that the gene, rather than the organism or species, is the true unit of reproduction and the primary driver and beneficiary of evolution. The genes are provocatively described as ‘selfish’ because in order to replicate and be successful they use organisms that contain them solely as vehicles to ensure survival (1989). Obviously, reproduction is vital to ensure that the genes survive.

This controversial view portrays organisms solely as mechanical methods of survival to pass genes on to as many offspring as possible. However, there are a number of arguments against this view. Organisms are not perfectly adapted; for instance, humans seem to have some non-advantageous genes such as those coding for the vermiform appendix. It could be argued that these genes have not been obliterated because other linked genes are advantageous and effectively protect them. The other important point is that species not only interact with their environment but also positively alter their environment to optimize survival. The selfish gene hypothesis also accounts for how genes that seem to be harmful can evolve by natural selection (Badcock and Crespi, 2008).

The environment interacts with genes (the nature/nurture debate) and has a tremendous influence on how they are expressed, affecting susceptibility and resistance to disease. Genes may act in competition with each other, which may explain certain pathophysiological conditions and their aetiology. Some organisms may use their genes to alter the phenotype of another animal to increase their chances of survival. For example, infection with the trematode parasite causes its snail host’s shell to become thicker (Dawkins, 1999). Co-evolution explains how the change of one organism can be linked to the change in a related organism. Each organism exerts selective pressure on the adaptation and evolution of the other. Examples include how angiosperm (flowering trees) and primates evolved, the existence of mitochondria in eukaryotic cells (see Chapter 1) and co-evolution of parasites with the acquired immunity of their hosts. Epigenetics and genetic imprinting (see p. 164) explain how gene expression can be affected by the environment.

Within the modern medical world there now exist ethical dilemmas surrounding the screening for, detection of and termination of abnormal fetuses. Current research in genetics is not solely medical (Box 7.1) as it can be applied to population studies, such as tracing the origins of human migration movements, and to genealogy, such as tracing the real families of children of the Argentinean ‘Disappeared’ (Jones, 1994) and the route the early Polynesians took to reach New Zealand (Sykes, 2001).

Genes are the units of inheritance. Each gene is a length of DNA on a chromosome that contains the coded information to direct the synthesis of a specific protein chain. The differences between organisms are related to different proteins being synthesized that have different structures and functions. Effectively the genes act as a blueprint, or instruction manual, for the total development of the organism and how it will function and change during its lifetime (Box 7.2). Chromosomes are packages of DNA in the nucleus, on which the genes are linearly arranged. Chromosomes have two arms: a shorter p arm and a longer q arm, with a centromere between them. Chromosomes are important in cell replication and the passing of the genetic message from one generation to the next. Usually the DNA, about 180 cm per nucleus, exists as an unstructured mass of threads in the nucleus. However, when the cell is undergoing division the DNA becomes organized and compacted into chromosomes, which can be visualized by microscopy (see Chapter 1). This chromosomal organization allows biologists to identify genes and localize them to a particular chromosome to follow their pattern of inheritance. Each cell has the same genetic information in its nucleus as the original zygote (fertilized ovum) and all of the cells derived from it. Different cells behave in different ways because they express different subsets of information from the DNA.

Watson, Crick, Franklin and Wilkins elucidated the biochemical structure of DNA in 1953. Their description of the helical structure revealed how the molecule was able to replicate itself and thus explained the cellular mechanism of reproduction. DNA is composed of two strands of sugar phosphate molecules that are joined together to form long chains (Fig. 7.1). The strands of DNA are made up of repeating units called nucleotides. The DNA nucleotide has three components: a deoxyribose sugar, a phosphate group and a base. There are four types of bases: thymine and cytosine, which have single-ring structures, and adenine and guanine, which have double-ring structures. DNA exists as a double-stranded molecule wound into a helix. The strands are kept together by hydrogen bonding between the bases. The bases are of different sizes and have a different potential number of hydrogen bonds so they always pair in the same ways. Adenine (A) and thymine (T) pair with two hydrogen bonds: cytosine (C) and guanine (G) pair with three. This means that the sequence of the bases is complementary; the sequence of bases on one strand can be deduced from the sequence on the other strand.

