1 – Topic 1 – Basic Human Genetics

Topic 1 – Learning outcomes

Key:
Lecture content
Practical content
1.1 Describe the structure of the human genome
1.2 Demonstrate knowledge of the structure of DNA
1.3 Understand the processes of DNA replication; transcription and translation
1.4 Describe different sources of genetic variance, including gene mutations, triplet repeats,
SNPs, CNVs; chromosomal changes
1.5 Appreciate how genetic variation, through affecting protein functioning, can ultimately
affect the phenotype
1.6 Describe the key principles of genetic transmission
1.7 Understand how simple genetic ‘laws’ can underlie complex processes
1.8 Recognise the different mechanisms underlying genetic influence on phenotypes, including
singe gene, sex-linked and polygenic effects
Covered in: Lecture week 1 (1.1 – 1.5); practical week 2 (1.6 – 1.8)

Lecture 1 – Basic Human Genetics – Part 1

Lecture 1 – Learning outcomes
• Describe the structure of the human genome
• Demonstrate knowledge of the structure of DNA
• Describe different sources of genetic variance, including gene mutations, triplet repeats, SNPs,
CNVs; chromosomal changes
Definition of genetic variance - Genetic variation encompasses the differences in DNA sequences
between individuals, which can lead to variations in traits or phenotype.
• Appreciate how genetic variation, through affecting protein functioning, can ultimately affect
the phenotype

Genetic approaches to studying individual differences

This module is interested in - Why do people differ from one another?
Genetic approaches to studying individual differences aims to understand how genetic variation
contributes to the variation in psychological traits behaviours and abilities.
Some methods/approaches for this approach are:
Twin studies – looks at identical twins – or also known as Monozygotic Twins
Adoption studies – Looks at both the family and the child who has been adopted from that family
Genome-wide association studies (GWAS)
Epigenetics
Candidate gene studies – Outdated method
Molecular genetics – Outdated Aswell

Heritability of a trait/disease
 When looking at the heritability of a condition or a disease, we will use twin/family or adoption
studies.
 From twin studies we are able to measure to what extent the variability of this trait exists in a
population and what percentage of this consists of environmental factors or genetic factors.
Doesn’t tell us which particular genes or which particular environmental influences are of
importance.
 This will give us an estimate of how much nature or nurture is important

Gene Localisation
 Once we have established there is some evidence of heritability of this trait that we are studying,
we can use another method of studying called Gene Localisation, where we can approximately
look on the human genome, as to where the genes are located that may be of influence to this
trait.
 An example of where Gene Localisation can be used is in Linkage Studies which can give us a
rough idea of where the gene may be located

Gene Identification
  However, linkage studies are not used as much anymore and Gene Association studies are
becoming more common, and these association studies can give us an idea of where exactly, on
the genome, the genes that are of importance are located. – Now we are identifying genes.
 Once this has been used in many studies and a particular gene has been shown to be of interest
then we can start doing further biological studies to study the gene structure and what type of
protein the gene codes for, so what the role is of the gene in functioning of the body.

Genetic differences
 This module is interested in individual variation/genetic variation. Differences between people
are due to genetic differences.
 For example if we are studying gene variants that influence individual differences in height, we
are not studying why everyone grows up to a certain minimum height. Why, for example, does
everyone in a particular classroom have at least a height of 1.50 meters? We are interested in,
why do people differ in their height? Why is the one person taller than the other? Might there
be genetic variants that explain part of these differences in height?
 And so to appreciate possible roles in genes, in individual differences of traits and disease, it is
essential to understand the basics of human genetics and the sources of genetic variation.

