Anatomy & Physiology for Midwives 3: Third Edition

Chapter 7. Overview of human genetics and genetic disorders

Learning objectives

• To describe the packaging of genes in the chromosome and how they are expressed.

• To describe the general characteristics of dominant, recessive and X-linked genetic traits.

• To interpret a pedigree chart and make simple genetic predictions.

• To discuss the principles of genetic screening.

• To relate current genetic research to midwifery practice.

• To discuss evolutionary influences upon human reproduction.

Introduction

Genetics is the science of genes, heredity and the variation of organisms. Although genetics is a component of virtually all areas of biology, it tends to be reductionist in nature. Life is the result of the genetic codes that all living things carry in almost all of their cells. The mechanisms that govern the manner in which genetic information is duplicated, altered, transferred and expressed provide a wealth of information about the biochemical processes of all living organisms. The advent of molecular biology has meant that many problems considered formidable until very recently may now be understood and resolved. Molecular biology has added new dimensions to understanding the origin of the human species, to creating new drugs, and to sequencing of entire genomes of a variety of species, including disease-causing microorganisms, plants, insects and animals including humans.

Chapter case study

As part of the routine antenatal care, which Zara is receiving from her midwife at her local maternity unit, Zara is offered a 20-week anomaly ultrasound as part of the screening policy of the local maternity services. This scan examines the physical structures of the baby and enables a skilled ultrasonographer to identify major structural abnormalities of the internal organs and other signs of structural problems such as polyhydramnios, oligohydramnios, placental abnormalities and so on. Often the presence of a number of abnormalities (frequently referred to as a syndrome) could indicate the presence of many possible genetic disorders.

Zara is quite upset because one of her friends has just undergone amniocentesis as her ultrasound scan had revealed cardiac, brain and limb abnormalities. Zara's scan appears to be normal and the baby appears to be growing well but Zara is still concerned that all may not be well and wishes to discuss what further tests are available that would reassure her all is well.

• How would you, as Zara's midwife, reassure and counsel her and James through this difficult period?

Within living organisms, the genetic information is usually carried in chromosomes where organization of the DNA provides a gene or ‘blueprint’ (genotype) directing protein synthesis and thus the expression of the genes into physical characteristics (phenotype). Characteristics are passed from one generation to the next in the form of genes. In sexually reproducing species, the genes are shuffled and repackaged into the gametes. Variations between genes affect survival so the individuals with the best-adapted characteristics to cope with environmental conditions have an advantage. This is described as natural selection. Although DNA codes for the genes, not all the genes are expressed in any one cell or any one time. The phenotype is determined by which genes are expressed (turned on) and which are not. Epigenetics is the term used to describe the modifications to DNA which controls which genes are expressed. As well as the functions of the genes being identified as part of the determination of the DNA sequence (human genome), thousands of small non-coding RNAs have roles in mRNA stability, protein translation, protein modification and changes in the germline. All eukaryotic organisms (animals) have both nuclear DNA and mitochondrial DNA (mtDNA) (outside the nucleus) which is probably due to a serendipitous event in evolution whereby ancestral bacterial forebears of mitochondria were incorporated into eukaryotic cells (see Chapter 1).

The study of genetics focuses on inherited characteristics, particularly those that are considered abnormal, how these arise and their effects on the individual. Genetics is a predictive science and its rules are based upon the application of mathematical statistics and probability. Evolutionary effects on genetics may determine the penetration of recessive genetic disorders such as cystic fibrosis into gene pools. The impact of genetics upon antenatal screening to predict the probability of fetal abnormalities is of particular relevance for midwives.

A brief history of genetics

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).

Box 7.1

Areas of genetic research

• Screening for fetal abnormality

• Genetic counselling for parents with a family history of genetic disorders

• Identification of fetal sex in the early (indifferent) embryological phase

• Cloning of whole organisms

• Gene manipulation not only to eradicate disease but also to improve existing disease states

• Treatment by gene manipulation in animals to produce human proteins, hormones and so on

• Genetic modification

• Identification of individuals by genetic ‘fingerprinting’

Genes and chromosomes

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.

Box 7.2

Genetics as a language

Genetics can be considered as a language based on the DNA molecule. Linguistic development and evolution have a number of similarities. Studies looking at the origins of a particular word and how it has evolved to be slightly different in different languages are similar to the changes in genes (Jones, 1994). Genetic mutations are analogous to new words being introduced into the language (such as ‘email’).

• Language = genetics

• Vocabulary = genes

• Grammar = rules about the arrangement of information

• Literature = the instructions to make a human

• Alphabet = four bases of DNA

• Word = codon (three ‘letter’ code for an amino acid)

The structure of DNA and RNA

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.

DNA replication and cell division

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 replication of the entire human genome is achieved through the process of mitosis, which is part of the cell cycle (Fig. 7.3). Cellular replication results in growth of tissues through hyperplasia (an increase in the number of cells); each cell has the identical genetic message (DNA content) to its parent cell. Mitotic rates are different for different types of cells. Cells that divide rapidly (have a high mitotic index) include skin and gut epithelial cells, spermatogonia and tumour cells. With increased age the mitotic rate slows down so skin renewal, for instance, takes longer and the appearance of the skin is more aged. Drugs used to treat cancers also inhibit mitosis so their side effects are mostly clearly manifested in normal cells with high mitotic rates, causing problems with nutrient absorption and decreasing male fertility. Many cells, such as brain, heart and liver cells, have an extremely slow rate of mitosis and do not regenerate or heal well after injury. Mitosis is a continuous process but for ease of description is traditionally described in distinct phases: prophase, metaphase, anaphase and telophase (Fig. 7.4). Interphase is the name given to the gap between mitotic divisions.

The genetic message

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 process starts with the DNA strands separating like a zip pulling open in the middle. This is the reverse process to the way it coils when condensing into chromosomes (Fig. 7.5). Only one strand of DNA, the coding or ‘sense’ strand, is used as the template; the other is described as non-coding or ‘non-sense’. The mRNA chain is built by RNA polymerase enzymes as the bases pair with the DNA template. This is called transcription (Fig. 7.6).

The whole gene is transcribed but not all of it is used so the primary transcription product mRNA is modified (cut and spliced) into functional mRNA (Fig. 7.7). The parts of the mRNA that are removed have been copied from parts of the gene called introns and those that are retained come from the parts of the DNA known as exons. It is estimated that only about 2–5% of the total genome (genetic code or DNA) is composed of exons and actually codes for protein synthesis. Some of the DNA modulates genetic expression, switching the process of protein synthesis on and off; these control genes are referred to as operator, regulator and inducer genes. Introns form the majority of the DNA sequence and do not appear to be involved in coding for protein synthesis, although they may allow different proteins to be formed from the same length of DNA. Much of the genome (about 98%) may be composed of redundant genes that are no longer activated and involved in the synthesis of proteins. These unused stretches of DNA are used to compare tissue samples for DNA fingerprinting.

Single nucleotide polymorphisms or SNPs (pronounced snips) are DNA sequence variations that occur when a single nucleotide in the genome is altered, often with the substitution of cytosine with thymine. Variations that occur in at least 1% of the population are considered to be SNPs. There are more than 1.4 million SNPs in the human genome, occurring approximately every 100–300 bases and accounting for up to 90% of all human genetic variation. These variations in the human genome alter how individuals respond to disease, infection, drugs and so on. SNPs are valuable because they do not change much from generation to generation and can be targeted for biomedical research and developing drugs.

The term ‘genome’ refers to a complete DNA sequence of one set of chromosomes of an organism. As such, it does not describe the genetic polymorphism (diversity) of a species. To understand how variations in DNA cause particular traits or diseases will require comparison between individual genomes. The Human Genome Project (HGP) was established as a multinational cooperative research project in 1990 to map the common human nucleotide sequence of more than 3 billion DNA bases in some reference human genomes (the DNA of a few anonymous donors). It was hoped that identification of the 20000–25000 genes in the human genome would accelerate progress to diagnosing, treating and ultimately preventing diseases as well as answer questions about evolution. As individuals (except for identical twins) have unique genomes, the project involved determining the sequence of many versions of each gene. In April 2003, it was announced that 99% of the genome had been sequenced and in May 2006 the sequence of the final chromosome was published. There are still a few DNA sequences to be resolved including the repetitive central regions close to the centromeres and the telomeres, the repetitive terminals of the chromosomes which become progressively shorter with age. The mapping of the genome allows a framework for looking at differences in DNA sequences in individuals so variations in DNA sequence associated with diseases could be identified. The HGP has been supported by remarkable technological progress in bioinformatics, statistics and biotechnology. The HGP raises some complex ethical, legal and social implications such as gene patenting

When transcription and post-transcription modification are complete, the finished functional mRNA strand detaches from the DNA and leaves the nucleus, via a nuclear pore, to go to the ribosomes. Ribosomes are structures formed of two subunits made of protein and another type of RNA, ribosomal RNA (rRNA). mRNA attaches to ribosomes and the sequence of bases of the mRNA is decoded to direct the synthesis of a protein. This step is called translation (Fig. 7.8). The mRNA sequence is ‘read’ three bases at a time. A particular sequence of three bases is called a codon; each codon prescribes that a specific amino acid is incorporated into the final amino acid chain of the overall protein structure. There are 20 amino acids; however, as a three-base genetic code allows the potential of 4 × 4 × 4 = 64 permutations, most amino acids are coded for by more than one codon (Fig. 7.9).

