2D. Genetics

Question 1

What is PH genetics?

Answer 1

The study, at a population level, of genetics, genomics, and their links to biomedicine.

Question 2

How do genetics and genomics differ?

Answer 2

Genetics = study of how characteristics and diseases are inherited.

Genomics = study of all genes of an individual at DNA, protein, cell, or tissue level.

Question 3

What does DNA consist of?

Answer 3

4 chemical bases (‘nucleotides’) labelled A, G, C, T (adenine, guanine, cytosine, thymine).

○ A group of 3 base pairs represents instructions for a specific amino acid, the building block of proteins.

Question 4

How does gene expression occur?

Answer 4

• Info stored in a cell’s DNA is used to make proteins in a process known as gene expression.
• DNA acts as a template for RNA, which is produced by transcription.
• RNA then translated into amino acids.
• Next, a chain of amino acids joined together to produce peptides or polypeptides, which themselves may be joined together to produce proteins.
• Finally, protein folding occurs during which a polypeptide or protein assumes its 3D, functional form.
• All cells in the body contain the same DNA, however they do different things as genes are expressed in different types of cell, a process controlled by regulatory DNA sequences.

Question 5

How much of human genetic material is identical across the world’s pop?

Answer 5

The majority (99%) of human genetic material is identical across the world’s pop, with only 0.1% DNA differing between individuals. These differences are however responsible for individual characteristics, including propensity to different diseases.

Question 6

Why does genetic material differ between individuals?

Answer 6

1. 1/2 genes inherited from mother, 1/2 from father
2. Alterations may occur to DNA sequence during cell division
3. Persistent and heritable alternations in how genome expressed that do not involve alterations to DNA sequence itself (epigenetics)

Question 7

What are some examples of multifactorially inherited disease?

Answer 7

Diseases have multiple genetic and environmental factors

E.g. CHD, diabetes, many cancers

• Some genetic variants carry higher risk than others e.g. BRCA 1 assoc with 50-80% lifetime risk breast cancer

Question 8

What are single-gene disorders and what are some examples?

Answer 8

• Also known as Mendelian disease
• One altered gene responsible for illness
• Can be classified as autosomal dominant/recessive, X-linked dominant/recessive, Y linked

E.g. Huntington’s, CF

Question 9

What are chromosomal disorders?

Answer 9

• Affect either whole chromosome or large parts of a chromosome and can either be numerical disorders or structural abnormalities.
• Numerical disorders (e.g. Down’s where there is extra chromosome 21)
• Structural abnormalities (e.g. Charcot-Marie-Tooth, neuropathy caused by duplication of part of chromosome 17)

Some, but not all, chromosomal disorders may be inherited.

Question 10

What are alleles?

Answer 10

Two different forms of the same gene occurring at the same location (genetic locus) on corresponding chromosomes

Question 11

What does genotype consist of?

Answer 11

A person’s set of alleles

Question 12

What is phenotype?

Answer 12

Set of characteristics coded by a genotype and expressed in a person

Question 13

Why might a particular genotype not lead to a specific phenotype?

Answer 13

Variable phenotypes arise for many reasons, including:
- Incomplete penetrance
- >1 mutation of gene associated with characteristic or disease
- >1 gene relating to one protein or characteristic

Question 14

Summarise cystic fibrosis

Answer 14

• Autosomal recessive inherited disorder
• Mutation on gene that codes for cell membrane channel called cystic fibrosis transmembrane conductance regulator (CFTR)
• Sx may include respiratory, pancreatic insufficiency, elevated chloride in sweat, sterility in men
• Most common mutation on CFTR gene is DF508
• Gene-environment interactions play a part, factors such as smoking and nutrition can influence severity of lung disease.

Question 15

What are the patterns of Mendelian inheritance?

Answer 15

Autosomal dominant
E.g. Huntington’s disease

Autosomal recessive
E.g. Sickle cell, CF, PKU

X-linked recessive
E.g. Haemophilia, Duchenne

X-linked dominant (v rare)
E.g. Coffin-Lowry syndrome

Y linked (v rare)
E.g. Male infertility

Question 16

What is non-Mendelian inheritance?

Answer 16

Most human diseases don’t follow strict Mendelian rules of inheritance and instead are multifactorial .

Another unusual form of inheritance relates to mitochondrial genes, always inherited maternally.

Question 17

What is penetrance?

Answer 17

Proportion of people with a given genotype that express its phenotype (i.e. proportion of people with gene for a particular disease who develop that disease). Penetrance varies between different genes.

E.g. Huntington’s has 100% penetrance, BRCA female breast cancer 50-80% penetrance.

