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Genetics & Inheritance

Genetics & Inheritance


A gene is a stretch of DNA that codes for a particular protein. In other words, it is a functional unit of DNA that
codes every protein in the body. It is also defined as a sequence of DNA nucleotides that contain information
for coding a protein.
For instance, DNA sequence (i.e., a gene) of haemoglobin (the iron-containing protein that carries oxygen in
the body) consists of 1,606 DNA nucleotides (see Figure 1 below).

Figure 1: DNA nucleotides of haemoglobin in Homo sapiens1

In general, genes act as the instruction for building proteins, such as structural proteins, enzymes, signalling
proteins (e.g. hormones) and regulatory proteins, in the body (see Figure 2 below).

Figure 2: Genes and Proteins (University of Washington 2012)


Alternations in some of these genes can result in an altered function and a genetic disorder (e.g. inherited
genetic disorders such as Huntingtons disease and cystic fibrosis). Some genes influence a set of
characteristics in a particular way, and hence are responsible for traits such as hair and eye colour, blood group
and facial features. Therefore, a gene is also considered a physical unit of inheritance.

http://www.ncbi.nlm.nih.gov/nuccore/NC_000011.9?report=fasta&from=5246696&to=5248301&strand=true

Genetics & Inheritance

Alleles
Alleles are alternative forms of a gene, that is code for alternative forms of trait (e.g. Hair colour B for brown
hair and b for blonde hair). Alleles are located at a specific position (locus, plural: loci) on the chromosome
(chromosome is the structural organisation of DNA). Because cells (except gametes) contain paired
chromosomes, virtually every cell in the body has a pair of each gene (and therefore, two alleles).
For example, ABO blood group of an individual is determined by alleles of the ABO gene. There are three
main alleles of this gene A, B and O which are located at a specific position on the chromosome 9. Because
chromosomes (and so genes or alleles) are paired, each individual has two ABO alleles which interact to dictate
his/her blood type. For instance, a person with the B allele and O allele will have the B blood type (because O
allele is recessive and B allele is dominant), whereas a person with the A allele and B allele will have the AB
blood type (this interaction, in which both dominant alleles are expressed, is known as co-dominant ).
It is important to note that gametes (sperm and eggs) contain single copies of every allele in the human genome.
That is, chromosomes in gametes are not paired, so gametes contain 23 different chromosomes (22 autosomes
and one sex chromosome). At fertilisation, the sperm and ovum fuse to form an embryo which contains two
copies of each autosomes and two sex chromosomes, that is 46 chromosomes in total). Therefore, one allele is
received from each parent when gametes fuse.

(a) Genotype vs. Phenotype


Genotype
The genotype is the genetic constitution of an individual, represented by the alleles that the individual has (e.g.
F/F or F/f). Simply, it is a persons genetic makeup.
Phenotype
The phenotype is the observable characteristics of a cell or physical features of an individual, usually being the
result of the product coded by a gene (i.e., genotype). Simply, it is the expression of an individuals genotype.
For example, a person with genotype F/F (two dominant freckle alleles) will display freckled phenotype. It is
important to note that the phenotype may, in some instances, be altered by environmental factors and lifestyle
influences.

(b) Homozygous vs. Heterozygous


Homozygous
If an individual receives two identical copies of an allele, they are described as being homozygous for that
particular allele (homo meaning the same). For example, an individual who has received an allele for brown
eyes from the mother and the father (i.e., Brown/Brown or B/B), the offspring will be homozygous for the eye
colour.
Heterozygous
If an individual receives a different allele from each parent, they are said to be heterozygous for the allele
(hetero meaning different). For example, an offspring, who receives one allele for blue eyes and another for
brown eyes, will be heterozygous (i.e., Brown/Blue or B/b).

Genetics & Inheritance

(c) Dominant vs. Recessive


Many genes have two alternative alleles: dominant (represented by a capital letter) and recessive (represented
by a lower case) alleles.
i.

Dominant
An allele that masks or suppresses the expression of a recessive allele. Its presence always leads to
expression of a dominant allele (i.e., dominant allele is expressed in F/F or F/t).

ii.