Another form of RNA in the cytoplasm, called transfer RNA (tRNA), carries amino acids to the ribosome to be incorporated into the protein chain. There are different types of tRNA, each one with a specific binding site for a particular amino acid at one end and an ‘anticodon’, which recognizes the codon on the mRNA at the other end. The first amino acid of a new protein is methionine. The next amino acid joins to the carboxyl group of methionine with a peptide bond. Successive amino acids join, forming a chain of amino acids until a ‘stop’ codon on mRNA signals the end of the chain. The sequence of amino acids determines the primary structure of the protein. The further configuration of the protein is determined by the interactions between different amino acids on the chain, which change the protein shape into a ‘folded’ structure, the final shape determining its function. Hence the sequence of bases of the gene, or region of DNA, determines the sequence of amino acids, which in turn prescribes the structure and function of the protein.

Mutation

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).

Box 7.3

Sickle cell anaemia

Most haemoglobin (Hb) in adults is HbA, which has two α-peptide chains and two β-peptide chains forming the haemoglobin molecule. Sickle cell anaemia is an example of a single point mutation where the substitution of one base changes the codon and results in the substitution of one amino acid (Fig. 7.10). Uracil replaces adenine so, instead of glutamic acid, valine is inserted in the protein chain at position 6. Valine has a different charge to glutamic acid so the protein folds differently. The result is that the protein structure of the β-chain of haemoglobin is changed, which affects the molecular shape and oxygen-binding properties. The red blood cells distort into a characteristic sickle shape, particularly at low oxygen tension. Sickle cell anaemia is inherited as an autosomal recessive condition; affected patients have two mutant haemoglobin S genes, one from each parent. The parents are heterozygotes (HbA/HbS) and are thus clinically normal but carry the sickle cell gene. Homozygotes (HbS/HbS) have chronic haemolytic anaemia and are prone to infarction; lifespan is shortened.

Meiosis

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.

Autosomes and sex chromosomes

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.

Box 7.4

Karyotyping

Karyotyping is the method of visualizing the chromosomes in an ordered display of the chromosomes as they appear in the nucleus of a cell during metaphase of mitosis. For a fetal karyotype, a sample of amniotic fluid is removed. The cells are centrifuged to concentrate the fetal cells. The supernatant can also be used diagnostically for biochemical tests such as investigation of enzyme deficiencies, protein defects and gene alterations. Alternatively, cells may be taken from the chorionic villus. A karyotype of adult cells is usually derived from a sample of venous blood, where the anuclear red blood cells are lysed and the washed remaining cells are, therefore, white blood cells containing nuclei.

The fetal cells or white blood cells are grown in cell culture. The time taken for this depends on the number of cells in the original sample. Contamination of the sample can interfere with the success of the method. Colchicine, a chemical poison, is added to the culture medium to prevent spindle formation. Thus, mitosis in all cells is halted at the metaphase stage when the chromosomes are maximally contracted and well defined as paired chromatids (therefore they take on the typical X-shaped appearance). The cells, all halted at the same stage, can be separated from the culture medium. Exposure of the cells to hypotonic saline causes the nucleus to swell so the chromosomes are spread out. The cells are then fixed and stained. Visualization of the karyotype is done by computer-aided photographic techniques. The chromosomes are ordered according to size with the homologous autosomes being paired together. The chromosomes of pair number 1 are the longest and those of pair number 22 are the shortest. The position of the centromere is also used to sort the chromosomes into order. Stains that bind preferentially to some areas of the chromosome, producing a distinct pattern of bands, can be used to identify the chromosomes. Karyotypes can be used to identify gross abnormalities such as additional or missing chromosomes and missing or duplicated parts of chromosomes. However, a normal karyotype does not reveal the presence of abnormal genes at specific loci. In order to identify such genes, the chromosomes are stained, which produce a pattern or banding enabling an abnormal gene or a marker gene to be identified. A marker gene is a gene that is often found in close proximity to an abnormal gene; the closer the marker gene to the abnormal gene, the higher is the association.

Occasionally, results from karyotyping may be complicated by mosaicism. Mosaicism, a different number of chromosomes in different populations of cells may occur for instance where the chorionic tissue has a different number of chromosomes to the fetus.

Case study 7.1

Surya presents herself to a midwife at 8 weeks' gestation demanding that she needs to know the sex of her baby because if it was a female infant she would rather have a termination than proceed with the pregnancy. What should the midwife do in this situation? Are there any circumstances when fetal sex determination is justified?

The sex chromosomes provide the mechanism for the determination of sex and the differentiation into male morphology, which is usually dependent on the inheritance of a Y chromosome (see Chapter 5). As well as sex determination and identity, other genetic traits can be inherited on the sex chromosomes (see below).

It is thought that the sex chromosomes originated from a pair of autosomes (see Chapter 7) during the evolution of sex determination (Graves, 2002). The X and Y chromosomes are very different in size and sequence compared to the other 22 pairs of autosomes. The Y chromosome is very small in comparison to the X chromosome and is completely different from the X chromosomes except at its tips. These identical regions at the tips, known as the pseudoautosomal regions, contain most of the Y chromosome genes involved in control of growth and allow the pairing of the X and Y chromosome and crossing over during cell division. The X chromosome is about 5% of the total length of a single set of chromosome and bears about 3000–4000 genes, many of which are conserved (identical to those of other placental mammals). The Y chromosome contains only about 45–50 genes, many of which appear to be non-functional; others are involved with male differentiation and spermatogenesis, implantation and promoting placental growth. It is suggested that the Y chromosome is particularly vulnerable to mutations and gene deletions because it cannot retrieve lost genetic information by homologous recombination and that, over the past 300 million years, it has already lost most of its original 1500 genes and continues to deteriorate; at its present rate of decay (losing about five genes per million years), it will self-destruct in about 10 million years (Aitken and Graves, 2002). This has already happened in the mole vole, which has lost the Y chromosome and all of its genes from the genome. An alternative view is that the Y chromosome, rather than being ‘damaged’, is an efficient carrier of male-specific genes, rationalized by evolutionary selection (Craig et al., 2004); there has not been any genes lost from the Y chromosome since the ancestral paths of humans and chimpanzees diverged (Goto et al., 2009).

Each pair of autosomes is homologous; this means that their gene arrangements, although not necessarily the specific gene at each locus, are identical. So although the genes at a specific locus code for a specific physiological feature these features in themselves may vary. For instance, the genes at a particular locus may code for eye colour, but this could be blue eye colour on the chromosome inherited from one parent and brown eye colour on the chromosome inherited from the other parent. Genes that code for the same physical feature but produce variations in that feature are called alleles.

If the genes are identical alleles, then the structure and coding of the pair are referred to as being homozygous. If the genes are differing alleles then the pair is referred to as being heterozygous. If one copy of a gene is required for a trait to be expressed (i.e. for the feature to be ‘visible’ in the resultant individual), the gene is described as being dominant. If two copies are required, the gene is described as being recessive. Autosomal traits (genetic instructions carried on the autosomes) can be expressed as either dominant or recessive traits. Simple inheritance of these traits can be predicted diagrammatically (see Figs. 7.12 and 7.16).

Prediction of genetic outcomes

Genetic predictions forecast the chance of an ovum carrying a specific combination of genes being fertilized by a sperm carrying a specific combination of genes. The convention is to show the dominant gene as a capital letter. The genetic potential is described as the genotype; how it is expressed is called the phenotype. Combination diagrams and Punnett squares give the same results, predicting the chance of a particular outcome (Figs. 7.12 and 7.13).

The genetic rules that dictate eye colour follow the traditional form of dominant and recessive interaction (see Box 7.5). However, it is important to realize that, like so many other physiological states, expressed characteristics may be the outcome of multifactorial genes where more than one gene is involved. The environment may also influence the expression of genes. For instance, inheriting genes for tall stature does not necessarily mean the child will be tall. In the absence of appropriate nutrition at critical times of growth, the genetic potential may not be realized.