The Human Genome

 The human body consists of 23 PAIRS of chromosomes altogether
 22 pairs of these are in both males and females and these are called autosomes
 Autosomes contain most of the genetic information in your body. For example, this is
information like hair, colour, height – everything except for biological sex
 The remaining 1 pair are sex chromosomes.
 1 pair of this is the sex chromosome which makes up the gender of the child and this is XX and
XY
 XY = Males
 XX = Females
 The ‘Y’ chromosome in male individuals instructs the development of the testes, so when ‘Y’ is
present testes will be developed, resulting in a male phenotype
Genes on Chromosomes
• Genes organised along the chromosome; and these genes are positioned in the same order in
homologous pairs. You inherit one chromosome from your mother and one from your father.
Genes on these chromosomes are usually very similar but their also may be differences.
• Different variants of genes : alleles

GENES THAT EXIST IN DIFFERENT VERSIONS = ALLELES

Gene Variants/ Allele

 These differences in alleles can induce differences in bodily functioning and result in observable
differences in the phenotype. E.g., Albinism – aa – shows albinism, AA – normal skin and Aa –
normal skin.
 A – Dominant allele
 a – Recessive allele
 An allele is a variant form of a gene. Genes, which are located on chromosomes, are responsible
for the inheritance of traits. Alleles are the different versions of that gene that can exist.
 Heterozygous and homozygous - these are the ways in which genes can be expressed
Heterozygous - Two Different Alleles (Aa) - usually expresses the dominant trait
Homozygous - Identical Alleles (AA) (aa) - can express a dominant or recessive allele
Dominant Allele - An allele that expresses its trait even when only one copy is present. It masks the
presence of a recessive allele in a heterozygous pairing
Recessive Allele - An allele that only expresses its trait when two copies are present (homozygous). Its
effect is masked by the presence of a dominant allele in a heterozygous pairing.
 Soo, in example, the a is the the like trait that is different from the normal one, so for example, a
= albinism and A = normal skin

Phenotype and Genotype

Genotype = Unique combination of all alleles in individual – combination of all alleles
Exception: identical twins (have the same genotype)

Phenotype = Observed characteristic of individual and in this is something we can measure or something
that clinical psychologists may want to measure, e.g. ‘blood pressure’; ‘weight’; ‘extraversion score’;
‘depressive symptoms score’

Phenotype/individual differences is due to = differences in genotype + differences in environment

In family studies differences might be shared:

Phenotype = individual differences in genotype + shared environment – e.g., live in same house
environment etc + unique environment – this is environmental influences that family members don’t
share
 Unique is what the individual alone has but what they do not share with their family

Chemical Structure of DNA

 In 1953 Watson, Crick & Franklin discovered the 3-dimensional structure of DNA: the double
helix
 Watson & Crick were awarded the Nobel prize for Medicine in 1962
Chemical structure of DNA
• DNA’s double helix: 2 strands of DNA coiled around each other like a spiral staircase
• A nucleotide is the basic unit of DNA is made up of 3 parts:
- Phosphate – This provides a backbone structure for DNA
- Deoxyribose also known as sugar
- A nitrogenous base – There are 4 bases

Sugar: deoxyribose; hence Deoxyribose Nucleic Acid

These 2 strands are complementary to each other. This means that the sequence of
bases (adenine, thymine, guanine, and cytosine) on one strand dictates the sequence
on the other, with adenine (A) always pairing with thymine (T) and guanine (G) always
pairing with cytosine (C).
There are 4 types of bases:
1. Adenine
2. Guanine
3. Cytosine
4. Thymine

The sugar and the phosphate of the different nucleotides bind together to form one
single DNA strand.
• Sugar and phosphate of different nucleotides bind together to form one single DNA strand
Pairings of the two DNA strands

 CG will always be paired together

 The C always pairs with the complementary strands, with the G base
 So Cytosine and Guanine will always be paired together
 TA will always be paired together
 The T base always pairs with the complementary strands, so with the
A base, so Adenine and Thymine will always be paired together
 We only need to know what is on one strand to know what is on the
next strand
 These are called complementary based pairings

Lecture 2 – DNA replication/translation/transcription

Learning outcomes
• Understand the processes of DNA replication; transcription and translation
How can we create new cells with identical copies of DNA?

DNA replication
Base pairing between 2 DNA strands:
• A pairs with T
• C pairs with G
 2 strands are complementary.
DNA Replication

• The original double helix unwinds and comes apart at the end, revealing two single strands of
DNA. This process of unwinding is done by an enzyme called Helicase.
• Each single strand now forms the template for the creation of its complementary strand.
• The enzyme DNA polymerase is responsible for the creation of these new strands, shown here
in the image.
• T on the template strand results in creation of an A on the new strand, a C on the template
strand to a G on the new strand, and so on, so that ultimately the new strands form identical
copies of the original molecule.
• Once the new strands are created they coil up together with their parent strand into two
daughter double helices.