The arrangement of base pairs of the two strands is like the rungs of a ladder or teeth of a zip. When DNA replicates, the strands unwind and the hydrogen bonds holding the base pairs together separate (unzip). Each strand acts as a template for the synthesis of another new strand of complementary DNA bases to form from nucleotides that enter the nucleus through the nuclear pores (Fig. 7.2). So two new DNA double helices are formed, each with one strand of ‘old’ DNA and a newly synthesized strand. Thus the replication is described as semiconservative. Replication occurs as part of mitosis or cell division. Replication of DNA means that the chromosomes have double their nuclear material in preparation for dividing into two separate cells. Therefore, the chromosome is formed of two identical chromatids.

The structure of DNA allows both ease of replication and duplication of the genetic message prior to cell division, and also a method of directing protein synthesis and ultimate cell function. The DNA message is interpreted as a specific protein product. The genes in the DNA strand contain exons, regions that will be translated to proteins, interspersed with introns, regions which are not transcribed into proteins. Proteins are synthesized at the ribosomes of the cell, whereas the encoded information, in the form of DNA, remains within the nucleus. The information is carried from DNA to the site of protein synthesis by the second type of nucleic acid, RNA. Whereas DNA is a double strand, RNA exists as a single strand of sugar phosphate units, and has ribose sugar units (instead of deoxyribose) and similar complementary base molecules to those found in DNA, except that uracil instead of thymine pairs with adenine. RNA also exists as different forms with different functions. Initially a gene is transcribed as nuclear (or ‘premessenger’) RNA (nRNA). nRNA is modified to form mRNA. It is messenger RNA (mRNA) that carries the message from the nucleus to the ribosome, as a complementary strand of mRNA is formed using a stretch of unwound DNA as a template. mRNA is shorter than nRNA because nRNA contains the introns that are spliced out (removed) as the nRNA moves from the nucleus where it is formed to the cytoplasm where it is translated to form an amino acid chain that will form the protein. Splicing allows genes to form different proteins because the exons can be spliced in different patterns with each pattern generating a specific protein. The process of splicing is carried out by small nuclear RNAs (smRNA) called spliceosomes. The process where one gene can code for multiple proteins (‘splice variants’) means that there are about three times as many possible proteins as there are genes which is why the human genome project identified far fewer genes than was originally anticipated.

The DNA contains genes but only specific genes will be expressed in any particular cell at any particular time. Gene expression describes the means by which information from a gene drives the synthesis of a functional gene product which is usually a protein. Molecular biology techniques have allowed in-depth investigation of the function of single genes. There are several ways in which gene expression can be regulated. These include controlling which particular genes are transcribed, selective processing of the transcribed DNA to control which RNA become cytoplasmic mRNA, selective translation of mRNA and post-translational modification of the proteins produced from mRNA (Sadler, 2010).

The copying of DNA has to be accurate. If mistakes are introduced into a region of DNA that is expressed as a protein (i.e. into an exon), the altered sequence of amino acids can change the structure of the protein. This permanent and transmissible change in base sequence of DNA is described as a mutation. Mutations can lead to death of a cell or cause cancer. They are considered to be the driving force of evolution; favourable mutations tend to accumulate and less favourable ones tend to be removed by natural selection. It is estimated that mutations occur every half an hour in each person but a mutation in a functional gene only occurs once in five generations. A mutation can be described as ‘descent with modification’. DNA has regions of ‘hotspots’ where the mutation rate can be up to 100 times more frequent than normal. New gene mutations are associated with increasing paternal age (above 35 years); it is suggested that new gene mutations are exclusively inherited from the father and occur during spermatogenesis. All dominant mutations seem to arise in the male germline and may be caused by fragmentation induced by free radical damage (Aitken and Graves 2002). In mitosis, there are accumulated errors in copying the genetic message. Each chromosome has a specialized length of DNA at its end, which gets shorter with each successive division. About four bases seem to be lost with each successive cell division.

A base pair may be spontaneously replaced by a different base pair (a ‘point mutation’) thus altering the codon and ultimately the amino acid sequence. Age, environmental pressure, radiation and chemicals increase mutation rate. One notable example is haemophilia, the sex-linked genetic condition that afflicted male members of the European Royal Family for several generations. The spontaneous mutation for changed haemoglobin structure may have occurred in one of the gametes forming the zygote that became Queen Victoria. This type of mutation is referred to as a substitution. Mutations may arise as an insertion or deletion of a nucleotide into or from the DNA strand; these mutations could cause a shift in the ‘reading frame’ of the codons or alter splicing of mRNA thus altering the gene product. Mutations may also occur by the complete insertion of new codons or by the deletion of a complete codon, thus altering protein structure by introducing or deleting amino acids in the protein. This can be complicated if codons are duplicated and repeated one after the other, for example in fragile X syndrome.