Recessive
An allele that is expressed only in the homozygous recessive genotype (i.e., two identical copies of
recessive allele e.g. f/f or b/b).

Genetic disorders can be caused by either dominant (e.g. Huntingtons disease) or recessive (e.g. albinism and
cystic fibrosis) alleles.
Because the presence of a dominant allele always results in the expression of its trait, dominant genetic
disorders have a higher chance to get passed to the next generation, than that of recessive genetic disorders.
Recessive genetic disorders that absent when dominant alleles are either homozygous or heterozygous. Unlike
dominant genetic disorders, a single recessive allele (responsible for the disorder) cannot cause the genetic
disorder (e.g. A/a where A is the normal allele and a is the albinism allele). Individuals with such recessive
heterozygous genotype are said to be a carrier of the recessive genetic disorder. Carriers will pass these
harmful genes (i.e., recessive allele responsible for the disorder) onto offspring.

Punnetts square
The Punnetts square is a simple way to represent the pairing of all possible gamete types for a single trait. It is
used to predict genotypes of offspring and expected frequency (or probability) from known genotypes of two
parents.

The genotypic ratio is the ratio of the resultant genotypes. In the table above, the genotypic ratio is X/X:X/Y =
1:1, which means there is a 50% chance of receiving either X/X or X/Y.
The phenotypic ratio is the ratio of the phenotypes expressed by the resultant genotypes (X/X is female and
X/Y is male). The phenotypic ratio of the example above is therefore female:male = 1:1.
It is important to note that the probability of genotype (i.e., the genotypic ratio) never changed, that is, each
offspring has the same probability of receiving genotype. And each is an independent event which has no
influence on the next one (e.g. older siblings genotype has no influence on the probability of genotype that
younger siblings will have).

Genetics & Inheritance

Pedigree
A pedigree is one of major avenues for identifying carriers of detrimental genes; used in diagnosis of genetic
disorders, and genetic screening and counselling. It represents the family history by tracing a genetic trait
through several generations, which helps predict the future.

Carrier

A method of drawing a pedigree:


1)
2)
3)
4)
5)
6)
7)

Collect phenotype information from family members


Note name, D.O.B, gender and medical history etc.
Record partners (spouse)
Proceed through offspring, parents & siblings
Record partners siblings and their children
Record siblings of parents, and their parents and children
Record all four grandparents, and their siblings if possible

* Apply the rules of traits inheritance modes to deduce the genotypes of any family member with unknown genotype.

Genetics & Inheritance

Modes of Inheritance
(a) Autosomal dominant-recessive inheritance
The mode of inheritance in which the gene responsible for the traits of interest is carried on one of the
autosomes (non-sex chromosomes). One allele is dominant over the other in appearance. Examples of this
inheritance are widows peaks, dimples and freckles. The trait of interest can be either dominant or recessive.
i.

Autosomal dominant
This mode of inheritance has a vertical pedigree pattern (see Figure 3); that is, the trait is expressed (or
found) in multiple generation.

Males & females are equally affected


The trait is transmitted by both genders
Each affected individual usually has an affected
parent
Each offspring of an affected individual has a
50% chance of being affected.

For example, Huntingtons disease (HD).

Figure 3: The vertical pedigree pattern of autosomal dominant inheritance

ii.

Autosomal recessive
The autosomal recessive inheritance has a horizontal pedigree pattern (see Figure 4); that is, the trait
(or disorder) is found in the same generation but often skips the generations.

Males & females are equally affected


Consanguineous mating is sometimes involved
Parents & children of affected individuals are
often unaffected
Subsequent siblings of affected individuals have
a 25% chance of being affected.

For example, albinism, cystic fibrosis, Tay-sachs


disease and sickle cell disease.