Gene to protein
How do genes exert their effects? Genes code for proteins and these
proteins in turn affect bodily functioning by for example influencing
muscle function; the endocrine system, or the nervous system. These
bodily functions ultimately affect our cognition and behaviour, for
example, motor movements; emotions; and thought processes.
This is not just a one-way process: bodily functioning; cognition /
behaviour can also affect gene expression and affect how much of the
protein is produced.
DNA to protein – how does the DNA code result in the production of a protein

From DNA – to RNA

 This process comprises of two phases transcription and translation.
 First DNA is transcribed into RNA; RNA is then translated into protein.

In DNA the sugar is a deoxyribose, hence the name Deoxyribose Nucleic Acid, or DNA;
In RNA instead, the sugar is a Ribose, and thus called Ribose Nucleic Acid.
In RNA, the 4th base is a U (Uracil) instead of a T.
• RiboNucleic Acid
• single strand instead of double strand
• Bases
- Adenine (A)
- Guanine (G)
- Cytosine (C)
- Uracil (U) – we will never find a T base in RNA

DNA Transcription
In the first step of DNA transcription the DNA double helix unwinds. Unlike in DNA replication, this time
only one of the strands is used as a template for RNA synthesis. This strand is called the template
strand. The other one that will not be copied is called the non-template strand. The enzyme RNA
polymerase induces the production of RNA. A T in the DNA template strand results in the production of
and A on the RNA strand, a C to a G and an A on the template strand results in the addition of U, for
Uracil to the RNA molecule.

Translation
• RNA code composed of consecutive 3-base sequences: also known triplets or codons
• Each codon codes for amino acid
• RNA bases: letters; triplets: words
 words form sentences: instructions to build protein

 The RNA code is composed of 3-base sequences, also called triplets or codons. Each codon codes
for one specific amino acid. A chain of different amino acids in turn forms the resulting protein.
 So, another way of thinking of it is that the RNA bases are the letters, and triplets are the words.
The words form sentences, these sentences are the instructions to build the protein.

Translation
 • RNA transcribed from DNA is called messenger RNA (mRNA). mRNA is produced in the nucleus
• Translation into amino acid sequences to form protein takes place on ribosomes in cytosol
• With help of transfer RNA (tRNA)
RNA that is transcribed from DNA is called messenger RNA or mRNA. It is produced in the nucleus of the
cell. Translation into amino acid sequences to form protein takes place on the ribosomes in the cytosol of
the cell. Messenger RNA is like the postman, delivering the message from the nucleus to the ribosomes.
ON the ribosomes the transfer RNA supports the translation from RNA sections of codons into sequences
of amino acids.

Translation
  The transfer RNA carries the amino acid corresponding to the codon of the mRNA. Consider the
image shown here. One tRNA molecule is already bound to the mRNA. A second tRNA,
corresponding to the second codon of the mRNA is about to bind. The two tRNAs bind together
and this leads to binding of the two amino acids they carry. Once they are bound the first tRNA is
released. One by one other tRNAs are added and released, resulting in a growing amino acid
chain.

Translation
• Translation always begins with start codon ‘AUG’ (coding for Methionine)
• Translation ends with one of three stop codons

Each codon codes for one of 20 amino acids. For example, UUU and UUC code for the amino acid
Phenylanaline.
Translation always starts with start codon ‘AUG’ in RNA code, coding for Methionine.
Translation ends with one of three stop codons: UAA, UAG or UGA. With a stop codon the production of
amino acids stops and no further amino acids are added to the chain.

Protein structure and function

• Each amino acid chain has its own 3-D shape
• Unique shape of each protein is important to carry out its function

Example: 3D shape myoglobin

 Shape enables protein to carry oxygen
Each chain of amino acids has its own 3D shape. The
unique shape of each protein is important in order for
it to carry out its function. Take for example the
protein myoglobin. Myoglobin transports oxygen in
muscle cells. The unique 3D shape of myoglobin means that it is perfectly suited to carry the oxygen,
shown as the red disk here.

