Early Beginnings

Developments in genetics during the twentieth century have been truly spectacular. In 1900 Mendel’s principles were awaiting rediscovery, chromosomes were barely visible, and the science of molecular genetics did not exist. By contrast, at the time of writing this text in 2010, chromosomes can be rapidly analyzed to an extraordinary level of sophistication by microarray techniques and the sequence of the entire human genome has been published. Some 13,000 human genes with known sequence are listed and nearly 6500 genetic diseases or phenotypes have been described, of which the molecular genetic basis is known in approximately 2650.

Few would deny that genetics is of major importance in almost every medical discipline. Recent discoveries impinge not just on rare genetic diseases and syndromes, but also on many of the common disorders of adult life that may be predisposed by genetic variation, such as cardiovascular disease, psychiatric illness, and cancer, not to mention influences on obesity, athletic performance, musical ability, and longevity. Consequently a fundamental grounding in genetics should be an integral component of any undergraduate medical curriculum.

To put these exciting developments into context, we start with an overview of some of the most notable milestones in the history of medical genetics. The importance of understanding its role in medicine is then illustrated by reviewing the overall impact of genetic factors in causing disease. Finally, new developments of major importance are discussed.

It is not known precisely when Homo sapiens first appeared on this planet, but according to current scientific consensus based on the finding of fossilized human bones in Ethiopia, man was roaming East Africa about 200,000 years ago. It is reasonable to suppose that our early ancestors were as curious as ourselves about matters of inheritance and, just as today, they would have experienced the birth of babies with all manner of physical defects. Engravings in Chaldea in Babylonia (modern-day Iraq) dating back at least 6000 years show pedigrees documenting the transmission of certain characteristics of the horse’s mane. However, any early attempts to unravel the mysteries of genetics would have been severely hampered by a total lack of knowledge and understanding of basic processes such as conception and reproduction.

Early Greek philosophers and physicians such as Aristotle and Hippocrates concluded, with typical masculine modesty, that important human characteristics were determined by semen, using menstrual blood as a culture medium and the uterus as an incubator. Semen was thought to be produced by the whole body; hence bald-headed fathers would beget bald-headed sons. These ideas prevailed until the seventeenth century, when Dutch scientists such as Leeuwenhoek and de Graaf recognized the existence of sperm and ova, thus explaining how the female could also transmit characteristics to her offspring.

The blossoming of the scientific revolution in the 18th and 19th centuries saw a revival of interest in heredity by both scientists and physicians, among whom two particular names stand out. Pierre de Maupertuis, a French naturalist, studied hereditary traits such as extra digits (polydactyly) and lack of pigmentation (albinism), and showed from pedigree studies that these two conditions were inherited in different ways. Joseph Adams (1756–1818), a British doctor, also recognized that different mechanisms of inheritance existed and published A Treatise on the Supposed Hereditary Properties of Diseases, which was intended as a basis for genetic counseling.

Our present understanding of human genetics owes much to the work of the Austrian monk Gregor Mendel (1822–1884; Figure 1.1) who, in 1865, presented the results of his breeding experiments on garden peas to the Natural History Society of Brünn in Bohemia (now Brno in the Czech Republic). Shortly after, Mendel’s observations were published by that association in the Transactions of the Society, where they remained largely unnoticed until 1900, some 16 years after his death, when their importance was first recognized. In essence, Mendel’s work can be considered as the discovery of genes and how they are inherited. The term gene was first coined in 1909 by a Danish botanist, Johannsen, and was derived from the term ‘pangen’ introduced by De Vries. This term was itself a derivative of the word ‘pangenesis,’ coined by Darwin in 1868. In acknowledgement of Mendel’s enormous contribution, the term mendelian is now part of scientific vocabulary, applied both to the different patterns of inheritance shown by single-gene characteristics and to disorders found to be the result of defects in a single gene.

FIGURE 1.1 Gregor Mendel.

(Reproduced with permission from BMJ Books.)

In his breeding experiments, Mendel studied contrasting characters in the garden pea, using for each experiment varieties that differed in only one characteristic. For example, he noted that when strains bred for a feature such as tallness were crossed with plants bred to be short all of the offspring in the first filial or F1 generation were tall. If plants in this F1 generation were interbred, this led to both tall and short plants in a ratio of 3 : 1 (Figure 1.2). Characteristics that were manifest in the F1 hybrids were referred to as dominant, whereas those that reappeared in the F2 generation were described as being recessive. On reanalysis it has been suggested that Mendel’s results were ‘too good to be true’ in that the segregation ratios he derived were suspiciously closer to the value of 3 : 1 than the laws of statistics would predict. One possible explanation is that he may have published only those results that best agreed with his preconceived single-gene hypothesis. Whatever the truth of the matter, events have shown that Mendel’s interpretation of his results was entirely correct.

