Genetics

What is an autosomal dominant disorder?

heterozygous - one copy of the gene results in expression of the gene

What are autosomes?

Types of chromosomes, 22 pairs and and one sex pair of chromosomes

Which gene is responsible for eye colour and what does it control?

OCA-2 controls amount of melanin in melanocytes in the eye

Why are brown eyes dominant?

due to the presence of the active form of OCA-2, so only one copy gives brown

A child has an affected parent for an autosomal dominant condition. What is the chance that they will be affected?

1 in 2

Males and females equally affected/ likely to pass condition

What are characteristics of an autosomal dominant disorder?

• single gene/allele diseases

• passed down with multiple generations affected

• affected person normally has affected parent BUT can occur de novo (during embryo dev etc)

• possible mosaicism - gene only expressed in some cells not all of them

What pedigree pattern is seen with dominant autosomal disorders?

vertical pedigree pattern

What are the most common consequences of an autosomal dominant mutation?

1. gain of function

2. dominant negative effect

3. haploinsufficient

what is gain of function?

gene makes protein with a new function

what is dominant negative effect?

mutated form interferes with the activity of the protein it binds

what is haploinsufficient?

not enough of a protein made

What is an autosomal recessive disorder?

2 copies of faulty gene = DISEASE or trait to develop

What is the genotype of carriers if autosomal recessive disorders?

• 1 mutated copy

• 1 functioning copy (thats sufficient to maintain normal function)

Both parents of a child are carriers of an autosomal recessive disorder. What is the chance that each subsequent child will be affected?

• 25%, 1 in 4, males and females equally affected, one or more siblings may be affected

• parents and children of affected people are normally unaffected

What pedigree pattern is shown in autosomal recessive disorders?

horizontal - people affected ACROSS generations rather than down generations

What is the most common consequence of an autosomal recessive mutation?

loss of function e.g deletions in gene

What is consanguinity?

genetic relation between individuals who share a common ancestor

Give an example of an autosomal recessive disorder.

cystic fibrosis

(cystic fibrosis transregulatory gene) → defective chloride channel, so build up of mucus, recessive means you lost all function

What determines sex?

• foetuses start out as female, only in presence of SRY gene you start developing male characteristics

• Y chromosome determines this

(Y chromosome is much smaller)

Why are recessive X-linked disorders more common in males?

males only have one X chromosome so will develop the disease

What conditions must be met for a female to inherit an X-linked recessive disorder?

females must be homozygous for the mutation

Give an example of an X- linked recessive disorder.

Haemophilia- more frequent or severe bleeds, different levels of severity, factors VIII or IX affected

Give an example of an X-linked dominant disorder.

X-linked hypophosphataemia (overproduce FGF21 which inhibits kidney phosphate resorption so don’t retain phosphate, which results in vitamin-D resistant rickets)

What is the pedigree pattern from Y-linked disorders?

vertical pedigree pattern - only affecting males

Give an example of a Y-linked disorder.

retinitis pigmentosa - Mutations in RPY gene, cells of retina produce a defective protein → eventually go blind

What are mitochondrial inherited disorders?

disease caused by mutations in mtDNA

How are mitochondrial inherited disorders inherited and why?

• maternally inherited - ALL mitochondria inherited from mother

• only egg contributes to mitochondria

• passed onto offspring

What is the pedigree pattern of mitochondrial inherited disorders?

vertical degree pattern

What is true about the children of a mother with mtDNA disorder?

all children affected (however mitochondrial conditions typically variable even within same family)

When would symptoms in mitochondrial diseases be expressed?

if no. of mutated mtDNA exceeds a threshold

By what process do mitochondria replicate?

binary fission

What affects the severity of mitochondrial disease?

no. of affected mitochondria

What changes over time in mitochondrial diseases?

the number of mutated mitochondria within a cell (increase or decrease)

symptoms tend not to get better due to build up of effect

What gives rise to variability of mitochondrial disease (heteroplasmy)?

• mitochondrial genome have constant turnover and randomly select which genome to copy

• means you can gain or lose mutated genes

• during binary fission, random segregation occurs

• cells with different amount of mutant mitochondria

• disease only developed if no. of mutant cells > threshold

What is cancer?

cells that grow and reproduce uncontrollably, can metastasise

What are cancer genes?

key genes that cause the abnormal behaviour of cancer cells due to changes in their DNA sequence

features of benign tumours:

• grows more slowly

• well differentiated

• capsulated

• doesn’t invade neighbouring tissues

• doesn’t metastasise

features of malignant tumours:

• grows faster

• poorly differentiated

• not capsulated

• invades neighbouring tissue

• invades basement membrane and metastasises

What are proto-oncogenes and how do they lead to cancer?