Protein structure and function

• Example 1: enzymes (proteins that speed up chemical reactions) have
uniquely shaped ‘binding sites’ so that their function is very specific
• E.g. enzyme lactase only binds to lactose, doesn’t break down other
substances
• If amino acid chain changes (e.g. because of change in DNA code)
then 3D shape of enzyme changes and will no longer function
properly

The exact 3D shape of the protein determines how well the protein can carry
out its function. Take for example enzymes, these are proteins that speed up
chemical reactions. Enzymes have uniquely shaped binding sites and this
makes their function very specific. For example, the enzyme lactase only binds
to lactose and causes the lactose to be broken down into smaller
components. Lactase doesn’t break down any other substances, only lactose
If the amino acid chain changes, for example because of a change in the DNA
code, then the 3D shape of the enzyme changes and the enzyme will not
longer function properly.
Protein structure and function
• Example 2: transport proteins allow transportation of particular
substances through the cell membrane
• Change in amino acid would result in change of protein shape and
loss of (or impaired) function.

Here is a second example: Cells have transport proteins embedded in the

cell’s membrane. These proteins allow transportation of particular
substances through the cell membrane, while others are blocked. A change
in amino acid would result in a change of protein shape and a loss of or
impairment of function of the protein: the transport protein no longer
allows transportation of the substance so well, or it lets through substances
that it would previously have blocked.

Summary
Messenger RNA is acting as a messenger carrying a copy of a code for a specific protein.
The MRNA is leaving the nucleus and moving towards the ribosome where the proteins are made and
the ribsome then reads the code that the MRNA has delivered in a group of letters called codons.
What are codons. A codon is a seqyence of three bases in which they form a word that tells the
ribosome whcih amino acid to add next in the chain when building a protein. MRNA is along list of
nucleotides which are made up of 4 bases (Adenine, Guamine, Uracil, Cytocine. There are around 20
different amino acids whcch are able to poduce 64 codons. So from here each codon tell the ribosome
what amino acids are needed in order to build the protein and Transfer RNA comes into place here and
directs the right amino acids based on the instructions provided by the codons.

Lecture 3 – Basic Human Genetics

Gene expression/Mutation/Triplet repeats/ CNVs/ SNPs

Gene Expression
• Only 2% of DNA codes for proteins
• What is the role remaining 98%? This 98% is non-coding DNA THAT DO NOT code for amino
acids
• Previously referred to as ‘junk DNA’ but now known that ‘non-coding’ DNA serves important
purposes, especially in gene expression.
• Genes are not ‘switched on’ in all cells, and may be switched on and off over time

Gene expression
Example – Protein Myoglobin
 Myoglobin plays an important role in the transportation of oxygen in muscle cells. So, in muscle
cells the gene coding for myoglobin will be switched on when myoglobin is needed.
 However, in other cell types, away from the muscles, myoglobin isn’t needed, so the gene is
permanently switched off. Even within muscle cells new myoglobin production won’t be needed
all the time, so the gene coding for myoglobin will be inactive when it’s not needed.
 Developmental periods – Genes may also be switched on or off in particular developmental
periods. For example, some genes are only active during puberty. But changes in gene
expression may also occur in much shorter time spans. You are changing the rates of
transcription of genes for neurotransmitters in your brain by listening to this sentence.

Non-coding DNA
• Some of non-coding DNA has role in regulating gene expression (switching genes on and off)

• Exons: protein-coding DNA

• Introns: Non-coding DNA – they regulate gene expression

Transcription Factors
 • Transcription factor regulates whether gene is transcribed or not
• Most genes: many different expression regulation mechanisms  many different transcription
factors together ‘act as a committee’ to regulate expression

• Here is an illustration of how regulation often works for classical protein-coding genes.
• These genes include regulatory sequences that normally block the gene from being
transcribed.
• If a particular molecule, also called a transcription factor, binds to the regulatory sequence, it
will free the gene for transcription. The regulatory sequence is part of the intron: it does not
itself code for a protein but regulates the expression of the nearby exon that DOES code for a
protein. Most genes have many different expression regulation mechanisms. All these different
transcription factors together act as a committee to regulate the gene’s expression.