Box 7.5

Selected examples of recessive and dominant traits

Autosomal trait	Recessive trait
Brown eye colour	Blue or grey eye colour
Curly hair	Straight hair
Dark brown hair	All other colours
Near or far sight	Normal vision
Normal skin pigment	Albinism
Normal hearing	Deafness
Migraine headaches	Normal
A or B antigen (A, B or AB blood group)	No A or B antigen (O blood group)
Rhesus antigen (Rh+ blood group)	No Rhesus antigen (Rh− blood group)

Characteristics of different types of inheritance

The trait is expressed by a gene on an autosome and is expressed provided that at least one chromosome has the dominant gene. Each person expressing the trait usually has a parent with the trait (Fig. 7.14shows a pedigree chart for a pattern of autosomal dominant inheritance; the symbols used in these charts are shown in Box 7.6). This means that a particular characteristic or disorder can be traced through several generations if it has little effect on survival. However, a trait occurring in a new generation may be the result of polygamic behaviour (illegitimacy) or a fresh mutation. Autosomal dominant traits also tend to be extremely variable in expression so they may be undetectable and appear to ‘skip’ a generation. For instance, polydactyly (an extra digit) may be manifest as a tiny pedicle, rather than an extra finger. Autosomal dominant disorders are often caused by defects in structural proteins.

Box 7.6

Symbols used in pedigree charts

If an affected person mates with an unaffected person, the chances of any child being affected are one in two (i.e. 50%). Some autosomal diseases or traits do not affect the predicted 50% of offspring. These are described as having incomplete penetrance. Conversely, a highly penetrant gene is expressed regardless of environmental and other factors.

In the UK, the most common dominantly inherited traits are Huntington's disease and achondroplasia (Table 7.2). Huntington's disease, a degenerative neuropsychiatric disorder initially characterized by spasmodic movements of the body and limbs and ultimately dementia, is usually not expressed until the third or fourth decade when the person affected is likely to have reproduced. The age at onset and progression of the disease is linked to the number of polyglutamine sequence repeats in the disease protein (coded by CAG bases in the gene).

A complication occurs in the case of inherited achondroplasia (dwarfism) (note that 80% of cases of achondroplasia are caused by new mutations in the offspring of parents of normal height). Humans exhibit selective rather than random mating, often being attracted to partners of similar height, intelligence and other physical attributes. In consequence, individuals with achondroplasia partner each other with a higher frequency than expected by chance. If two people with achondroplasia mate, there is an expected prediction of a one in four chance of a child having normal stature (Fig. 7.15). However, homozygosity (two genes for achondroplasia) results in the fetus having lethal respiratory problems, which are incompatible with survival. Hence the actual ratio of newborn children is one in three. (Arguably, achondroplasia could be viewed as a recessively inherited respiratory condition that confers dwarfism on the heterozygote.)

As with autosomal dominant inheritance, this type of inheritance can affect both sexes equally. However, the recessive trait is expressed only if the gene is present on both alleles, which means it has been inherited from both parents. If the parents are heterozygotes, each carrying one recessive gene for the trait and one normal dominant gene, they express the dominant gene and are described as ‘carriers’ of the recessive gene. In some conditions, the carriers may exhibit mild signs of a disease or have an unusual level of certain biochemical markers that can be measured in genetic testing.

Most inherited enzyme disorders are recessive. Another characteristic of recessive disorders is that they show a variation in birth frequency among different populations (Table 7.3). It is suggested that the reason some recessively inherited disorders reach such a high incidence within a population is because advantages are conferred on the heterozygotes. For example, it is recognized that carriers of the gene for sickle haemoglobin (see Box 7.3), namely HbS or C, have a resistance to malaria falciparum, the most dangerous form of malaria (but not to other types). Obviously, such an advantage will selectively increase the number of people within the population who carry the gene. The incidence of malaria and the inheritance of other forms of altered haemoglobin, such as β-thalassaemia, can be mapped to the same parts of the world.

In the Caucasian population, the most common autosomal recessive condition is cystic fibrosis. The carrier rate within the population is about 1 in 25 people. This means that there is a 1 in 25 chance that any person might be heterozygous for (i.e. carry) the cystic fibrosis gene. The chance, therefore, of two carriers mating is 1 in 625 (25 × 25) (Fig. 7.16). If two heterozygous parents have children, there is a one in four chance that any child will be affected and a one in two chance that any child will be a carrier of the gene themselves. The live-birth rate of children with cystic fibrosis is about one in 2500 (625 × 4). Because of the relatively high incidence of the disease, parents who already have an affected child or those whose family history has a strong incidence of the disease will be offered genetic counselling. Carriers of the cystic fibrosis gene appear to have resistance to gastrointestinal conditions, tuberculosis and cholera, and to have increased fertility. Cystic fibrosis is a condition which has the potential to be treated by gene therapy (Box 7.7).

Box 7.7

Advances in gene therapy

Recent advances in gene therapy have led to techniques to insert normal genes into human cells and tissues which express abnormal genes. Gene therapy aims to supplement a defective allele with a functional allele and focuses on single-gene defects such as cystic fibrosis, muscular dystrophy, sickle cell anaemia and haemophilia. This is achieved by using a modified virus that acts as a vehicle by which the normal gene is carried into and thus incorporated into the genome. The altered virus is unable to replicate and so causes no harm to the recipient. In treatment of cystic fibrosis, the cells of the nasal passages and lining of the lungs are exposed to the virus in the form of an inhaled spray. So far, all human gene therapy has targeted at somatic (body) cells; germline engineering (altering stem cells or gametes) remains controversial.

The sex chromosomes not only determine the sex of the embryo but also have other structural genes. Female and male genetic endowments are different. Very few genes appear to be carried on the Y chromosomes so sex-linked inheritance usually relates to X-linked inheritance. Most genes carried on the X chromosome are recessive. The effects of a recessive X-linked gene are usually masked in the female by the presence of the paired normal gene upon the other X chromosome. However, should such a woman carry an abnormal gene, she may pass it on to her sons. Males inherit only one of the paired X chromosomes; therefore, if they acquire the abnormal gene on the X chromosome the disease will automatically be manifest because the Y chromosome lacks the corresponding allele of the other X chromosome that is found in the female. Also, if a female inherits two abnormal genes, one on each X chromosome, the condition is usually incompatible with life and the embryo is lost at a relatively early stage. X-linked recessive disorders therefore affect many more males than females. Very few sex-linked abnormalities are inherited as dominant traits which affect would both male and female offspring. One example is vitamin D-resistant rickets.

Most sex-linked diseases (Table 7.4) involve a female carrier partnered with a trait-free man (Fig. 7.17). There is a one in two chance that any male offspring will inherit and express the disorder and a one in two chance that any female offspring will carry the trait. An affected man cannot pass the disorder to his sons because they will receive a Y chromosome only, but all of his daughters will be carriers of the disease.

Only males have the genes from the Y chromosome which is small and contains very little active genetic coding. However, it does contain the SRY (sex-determining region of the Y chromosome) gene, which, when activated, directs male embryonic development (see Chapter 5). The male, however, still requires the presence of an X chromosome as this contains many genes that are vital for normal development to occur.

The female inherits two X chromosomes but evidence suggests that only one of the chromosomes is activated within the cell. On examination of the cell nucleus, one chromosome is always contracted, forming a characteristic Barr body at the outskirts of the nucleus. The number of Barr bodies is one of the tests used in determining the sex of a baby born with ambiguous genitalia. The contracted Barr body chromosome was assumed to be inert, but a small number of genes appear to remain active and expressed. Although the second X chromosome in females is inactivated this is usually incomplete so a proportion (perhaps 15%) of X-linked genes will be expressed at higher and variable levels in women. As X chromosome inactivation is random, some female cells will express the paternal X chromosome, whereas the others will express the maternal X chromosome so women are genetic mosaics with respect to X-linked gene expression.

There are examples of mosaic phenotypes where a heterozygous woman has a mix of dominant and recessive expression. For instance, in X-linked ectodermal dysplasia, affected males have smooth skin with no sweat glands. Female carriers may have patches of normal skin interspersed with patches of dysplastic skin. Similarly, females who are heterozygous for ocular albinism may have a mosaic pattern of pigmentation in their irises. There also seems to be some form of dosage compensation, as the inheritance of two X chromosomes does not result in twice the amount of proteins coded for by genes on the X chromosome. The explanation is that, early in embryonic development, a process called X-inactivation or ‘Lyonization’ occurs in which one of the X chromosomes is permanently inactivated (Box 7.8 and Fig. 7.18). As random chromosomes are selected for inactivation, different regions of the adult body have different chromosomes inactivated.

