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INHERITANCE

LEARNING OUTCOMES

The following topics are covered in this chapter:

• The Mendelian principles of transmission:

♦ unit inheritance: genes and alleles;

♦ dominance: allelic relationships;

♦ segregation – single gene inheritance patterns, Punnet squares;

♦ independent assortment – inheriting two or more genes.

• Exceptions to the rules:

♦ mitochondrial inheritance;

♦ penetrance;

♦ genomic imprinting;

♦ sex-related effects;

♦ mutations;

♦ genetic linkage;

♦ polygenic and multifactorial inheritance;

♦ epistasis;

♦ pleiotropy.

INTRODUCTION

The fact that biological traits can be inherited has long been established. The first significant discoveries regarding the mechanisms of inheritance resulted from the work of Gregor Mendel in the late nineteenth century.

Mendel studied the patterns of inheritance within pea plants while he was working as a monk. His work went largely unnoticed until after the start of the twentieth century. Scientists who were studying the function of chromosomes rediscovered Mendel’s publications and realised that Mendel had discovered the way in which biological traits were inherited. Mendel became known as the Father of Genetics, and the branch of genetics involved with simple inheritance is known as Mendelian genetics.

Although Mendel’s work involved plants, his findings are relevant to human genetics. From his work, he derived certain laws that have become the principles of transmission genetics. Mendel proposed four principles of inheritance: unit inheritance, dominance, segregation and independent assortment. It is these four principles that form the basis of inheritance today.

1. The Principle of Unit Inheritance

Biological traits are determined by genes. Genes are the basic units of heredity. Strands of DNA that encode for one protein form a gene. As chromosomes occur in pairs after fertilisation, genes can be found on both the paired chromosomes. The individual ‘genes’ on each chromosome are termed alleles.¹ An allele is a version of a gene that has a paired version of the same gene in the same location on the opposite chromosome (see Figure 2.1).

Figure 2.1 A gene is usually made of two alleles, one on each of the paired chromosomes.

2. The Principle of Dominance

Alleles can present as different versions of the same gene. If two alleles carried a different sequence of DNA, the effect of one allele might be masked by its partner allele. A dominant allele will be expressed regardless of any instructions carried by the other allele.

In humans, the allele that codes for freckles is dominant over the allele for no freckles. Therefore, an individual who carries two different alleles for this gene – an allele for freckles and an allele for no freckles – will have freckles on their skin. This is because the freckles gene is dominant and will be expressed in that individual. An individual who has two different types of alleles for a single trait (like freckles) is said to be heterozygous for that trait.

An allele that is not expressed, due to the presence of a dominant partner allele, is termed recessive. Recessive alleles are only expressed when both alleles are in a recessive form. Individuals who have either two recessive alleles or two dominant alleles (i.e. two identical alleles) are said to be homozygous for that trait.

Whether an individual is said to be homozygous or heterozygous for a particular trait indicates whether they carry the same or different alleles within that gene. This can be described as the individual’s genotype. A person’s genotype is the genetic make-up for a particular trait. The term phenotype is used to describe the expression of the gene (or paired alleles) for the same trait (Table 2.1).

Table 2.1 Genotypes and phenotypes for freckles

Genotype	Classification	Phenotype
Allele 1	Allele 2
freckles	freckles	homozygous	has freckles
freckles	no freckles	heterozygous	has freckles
no freckles	freckles	heterozygous	has freckles
no freckles	no freckles	homozygous	no freckles

Allelic relationships

Dominant alleles are phenotypically expressed in both heterozygotes and homozygotes. Recessive alleles are only expressed if the alleles are both in a recessive form (homozygous recessive).

Upper and lower case letters are used to represent dominant and recessive alleles. Upper case letters are used to represent a dominant allele and lower case for a recessive allele. If the letter ‘F’ was chosen to represent the gene for freckles, then ‘F’ would represent the dominant allele and ‘f’ would represent the recessive allele. An individual who is heterozygous for the freckles gene would be represented as an ‘Ff’ genotype. A homozygous dominant genotype would be ‘FF’, while a homozygous recessive would be ‘ff’.