FIGURE 1.2 An illustration of one of Mendel’s breeding experiments and how he correctly interpreted the results.

Mendel’s proposal was that the plant characteristics being studied were each controlled by a pair of factors, one of which was inherited from each parent. The pure-bred plants, with two identical genes, used in the initial cross would now be referred to as homozygous. The hybrid F1 plants, each of which has one gene for tallness and one for shortness, would be referred to as heterozygous. The genes responsible for these contrasting characteristics are referred to as allelomorphs, or alleles for short.

An alternative method for determining genotypes in offspring involves the construction of what is known as a Punnett square (Figure 1.3). This is used further in Chapter 8 when considering how genes segregate in large populations.

FIGURE 1.3 A Punnett square showing the different ways in which genes can segregate and combine in the second filial cross from Figure 1.2. Construction of a Punnett square provides a simple method for showing the possible gamete combinations in different matings.

On the basis of Mendel’s plant experiments, three main principles were established. These are known as the laws of uniformity, segregation, and independent assortment.

The Law of Uniformity

The law of uniformity refers to the fact that when two homozygotes with different alleles are crossed, all of the offspring in the F1 generation are identical and heterozygous. In other words, the characteristics do not blend, as had been believed previously, and can reappear in later generations.

The Law of Segregation

The law of segregation refers to the observation that each person possesses two genes for a particular characteristic, only one of which can be transmitted at any one time. Rare exceptions to this rule can occur when two allelic genes fail to separate because of chromosome non-disjunction at the first meiotic division (p. 43).

The Law of Independent Assortment

The law of independent assortment refers to the fact that members of different gene pairs segregate to offspring independently of one another. In reality, this is not always true, as genes that are close together on the same chromosome tend to be inherited together, because they are ‘linked’ (p. 136). There are a number of other ways by which the laws of mendelian inheritance are breached but, overall, they remain foundational to our understanding of the science.

The Chromosomal Basis of Inheritance

As interest in mendelian inheritance grew, there was much speculation as to how it actually occurred. At that time it was also known that each cell contains a nucleus within which there are several threadlike structures known as chromosomes, so called because of their affinity for certain stains (chroma = color, soma = body). These chromosomes had been observed since the second half of the nineteenth century after development of cytologic staining techniques. Human mitotic figures were observed from the late 1880s, and it was in 1902 that Walter Sutton, an American medical student, and Theodour Boveri, a German biologist, independently proposed that chromosomes could be the bearers of heredity (Figure 1.4). Subsequently, Thomas Morgan transformed Sutton’s chromosome theory into the theory of the gene, and Alfons Janssens observed the formation of chiasmata between homologous chromosomes at meiosis. During the late 1920s and 1930s, Cyril Darlington helped to clarify chromosome mechanics by the use of tulips collected on expeditions to Persia. It was during the 1920s that the term genome entered the scientific vocabulary, being the fusion of genom (German for ‘gene’) and ome from ‘chromosome’.

FIGURE 1.4 Chromosomes dividing into two daughter cells at different stages of cell division. A, Metaphase; B, anaphase; C, telophase. The behavior of chromosomes in cell division (mitosis) is described at length in Chapter 3.

(Photographs courtesy Dr. K. Ocraft, City Hospital, Nottingham.)

When the connection between mendelian inheritance and chromosomes was first made, it was thought that the normal chromosome number in humans might be 48, although various papers had come up with a range of figures. The number 48 was settled on largely as a result of a paper in 1921 from Theophilus Painter, an American cytologist who had been a student of Boveri. In fact, Painter himself had some preparations clearly showing 46 chromosomes, even though he finally settled on 48. These discrepancies were probably from the poor quality of the material at that time; even into the early 1950s, cytologists were counting 48 chromosomes. It was not until 1956 that the correct number of 46 was established by Tjio and Levan, 3 years after the correct structure of DNA had been proposed. Within a few years, it was shown that some disorders in humans could be caused by loss or gain of a whole chromosome as well as by an abnormality in a single gene. Chromosome disorders are discussed at length in Chapter 18. Some chromosome aberrations, such as translocations, can run in families (p. 44), and are sometimes said to be segregating in a mendelian fashion.