Gene Expression

 Some of developmental timing of gene expression is regulated by genes. For example,

homeobox genes control the timing of development of body parts prenatally, making sure that a
hand is formed at the end of an arm, and that on that hand there will be 5 fingers. This process
of timing is regulated by homeobox genes, which control the expression of relevant genes coding
for the development of these different body parts.
  However, many aspects of timing of gene expression is not programmed in DNA but dependent
on products of earlier gene transcription, and on environmental influences. The environment
can play an important role in gene expression. For example, tweaking a rat’s whiskers causes
changes in the gene expression in cells of the rat’s sensory cortex. So it’s important to remember
that the effect of DNA is not set in stone. Whether that DNA is actively transcribed and
translated into proteins that affect bodily functioning and our behaviour and cognition is
influenced by the environment.

Human genome: similarities and differences

 The 23 chromosomes that comprise the human genome include approximately 3 billion base
pairs. These base pairs code for around 25,000 protein coding genes. Most of the DNA code is
shared between all humans and make us similar.
 There are differences in about 1 in every 1000 base pairs. These genetic differences may in turn
affect individual differences in behaviour, or susceptibility for disease.
 For about 2 million base pairs these differences occur among at least 1% population.
 When this genetic variation occurs in at least 1% of the population we call it a common gene
variant. If the gene variant is present less often than 1% of the time, we call it a rare gene
variant.

Gene transmission from parents to offspring

 This image shows how genes are transmitted from parents to offspring. Cells in the parents’
bodies, also called comatic cells, each have 2x 23 chromosomes. There are two copies of each
chromosome, also called a diploid number of chromosomes. The only exception are germline
 cells, or the cells present in the sperm of the father and the eggs of the mother. IN these cells,
also called gametes, there is only 1 copy of each chromosome, or 23 in total, that is 1 copy of
each of the 22 autosomes; + 1 X or 1 Y chromosome. These are called haploid cells.
 When the egg gets fertilised by the sperm, the genetic information of both haploid cells
combines into a new diploid cell, which includes 23 chromosomes from the father and 23 from
the mother. The result is a child who is a genetic mixture of both parents.
Di= two
Half = haploid = 1
Parent cells = somatic cells
All have 2 x 23 = 46 chromosomes
Haploid cell are only sex cells – so only gametes – there is only 1 of each cell in this – 23 – SINGLE COPIES
In a sperm cell = 23 – either x or y chromosomes
In egg cell = 23 – only x chromosomes
When sperm and egg cell join – they make a diploid – children get half of their dna from each parent

Genetic variation

Variation between gametes that parent can transmit to offspring

• Segregation (only 1 of each pair of chromosomes transmitted)
• Independent assortment (which chromosome within pair is transmitted is random)
• Crossing-over between members of homologous pairs
Which combination of 23 chromosomes a parent transmits through their gametes is highly variable: each
parent only transmits one of each pair of chromosomes and exactly which one is a random process. The
genetic variation is made even greater through a process called crossing over. When gametes are
produced during the cell division process meiosis, rather than each pair of homologous chromosomes
neatly going into their own respective daughter cell, the process is much messier and complex in
practice. Throughout the process of meiosis a chromosome often breaks and is then later glued back on.
Often this rejoining is done to the other member of the chromosome pair, and the result is a
chromosome that is much more a genetic mixture than its original. This genetic mixing becomes
especially apparent after several different generations.

Summary
 Each parent has 2 pairs of chromosomes, but when they make the sex cells (gametes) they only
pass 1 copy from each pair
 Which pair you get is random
  During meiosis (the process that makes sperm and egg cells), homologous chromosomes (the
matching pairs) line up
 While they’re lined up, they swap pieces with each other.
 This is called crossing over.
 The result is that the chromosome that gets passed on to the sperm or egg is not an exact copy
of either parent's chromosome — it’s a mix.
 They can break and rejoin in different ways during meiosis.
 Often, the broken pieces rejoin on the other chromosome in the pair.
 This makes a new version of the chromosome with bits from both parents' original versions.
 So the final result is even more genetically mixed.
 With each generation, crossing over and random selection happens again.
 So over time, the chromosomes passed down get more and more mixed — like blending
different paints together.
 You inherit 1 of each chromosome pair from each parent — randomly.
 Crossing over during meiosis mixes the genes even more.
 This is why siblings look different, and why everyone (except identical twins) is genetically
unique.
 It’s also how genetic diversity happens naturally in populations.