Any letter can be chosen to represent different allelic traits. However, it is good practice to choose a letter that has a different form in upper case compared with lower case. For example, A and a, B and b would be good to use but avoid C and c. This helps when drawing out inheritance patterns as different forms can be visually recognised as dominant or recessive, and it avoids errors due to poor handwriting.

Examples of Mendelian traits

Cleft chin

A cleft chin is due to a dominant allele (Figure 2.2). A person without a cleft chin has two recessive alleles for no cleft in their chin.

Figure 2.2 A cleft chin

Ear lobes

Free-hanging ear lobes, as in Figure 2.3, is a dominant trait.

Figure 2.3 Free-hanging ear lobes

Attached ear lobes, as in Figure 2.4, is a recessive trait.

Figure 2.4 Attached ear lobes

Tongue rolling

The ability to form a U shape with the tongue is a dominant trait (Figure 2.5).

Figure 2.5 Tongue rolling

Widow’s peak

When the hairline forms a V shape on the forehead, it forms a widow’s peak (Figure 2.6). This is a dominant trait. Any individual who does not have a widow’s peak is homozygous recessive for a straight hairline.

Figure 2.6 Widow’s peak

Dimples

Having dimples is due to a dominant gene (Figure 2.7). Individuals who do not have dimples when they smile have two recessive genes.

Figure 2.7 A cheek with dimples

Hitchhiker’s thumb

The ability to bend the thumb forward is due to a dominant gene (Figure 2.8). Individuals who have straight thumbs have two recessive alleles.

Figure 2.8 Hitchhiker’s thumb

Carriers

A carrier refers to an individual who ‘carries’ a recessive allele for a particular trait but does not express that trait due to the presence of a dominant allele. Carriers are heterozygous, in that the recessive allele is present but is not expressed. An individual who carries a dominant and recessive allele for the freckles gene (heterozygous) has freckles but is also a carrier of the ‘no-freckles’ allele.

ACTIVITY 2.1

a. Which of the following would be a possible abbreviation for a genotype?

AB Cd Ee fg

b. Do the letters AA describe a heterozygous individual or a homozygous individual?

c. How many alleles for one trait are normally found in the genotype of an individual : 1, 2 or 3?

3. Principle of Segregation

During gamete formation alleles separate so that the gametes contain only one allele of each pair. Allele pairs are restored again after fertilisation.

All the nucleated cells in the body, except for the germ cells (sperm and ova), contain 46 chromosomes. These chromosomes consist of 22 paired autosomes and two sex chromosomes. Mendel’s experiments were only on the traits carried by the autosomes of the plants and, therefore, the principles that he postulated apply to the 22 paired autosomes in humans (see Chapter 4 for sex-linked inheritance).

Somatic cells have the full set of paired chromosomes and are diploid (two copies of each chromosome). Germ cells have only half that amount (haploid) as none of the chromosomes are paired. The separation of the chromosomal pairs occurs during meiosis, leading to the formation of a haploid gamete. When fertilisation occurs between a sperm and an ovum to produce a zygote, the two sets of unpaired chromosomes unite to form a diploid zygote. Alleles combine in the offspring (see Figure 2.9).

Figure 2.9 Meiosis

Working out the different allele combinations in the offspring is straightforward with single gene inheritance. The union of gametes that carry identical alleles will only produce a homozygous genotype (see Figure 2.10).

Figure 2.10 Single gene inheritance

For example, a mother who is homozygous recessive for straight hairline (not a widow’s peak) and a father who is also homozygous recessive for this trait will only produce an offspring who is also homozygous recessive and will also have a straight hairline (see Figure 2.11).

Figure 2.11 A homozygous recessive genotype ‘a’ represents the recessive gene for straight hairline. The dominant gene ‘A’ for widow’s peak is not present.

The union of gametes carrying different alleles for the same gene will produce an offspring with a heterozygous genotype (see Figure 2.12).