Many mutations occur in the non-coding areas of DNA, so protein structure and function are not affected by the change; these mutations are described as ‘silent’ as they have no effect. If the mutation results in a different codon that codes for the same amino acid as the original, there will also be no effect. However, a different base, or a missing base, will cause a change in the final sequence of amino acids of the protein, which may have serious effects on protein structure and function. An example is sickle cell anaemia (Box 7.3 and Fig. 7.10).

The basic characteristics of meiosis – two cell divisions without intervening DNA replication, halving the chromosome complement of the resulting cells – are conserved in evolution. Each species has a characteristic number of chromosomes; humans have 46 chromosomes, arranged as 23 pairs. One chromosome of each pair is maternally derived (from the ovum); the other is paternally derived (from the sperm). (The members of each pair are called homologous; see below.) Human gametes contain only 23 chromosomes, that is half the normal number of chromosomes in other human cells. This reduction from the diploid number of chromosomes (46) to the haploid number (23) is accomplished by meiosis. Meiosis is the process whereby a diploid parent cell produces four haploid daughter cells, resulting in gametes, or sex cells, that are not identical to their parent cells. These gametes are haploid and during meiosis the genetic instructions are randomly assorted, thus generating unique combinations. Meiosis is also described as ‘reduction division’ because the number of chromosomes is reduced from 46 (i.e. 23 pairs) to 23. It occurs in two successive divisions (meiosis I and II), each of which can be divided into steps (Fig. 7.11). Meiosis II is very similar to mitosis.

In anaphase I, there is random segregation of each member of the chromosome pairs with a maternal and a paternal chromosome randomly going to a particular end of the cell. This would theoretically generate 2²³ (i.e. 8,388,608) different possibilities of gamete combination. However, the crossing over of genetic material between the chromosomes adds far more variation. Meiosis allows the genomes of the parents to be combined to form an individual whose genome is related to their parents and siblings but is unique.

Mammalian oogenesis begins meiotic development during fetal development but arrests in meiosis I and does not complete meiosis I until ovulation; the second division is only completed if the egg is fertilized. Oogenesis, therefore, requires several stop and start signals and, in humans, may last for several decades. The longer an oocyte is immobilized at prophase I, the greater is the chance of failure of separation of the homologous chromosomes (non-disjunction). Often genetic abnormalities arise as extra genetic material is incorporated into the genome. If an extra chromosome is inserted, the condition is referred to as trisomic (Table 7.1). Most combinations of trisomy are not seen, but there is no reason to believe that certain chromosomes are more susceptible to failed disjunction. Those seen are probably those that are compatible with fetal survival, although they may cause congenital abnormalities or affect neonatal survival. Sometimes extra chromosomal material may become attached to a chromosome, making it abnormally long. Rarely, a condition called triploidy occurs where the chromosomes of the zygote are in triplicate rather than the normal duplicate complement. This condition is not compatible with embryo survival but is sometimes found in products of a failed conception (early miscarriage) and is associated with a high incidence of hydatidiform mole (see Chapter 6). Imperfect disjunction also causes conditions where the genome is lacking part or a whole chromosome. For example, there is only one X chromosome present in Turner’s syndrome (see Chapter 5) and Wolf–Hirschhorn syndrome is caused by loss of chromosomal tissue from chromosomes 4 and 5.

Each gene has a specific location on a specific chromosome, which is referred to as a locus (plural: loci). Each chromosome may have 1000–2000 different genes, each with its own location and function. The visualization of the chromosomes from a cell is described as a karyotype (Box 7.4) (Case study 7.1). Of the 23 pairs of chromosomes that constitute the human genome, 22 pairs of chromosomes can be seen in both sexes; these are referred to as the autosomes and contain the autosomal genes. The 23rd pair of chromosomes comprises the sex chromosomes; these are homologous within the female (i.e. XX) but in the male the XY arrangement consists of a pair of non-homologous chromosomes.