Genetic variation explained through gummy bears

 This photo explains genetic variation through gummy

bears.
 Here you see two parent gummy bears, one red and
one white.
 They have children that are a genetic mix of the
parents, half red, half white.
 One of the children then has children with a partner,
who is green.
 Their kids are each a different unique mix of red,
green and white.
rd
 One of the kids in the 3 generation has children with an orange bear.
 This 4th generation is each a unique mix of green, red, white and orange.
 Each child inherits 50% of their genes from each parent.
 On average each child shares 50% of their genes with their siblings, but exactly which genes they
have in common or where they are different is completely due to chance.

Mutations
 Genetic variation stems from changes in the DNA, also called mutations.
 Mutations can happen in all types of cell.
 They often happen in somatic cells, these are the bodily cells other than gametes.
 If a mutation happens in a somatic cell they are not inherited by the offspring, so the genetic
change will not be transmitted to the next generation.
 Some of these somatic mutations can be the cause of cancer.
  If a mutation happens in a gamete they will be passed on to offspring and result in new alleles
that cause heritable genetic variation.
 So these are mutations that cause different forms of DNA within the population, also called
polymorphisms.

Different types of mutation

 The most common DNA polymorphisms are Single Nucleotide Polymorphisms, or SNPs.
 These are gene variants where only a single nucleotide in the DNA sequence has changed. For
example, a C has been replaced by a G, or a G has been replaced by a T.
 SNPs have only two versions, for example TTT is the most common version of the gene, and TTC
occurs in 2% of the population. – they will have a one base change
 There are two types of SNPS: - Nonsynonymous SNPs are SNPs that involve a change in the
amino acid sequence they code for. Synonymous SNPs are SNPs where the DNA code has
changed, but the codon still codes for the same amino acid, so the resulting protein chain
doesn’t change.
Other types of mutation are insertions or deletions, where one or more bases are inserted or deleted,
leading to a longer or shorter code and a longer or shorter protein chain.
Synonymous – one change in the base of the DNA WILL NOT CHANGE the protein your body makes – the
new sequence will code for the same protein
Non-synonymous – one change in the base of the DNA WILL not change the protein your body makes.
The new sequence will code for the same protein

Effect gene mutation

Consider image a, showing a sequence of DNA within a gene, coding for a sequence of amino acids that
form a protein.
Now consider image b) Here in the 5th codon a point mutation has occurred: the C has changed into an
A, so the codon now reads AAT instead of CAT. This codon codes for a different amino acid, meaning the
sequence of amino acids in the resulting protein is now different. This slightly different sequence will
have a slightly different 3D shape, and will therefore function slightly differently. – this is a non-
synonymous SNP.
Now look at image c). Here a second type of mutation has occurred: due to a deletion, 6 nucleotides, or
2 codons, have been lost. The resulting protein is 2 amino acids shorter, and this again will alter the 3D
shape and thus the function of the protein.

Effect single nucleotide gene mutations

• TTT  phenylalanine
• TTC  phenylalanine (synonymous mutation)
• GTT  valine (non-synonymous mutation, called ‘missense’)
• AAA  lysine
• TAA  stop codon  truncates protein (non-synonymous mutation, called ‘nonsense’)
•  effect nonsense mutations usually more severe than missense mutations

 Different types of mutation are possible, causing serious or less serious effects.
 For example, when a mutation occurs in the codon TTT, replacing the final T with a C, the result
is a synonymous mutation: the mutated codon still codes for the same amino acid,
phenylalanine.
 A different type of SNP mutation results in the new codon GTT. This codon codes for a different
amino acid, valine. It is thus a non-synonymous mutation, called ‘missense’.
 Sometimes a SNP has a bigger effect, for example, when the resulting mutation codes for a stop
codon instead of an amino acid, as in the second example here, where AAA turns into TAA after a
mutation.
 This sudden stop codon stops protein production so truncates the resulting protein.
 This is also a non-synonymous mutation, it’s a mutation resulting in a different outcome, but this
time it is ‘nonsense rather than missense’, the end result of the simple point mutation is more
pronounced. The end effects of nonsense mutations are usually more severe than missense
mutations.
The terms missense, nonsense, etc are introduce here to help you understand genetics papers that you
may be reading discussing the effects of SNPs.