Figure 2.12 A heterozygous genotype

There are in fact six basic types of mating for single gene inheritance (Table 2.2). The examples that follow (Figures 2.13i–vi) are for ear lobe shapes, although these examples apply to all single gene recessive and dominant traits. Some individuals have ‘free’ ear lobes while others have elongated attachment of the lobe to the neck. Both ‘free’ ear lobes and ‘attached’ ear lobes are determined by different alleles of the same gene. The allele for free ear lobes is dominant over the allele for attached lobes. The letter chosen to represent the alleles in this instance is ‘E’ (E for ear lobes).‘E’ represents the dominant ‘free’ lobe allele and ‘e’ represents the recessive ‘attached’ lobe.

Figure 2.13i

Figure 2.13ii

Figure 2.13iii

Figure 2.13iv

Figure 2.13v

Figure 2.13vi

Table 2.2 Summary of the six basic types of single gene inheritance

Number	Parents	Genotypes	Phenotypes
i	EE x EE	100% EE	100% free lobes
ii	EE x Ee	50% EE, 50% Ee	100% free lobes
iii	EE x ee	100% Ee	100% free lobes
iv	Ee x Ee	25% EE, 50% Ee, 25% ee	75% free lobes, 25% attached lobes
v	Ee x ee	50% Ee, 50% ee	50% free lobes 50% attached lobes
vi	ee x ee	100% ee	100% attached lobes

Punnet square

An alternative method for working out the possible genotype of an offspring is the Punnet square. The Punnet square helps to visualise the segregation of alleles and the possible combinations within the offspring.

Drawing a Punnet square is quite straightforward once you realise that the parents’ alleles segregate to form a gamete. The main framework consists of a grid composed of four perpendicular lines (see Figure 2.14i).

Figure 2.14i Punnet square

The genotype of one parent is then written across the top of the grid and the genotype of the other parent is written down the left-hand side of the grid. It makes no difference which parent’s genotype is written at the top or the side (see Figure 2.14ii).

Figure 2.14ii As alleles segregate to form a gamete, only one letter is inserted in each box at this stage

By copying the column and row letters in each square, the possible combinations within the offspring can be worked out (see Figure 2.14iii).

Figure 2.14iii Punnet squares can be used to work out the possible genotype of offspring

ACTIVITY 2.2

a. By drawing a Punnet square, what possible genotypes could the offspring of a Bb father and a bb mother have?

b. In the mating of two Bb individuals, what percentage of the offspring would have the same genotype as the parents? What percentage would have the same phenotype?

The maximum number of possibilities for a single gene inheritance is four (corresponding to the four squares in the Punnet square). However, these four possible outcomes can only contribute to a maximum of two phenotypes. In some situations there can only be one possible genotype and phenotype shared by all the offspring. For example, if one parent is homozygous dominant for a particular trait (GG) and the other parent is homozygous recessive (gg) the only possible outcome is for a heterozygous offspring (Gg).

The ability to form a U shape with the tongue is a dominant trait in humans. Consider the dominant allele being represented by the letter T and the recessive allele by the letter t. If two tongue rollers who were both heterozygous for this trait (Tt) had a child, what is the chance that the child would also be a tongue roller?

To work out this problem, a Punnet square needs to be drawn with the parents’ genotypes inserted on the top and side of the square, and the possible offspring combinations inserted into the square (see Figure 2.15).

The results show:

• one homozygous dominant offspring (a tongue roller);

• two heterozygous offspring (tongue rollers);

• one homozygous recessive offspring (a non-tongue roller).

Figure 2.15 Punnet square for tongue rollers

As three out of the four outcomes are tongue rollers, the chance of having a tongue rolling child is 75 per cent.

