4: Genetic Basis of Disease

Question 1

How can mutations arise in genes?

Answer 1

At random in somatic cells, as a normal part of biology
Can also arise ‘de novo’ (of new) in germ cells

Question 2

What are germ cells?

Answer 2

Reproductive cells
I.e. sperm and egg

Question 3

Describe the male karyotype.

Answer 3

22 pairs of autosomes
1 pair of sex chromosomes (XY)

Question 4

Describe the female karyotype.

Answer 4

22 pairs of autosomes
1 pair of sex chromosomes (XX)

Question 5

What are autosomes?

Answer 5

Non-sex chromosomes in an organism
These carry the majority of genetic information excluding those that determine sex

Question 6

What are alleles?

Answer 6

Individual versions of a gene or DNA sequence at a locus on a single chromosome

Question 7

What does ‘homozygous normal’ mean?

Answer 7

Both alleles in the pair are the wild-type version of the gene

Question 8

What is meant by ‘heterozygous’?

Answer 8

Meaning one allele is normal and one allele is mutant

Question 9

What does ‘homozygous affected’ mean?

Answer 9

Both alleles are mutant (e.g. aa for a recessive mutation or AA for a dominant mutation)

Question 10

In a heterozygous individual, when is the dominant phenotype expressed?

Answer 10

If the mutant allele is dominant
E.g. Aa for the dominant mutation

Question 11

What is dominant inheritance?

Answer 11

The pattern of inheritance where a single copy of a dominant allele is enough to express a specific trait or phenotype
The individual inherits one dominant allele from one parent, and one recessive allele from the other parent
Therefore homozygous dominant and heterozygous individuals will express the dominant trait

Question 12

Which disease is an example of dominant inheritance?

Answer 12

Achondroplasia

Question 13

What is achondroplasia?

Answer 13

An example of a dominant inheritance pattern
A disease characterised by shortened limbs
Caused by a mutation in the FGFR3 gene

Question 14

What mutation causes achondroplasia?

Answer 14

FGFR3 - encodes receptor
98% of mutations affecting this gene change G1138 to A1138
Changing glycine to arginine in the translated protein

Normal function of the receptor shows a negative regulatory effect on bone growth
When mutated, the receptor is constantly active, leading to severely shortened bones

Question 15

What does homozygous lethal mean?

Answer 15

That if two copies of the gene are present in a dominant disorder, (i.e. AA) this will be invariably fatal before or soon after birth
Lots of dominant mutations are homozygous lethal, achondroplasia included

Question 16

What is recessive inheritance?

Answer 16

When both parents must carry a wild-type allele and one mutant allele
There will be a 25% inheritance of two normal copies, 25% mutant, and 50% heterozygous

Question 17

What is PKU?

Answer 17

Phenylketonuria
An autosomal recessive disorder
Results from deficiency in phenylalanine hydroxylate
Untreated, can lead to impaired postnatal cognitive development due to the neurotoxic effect of high phenylalanine levels
Can be treated by monitoring diet to limit ingestion of phenylalanine

Question 18

What is sex-linked inheritance?

Answer 18

A pattern of inheritance where a gene is located on a sex chromosome, leading to traits that often appear more frequently in one sex - commonly males for X-linked traits

Question 19

Why are men most likely to develop recessive X-linked mutations?

Answer 19

Because they lack the additional X chromosome to compensate for being a carrier
Therefore for these mutations, men only need to be a carrier in order to be affected, whereas women would need both copies

Question 20

How does the X chromosome compare to the Y chromosome?

Answer 20

The X chromosome is very large, but the Y chromosome is much smaller
Therefore the Y chromosome is missing many genes that are present on the X chromosome

Question 21

Give two examples of recessive X-linked disorders.

Answer 21

Haemophilia
Red-green colour blindness

Question 22

What causes red-green colour blindness?

Answer 22

Recombination occurs during meiosis when gametes are formed
Sister chromosomes line up next to each other and cross over, so they transfer their DNA to form recombinant chromosomes
If normal recombination happens with the opsin genes for R and G, it will just swap them and make no difference to the phenotype (homologous recombination)
If misaligned recombination occurs, there will be an unequal crossing over

Question 23

Why is red-green colour blindness more common in men?