Single-Gene Disorders

In addition to alkaptonuria, Garrod suggested that albinism and cystinuria could also show recessive inheritance. Soon other examples followed, leading to an explosion in knowledge and disease delineation. By 1966 almost 1500 single-gene disorders or traits had been identified, prompting the publication by an American physician, Victor McKusick (Figure 1.5), of a catalog of all known single-gene conditions. By 1998, when the 12th edition of this catalog was published, it contained more than 8500 entries (Figure 1.6). The growth of ‘McKusick’s Catalog’ has been exponential and is now available electronically as Online Mendelian Inheritance in Man (OMIM) (see Appendix). By 2010 OMIM contained a total of almost 20,000 entries.

FIGURE 1.5 Victor McKusick in 1994, whose studies and catalogs have been so important to medical genetics.

FIGURE 1.6 Histogram showing the rapid increase in recognition of conditions and characteristics (traits) showing single-gene inheritance.

(Adapted from McKusick, 1998, and OMIM—see Appendix.)

Chromosome Abnormalities

Improved techniques for studying chromosomes led to the demonstration in 1959 that the presence of an additional number 21 chromosome (trisomy 21) results in Down syndrome. Other similar discoveries followed rapidly—Klinefelter and Turner syndromes—also in 1959. The identification of chromosome abnormalities was further aided by the development of banding techniques in 1970 (p. 33). These enabled reliable identification of individual chromosomes and helped confirm that loss or gain of even a very small segment of a chromosome can have devastating effects on human development (see Chapter 18).

Later it was shown that several rare conditions featuring learning difficulties and abnormal physical features are due to loss of such a tiny amount of chromosome material that no abnormality can be detected using even the most high-powered light microscope. These conditions are referred to as microdeletion syndromes (p. 280) and can be diagnosed using a technique known as FISH (fluorescent in-situ hybridization), which combines conventional chromosome analysis (cytogenetics) with newer DNA diagnostic technology (molecular genetics) (p. 34). Already, however, the latest technique of microarray CGH (comparative genomic hybridization) is revolutionizing clinical genetics through the detection of subtle genomic imbalances (p. 36).

Multifactorial Disorders

Francis Galton, a cousin of Charles Darwin, had a long-standing interest in human characteristics such as stature, physique, and intelligence. Much of his research was based on the study of identical twins, in whom it was realized that differences in these parameters must be largely the result of environmental influences. Galton introduced to genetics the concept of the regression coefficient as a means of estimating the degree of resemblance between various relatives. This concept was later extended to incorporate Mendel’s discovery of genes, to try to explain how parameters such as height and skin color could be determined by the interaction of many genes, each exerting a small additive effect. This is in contrast to single-gene characteristics in which the action of one gene is exerted independently, in a non-additive fashion.

This model of quantitative inheritance is now widely accepted and has been adapted to explain the pattern of inheritance observed for many relatively common conditions (see Chapter 9). These include congenital malformations such as cleft lip and palate, and late-onset conditions such as hypertension, diabetes mellitus, and Alzheimer disease. The prevailing view is that genes at several loci interact to generate a susceptibility to the effects of adverse environmental trigger factors. Recent research has confirmed that many genes are involved in most of these adult-onset disorders, although progress in identifying specific susceptibility loci has been disappointingly slow. It has also emerged that in some conditions, such as type I diabetes mellitus, different genes can exert major or minor effects in determining susceptibility (p. 233). Overall, multifactorial or polygenic conditions are now known to make a major contribution to chronic illness in adult life (see Chapter 15).

Acquired Somatic Genetic Disease

Not all genetic errors are present from conception. Many billions of cell divisions (mitoses) occur in the course of an average human lifetime. During each mitosis, there is an opportunity for both single-gene mutations to occur, because of DNA copy errors, and for numerical chromosome abnormalities to arise as a result of errors in chromosome separation. Accumulating somatic mutations and chromosome abnormalities are now known to play a major role in causing cancer (see Chapter 14), and they probably also explain the rising incidence with age of many other serious illnesses, as well as the aging process itself. It is therefore necessary to appreciate that not all disease with a genetic basis is hereditary.

Before considering the impact of hereditary disease, it is helpful to introduce a few definitions.

Spontaneous Miscarriages

A chromosome abnormality is present in 40% to 50% of all recognized first-trimester pregnancy loss. Approximately 1 in 6 of all pregnancies results in spontaneous miscarriage, thus around 5% to 7% of all recognized conceptions are chromosomally abnormal (p. 273). This value would be much higher if unrecognized pregnancies could also be included, and it is likely that a significant proportion of miscarriages with normal chromosomes do in fact have catastrophic submicroscopic genetic errors.