Figure 4: The horizontal pedigree pattern of autosomal recessive inheritance

Genetics & Inheritance

(b) X-linked inheritance


Genes responsible for the trait of interest is carried on the X-chromosome (sex-linked disorders are usually Xlinked because Y-linked disorders are extremely rare). It is important to note the difference between X and Y
chromosomes because they are not homologous in the true sense (see Figure 5 below).
X-chromosome
carries 2,500 genes
many of these genes code for proteins important
for brain functions (X-chromosome found in
both genders)
Y-chromosome
carries about 15 genes
most genes related to maleness factors
only 5% code for non-sexual traits

Figure 5: Two sex chromosomes, X and Y.

It is also important to note the difference in genotypes between different genders:


Female (XX) inherits two X-chromosomes one X from each parent.
Male (XY) always inherits one X chromosome from mother and one Y chromosome from father.
Because males have no corresponding allele on Y-chromosome, X-linked disorders (which are usually
recessive) affect males almost exclusively. And X-linked traits typically inherited from his mother.
The difference between X and Y chromosomes, and the difference in genotypes between genders account for
gender-biased nature of X-linked recessive disorders.
For example, punnets square for colour-blindness:

normal
colour blindness (recessive allele)
Note that Y chromosome does not carry
colour-blindness allele

Based on this Punnett square information, determine the proportion of children will be colour blind.
Also, compare the phenotypic ratio of male offspring and of female offspring, and if there is a difference,
explain why.

Genetics & Inheritance

Answer:
There is a 25% chance of being affected.
All female offspring will have normal vision, but there is a 50% chance of becoming a carrier of colourblindness. For male offspring, there is a 50% chance of being affected (X cb/Y).
Red/green colour blindness is therefore more common in males. This is because they have one Y chromosome
which does not carry either normal allele (CB) or colour-blindness allele. Thus, males with one affected Xlinked allele (X cb/Y) will become affected (which is typically inherited from his mother).
Now, lets look at the pedigree pattern of this mode of inheritance (see Figure 6).
Knights move:

may appear to
skip a generation
Usually affected
grandfather to
grandson

Figure 6: Knights move pedigree pattern of X-linked recessive inheritance

Males affected almost exclusively


Transmitted from mothers to sons
Never direct male-to-male transmission

It is important to note that transmission of X-linked recessive genetic disorder never occurs between male and
male (i.e., father to son). This is because father always pass his Y chromosome to his son, and son always
receives X chromosome from his mother (who may be a carrier female).

(c) Co-dominant inheritance


Co-dominance, also known as multiple-allele inheritance, is common mode of inheritance. It involves more
than two alternative alleles. For example, the ABO blood groups are determined by three alleles on
chromosome 9, designated A, B, and o. Note that there are two dominant alleles for the ABO blood groups.
As the name of co-dominance (co- means with or together) suggests, when two dominant alleles (i.e., A and B)
appear together, their phenotypes will be evenly expressed. Therefore, an individual with type AB blood has a
genotype of A/B which means that both A and B surface antigens are present on red blood cells. Neither of
dominant alleles is dominant nor recessive to each other.
Blood group
A
B
O
AB

Genotype
I or I Ao
I BB or I Bo
I oo
I AB
AA

Phenotype (Surface Antigen)


antigen A
antigen B
nil
antigen A and B
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Genetics & Inheritance

(d) Other mode of inheritance


In addition to three main modes discussed earlier, there are other unusual or more complex modes of
inheritance such as incomplete dominance and polygenic dominance.
Many phenotypes or physical traits of individual human beings are not determined by a particular gene, but
represented by more than one gene. This type of inheritance is therefore called polygenetic (poly- means
multiple or many) inheritance. As a result, the genetic possibilities of offspring are more complicated to predict
(compared to autosomal dominant-recessive inheritance).
Such variations in phenotypes explain many human characteristics such as skin colour, height, metabolic rate
and intelligence. For example, there are multiple genes for skin colour, so the potential numbers of
combinations of alleles from mother and father that are responsible for skin colour are quite high.
Genetics of skin colour variation can be simplified as below (Note that there are a number of genes and its
alleles responsible for skin colour; more than below):
Dark skin alleles A, B, C
Light/pale skin alleles a, b, c
So an individual with AABBCC genotype would be expected to have very dark skin colour (phenotype),
whereas those with aabbcc genotype would have very pale skin colour.
In addition to these genetic variations, environmental factors, such as amount of time in the sun and usage of
sun protection, influence the ultimate phenotype of the individual.
The concept of polygenetic inheritance will be discussed further in the next chapter in relation to the
inheritance of genetic disorders.