Answer 23

Because if an XY male inherits a R+G- X chromosome from the mother, then he will lack the ‘green opsin’ from the maternal X chromosome
The Y chromosome does not have the opsin gene, so he will lack green opsin and be colour-blind
If an XX female inherits one R+G- X chromosome from one parent, they’ll only lack green opsin if the other parent’s X chromosome is also R+G-
Therefore only 1 in 200 females have RG colour blindness compared to 1 in 13 males

Question 24

What is sickle cell disorder?

Answer 24

A disorder caused by a point mutation in the B-globin (oxygen-carrying molecule in RBCs) gene
Means that in low oxygen conditions, HbS (sickle haemoglobin) forms long aggregates, distorting the shape of red blood cells
Meaning they can’t pass through narrow blood vessels

Question 25

How is sickle cell disorder treated?

Answer 25

Blood cells are generated by stem cells in bone marrow Therefore the patient's bone marrow is producing diseased bone haemoglobin Stem cells can be extracted, genetically modified to correct the HbS into Hb, then restored to bone marrow So eventually, healthy haemoglobin will be produced

Question 26

What is spinal muscular atrophy?

Answer 26

Severe neuromuscular disorder Causes death of motor neurones Progressive muscle wastage Early childhood onset and fatal if left untreated

Question 27

What causes SMA?

Answer 27

Point mutation in SMN1 gene (survival motor neurone) Normal SMN1 is comprised of multiple exons, so when mRNA is transcribed, introns are removed and exons are spliced together In SMN2, a similar gene, it has a T instead of a C on exon 7 Sometimes 'exon skipping' can occur where exon 6 is directly spliced onto exon 7 This makes the protein non-functional as exon 7 is essential for proper SMN1 and 2 function Nusinersen is gene therapy for this disorder, blocks exon skipping

Question 28

What is penetrance?

Answer 28

The frequency with which a genotype manifests itself in a given phenotype

Question 29

How do we know if a disease has a genetic basis?

Answer 29

If it displays a clear Mendelian pattern of inheritance E.g. dominant and recessive inheritance

Question 30

What is λ?

Answer 30

Risk ratio Risk for a group of people compared to population risk If λ = 1, there is no risk compared to the population risk Increasing λ indicates increased risk

Question 31

What is OR?

Answer 31

Odds ratio A statistic that quantifies the strength of the association between two events: Odds ratio = people with allele with disease / people with allele without disease

Question 32

What is the odds ratio like for monogenic conditions?

Answer 32

High odds ratio As one allele is extremely likely to associate with a disease, so is effectively sufficient by itself High number of people with allele with disease / Low number of people with allele without disease = high OR

Question 33

What is the odds ratio like for polygenic conditions?

Answer 33

Modest odds ratio Each allele itself is not sufficient to cause the condition However, when multiple alleles are taken into account there is a cumulative effect on odds ratio

Question 34

Give examples of simple genetic diseases.

Answer 34

Achondroplasia Spinal muscular atrophy Phenylketonuria Cystic fibrosis Sickle cell anaemia Each of these are monogenic and mostly rare

Question 35

Give examples of complex genetic diseases.

Answer 35

Hypertension Schizophrenia Diabetes Bipolar disorder Obesity Each of these is not inherited in a simple Mendelian pattern and environmental factors often come largely into play

Question 36

What is schizophrenia?

Answer 36

A long term mental health condition Has a range of symptoms including hallucinations and delusions Drugs are not always effective and have significant side effects Mutations associated with schizophrenia fall into two main classes: Relatively common variants with small effect (OR>1) Very rare variants with a large effect (OR much >1)

Question 37

What is obesity?

Answer 37

A disorder characterised by hyperphagia, an abnormally incessant cessation of hunger Caused by a mixture of genetic and environmental factors Often defined with BMI

Question 38

How do you calculate BMI?

Answer 38

Weight / (height)^2

Question 39

What is the 'effect size' or 'beta value'?

Answer 39

The effect each allele has on a phenotype Effect size can be derived from odds ratio Beta value = ln(OR) If β > 0, increased risk If β = 0, no risk If B < 0, decreased risk

Question 40

What is the polygenic risk score?

Answer 40

A score that can be calculated to show the effect of all the alleles on an individual to give an overall estimated risk β = risk associated with disease Dosage = number of alleles someone has (0,1, or 2) Risk contributed by each allele = beta x dosage The polygenic risk score is the sum of each of these risk values

Question 41

What is leptin?