Box 7.8

X-inactivation or Lyonization

X chromosome inactivation or Lyonization (named after Dr. Mary Lyon who first proposed the hypothesis in 1961) occurs at approximately 15 days into the gestation (Huynh and Lee, 2005). In humans, the cell mass of the embryo at around this stage is approximately 5000 cells (Fig. 7.18). The female embryo randomly inactivates all but one X chromosome on each cell; once inactivated, all the cells descending from each parent cell retain their pattern of either paternal or maternal inactivation. In some animals, such as marsupials, it is always the paternally derived X chromosome that is deactivated but in mammals it appears that either one of the pair is inactivated. Random inactivation would predict that 50% of female cells would have an active paternal X and 50% have an active maternal X; however, skewed patterns of inactivation can arise which means that the X chromosomes from one parent may be predominantly inactivated so the X chromosomes from the other parent will then be expressed. This could lead to the dominant proportion of expressed X chromosomes carrying a disorder that can be expressed. The inactivated chromosome appears as a sex chromatin body (Barr body) and is identified as it always divides late in mitosis. However, not all the chromosomes are totally inactivated: the pseudoautosomal region of the short arm and other loci remains active to prevent the manifestation of Turner's syndrome in all normal genotypical women.

The three main types of inheritance are summarized in Box 7.9.

Box 7.9

Characteristics of different types of inheritance

Autosomal dominant inheritance

• Effects are manifest in heterozygotes

• Affected person + person: half of offspring are affected

• Unaffected persons do not transmit condition

• Fresh mutation may produce abnormal genes

• An affected person usually has an affected parent

• Traits are often variably expressed and may not be penetrant (an individual can have the mutant gene but have a normal phenotype)

• Often structural, receptor or carrier proteins are affected and clinical effects tend to be less severe than those due to recessively inherited traits

Autosomal recessive inheritance

• Effects are manifest in homozygotes

• Affected person receives genes from both parents

• Heterozygote = ‘carrier’

• Heterozygote parents

- One in four chance that offspring will be affected

- One in two chance that offspring will be carriers

- One in four chance that offspring will be unaffected

• Variation in birth frequency

• Recessive traits usually result in enzyme defects

Sex-linked inheritance

• Sex chromosomes carry genes and determine sex

• Sex-linked = X-linked

• Most conditions are rare

• Genes involved are usually recessive

• Female carrier

- One in two chance that male offspring will be affected

- One in two chance that female offspring will also be carriers

• Affected male

- All sons will be normal

- All daughters will be carriers

Blood groups A and B are inherited as co-dominant genes, whereas the gene for blood group O is recessive (Fig. 7.19 and Box 7.10). Some disorders are inherited via the mitochondria. The mitochondria of the zygote and subsequent cells are exclusively derived from the oocyte (see Chapter 6); therefore, no paternal mitochondria are passed on to the next generation. Disorders of mitochondrial metabolism are passed from mother to child but never from father to child. The unique matrilineal transmission of mtDNA has been particularly useful for the study of population genetics and evolutionary biology. This has been particularly useful in determining family lineage, such as the notable case of Anastasia, the Russian princess. DNA analysis showed that the mtDNA of members of the present Royal Family was different to that of the person who claimed to be Anastasia (Sykes, 2001). Determining patterns of inheritance can be complicated, however, where different inherited disorders apparently cause the same effect, such as blindness.

Box 7.10

Erythrocyte surface antigens: blood group classifications

The reason for the evolution of differing blood groups in humans remains a mystery except that at some point during evolutionary history they may have been advantageous to ensure overall survival of the population. Other animals do not have the same number or type of blood groups. The more common human blood cell antigens give rise to the blood groups A, B, AB and O (Table 7.5).

Table 7.5. ABO blood groups
Blood Type	A	B	AB	O
Antigen on RBC (agglutinogen)	A	B	A + B	None (universal donor)
Antibody in plasma (agglutinin)	b	a	None (universal recipient)	a + b
Can donate to	A and AB	B and AB	AB	All
Can receive from	A and O	B and O	All	O
Distribution in UK (%)	42	9	3	46
Genotype	AA, AO	BB, BO	AB	OO
Phenotype	A	B	AB	O

Other surface antigens commonly found in practice are Duffy, Rhesus D, C, E and Kell. The presence of other antigens explains why, even with closely matched blood, recipients can react to the blood of the donor. The Rhesus antigen, which is present in approximately 85% of the population, has implications for fetal survival (see Chapter 10).

The presence of 23 pairs of normal chromosomes indicates a normal karyotype (see Box 7.4).

Chromosomal abnormalities

Changes within the genetic message, for instance those due to mutation, may involve large parts of the chromosome (Box 7.11). If the changes can be seen by light microscopy, they are termed gross aberrations and can be detected from an examination of the karyotype. Chromosomal abnormalities can be classified as numerical or structural, affecting either the autosomes or the sex chromosomes. These types of abnormality are easier than a single-gene abnormality to detect.

Box 7.11

Incidence of chromosomal abnormalities

• Incidence of major chromosomal abnormality

- About 1 in 200 live births

- About 1 in 20 perinatal deaths (stillbirths and early neonatal deaths)

- About 1 in 2 early spontaneous abortions

• About 1 in 100 births: single-gene (unifactorial) disorder

• About 1 in 50 births: +major congenital abnormality

The loss or gain of one or more chromosomes is described as aneuploidy (wrong number of chromosomes), whereas cells with the correct number of chromosomes are euploidic. It is estimated that 10–25% of all human fetuses are aneuploidal, predominantly due to non-disjunction in maternal meiosis (Hunt and Hassold, 2002), although trisomy 18 most often results from non-disjunction in meiosis II. Aneuploidy occurs more frequently in humans than in other species which is probably the reason for such a high rate of miscarriage in humans. Aneuploidy is usually due to non-disjunction in the formation of the gametes resulting in a zygote that does not have 46 chromosomes. Monosomy describes the loss of a complete chromosome and trisomy the addition of a single chromosome, as in Down's syndrome (trisomy 21) (see Table 7.1). Monosomy and triploidy (an extra complete set of 23 chromosomes) are usually lethal. Most autosomal trisomies are also lethal except those involving chromosomes 13, 18 or 21 but these, and the sex chromosome trisomies, are the main cause of mental retardation and developmental disability. It is interesting to note that chromosomes 13, 18 and 21 carry the fewest genes. Abnormal numbers of sex chromosomes have a less serious effect on development; for instance, a missing sex chromosome can result in a Turner's syndrome monosomy (45,X0). Although it might be possible that paternally derived aneuploidies are preferentially eliminated, it is more likely that more errors occur in maternal meiosis and/or that the mechanisms for detecting and correcting or eliminating them are less stringent. The most likely reason for non-disjunction is age-related deterioration of the meiotic spindle and the motor proteins which move chromosomes along it.

Down's syndrome

Down's syndrome is the most common chromosomal anomaly at birth affecting about one in 700 live births. The conception rate is much higher but it is associated with a high incidence of spontaneous abortion and stillbirth. Either the ovum or the sperm carries the extra chromosome 21. Although non-disjunction is associated with older maternal age, there is evidence to suggest that older men, perhaps because of a lower incidence of coitus, also have an increased rate of non-disjunction in their sperm formation. There is also a slight increase in the incidence of Down's syndrome in teenage pregnancies which may reflect a tendency to non-disjoin in early ovarian cycles (Hassold and Hunt, 2001).

Affected children have typical stigmata of Down's syndrome (Box 7.12). Their life expectancy tends to be shorter because of increased susceptibility to infection, congenital heart disease and leukaemia. It is also hypothesized that individuals with Down's syndrome have increased oxidative damage to neurons, which results in accelerated brain ageing similar to that of Alzheimer's disease.

Box 7.12

Down's syndrome: clinical features

• Slanting palpebral fissure, almond-shaped eyes

• A roundish head and flat facial profile

• Small nose

• Low-set ears

• Simian crease (single palmar crease) in 50% of cases

• Folds of redundant skin around neck

• Clinodactyly (inwardly curved little finger) in 50% of cases

• Usually mentally retarded with IQ < 60

• Congenital heart malformations occur in 40% of cases

• Prone to presenile dementia in fifth decade

Over half of the conceptions with trisomy 21 fail, suggesting that the extra copy of chromosome 21 interferes with intrauterine development. Although males with Down's syndrome are infertile, females with Down's syndrome can reproduce; theoretically, half the ova will have an extra copy of chromosome 21 but the effects on uterine development mean that the live-birth rate does not correlate with the conception rate. Amniocentesis for cytogenetic screening is offered to all mothers over 35 years of age and the triple test is available to all women in the UK regardless of their age (see p. 169). Some women may also be offered ultrasonography screening.

About 4% of babies with Down's syndrome have 46, rather than 47, chromosomes. The extra chromosomal material from a chromosome 21 is attached to another chromosome (Robertsonian or balanced translocation; see Table 7.1). Usually, one of the parents is a carrier of Down's syndrome and has the translocation in a balanced form; 45 chromosomes with the extra copy of chromosome 21 attached to another chromosome (Fig. 7.20). This means that the translocation carrier is not directly affected but will produce a proportion of gametes with an unbalanced complement of chromosomes. There is frequently an associated history of recurrent spontaneous abortion due to lethal arrangements of chromosomes in the gametes.