ACTIVITY 2.3

Albinism is a condition that results in the lack of melanin pigmentation in skin. Individuals with this condition also lack pigmentation in both hair and the irises of the eyes. It is a recessive disorder and the condition only affects individuals if they have two recessive alleles for this condition (aa).

a. If two heterozygous individuals had a child together, what is the chance that one of their offspring will be albino? Work out your answer by drawing a Punnet square.

b. If a female carrier for the albino allele (she has normal skin colouring) has a child with an albino male, what are the possible genotypes and phenotypes for their offspring?

c. What are the chances that their offspring will also be albino like their father?

4. The Principle of Independent Assortment

Mendel’s first three principles address traits that are inherited by single genes. Although there are quite a few genetic traits and conditions that are encoded for by a single gene, most are due to a number of genes that interact together. Since the sequencing of the human genome, scientists have discovered that single gene traits are relatively rare.

Mendel’s fourth principle concerns the inheritance patterns of two different genes. The principle of independent assortment states that different genes control different phenotypic traits and the alleles reassort independently from each other. So even different genes within the same chromosome are independently assorted before the formation of a gamete. This occurs during the crossing-over of genetic material between chromosome pairs at meiosis (see Figure 2.16).

Figure 2.16 Crossing over during meiosis

So, the fourth principle considers genes transmitted on different chromosomes and that the transmission of one gene does not influence that of another gene. Independent assortment is explained through meiotic cell division. Chapter 5 looks at the inheritance of polygenic traits (multiple genes) in more detail.

ACTIVITY 2.4

The eldest son of two curly black-haired parents also has curly black hair. The middle son has straight black hair and the youngest son has curly blond hair. Which of the following Mendelian principles does this illustrate? Dominance, segregation or independent assortment?

EXCEPTIONS TO THE RULES

Mendelian genetics explains the rules of recessive and dominant inheritance. In the last 100 years the science of genetics has developed, giving us more understanding of how traits are inherited on a biological level. Although Mendelian principles still hold true today, there are a few exceptions to the rules.

1. Mitochondrial inheritance

In addition to the 46 chromosomes within the cell’s nucleus, the mitochondria have their own genome. The mitochondrial DNA is not inherited in the same way as the nuclear DNA as it is only inherited from the mother and not from the father. Sperm never contribute mitochondria during the fertilisation of an ovum, so the mitochondrial genome within the ovum remains unchanged. This forms an exception to Mendel’s law of segregation in that both parents do not contribute equally mitochondrial DNA to their offspring.

The mitochondrial DNA only forms a small part of the human genome. To date only 37 genes have been mapped to the mitochondrial DNA, most of which (24 genes) encode RNA molecules that are needed for protein synthesis within the cell’s cytoplasm. The remaining 13 genes encode for proteins that are needed for cellular respiration. The mitochondria, although it has its own genome, is still reliant on genes from the nuclear genome to function adequately.

2. Penetrance

Penetrance relates to the expression of phenotypic features by a single gene. All Mendelian inheritance has a 100 per cent penetrance, but not all inheritance occurs in a Mendelian fashion. The degree of penetrance is measured in percentages. For example, achondroplasia (dwarfism), which is inherited in an autosomal dominant fashion, shows 100 per cent penetrance. This means that all individuals who carry this dominant allele will display the effects of achondroplasia. Other dominant autosomal genes are not always expressed and are said to have reduced penetrance. Ectrodactyly, a condition where the central parts of the hands and feet are not adequately formed, is an example of reduced penetrance. Not all individuals who carry this dominant gene will have deformities in the hands and feet. Degrees of penetrance are measured according to how many people display the phenotype of the gene in question. The BRCA 1 gene defect, which can cause breast cancer, is measured at 75 per cent penetrance, in that 75 per cent of individuals who have this genotype will develop breast cancer and 25 per cent will not.

3. Genomic imprinting

The imprinting of genes is a mechanism where the expression of a gene is governed by whether it was inherited from the mother or the father. Imprinted genes do not fit into the usual rules of inheritance as the contribution from one parent has been silenced. Both dominant and recessive genes can be imprinted. These genes are ‘marked’ with the sex of the parent that contributed it. There is no change to the actual DNA structure within these genes but a molecule of methyl is attached to the gene.