Lecture 4 – Basic Human Genetics

Learning Outcomes
 Describe different sources of genetic variance, including gene mutations, triplet repeats, SNPs,
CNVs; chromosomal changes
 Appreciate how genetic variation, through affecting protein functioning, can ultimately affect
the phenotype

Other Types of Gene Variants

 Triplet Repeats
 Structural DNA variation: copy number variation
 Gross alterations: Chromosomes
 Triplet Repeats
 Multiple repeats of three nucleotides, and when these repeats become long they can cause a
mutation
 An example is Huntington's Disease
 This is a neurodegenerative disease that starts when a person is around 30 years of age
 It is a dominant single gene disorder
 There are multiple repeats of the code 'CAG'
 In a normal person, there are '11-34 'CAG' repeats, however in a person with Huntington's they
have '40-100' repeats

CAG in Huntington's
 CAG codes for glutamine
 The Huntington's gene is switched on (active) in nerve cells.
 The normal version of the protein glutamine has function in nerve cells, including transport to
other proteins
 The mutated version of protein includes much longer chain glutamine amino acids which can be
toxic to nerve cells, leading to neurodegeneration (Huntington's)

Fragile X Syndrome
 Genetic cause of intellectual disability
 Individuals with this intellectual disability have expanded repeats of the triplets 'CGG' and this is
located towards the end of the X chromosome
 It makes the X chromosome break
 When researchers try to study this in the lab it often breaks
 In a normal person they will have up to 6 to 54 repeats of CGG
 Individuals with Fragile X have more than 200 of these repeats

 Full mutation blocks transcription of FMR1 gene which is expressed in brain.

 FMR1 gene codes for the FMR1 protein, which is thought to have a role in establishing
connections between brain cells and making connections more efficient.
 When the protein cannot function it will lead to developmental disabilities including intellectual
disabilities

Fragile X Syndrome
 Nearly twice as common in males (about 1: 7,000) than in females (about 1:11,000)
 Fewer girls are affected because one of 2 X-Chromosomes is inactivated àeven though females
have 2 copies, only one is active (i.e. DNA of only one is transcribed)
 Which X chromosome is inactivated is random: one is active in some cells, other is active in
other cells. àin girls, Fragile X mutation will be active in some cells, but not others, resulting in
much more variable symptoms in affected girls

X Inactivation
Example: Calico cats
 Calico cats are always female
 Alleles for the black or ginger fur reside on X chromosome in cats àmale cats are either always
black or ginger
  Female cats with 1 ‘ginger allele’ and 1 ‘black allele’: this is called X-inactivation which results in
patches of ginger fur and patches of black fur

Copy Number Variants

 These are large regions of the genome that are deleted or duplicated.
 A relatively large area of a chromosome is duplicated, resulting in a considerably longer
chromosome.

 CNVs are much larger, and span thousands to millions of DNA

bases, they may span multiple genes.
 When an individual has a CNV duplication, instead of 2 copies
of each gene (one on each chromosome), individuals may have
three or more copies. Or alternatively, if there is a CNV
deletion, a person may have only one copy of the gene, on the
unaffected chromosome. This will ultimately lead to more or
less protein synthesis and can therefore affect bodily
functioning.