Case study 7.2 looks at concerns related to Down's syndrome.

Case study 7.2

Josie is 48 years old and has four children between 14 and 24 years of age. She attends the midwives' clinic in a state of shock as her doctor has just informed her she is 8 weeks' pregnant.

• What advice would the midwife need to give to Josie in relation to antenatal screening?

Josie attends her local maternity unit at 12 weeks' gestation for a nuchal translucency scan and is given an estimated risk of a one in six possibility of a Down's syndrome baby.

• What further investigations could be offered to Josie and how can the midwife best support her during this period of investigation?

Autosomal abnormalities

Structural chromosomal abnormalities include translocations, where material is exchanged between chromosomes, inversions, where a segment of the chromosome is rotated through 180°, and deletions, where segments of chromosomes are lost (Fig. 7.21). Cri du chat syndrome is associated with deletion of the short arm of chromosome 5. Deletions leave the affected chromosomes with fragile sites that adhere to each other, forming ring chromosomes. In inversions, a parent may have the correct amount of chromosomal material and therefore no clinical problem, but the chromosomes align inappropriately in meiosis so gamete formation is affected. Many chromosomal disorders affect fertility.

Sex chromosome abnormalities

Sex chromosome anomalies are relatively common but produce fewer ill-effects than autosomal anomalies. Generally, the greater the number of extra sex chromosomes, the higher is the degree of mental retardation. Many sex chromosome anomalies also affect reproductive performance (see Chapter 5).

An example of an X chromosome abnormality is fragile X syndrome (Box 7.13).

Box 7.13

Fragile X syndrome

Fragile X syndrome is one of the commonest causes of mental retardation in males. It is inherited as an X-linked trait, affecting one in 1000 male babies. The fragile site on the X chromosome is on the long arm. Affected males often have a large head, prominent chin and ears and may develop large testes at puberty. A significant proportion of carrier women are mentally retarded.

Epigenetics and imprinting

Epigenetic modifications to the genome produce inheritable changes in gene expression which do not involve a change in sequence of bases in DNA. Thus the phenotype of the offspring is changed because bases in DNA are modified in some way without their sequence being altered. Epigenetics is the basis of genetic imprinting (see below). The expression of genes can be switched on or off by DNA methylation (the addition of a methyl group to a cytosine residue of DNA), by phosphorylation or by modification of the DNA-associated histone proteins. During embryonic development, for example, imprinting switches off the expression of key genes so that only the gene from one of the parents is expressed as the functional protein. This additional mechanism of regulation of gene expression has created challenges in animal cloning experiments and in human ovarian tissue cryopreservation.

Imprinted genes cluster in particular parts of the genome which are rich in CpG nucleotides (where a cytosine nucleotide is next to a guanine nucleotide linked by a phosphate group – CpG denotes Cytosine–phosphate–Guanine). CpG dinucleotides do not occur as often as predicted suggesting that they are vulnerable to mutation. The regions of the DNA strand which have a high prevalence of CpG nucleotides are called ‘CpG islands’. CpG islands often occur at the beginning of a gene. Most of the cytosine nucleotides in CpG islands are methylated with the methyl group being attached to the cytosine. Methylation usually switches off – ‘silences’ – the gene. Histone modification of the DNA strand affects whether transcription factors can access the DNA to direct the transfer (transcription) of genetic material to RNA. There are about 20000 genes in the human genome of which several hundreds are thought to be imprinted, predominantly affecting growth (including function of the placenta) and development including brain development (Keverne, 2010) (see Box 7.14).

Box 7.14

Epigenetic control of growth

Insulin-like growth factor 2 (IGF2) is encoded by the IGF2 gene which is imprinted. A fetus inherits two copies of the IGF2 gene, one from each parent. Usually, the paternal copy is expressed and the maternal gene is silenced. If the maternal gene is expressed as well as the paternal gene, the fetus has Beckwith–Wiedemann Syndrome which results in a high birthweight and other markers of overgrowth such as macroglossia (enlarged tongue) and an increased risk of childhood cancer (Eggermann et al., 2008). If both the maternal and paternal genes are silenced, the result is Silver–Russell (or Russell–Silver) syndrome which is due to fetal undergrowth. Both conditions are rare but they occur with increased frequency in offspring derived from ICSI (see Chapter 6) suggesting the manipulation of gametes and embryos may affect imprinting.

Some genes are expressed when inherited from one parent but are not expressed when inherited from the other parent. This is genetic imprinting, the suppression or silencing of certain alleles on the chromosomes depending on their parental origin. Following fertilization, some genes are only expressed if they were inherited from the mother (the paternal gene being imprinted and therefore silenced), whereas others are expressed only if they were inherited from the father with the maternal gene being imprinted. Expression of some imprinted genes is spatially and temporally regulated and may only be active for a limited window during development.

Imprinted genes result in monoallelic gene expression and a number of diseases have been linked to defects in the normal imprinting process. The importance of genetic imprinting can be clearly seen in situations where imprinted genes are either inactivated or deleted on the normally active allele. The diseases Präder–Willi syndrome (PWS) and Angelman syndrome (AS) result, respectively, from a paternal (PWS) or a maternal (AS) deletion of the same region of chromosome 15 and since the alleles derived from the other parent are silenced by being imprinted, the genes are not expressed and their proteins are absent. In PWS, genes are deleted from the paternal chromosome 15 which are also imprinted on the maternal allele. In AS, the same region of chromosome 15 as that affected in PWS is deleted on the female allele and imprinted on the allele derived from the male.

Paternally imprinted genes tend to enhance fetal growth, whereas maternally expressed genes tend to constrict growth (see p. 220 for discussion of the ‘conflict hypothesis’). Much of the research has been carried out in mice but in most genes, the imprinting status is conserved between species. Mouse genome manipulation demonstrates that androgenote mice, which have only paternal DNA, have a poor embryonic development and gynogenote mice, which have only maternal DNA, have poor placental development. In the mouse placenta, the paternal X chromosome is imprinted so that only the maternal genes are expressed and the paternal genes are silenced (Keverne, 2009). It is suggested that this may be important in avoiding a maternal immune rejection response to allogeneic fetal proteins that could be encoded by the paternal X chromosome (see Chapter 10). Gene expression in the brain is complex probably affecting behaviour, cognition and personality. In the preoptic area of the mouse brain, there is a high incidence of genes which are parentally imprinted; this area of the brain is a testosterone-dependent sexually dimorphic region which is important for male sexual behaviour and maternal care (Gregg et al., 2010).

The appropriate establishment and maintenance of the epigenetic imprints are essential for normal growth and development. Aberrant gene expressions due to imprinting problems are called ‘epimutations’. These can occur during imprint erasure, when the primordial germ cells migrate to the gonadal ridges in embryonic development (see Chapter 9), during imprint establishment when gametogenesis occurs or during imprint maintenance, throughout the life of the organism. The paternal genome is actively demethylated within a few hours of fertilization, whereas the maternal genome is demethylated passively during the first few cleavages of the embryo in a species-dependent manner. This pattern of demethylation, which erases most imprinted genes from the parents in the preimplantation stage, spares some imprinted genes which are then maintained throughout development. Assisted reproductive techniques (ART) are associated with an increased risk of epigenetic disturbance which is more likely when gametes are manipulated (affecting imprint establishment) or when the preimplantation embryo is manipulated (affecting imprint maintenance). As the first ART involving invasive manipulation of gametes and embryo are fairly recent events, it is not yet clear whether there will be any long term epigenetic-medicated repercussions, the so-called ‘ART ticking time bomb’ (Grace and Sinclair, 2009).

Genetic screening

The detection of abnormal genetic conditions such as cystic fibrosis (e.g. Case study 7.3) has been the focus of much ongoing research. There are three particular areas in which genetic investigation can be used to assess risk factors and confirm diagnosis of genetic disorder: parental screening, preimplantation screening and antenatal assessment.

Case study 7.3

Tania has a brother who was diagnosed as having cystic fibrosis some years ago. Tania has been identified as being a carrier. Tania presents herself at the midwives' clinic with an unplanned pregnancy at 8 weeks' gestation. Her partner, Paul, has no family history of cystic fibrosis.

• What reassurance and advice can the midwife give to Tania?

• What referrals should the midwife make and how should this be explained to Tania?

Individuals from families with a known prevalent genetic disorder may be tested to confirm whether they carry the abnormal gene. The findings form the basis of genetic counselling in which both the risks of passing on the abnormal gene and the possible consequences for a child are discussed. Frequently, this follows the delivery of an affected baby, especially if there is no family history. The condition may have arisen by spontaneous mutation and so the chances of it reoccurring in subsequent pregnancies may be much smaller than if the parents were actually carrying the defective gene.