Question 18

When do polygenic disorders occur?

Answer 18

Polygenic forms of diseases occur where several gene variants increase susceptibility to the disease.

Patterns of heredity for polygenic disorders complex, and the mechanisms by which different genes interact tend to be poorly understood.

Question 19

What are some challenges to identifying genes in polygenic disorders?

Answer 19

Many susceptibility genes
Population heterogeneity
Incomplete understanding of disease biology

Question 20

What is an example of a condition that can be avoided by avoiding certain environmental conditions?

Answer 20

Phenylketonuria (PKU) -
- Abnormality in gene that produces enzyme phenylalanine hydroxylate which converts amino acid phenylalanine to tyrosine.
- Absence of enzyme leads to build up of phenylalanine which is toxic to brain, leading to mental retardation.
- Disease autosomal recessive, usually detected through universal screening of newborns
- Limiting dietary intake of phenylalanine between birth and adolescence means no symptoms ever develop.

Question 21

How can the study of gene-environment interactions help us in health promotion?

Answer 21

○ ID people at high genetic risk of disease
○ Understand which environmental factors increase risk for some people
○ Target health promotion messages and disease prevention interventions to people most likely to benefit

Question 22

What does pharmacogenomics do?

Answer 22

Uses individuals’ genetic characteristics as a basis for understanding relative effectiveness of different pharmaceutical treatments.

Better understanding of these differences could mean we can design Rx regimes based on individual genotypes.

Question 23

What is gene therapy (provide an example)?

Answer 23

• Vehicles such as viruses or plasmids used to insert genetic material into cells of people with a particular disease
• Has been applied in SCID.
  In the UK, gene therapy is approved and used for severe blood disorders like Sickle Cell Disease (SCD) and Beta-Thalassemia (using Casgevy), various rare inherited conditions affecting immunity or sight (like ADA-SCID at GOSH), and even some cancers (CAR-T cell therapy for leukaemia).

Question 24

What are two types of genetic testing for relatives of people who have a disease with a genetic component?

Answer 24

Predictive genetic testing (‘susceptibility’ testing)

Individual carrier testing

Question 25

What is predictive genetic testing?

Answer 25

Useful when FHx of highly penetrative genetic disease that develops in adulthood e.g. Huntington's, BRCA

Question 26

What are some population carrier screening programmes in the UK?

Answer 26

In UK antenatal screening programme, pregnant women living in high-prevalence areas are offered blood test to ID whether they are carriers for sickle cell or thalassaemia. If mother identified as a carrier then father also offered testing.

Question 27

What is molecular biology?

Answer 27

The study and manipulation of biological processes and structures at a molecular level.

Question 28

What are some molecular biology techniques?

Answer 28

○ Use of restriction enzymes to cleave DNA at a particular nucleotide sequence, isolating a particular gene or DNA sequence, which can then be replicated and studied. ○ Amplification of DNA sequences using PCR. ○ DNA sequencing to ID order of nucleotides (A,C,G,T) in a strand of DNA or even whole genome sequencing.

Question 29

What are some implications of advances in molecular biological techniques for PH? and what are some challenges?

Answer 29

* Potential to target health promotion advice, screening, and medical treatment according to genetic profiles. * Genomic profiling used in areas such as cancer medicine to aid Rx decisions and determination of likely prognosis. * Challenges incl: cost, data storage issues, potential misuse by insurance companies or employers.

Question 30

What are some genes that confer virulence to pathogens?

Answer 30

○ Retroviruses such as HIV use reverse transcriptase to incorprate their genetic material into the genome of the host cell, enabling the virus to replicate as part of host's DNA. ○ Extranuclear DNA in form of plasmids may confer pathogenic advantage e.g. antibiotic resistance. Plasmids can be exchanged between bacteria. ○ Genes that enable rapid exchange of surface antigens may prevent recognition of pathogen by host's immune system.

Question 31

How is molecular biology used in TB?

Answer 31

- To identify TB strains - Performed on every +ve TB culture - Confirms bacterium as TB, and checks for Abx resistance - Allows HPT teams to link TB patients with same strain, helpful in outbreak investigations. - Also useful for detecting false +ve TB results.

Question 32

What is a LOD score?

Answer 32

A LOD score (Logarithm of the Odds) is a statistical estimate used in genetics to determine the likelihood of linkage between two genetic loci (or a marker and a trait) based on pedigree data. It measures how likely it is that two genes are close together on a chromosome and inherited together. A LOD score of 3 or higher is generally considered strong evidence of linkage, representing 1,000:1 odds.