Copy number variation

 CNVs are usually benign so they do not have an observable behaviour

 Some CNVs are thought to be implicated in mental disorders and intellectual delays.
 E.g.
 Schizophrenia (Malhotra & Sebat (2012)
 Autism (Leppa et al. 2016)
 Intellectual Disability (Cooper et al. 2011)
 Bipolar Disorder (Malhotra & Sebat (2012)

Copy number variation

  CNVs can be inherited from parents
 Can also be de novo (mutation that occurs in sperm or egg cell) – this does not get transferred
to the child
 De novo mutations appear more common in families with only 1 affected individual (simplex
families) compared to families with multiple affected individuals (multiplex families) (e.g. in
autism: Sebat et al., 2007; Leppa et al., 2016)

Gross Alterations on the Chromosome

 Humans: 46 chromosomes, 2x 23 pairs

 22 autosome pairs
 1 sex chromosome pair
 Change in the number of chromosomes is due to nondisjunction
 Nondisjunction
 When mistakes happen during meiotic cell division
 In normal meiotic cell division: each newly formed gamete gets one copy of each chromosome
pair (a)
 Sometimes cell division goes wrong; and the cell can end up with 1 gamete with 2 copies, and
another with none (b)

Nondisjunction’s occur when mistakes happen during meiotic cell division. Normally, each newly
formed gamete gets one copy of each chromosome pai, as shown in image a here. But sometimes this
cell division goes wrong, and one gamete ends up with two copies of the chromosome instead of 1, and
the other with none, as shown in image b here

Trisomy
 Most nondisjunction's are lethal and causes a lot of miscarriages
 An exception is chromosome 21 trisomy: three copies of chromosome instead of 2 cause Down
Syndrome, this genetic variation is the cause of down syndrome

Down Syndrome
  Older women are at increased likelihood of having a child with Down syndrome.
 Why is this? In females, meiotic cell division begins before birth.
 This process is halted until puberty begins and then continues until menopause.
 The production of an egg later in a woman’s life has been halted for many years.
 After this long it is more likely for nondisjunction's to occur, and this means that older mothers
at more likely to have a child with Down syndrome

XXX Syndrome - More variation of X in cells

XO Syndrome - Women just do not have one X chromosome
XXY Syndrome - Males, are more sensitive etc.

Chromosome Abnormalities
Other examples of abnormal chromosome numbers that are not lethal are women with three copes of
the X chromosome, XXX, or women with only one X chromosome, XO. Remember, the Y chromosome
carries the instructions for the development of the testes, so a person with XO has the female
phenotype not male
XXY individuals, who have 2 X chromosomes and 1 Y chromosome, have the male phenotype. Because of
X inactivation none of these abnormalities are lethal: a female with XXX will still only have one X
chromosome activated in each of her cells, there is just more variation in which X is active.
Chromosome Abnormalities
Other chromosomal abnormalities: not nondisjunction, but breaks in chromosomes during meiosis,
resulting in:
(a) inversion
(b) deletion
(c) duplication
(d) translocation between different chromosomes
Practical 1 – Genetic Transmission
Learning outcomes
Introduction to genetic transmission
 Revise the key principles of genetic transmission
 Understand how simple ‘laws’ can underlie complex processes
 Recognise the different mechanisms underlying genetic influence on phenotypes, including singe
gene, sex-linked and polygenic effects

Understanding genetics
Mendel (1822-1884) conducted a series of carefully-designed pea plant experiments to investigate the
heredity effects of different types of breeding. He identified 2 key laws of genetic heritability:
1. The principle of segregation
2. The principle of independent assortment.

Mendel’s First Law: The principle of segregation

The two members of a gene pair (alleles) segregate (separate) from each other in the formation of
gametes. Half the gametes carry one allele, and the other half carry the other allele.

Offspring are formed from a gamete from each parent.

Thus each offspring carries two alleles of a given gene, one from the father and one from the mother.

Heritability patterns of a dominant allele

• Huntington’s disease is due to a mutation in a single gene, let’s call it ‘h’. ‘h’ comes in two allele
forms. The unaffected form ‘h’ is recessive. The affected form ‘H’ is dominant.
• Thus if an individual has one unaffected allele ‘h’ and one dominant allele ‘H’ they will develop
Huntington’s disease.

Heritability patterns of a recessive allele

• PKU is due to a single gene, let’s call it ‘d’ (disease). ‘d’ comes in two allele forms. The unaffected
form ‘D’ is dominant. The affected form ‘d’ is recessive.
• Thus an individual will only develop PKU if they have 2 copies of the ‘d’ allele.