Genetics & Inheritance

Genetic Disorders
In addition to the genetic disorders introduced in the previous chapters (which involve alleles or a single gene),
there are other types of genetic disorders such as chromosomal disorders and multifactorial (polygenic)
disorders. Characteristics of these types of genetic disorders are summarised in the box below:

(a) Chromosomal abnormalities


Genetic disorders in which the entire chromosome or large segments of chromosomes are missing, duplicated
or altered. Chromosomal abnormalities can be categorised as structural or numerical. Structural abnormalities
are usually due to breakage, resulting in multiple congenital abnormalities at birth. Numerical abnormalities are
due to abnormal numbers of chromosomes such as one excess X chromosome in male (i.e., XXY).
As you may have imagined, this is a very severe form of genetic disorders, affecting more than one gene. Under
two main categories of chromosomal abnormalities, there are a number of different types of disorders, but here
we will focus on two types: autosomal trisomy and sex chromosome trisomy. Both types are numerical type of
chromosomal abnormalities as trisomy means three chromosomes of one particular chromosome (i.e., one extra
chromosome present).
i.

Autosomal trisomy
Autosomal trisomy is a trisomy in which there are three copies of a particular autosome (non-sex
chromosome), instead of the normal two (a pair). For example, Downs syndrome is a trisomy-21
which means there are three copies of chromosome 21 (see Figure 7 below).

Figure 7: Inheritance of Downs syndrome


Downs syndrome is the commonest autosomal trisomy with a high incidence in children of older
mothers.
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Genetics & Inheritance

ii.

Sex chromosome trisomy


Sex chromosome trisomy is a trisomy in which there are three copies of a particular sex chromosome
(either X or Y), instead of the normal two (a pair). In comparison to autosomal trisomy, this type is not
severe, and can be tolerated.
For example, Turner syndrome (45, X)2 is caused by the loss of one X chromosome in foetal cells,
producing a female foetus with 45 chromosomes (normally we have 46 chromosomes). This syndrome
is associated with pubertal failure3, or infertile, often short stature but a female with normal intelligence.

Figure 8: Karyotype of Turner syndrome (on the left) and of Klinerfelter syndrome (on the right).
Another example is Klinefelter syndrome (47, XXY) is caused by one excess X chromosome in foetal
cells, producing a male foetus with 47 chromosomes. This syndrome is associated with pubertal failure,
infertile, slightly lower IQ than his siblings (but still within the normal range), often tall with female
distribution of body fat (i.e., larger hips and breasts than normal 46, XY males).

(b) Single-gene disorders


Single-gene disorders involve an alternation in one particular gene, which were discussed in the previous
chapters. Types of single-gene disorders include (but not limited to) autosomal dominant or recessive, and Xlinked recessive disorders.
Of many single-gene disorders, lets explore Huntingtons disease (HD) further which is an autosomal
dominant genetic disorder.

This is a way of reporting karyotypes. Normal karyotype is represented as 46, XX or 46, XY (the number is referring to the total number of all
chromosomes present).
3
Over 95% of cases is reported to be resulted in early spontaneous loss of the foetus

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Genetics & Inheritance

Huntingtons disease (HD)


A progressive neurodegenerative disease characterised by frequent uncontrollable movements and severe
dementia. It is a late-onset disease with mean onset in between 35 to 44 years of age. Individuals with HD have
a median survival time of 15 to 18 years after the onset of symptoms. As the disease slowly progress, individual
with HD experience new symptoms.
Generally, the progression of symptoms is as follows:
Early symptoms mood disturbances4, cognitive defects, clumsiness, impairment of voluntary movement
Second stage slurred speech, hyperreflexia, chorea, gait abnormalities, behavioural disturbances
Advanced symptoms bradykinesia, rigidity, dementia, dystonia, dysphagia
Pathophysiology: Mechanism of HD
The mutation responsible for HD is an expansion of a repeated DNA sequence in the HD gene. This leads to
production of a toxin protein in the structure called basal nuclei (which mainly coordinate voluntary movement,
allowing a fine tuned movement). Toxin proteins will be gradually accumulated in the brain, and finally reach
sufficient toxicity to kill off neurons. Over time, HD causes widespread deterioration of brain tissues outside
the basal nuclei, which explains its late-stage symptoms.
As explained previously, offspring of an individual with HD have a 50% chance of inheriting the disease. This
is because the mode of inheritance of HD is autosomal dominant.