• normal gene that produces protein promotes cell growth and proliferation

• proto-oncogene with driver mutation is called oncogene

• leads to cancer if permanently switched on → continued proliferation → cancer

What are tumour suppressor genes and how can they lead to cancer?

• normal gene produces protein that limits cell growth and proliferation

• driver mutation occurs

• TSG unable to produce protein → continued cell proliferation → cancer

What is tumour heterogeneity

The observation that different tumour cells can show distinct morphological and phenotypic profiles

• inter-tumour heterogenity → occurs between tumours

• intra-tumour heterogenity → occurs within a tumour

what is a passenger mutation?

changes in DNA sequence but don’t cause problems: occur randomly and no selective growth advantage → don’t drive cancer initiation

what is a driver mutation?

give tumour cells a specific growth advantage and contribute to the development of cancer → contributes to cancer growth

driver mutation with kRAS

1. kRAS is a proto-oncogene so promotes cell growth and proliferation

2. driver mutation to oncogene → one mutation enough to lead to tumour growth as oncogenes are dominant (haploinsufficient)

are oncogenes dominant or recessive?

dominant

• tumour growth can be caused by one mutated allele

• haploinsufficient

are TSGs dominant or recessive?

• recessive

• mutation required in both TSGs to lead to a tumour growth

• called 2-hit hypothesis

Whats the definition of the hallmarks of cancer?

set of functional capabilities acquired by human cells to grow from normalcy to cancer, driver mutations in cancer risk genes can result in 1 or more of these hallmarks

What are the 14 hallmarks of cancer?

1. evading growth suppressors e.g p53

2. non-mutational epigenetic reprogramming - tags on DNA that can be switched on or off

3. avoiding immune destruction -they evade immune system

4. enabling replicative immortality - continue to divide and accumulate additional mutations → more aggressive over time

5. tumour-promoting inflammation - chronic inflammation → development of cancer (as cytokines contribute to cancer growth)

6. polymorphic microbiomes - pathogens can release things that contribute to cancer (diverse microbiome)

7. activating invasion & metastasis - invade surrounding tissues

8. inducing or accessing vasculature - release factors that cause angiogenesis to provide nutrients and oxygen for survival

9. senescent cells - cessation of cell division, they can recruit these and make them start dividing again

10. genome instability & mutation - cancer cells have high mutation rate and genetic instability so more likely to promote tumour growth

11. resisting cell death (apoptosis)

12. deregulating cellular metabolism - cancer cells change their metabolism to support survival (faster or better for them)

13. unlocking phenotypic plasticity - switch between different cellular states depending on their environment

14. sustaining proliferative signalling - defects in signalling pathways that normally regulate cell growth e.g. KRAS

What are germline mutations?

mutations present in the gametes → passed onto offspring → all cells in the offspring carry the mutation

What are somatic mutations?

• mutations that occur in the body cells (not in the gametes)

• not passed on from parents to offspring

How may cancer be treated? (5)

1. surgery - directly remove tumour

2. chemotherapy - chemicals to kill rapidly dividing cells

3. radiotherapy - radiation targeted at cancer cells

4. targeted therapy - identify the gene

5. immunotherapy - antibodies attached to anti-cancer drugs

What is a karyotype?

the arrangement of the complete set of chromosomes.

What is giemsa stain used for?

it produces a recognisable chromosome banding pattern

What is the short arm of a chromosome denoted by?

p-arm

What is the long arm of a chromosome denoted by?

q-arm

What do 'dark' bands on a chromosome banding pattern imply? (3)

• heterochromatin

• more compact

• fewer genes (generally inactive)

What do 'light' bands on a chromosome banding pattern imply? (3)

• euchromatin

• more open

• more genes (80% of active genes)

At what stage of cell division is banding staining done?

prophase - better staining (metaphase can still be used)

What is the purpose of meiosis? (3)

1. produce haploid cells (n=23)

2. genetic variation in gametes

3. enables random assortment and recombination

What is aneuploidy?

An abnormal number of chromosomes that is not a multiple of 23

• caused by loss or gain of chromosomes

What is a trisomy?

x3 copies of a chromosome

What is a monosomy?

only one copy of a chromosome

Which are the only trisomies compatible with life?

21,18 and 13

What syndrome is trisomy 21 associated with?

Down syndrome

What syndrome is trisomy 18 associated with?

Edward syndrome

What syndrome is trisomy 13 associated with?