Answer 41

A hormone released by adipose tissue, causing appetite restriction Individuals who lack leptin can't turn their appetite 'off' Congenital leptin deficiency is associated with severe early onset obesity

Question 42

What is a polymorphic locus?

Answer 42

The existence of two or more variants (of alleles, phenotypes, sequence variants, chromosomal structural variants) in a population The closer the two loci are, the less likely they are to be separated by meiotic recombination over the generations

Question 43

What is an SNP?

Answer 43

Single nucleotide polymorphism A locus where different individuals have a different DNA base in their genomic sequence

Question 44

What are SNPs used for?

Answer 44

Genome-wide association studies Most are equally common in cases and controls But some are found more frequently in patients with particular conditions So that SNP can be considered a genetic riskf actor for a particular disease

Question 45

What is an effect allele?

Answer 45

The DNA sequence that causes a particular condition by altering protein function

Question 46

How do SNPs relate to effect alleles?

Answer 46

'D' is the gap between an effect allele and an SNP As D decreases, SNP proximity to the effect allele increases, so more they are likely to remain linked through generations The association of the SNP with the disease 'piggybacks' on the effect allele and causes the disease It is common that an SNP is 'neutral' or 'silent'

Question 47

What is standard GWAS sequencing?

Answer 47

A method that scans the genomes of many individuals to identify genetic variants (usually SNPs) associated with particular traits or diseases

Question 48

What is trio analysis?

Answer 48

A genetic testing method that compares the DNA of a child and both biological parents to identify any 'de novo' mutations This is often used in diagnosing rare genetic disorders

Question 49

What is NGS?

Answer 49

Next-generation sequencing / massive parallel sequencing A technique used to sequence millions of DNA fragments simultaneously, making the process very efficient

Question 50

What are the four stages of the cell cycle?

Answer 50

Mitosis G1 S phase G2

Question 51

What are germline mutations?

Answer 51

Mutations that affect germ cells (gametes)

Question 51

What is apoptosis?

Answer 51

Programmed cell death Genetically controlled process that cells use to detect problems E.g. errors in DNA replication Cell goes through an 'auto-destruct' process where it digests its cytoplasmic components, condenses chromatin, and forms apoptotic bodies

Question 52

What are somatic mutations?

Answer 52

Mutations that affect any body cell except germ cells

Question 53

What is the key difference between somatic and germline mutations?

Answer 53

Germline mutations can be passed on to subsequent generations, somatic mutations cannot

Question 54

What are proto-oncogenes?

Answer 54

Genes that promote cell division When mutated, they form oncogenes, and become overly active Which leads to excessive cell survival and proliferation

Question 55

What are tumour-suppressor genes?

Answer 55

Genes that inhibit cell division When mutated, they become inactive Which leads to uncontrollable cell division

Question 56

What is Knudson's two-hit hypothesis?

Answer 56

Mutations to both alleles of a TSG is needed in order to develop cancer Individuals may inherit one mutated allele, which would increase the likelihood of developing cancer, because they only need one 'hit' for the other allele to be mutated as well

Question 57

What protein do many oncogenes and TSGs encode?

Answer 57

Kinases and phosphatases Kinases: widely used in regulating many cellular functions, including proliferation Phosphatases: altering activity of target proteins by phosphorylation, may either activate or inhibit

Question 58

What is CML?

Answer 58

Chromic myeloid leukaemia Chromosomes break and form 'Philadelphia chromosomes' abl region fuses with bcr region, forming bcr-abl link The bcr-abl fusion protein has two kinase domains, one from bcr (breakpoint cluster region), the other from abl (abelson leukaemia virus) Normally the substrate will bind to the kinase domain, will be activated by phosphorylation and cause proliferation of the tumour cell

Question 59

What is medulloblastoma?

Answer 59

The most common type of brain tumour in children Caused by mutations in WNT and SHH signalling pathways Different subgroups, some more aggressive and rapidly growing than others Often requires aggressive, invasive treatment

Question 60

A mutation in which gene increases risk of breast cancer?

Answer 60

The BRCA gene BRCA is involved in gene repair Individuals with BRCA mutations use alternative pathways for DNA repair as cancer cells need functional DNA repair pathways in order to divide