Preimplantation genetic diagnosis (PGD) is a technique which allows diagnosis of genetic and chromosomal disorders in an embryo before pregnancy is established (Basille et al., 2009). It was developed as a test for couples carrying genetic disorders who were at risk of having a child with the disorder. However, the technique is also now used extensively for optimizing IVF outcome in couples who do not carry a genetic disorder (Spits and Sermon, 2009) because chromosomal aberrations occur at high frequency in all embryos and can be detected before implantation thus reducing the otherwise inevitable early pregnancy loss and increasing pregnancy rate in women who have poor IVF success rates. In vitro fertilization techniques (see Chapter 6) allow genetic analysis on polar bodies extracted from the oocyte before fertilization (first polar body) and/or after fertilization (second polar body). Genetic testing can also be carried out on a single cell from a 3-day-old embryo (at the cleavage stage) or on trophoblast cells from the blastocyst at day 5. These techniques thus allow selection of normal embryos for subsequent implantation. PGD and preimplantation genetic screening (PGS) utilize molecular techniques such as fluorescent in situ hybridization, DNA analysis and polymerase chain reaction (PCR; see Box 7.15) to detect single-gene disorders, such as thalassaemias or cystic fibrosis, or to screen for structural or numerical chromosome disorders. PGD offers an alternative to prenatal diagnosis and selective termination of an affected pregnancy, which may be important for couples who cannot contemplate termination of a pregnancy. The identification and selection of euploid embryos also has a positive effect on the clinical outcome of assisted reproductive technologies (see Chapter 6) as chromosomal abnormalities are one of the major causes of spontaneous abortion and implantation failure. There are, however, detrimental effects of the biopsy procedures and removal of embryonic cells (Diedrich et al., 2007).

Box 7.15

Molecular detection of abnormal genes

Molecular genetics studies human variations and mutations at the level of the gene and is important for understanding and identifying genetic diseases. Application of molecular genetic methods allows DNA diagnosis from very small amounts of tissue.

Fluorescent in situ hybridization

This involves the use of a genetic probe, which attaches to the target gene that it is designed to detect. The probe has a fluorescent label and so the abnormal gene can be visualized. Fluorescent in situ hybridization is used to identify microdeletions, aneuploidy and translocations.

Polymerase chain reaction

A small fragment of DNA is selectively amplified (at least a million times) by enzymatic procedures to produce large quantities of the relevant restriction fragments. These fragments can then be visualized by electrophoresis through an agarose gel, which is stained with a fluorescent dye. Polymerase chain reaction (PCR) is used to identify single-gene disorders such as fragile X syndrome, Huntington's disease and muscular dystrophy. PCR can be used for any condition for which gene sequencing, and therefore the information required to design primers for selective amplification, is available.

It is common throughout the UK for the screening for certain genetic disorders to be offered to all women. The tests predict the mathematical probability of a pregnancy being affected. If a test results in a high risk of abnormality, a diagnostic procedure such as chorionic villi sampling or amniocentesis may be offered. The aim is to detect chromosomal and anatomical abnormalities. Minor structural variants that can be detected by ultrasound are described as ‘soft markers’ (Loughna, 2009); these cannot be used in isolation but together with other markers can predict the probability of risk. Clinical tests include first-trimester nuchal translucency (NT) ultrasound, second-trimester maternal serum screening and second semester ultrasound for anatomical survey. Methods of prenatal screening have to be adapted for women with multiple gestation (Cleary-Goldman et al., 2005); offspring of multiple gestation is at increased risk of abnormality but zygosity has to be first inferred from ultrasound diagnosis of chorionicity. In women, who conceive with egg donation, it is the age of the ovum donor that is important.

First-trimester NT ultrasound

At around 12 weeks' gestation, the nuchal fat pad at the back of the fetus's neck is measured using ultrasound assessment. NT increases with crown-rump length so the findings combined with maternal age and fetal size (crown-rump length) indicate a higher or lower risk of the fetus having Down's syndrome. The detection rate is about 83%. If the NT is raised, but the karyotype is normal, the fetus may be checked later for other physiological conditions such as cardiac abnormalities.

An increased NT (thicker fat pad) indicates an increased risk of a genetic or physical abnormality being present. Abnormal NT is also associated with other trisomies and fetal abnormalities (Souka et al., 1998). It is not clear why such conditions result in a thicker NT but this may be related to oedema due to cardiac conditions, or failure of the neck lymphatic structures to develop at the right time, or both. Each case has to be assessed on an individual basis taking into consideration the maternal age and fetal size, although measurements less than 1.9 mm are probably normal, whereas those greater than 3 mm are probably abnormal.

Second-trimester maternal serum screening tests

The risk of Down's syndrome can also be estimated by a combination of blood tests, such as the levels of hCG (human chorionic gonadotrophin, which is usually raised in singleton Down's syndrome pregnancies), AFP (alpha-fetoprotein, which is usually low in a Down's syndrome pregnancy), unconjugated oestriol and inhibin-A at around 16 weeks in combination with maternal age (Table 7.6). These tests have various formats and are often referred to as double, triple or Bart's, and quadruple test and so on. Trisomy becomes more common with an increase in maternal age and is linked to an increasing failure of the division of the oocyte to be completed normally. The results from the biochemical indicators are combined with the maternal age risk and compared with normal values, adjusted for gestational age, to establish the likelihood ratio (probability or risk) of the pregnancy being affected.

Combined testing refers to combining the results of blood tests and ultrasound scans before the completion of the 14th week of pregnancy to predict risk of Down's syndrome; this is more sensitive than using blood tests and ultrasound examination in isolation. Integrated testing involves two blood tests, one in the first trimester (ideally between 10 and 12 weeks) followed by another blood test in the second trimester (ideally between 15 and 20 weeks). The results of the tests are evaluated using sophisticated risk evaluation software.

Ultrasound

All pregnant women in the UK are currently offered an ultrasound scan at approximately 20 weeks' gestation. The scan entails the detailed examination of the gross anatomical structures, such as internal organs, head, limbs and spine, and assessment of fetal growth. Many physical abnormalities, such as cardiac defects and limb length, are markers which may indicate the presence of a genetic abnormality. The more abnormal the ultrasound findings, the higher the risk of fetal aneuploidy. Abnormalities include structural malformations, increased nuchal thickness, short ear length, short femur or humerus, an extra vessel in the umbilical cord, a wide space between the toes and increased bowel echogenicity (Ott and Taysi, 2001). This has led to the development of ultrasound scoring systems to identify fetuses at risk and support to the suggestion that ultrasound alone may be an alternative method of detecting genetic abnormalities in women who are reluctant to undergo amniocentesis.

Diagnosis of the above disorders can be confirmed only with more invasive procedures such as chorionic villus sampling (CVS) and amniocentesis (withdrawal of amniotic fluid) (Fig. 7.22). Both of these procedures enable the karyotype of the fetus to be examined, enabling fetal sexing, the identification of a trisomy or the presence of markers indicating the presence of abnormal alleles. Other invasive techniques are fetoscopy and cordiocentesis (fetal blood sampling) and biopsy. These procedures carry a slightly increased risk of procedure-related loss; however, the spontaneous abortion rate is higher in pregnancies with chromosomal abnormalities.

The fetal cells in the amniotic fluid or villus sample are grown in culture to produce enough cells for testing. The time taken for a result depends on the number of cells in the original sample and their growth rate, which can be affected by contamination with blood or maternal cells. The cell sample is greater in CVS so results are usually quicker. Occasionally, results can be complicated by chromosomal mosaicism where an individual has two or more cell lines, each with different chromosome numbers, derived from one zygote. For example, 1% of people with Down's syndrome are mosaics with both trisomic cells and normal cells; the clinical outcome is much better in these cases but if the abnormal cells are in the gonads there may be a high risk of producing abnormal gametes.

Amniocentesis and CVS are both invasive methods of prenatal diagnosis with inherent risks for the pregnancy. Alternative less-invasive methods of obtaining fetal cells and nucleic acids (DNA and RNA) are being studied because they are not associated with the same increased risk of miscarriage. The placenta is not a totally impermeable barrier. Some fetal cells transfer to the maternal circulation (see microchimerism, p. 242); there is approximately one fetal cell per millilitre of maternal blood. These intact fetal cells can be separated from maternal cells by flow cytometry (automated cell sorting equipment) as the cells have different morphological characteristics. Developments in molecular biology mean that PCR amplification assays (see p. 169) can be used for prenatal screening and genetic diagnosis. The discovery that fetal cell-free DNA and RNA (nucleic acids probably derived from apoptosis of the trophoblast during placental development) can also be extracted from the maternal blood has potential widespread clinical applications, particularly as intact fetal cells in maternal blood are rare. Routine non-invasive prenatal diagnosis using nucleic acids extracted from maternal plasma has been used to detect blood group incompatibility, fetal sex and some single-gene disorders (Avent et al., 2009). Although DNA extraction from fetal cells isolated from cervical mucus appeared to also offer the potential for early non-invasive prenatal diagnosis, there have been some issues with cell collection and detection rate (Cioni et al., 2003).