Newborn Infants

Of all neonates, 2% to 3% have at least one major congenital abnormality, of which at least 50% are caused exclusively or partially by genetic factors (see Chapter 16). The incidences of chromosome abnormalities and single-gene disorders in neonates are approximately 1 in 200 and 1 in 100, respectively.

Childhood

Genetic disorders account for 50% of all childhood blindness, 50% of all childhood deafness, and 50% of all cases of severe learning difficulty. In developed countries, genetic disorders and congenital malformations together also account for 30% of all childhood hospital admissions and 40% to 50% of all childhood deaths.

Adult Life

Approximately 1% of all malignancy is caused by single-gene inheritance, and between 5% and 10% of common cancers such as those of the breast, colon, and ovary have a strong hereditary component. By the age of 25 years, 5% of the population will have a disorder in which genetic factors play an important role. Taking into account the genetic contribution to cancer and cardiovascular diseases, such as coronary artery occlusion and hypertension, it has been estimated that more than 50% of the older adult population in developed countries will have a genetically determined medical problem.

The Human Genome Project

With DNA technology rapidly progressing, a group of visionary scientists in the United States persuaded Congress in 1988 to fund a coordinated international program to sequence the entire human genome. The program would run from 1990 to 2005 and US$3 billion were initially allocated to the project. Some 5% of the budget was allocated to study the ethical and social implications of the new knowledge in recognition of the enormous potential to influence public health policies, screening programs, and personal choice. The project was likened to the Apollo moon mission in terms of its complexity, although in practical terms the long-term benefits are likely to be much more tangible. The draft DNA sequence of 3 billion base pairs was completed successfully in 2000 and the complete sequence was published ahead of schedule in October 2004. Before the closing stages of the project, it was thought that there might be approximately 100,000 coding genes that provide the blueprint for human life. It has come as a surprise to many that the number is much lower, with current estimates at slightly more than 25,000. However, many genes have the capacity to perform multiple functions, which in some cases is challenging traditional concepts of disease classification. The immediate benefits of the sequence data are being realized in research that is leading to better diagnosis and counseling for families with a genetic disease. A number of large, long-term, population-based studies are under way in the wake of the successful Human Genome Project, including, for example, UK Biobank, which aims to recruit 500,000 individuals ages 40 to 69 to study the progression of common disease, lifestyle, and genetic susceptibility.

The technique of microarray CGH is one of the most significant developments in the investigation of genetically determined disease since the discovery of chromosomes, but whole-genome sequencing is likely to be the future of genetic testing once rapid and affordable technologies are developed—but with these developments will come additional ethical challenges centered around their use and application. In the longer term an improved understanding of how genes are expressed will hopefully lead to the development of new strategies for the prevention and treatment of both single-gene and polygenic disorders.

Gene Therapy

Most genetic disease is resistant to conventional treatment so that the prospect of successfully modifying the genetic code in a patient’s cells is extremely attractive. Despite major investment and extensive research, success in humans has so far been limited to a few very rare immunologic disorders. For more common conditions, such as cystic fibrosis, major problems have been encountered, such as targeting the correct cell populations, overcoming the body’s natural defense barriers, and identifying suitably non-immunogenic vectors. However, the availability of mouse models for genetic disorders, such as cystic fibrosis (p. 301), Huntington disease (p. 293), and Duchenne muscular dystrophy (p. 307), has greatly enhanced research opportunities, particularly in unraveling the cell biology of these conditions. In recent years there has been increasing optimism for novel drug therapies and stem cell treatment (p. 356), besides the prospects for gene therapy itself (p. 350).

The Internet

The availability of information in genetics has been enhanced greatly by the development of excellent online databases, and a selection of the well established is listed in the Appendix—GenBank, Ensembl, DDBJ. By 2010 there were more than a thousand molecular biology databases, so navigating this ever-growing maze can be daunting—and not just for the novice. This has developed into the exciting growth area of Bioinformatics, the science where biology, computer science, and information technology merge into a single discipline that encompasses gene maps, DNA sequences, comparative and functional genomics, and a lot more. Familiarity with interlinking databases is essential for the molecular geneticist, but is increasingly relevant for the keen clinician with an interest in genetics, who will find OMIM a good place to start for an account of all mendelian disorders, together with pertinent clinical details and extensive references. Although it is unlikely that more traditional sources of information, such as this textbook, will become completely obsolete, it is clear that only electronic technology can hope to match the explosive pace of developments in all areas of genetic research.