H Huntingtons disease allele (dominant)


h Normal allele (recessive)

A problem with HD is that most affected people


have offspring before the onset of symptoms (which
is usually between 35 to 44 years of age).

(c) Multifactorial (Polygenic) disorders


The concept of multifactorial inheritance implies that a disease is caused by the interaction of several adverse
genetic (polygenic) and environmental factors. The genetic contribution to disease varies; some disorders are
entirely environmental and others are wholly genetic. However, many common disorders and disease do not
follow simply patterns of inheritance within a family.
The term multifactorial or polygenic inheritance haven been used to describe the aetiology of these disorders.
As you may expect, such complexity of diseases and disorders emphasises the importance of understanding
both genetic and environmental factors that contributed to development of a patients disease. This will help
you develop an individualised nursing/midwifery plan for each patient.
4

Possible mood disturbances may include: explosiveness, apathy, aggression, alcohol abuse etc.

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Genetics & Inheritance

The concept described in the first paragraph can be represented in a continuum of diseases (see Figure 9 below).

Figure 9: a continuum of some common disorders

More examples of multifactorial and polygenic disorders are provided in the table below.

You may wonder: Okay, I get that multifactorial diseases involve both genetic and environmental factors. But
what if a multifactorial disease involves more than one gene? Wouldnt it be then polygenic by definition?
In some other genetic textbooks or journal articles, the term multifactorial inheritance implies that a disease is
caused by the interaction of several adverse genetic and environmental factors5.
In general, multifactorial diseases involve the interaction between genetic and environmental factors, whereas
polygenic disorders involve multiple genes. Moreover, environmental factors (in general) have no effects on
polygenic disorders; that is, congenital (born with disorders).

http://ghr.nlm.nih.gov/handbook/mutationsanddisorders/complexdisorders; Kingston 2002, p. 72 from Clinical Genetics ABC

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Genetics & Inheritance

Complex Diseases
There are only some disorders that are caused by mutations in a single gene (e.g. sickle cell disease and cystic
fibrosis). The causes of many other disorders, however, are much more complex and may be inherited as
complex traits.
Common diseases and disorders, such as heart disease, diabetes and obesity, do not have a single genetic cause.
However, they are associated with the effects of multiples gene in combination with lifestyle and environmental
factors. Genetic researchers are learning more about genetics of common disorders, and studying the role of
various genes that play in disease. Their study and work are not limited to genetic disorders, but also include
common illnesses such asthma, arthritis and Alzheimer disease.
In general, genetic factors affect the susceptibility to these complex diseases. It is important to note that genetic
factors interact with environmental factors, which means that, if lifestyle and environmental factors are wellcontrolled (e.g. regular exercise and healthy diet), the risk of obesity will be reduced. Therefore, even if,
individuals have received obesity genes from their parents, there is still a good chance of preventing it.

Figure 10: a model of obesity (Note: there are other models of obesity).

Table: Some obesity genes found to be associated with obesity


As you study a pathophysiology course and other clinical courses, you will come across with genetics of a
particular disease or disorder, as well as environmental factors, in the Epidemiology section. Youll notice that
the major difference between these factors is that genetic risk factors are unmodifiable, whereas environmental
factors are modifiable.
For example, genetic factors account for about one-third of the susceptibility to type 1 diabetes, the inheritance
of which is polygenic. Of many different regions, one particular locus is designated type 1 diabetes, and is
associated with increases susceptibility in Caucasians.
Last updated: 15 June 2014 by DR J
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