Table 7.7 summarizes the prenatal diagnostic procedures and Box 7.15 describes the techniques for molecular detection of abnormal genes.

Evolution

Evolution is the study of genetic variation within populations and how this variation allows populations to evolve in response to changes within the environment in which they live. The variation of genes within a defined population is referred to as the gene pool. Charles Darwin's famous book ‘On the Origin of the Species by Means of Natural Selection, or the Preservation of Favoured Faces in the Struggle for Life’ (known as ‘The Origin of the Species’) (1859) presented the argument that all organisms descended from a common ancestor and advocated natural selection as the mechanism of evolution. The mechanism of evolution is still contested, particularly how other mechanisms such as random genetic drift have contributed to evolution and the effects of gradual accumulation of small genetic changes rather than fewer large ones.

As described earlier in this chapter, many disease processes have their aetiology in the physical expression (phenotype) of an abnormal gene (genotype). They are normally recessive, so the effects of the abnormal gene are masked by the presence of a normal gene. The physical effects of recessive genes are only seen when there are two recessive genes present in the genome, for instance, in cystic fibrosis (see also in Case study 7.4, which looks at the Rhesus-negative blood type). Some abnormal genes may be partially expressed or modified by the presence of a normal gene. Many heterozygous, partially expressed genetic conditions may, in the right environment, impart a beneficial effect on the individual. An example is the sickle cell trait HbA/HbS or HbA/HbC (see Box 7.3). If one recessive gene is present, the anaemia condition is expressed in a minor form. Whilst this can cause problems for individuals in periods of stress and physiological change, such as pregnancy, the symptoms are usually not life-threatening; on the contrary, in the malaria zones of the world the sickle cell trait is beneficial to heterozygotes as it affords some protection from the malaria parasite. This is because entry of the parasite into the red blood cell causes the cell to die before the parasite has time to reproduce. In the major form of the disease when the individual inherits two abnormal genes, one from each parent, the haemoglobin configuration is abnormal. The erythrocytes are sickle-shaped and fragile which leads to severe complications of blood cell lysis and coagulation. Hence, although the homozygous form has implications for the survival of the affected individual, the abnormal gene is maintained within the gene pool because its partial form confers advantage in the gene pool of the population by increasing resistance to falciparum malaria. The absence of the Duffy surface antigen, which is usually present on the erythrocyte cell membrane, also affords protection against malaria as the malarial parasite attaches itself to this particular antigen to enable it to enter the cell.

Case study 7.4

Jane is a 30-year-old woman expecting her second baby. Her first baby was born 3 years ago in rural Africa. She has now returned to this country at 36 weeks' gestation. The blood group results from her first antenatal visit show that Jane's blood group type is O, Rhesus negative.

• What are the implications of this?

• If it is known that her partner has the same blood group, what are the risks of the pregnancy being affected?

• If Jane's first baby was Rhesus positive, what risk is there to the current fetus and how does it depend on its own blood group?

• If a baby is affected by haemolytic disease of the newborn, what clinical symptoms are likely to be evident and how can they be treated?

• If the first baby had been born in England, how would Jane have been treated?

The environment is ever changing and so the process of evolution as a result continues to facilitate adaptation to such changes. The process of evolution itself may then complicate our own understanding of human physiological processes. More than one regulatory system may develop at different times within our evolutionary progression. Different prevailing environmental conditions would thus influence the evolution of changes within the regulation mechanisms to match the change within the environment. Human physiological processes can be described as being in two evolutionary states that are either progressing or declining. Our reproductive physiology may still be influenced by processes that evolved to cope with the Pleistocene environment, in which it is believed that the genus Homo first evolved, even though these may now be in a state of evolutionary decline. In contrast, it is believed that our physiological processes may be responding to ‘younger’ evolutionary influences and therefore be in a state of evolutionary progression. Depending on the external (exogenous) and internal (endogenous) conditions present, the response to either of these evolutionary types may still be initiated.

Key points

• Genetics is a reductionist science that uses mathematical probability to predict the risk of inheriting certain characteristics, usually of medical relevance. Techniques such as combination diagrams and Punnett squares can be used to predict the probability of inheriting single-gene traits.

• DNA is the ‘blueprint’ of the organism, which is organized into chromosomes within the cell nuclei. A gene is a unit of a chromosome, or length of DNA, that codes for a particular instruction. Humans have 23 pairs of chromosomes: 22 pairs of autosomes and a pair of sex chromosomes (XX in females and XY in males).

• The structure of DNA facilitates its semiconservative replication prior to cell division, thus each cell of an organism has the same DNA.

• Mitosis is normal cell division producing daughter diploid cells with 23 pairs (i.e. 46) of chromosomes. Meiosis is a specific cell division in gamete formation that results in the number of chromosomes being reduced to 23 (the haploid number).

• DNA controls protein synthesis by acting as a template for the formation of mRNA (transcription); mRNA induces protein synthesis by directing the incorporation of amino acids into the protein (translation).

• There are accumulated errors in replicating DNA, which may manifest as mutations causing proteins with abnormal structure and function to be formed.

• A trait that is dominantly inherited is expressed if the individual has at least one copy of the gene, whereas a recessively inherited trait is expressed only if the individual inherits the gene from both parents. Sex-linked traits affect males more than females, who may be carriers.

• Chromosomal abnormalities may be numerical or structural and have serious clinical implications for those affected.

• Detection of fetal abnormalities is a routine part of antenatal care, which has developed screening programmes to assess risk and tests to confirm diagnosis.

Application to practice

It is important to realize that the genetic diversity of a population drives the process of evolution and adaptation to changes in the external environment.

Many genes are labelled as abnormal but they may be essential variants that may at least contribute to the survival of the population as a whole.

The focus of antenatal screening of the fetus is based upon the detection of the abnormal using tests that are both invasive such as CVS and non-invasive such as ultrasound scanning. In many situations, the conditions being screened for have a genetic cause or dysfunction. Knowledge of this is essential for the midwife to be able to understand and explain what the tests actually involve and what the results may indicate.

Midwives have an increasing role in the care of women suffering from pregnancy loss for whatever reasons, so an in-depth knowledge of fetal abnormalities is essential in providing care for the women.

Preimplantation genetic diagnosis can be performed on early embryos following IVF before implantation. This means that some genetic conditions can be identified as part of the embryo selection procedures so that only non-affected embryos are replaced into the uterine cavity. This does not, however, guarantee a healthy infant and couples undergoing this technique may have high anxiety levels.

Annotated further reading

In: (Editors: Burley, J.; Harris, J.) Companion to genetics (2004) Wiley-Blackwell.

An interesting multidisciplinary and well-explained collection of essays describing the many ethical, legal, social and political issues raised by the recent developments in human genetics.

Butler, M.G., Genomic imprinting disorders in humans: a mini-review, J Assist Reprod Genet 26 (2009) 477–486.

A clear explanation of genomic imprinting and the effects of aberrant expression and silencing of genes, illustrated by the examples of Prader–Willi and Angelman syndromes.

Department of Health 2008 NHS Fetal Anomaly Screening Programme – Screening for Down's syndrome: UK NSC Policy recommendations 2007–2010: Model of Best Practice UK National Screening Committee.

This booklet gives in-depth details of current methods used in the UK for antenatal screening.

Dupont, C.; Armant, D.R.; Brenner, C.A., Epigenetics: definition, mechanisms and clinical perspective, Semin Reprod Med 27 (2009) 351–357.

A recent review about epigenetic mechanisms which considers the epigenetic issues for assisted reproductive technology and the potential clinical implications.

Emery, A.E.H.; Mueller, R.F.; Young, I.D., Emery's elements of medical genetics. ed 11 (2001) Churchill Livingstone, New York .

A comprehensive textbook which is divided into three parts. Section A focuses on genetic principles, risk prediction and factors influencing inheritance. Section B covers medical aspects of genetics including genetic diseases and genetic factors in diseases. Section C deals with clinical applications, including genetic counselling, ethical issues, screening and diagnosis.

Ferguson-Smith, M.A., Placental mRNA in maternal plasma: prospects for fetal screening, Proc Natl Acad Sci USA 100 (2003) 4360–4362.

A short description of the tests used for fetal screening including the use of placental DNA in maternal plasma.