Pateu syndrome

What leads to aneuploidy?

non-disjunction in meiosis

• in meiosis 1 all daughter cells affected

• in meiosis II half of daughter cells affected

• always results in ±1 chromosome

• when fertilised you get trisomy or monosomy

Why is sex chromosome aneuploidy tolerated? (2)

• only one active X-chromosome (as any extra copies are inactivated i.e. X-inactivation)

• Y chromosome has a low gene content

• (most common form of aneuploidy)

Why are symptoms of sex chromosome aneuploidy still expressed if the excess X chromosomes are inactivated?

pseudo-autosomal regions (PAR) on sex chromosomes (X+Y) which aren’t inactivated

What is the most common cause of trisomy 21?

maternal non-disjunction

What is mosaicism?

the presence of two or more genetically different sets of cells

How can X-inactivation result in mosaic expression?

random inactivation of the X chromosome means that half the cells have one X chromosome activated and the other half have a different X chromosome activated

What are the two most common mechanisms that cause mosaicism?

1. non-disjunction during early development

2. loss of extra chromosome in early development

What is crossing over and when in meiosis does it occur?

• pair of chromosomes align and form chiasma

• exchange of genetic material between chromosomes

• occurs in prophase 1

• increases genetic diversity

What happens during unequal crossover?

• chromosomes misalign at centromere

• one gains extra material, the other loses material

• duplication of DNA or deletion of DNA

What is paracentric inversion?

2 breaks in chromosome, inversion of a section of chromosome away from the centromere and reinserted in wrong way (therefore only affects either short/long arm)

What is pericentric inversion?

inversion of section of chromosome around the centromere (therefore affects both short and long arm)

What are two chromosomal abnormalities?

2 or more chromosomes affected

• insertion of genetic material from one chromosome to another in chromosomes that are not the same type

state the mutation for william’s syndrome

del7q11.23

What are features of Williams syndrome?

• long philtrum

• short, upturned nose

• arched eyebrows

• supravalvular aortic stenosis

• friendly, social ‘cocktail party’ personality - absence of social anxiety

What are some common features of 7q11.23 duplication syndrome? (6)

• delayed speech development

• autistic behaviours affect social interaction and communication

• flat eyebrows

• short philtrum

• broad nose

• dilatation of the aorta

What are the 3 classes of chromosomes?

1. metacentric - short and long arm roughly same size

2. submetacentric - short arm shorter than long arm (still encodes)

3. acrocentric - short arm is vestigial (doesn’t encode just tRNA)

What causes a Robertsonian translocation?

occurs when two acrocentric chromosomes join together to form a single chromosome

What is a Mendelian trait?

the expression of a trait is controlled by a single gene.

What is a complex trait?

the expression of a trait is controlled by multiple genes and the effect of the environment

What is heritability a measure of?

how much of our phenotypic differences are due to genetic differences

What are the 2 causes of phenotypic differences?

1. genetic differences

2. environmental differences

How did 'twin studies' measure heritability?

• compared the differences in intelligence and sleep time between identical and non-identical twins

• assume monozygotic twins share 100% of DNA and dizygotic twins share 50%

• comparing two can show genetic contribution e.g. in MZ any differences must be environmental

What is concordance?

• both individuals in pair have trait = concordant

• one individual has trait, other doesn’t = discordant

What are the problems with twin studies?

measure phenotype, doesn’t identify specific gene variants that influence traits

What is a single nucleotide polymorphism (SNP)?

a change in a single nucleotide in a genome sequence in coding or non-coding region

What are genetic association studies?

• candidate gene association studies (CGAS)

• genome wide association studies

• whole genome sequencing

What are candidate gene association studies?

Analyse a few genes and variants based on knowledge that they have an important role in physiology/disease pathophysiology

What was the purpose of genome wide association studies?

to examine association of multiple SNPs and disease across the entire genome

What is pharmacogenomics?

the study of variability in drug response due to genetic differences between individuals

Pharmacodynamic definition

how a drug affects the body

Pharmacokinetic definition

how the body affects the drug

What happens in a ‘normal pregnancy’?

• positive pregnancy test no longer at GP

• booked into antenatal care to see midwife (family history, psychosocial history and blood tests)

• nuchal scan - 10-14 weeks’ gestation (12 week scan)

• mid-trimester anomaly scan - 20-22 weeks’ gestation (20 week scan)

When during pregnancy is a nuchal scan done?

10-14 weeks gestation

When during pregnancy is a mid-trimester anomaly scan done?

20-22 weeks gestation