This process starts during gamete formation when certain genes are imprinted in either the developing sperm or the developing ovum. After fertilisation, the resulting offspring will have the same set of imprinted genes from both parents in all their somatic cells. However, the inherited imprinted genes will lose their methyl markers in the offspring’s germ cells (sperm or ova). The inherited markers are removed in the germ cells and are ‘reset’. This is done so that the new markers correspond to the offspring’s own sex. A particular gene can therefore be turned on or off as it is passed through successive generations, from male to female to male.

The function of imprinted genes is not well understood. One possible reason for imprinting genes might be due to their role in embryonic development. Some genes lose their markers after birth, which suggests that imprinted genes may have an important role in regulating protein synthesis during pre-natal development.

Imprinted genes are important for normal development and health. If an imprinted allele is not silenced the cell receives two active copies of the allele and this results in over-expression of that gene. Similarly, if both alleles are imprinted the result is under-expression of that gene. This is the reason that parthenogenesis (virgin birth) is not possible in humans. An offspring needs both male and female genes so that the right proportion of genes is activated.

4. Sex-related effects

Some phenotypic traits are not inherited in a Mendelian fashion as they may be influenced by the sex of the individual. Some traits will only be expressed in one sex and not another, like, for example, beard growth. This is an example of a sex-limited trait, as beard growth is limited to males (even though both sexes inherit the gene).

Other traits can act as dominant in one sex and as recessive in the opposite sex. An example is male-patterned baldness in men. The allele for baldness acts as a dominant allele in males but as a recessive allele in females. This is known as a sex-influenced trait. (Females do not usually go bald, even with two recessive alleles for the baldness trait, due to the absence of necessary hormones.)

5. Mutations

A mutation is a permanent change in the sequence of chromosomal DNA. Mutated genes can be inherited in a Mendelian fashion. However, mutations can occur by chance and alter the genetic trait inherited by the offspring. For example, two parents of normal stature having a child with achondroplasia (dwarfism). As achondroplasia is due to a dominant gene, the affected offspring must have inherited or developed a change within the parental DNA because neither of the parents has achondroplasia.

Dynamic mutations are progressive changes within the DNA that occur from one generation to the next. This usually involves expansion of the DNA molecule that encodes for a particular gene. The genetic disorder resulting from this mutation might not appear for a few generations until the DNA within the gene has reached a particular length. Fragile X syndrome and Huntington’s disease are just two examples of genetic conditions caused by dynamic mutations. Chapter 6 covers mutations in more detail.

6. Genetic linkage

Genetic linkage refers to different alleles that are positioned closely together on the same chromosome. Mendel’s experiments were mainly on traits found on different chromosomes. When genes are located close together on the same chromosome, Mendel’s prediction of independent assortment does not hold true.

Linkage refers to the transmission of genes on the same chromosome. The closer they lie, the less likely it is that they will separate during cross over in meiosis (see Figure 2.17). Individuals that have mixing of maternal and paternal alleles on a single chromosome have a parental or recombinant gene. These linked genes are inherited together and do not produce the Mendelian ratios of inheritance.

Figure 2.17 Linkage

7. Polygenic and multifactorial inheritance

Polygenic traits are controlled by the alleles of two or more genes without the influence of the environment. Many phenotypic traits are controlled in this way. However, both single gene and polygenic traits can also be multifactorial. Multifactorial traits are the result of both genetic and environmental influences. Most genes are actually multifactorial.

Human height is an example of a multifactorial trait. Genes are present that encode for height, but an adequate diet is needed to reach that height. Malnutrition in early childhood can have an effect not only on height but also on neurological development as well as other biological systems. Accidents at any stage of life can also alter an individual’s phenotype. Multifactorial traits tend to follow Mendelian inheritance patterns, but the phenotypic results are difficult to predict due to the influence of the environment. Polygenic and multifactorial traits are discussed in greater detail in Chapter 4.