Genetic Interest Group, A Guide to Cord Blood Banking for Families with Genetic Conditions. (2009) GIG, London .

A concise and well-written pamphlet aimed at families who are considering storing or donating cord blood for treatment of a child (or other relatives or unknown recipients) with a genetic condition. Contains links to useful websites.

Hartl, D.L., Essential genetics: a genomics perspective. ed 5 (2011) Jones and Bartlett Publishers, Inc .

A popular and well-illustrated textbook, suitable for beginners, which clearly explains genetic concepts from the principles of hereditary and genetic analysis to molecular genetics.

Kingston, H.M., ABC of clinical genetics. ed 3 (revised) (2002) BMJ, London .

A slim, well-illustrated volume, targeted at clinicians, which describes genetic mechanisms, diseases and diagnosis.

Maynard Smith, J.; Szathmary, E., The origins of life: from the birth of life to the origin of language. (2000) Oxford Paperbacks .

The authors present their hypothesis on the origin of life and alternative views of evolution focusing on seven transitions from the beginning of life on earth, the chemistry of molecular cycles and the origins of language.

Moore, J.; Bhide, A., Ultrasound prenatal diagnosis of structural abnormalities, Obstet Gynaecol Reprod Med 19 (2009) 333–338.

A succinct paper describing the detection of more common fetal anomalies by ultrasound.

National Collaborating Centre for Women's and Children's Health, Antenatal care: routine care for the healthy pregnant woman. (2008) National Institute for Clinical Excellence .

This guidance details the current recommendations and methods for routine antenatal screening in the UK.

Richards, J.E.; Hawley, R.S.S.H., The human genome: a user's guide. ed 3 (2010) Academic Press .

A description of the human genome project and its implications which considers how genetic issues affect health and public policy; includes chapters on forensics, stem cell biology, bioinformatics and ethical issues.

Ridley, M., Nature via nurture: genes, experience and what makes us human. (2004) Harper Collins, New York .

A readable discourse about the effects of environment on genetics which covers historical and social facets as well as biological aspects of various topics such as child development, schizophrenia and the experience of twins.

Russell, P.J., iGenetics: a Mendelian approach. (2005) Harper Collins, New York .

A modern approach to genetics which covers fundamentals of genetics using an experimental enquiry-solving approach includes experimental data from research studies, critical thinking skills, problems and worked examples.

Shenfield, F., Ethical aspects of pre-implantation diagnosis, Obstet Gynaecol Reprod Med 18 (2008) 312–313.

A brief overview of some of the ethical issues raised by PGD including eugenic practices, fair access to technology, ‘saviour siblings’, social sex selection and late onset disorders.

Tobias, S.T.; Connor, J.M.; Ferguson-Smith, M.A., Essential medical genetics. ed 6 (2011) Blackwell, Oxford .

An updated and well-written text that introduces the basic principles and clinical applications of genetics with a focus on the molecular mechanisms involved in genetic disorders and diseases. Also covers the genetics of common diseases and cancer, prenatal screening and gene therapy.

Turnpenny, P.; Ellard, S., Emery's elements of medical genetics. ed 13 (2007) Churchill Livingstone, New York .

A comprehensive textbook which is divided into three parts. Section A focuses on genetic principles, risk prediction and factors influencing inheritance. Section B covers medical aspects of genetics including genetic diseases and genetic factors in diseases. Section C deals with clinical applications, including genetic counselling, ethical issues, screening and diagnosis.

Wolpert, C.M.; Singer, M.L.; Speer, M.C., Speaking the language of genetics: a primer, J Midwifery Womens Health 50 (2005) 184–188.

A brief background to genetic concepts and terminology included for healthcare professionals working in primary care settings.

Wright, A.; Hastie, N., Genes and common diseases: genetics in modern medicine. (2007) Cambridge University Press .

This book explores the clinical implications of the recent advances in genetic and molecular research, and considers both the potential strengths and limitations of genetics in understanding common diseases.

http://fetalanomalyscreeningnhsuk/tests_about http://fetalanomaly.screening.nhs.uk/tests_about.

This website details current UK antenatal policy with information produced for both public and health care professionals.

References

Aitken, R.J.; Graves, J.A.M., The future of sex, Nature 415 (2002) 963.

Avent, N.D.; Madgett, T.E.; Maddocks, D.G.; et al., Cell-free fetal DNA in the maternal serum and plasma: current and evolving applications, Curr Opin Obstet Gynecol 21 (2009) 175–179.

Badcock, C.; Crespi, B., Battle of the sexes may set the brain, Nature 454 (2008) 1054–1055.

Basille, C.; Frydman, R.; El Aly, A.; et al., Preimplantation genetic diagnosis: state of the art, Eur J Obstet Gynecol Reprod Biol 145 (2009) 9–13.

Brooker, C.G., Human structure and function, In: ed 2 (1998) Mosby, St. Louis, p. 8; 20, 514.

Cioni, R.; Bussani, C.; Scarselli, B.; et al., Fetal cells in cervical mucus in the first trimester of pregnancy, Prenat Diagn 23 (2003) 168–171.

Cleary-Goldman, J.; D'Alton, M.E., Growth abnormalities and multiple gestations, Seminars Perinatol 32 (2008) 206–212.

Craig, I.W.; Harper, E.; Loat, C.S., The genetic basis for sex differences in human behaviour: role of the sex chromosomes, Ann Hum Genet 68 (2004) 269–282.

Darwin, C., On the origin of the species by means of natural selection. (1859) John Murray, London .

Dawkins, R., The selfish gene. ed 2 (1989) Oxford University Press, Oxford .

Dawkins, R., The extended phenotype: the long reach of the gene. revised edn (1999) Oxford University Press, Oxford .

Diedrich, K.; Fauser, B.C.; Devroey, P.; et al., The role of the endometrium and embryo in human implantation, Hum Reprod Update 13 (2007) 365–377.

Eggermann, T.; Eggermann, K.; Schonherr, N., Growth retardation versus overgrowth: Silver-Russell syndrome is genetically opposite to Beckwith-Wiedemann syndrome, Trends Genet 24 (2008) 195–204.

Goodwin, B., Health and development: conception to birth. (1997) Open University, Milton Keynes .

Goto, H.; Peng, L.; Makova, K.D., Evolution of X-degenerate Y chromosome genes in greater apes: conservation of gene content in human and gorilla, but not chimpanzee, J Mol Evol 68 (2009) 134–144.

Grace, K.S.; Sinclair, K.D., Assisted reproductive technology, epigenetics, and long-term health: a developmental time bomb still ticking, Semin Reprod Med 27 (2009) 409–416.

Graves, J.A.M., The rise and fall of SRY, Trends Genet 18 (2002) 259–264.

Gregg, C.; Zhang, J.; Butler, J.E.; et al., Sex-specific parent-of-origin allelic expression in the mouse brain, Science 329 (2010) 682–685.

Hassold, T.; Hunt, P., To err (meiotically) is human: the genesis of human aneuploidy, Nat Rev Genet 2 (2001) 280–291.

Hunt, P.A.; Hassold, T.J., Sex matters in meiosis, Science 296 (2002) 2181–2183.

Huynh, K.D.; Lee, J.T., X-chromosome inactivation: a hypothesis linking ontogeny and phylogeny, Nat Rev Genet 6 (2005) 410–418.

Jones, S., The language of the genes: biology, history and evolutionary future. (1994) Flamingo, London .

Keverne, B., Monoallelic gene expression and mammalian evolution, Bioessays 31 (2009) 1318–1326.

Keverne, E.B., Neuroscience: a mine of imprinted genes, Nature 466 (2010) 823–824.

Loughna, P., Soft markers: where are we now? Obstetr Gynaecol Reprod Med 19 (2009) 127–129.

Open University, Inheritance and cell division. Unit 20 in: Science foundation course (S102), In: (1987) Open University, Milton Keynes, p. 48.

Open University, DNA: molecular aspects of genetics. Unit 24 in: Science foundation course (S102), In: (1988) Open University, Milton Keynes, p. 14; 36.

Ott, W.J.; Taysi, K., Obstetric ultrasonographic findings and fetal chromosomal abnormalities: refining the association, Am J Obstet Gynecol 184 (2001) 1414–1421.

Sadler, T.W., Langman's medical embryology. (2010) Lippincott Williams & Wilkins, Baltimore .

Souka, A.P.; Snijders, R.J.M.; Novakov, A.; et al., Defects and syndromes in chromosomally normal fetuses with increased nuchal translucency thickness at 10–14 weeks of gestation, Ultrasound Obstet Gynecol 11 (1998) 391–400.

Spits, C.; Sermon, K., PGD for monogenic disorders: aspects of molecular biology, Prenat Diagn 29 (2009) 50–56.

Sykes, B., The seven daughters of Eve. (2001) Transworld Publishers, London .