8. Epistasis

When one gene masks the effect of another unrelated gene it defies normal Mendelian inheritance patterns. Epistasis refers to the interaction of different genes, not between alleles of the same gene. A simplified example of epistasis in humans is that of the curly hair gene and the baldness gene. Although the curly hair gene is still expressed, it cannot have any effect on the phenotype of a bald individual.

A large number of proteins encoded by genes are involved in metabolic pathways. The absence of one step within the pathway will alter the outcome of the whole pathway. In epistasis, the remaining proteins needed to complete the pathway are present but are unable to interact in the pathway due to the ‘missing step’.

The Bombay phenotype within the ABO blood grouping in humans is also an example of epistasis. ABO blood groups are due to the presence of A and/or B antigens on the surface of red blood cells. The A and B antigens are attached to the cell surface by proteins that are embedded in the cell membrane. The A and B antigen is encoded for by one gene and the protein attachments are encoded for by a different gene. If an individual does not have an effective gene to encode for the protein attachments, then the A and B antigens have no means of attaching to the cell surface. This individual would then display a blood group O phenotype, even though the genotype might be AB.

9. Pleiotropy

Pleiotropy is the expression of several different phenotypes by a single allele. Most single genes affect more than one observable trait. Pleiotropy occurs in genes which encode for a single protein that has more than one function within the body. Genetic disorders involving a pleiotropic gene are difficult to detect within families, as different members of the same family may display different symptoms. Marfan syndrome (see Chapter 7) is an example of a human condition arising from a pleiotropic gene, in that members of the same family can display different phenotypic traits arising from the same gene.

ACTIVITY 2.5

a. Benign epidermolysis bullosa is a condition that arises from an abnormal gene that encodes for collagen. The effect of this faulty gene results in the loss of skin and hair and in abnormal nails and teeth. Which of the following exceptions to Mendelian inheritance is this an example of: sex-related inheritance, genomic imprinting or pleiotropy?

b. One form of blindness is the autosomal dominant retinitis pigmentosa. The faulty gene that causes this type of blindness is incompletely penetrant. What do you understand by this statement?

Geneticists have identified thousands of genes that can lead to different traits, conditions and diseases. As more are discovered it is becoming clear that the ‘exceptions to the rules’ identified here are relatively common. However, a large proportion of traits are inherited in the Mendelian fashion.

SUMMARY

• Gregor Mendel, the father of genetics, outlined the four principles of inheritance. The principles of unit inheritance, dominance, segregation and independent assortment form the basis of Mendelian genetics.

• The principle of unit inheritance involves the transmission of hereditary units called genes. Genes are made up of two alleles, inherited from both parents.

• The principle of dominance involves the action of individual alleles within a gene, in that they are either dominant (will be expressed) or recessive. Recessive alleles are only expressed if both alleles are in a recessive form (or by the absence of a dominant allele).

• The principle of segregation refers to the separation of allelic pairs during meiosis. Allelic pairs are restored again at fertilisation.

• The principle of independent assortment concerns the inheritance patterns of two different genes. Alleles and genes resort independently from each other.

• An individual’s genotype refers to their genetic make up and their phenotype refers to the outward appearance or the measurable effect of that gene.

• The term homozygous refers to two alleles that carry the same DNA in the same gene and heterozygous refers to different alleles within the same gene.

• There are exceptions to the Mendelian principles that include:

♦ mitochondrial inheritance – maternal inheritance only;

♦ penetrance – not all dominant genes are expressed;

♦ genomic imprinting – some alleles may be silenced;

♦ sex-related effects – may be sex-limited or sex-influenced;

♦ mutations – DNA alterations can occur by chance as well as being inherited;

♦ genetic linkage – alleles that are positioned closely together on the same chromosome have a higher chance of being inherited together;

♦ polygenic and multifactorial traits – more common than single gene traits and may be influenced by the environment;

♦ epistasis – unrelated genes can mask the effect of a gene;

♦ pleiotropy – one single gene can result in the expression of different phenotypes, as one protein may have more than one function.