Single Gene Disorders, Genetics Of Complex Diseases And Cancer Genetics

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single gene disorder

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the genetic abnormality is the sole cause of disease

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multifactorial disease

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genetic variations interact with a wide variety of other factors leading to disease

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chromosomal disease

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-abnormal # of chr. or abnormal chr. structure

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mitochondrial disease

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rare type of disorders caused by mutations in non-chromosomal mtDNA

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mutations and disease (same gene diff disease)

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-~10,000 disease attributed to mutations in ~6000 genes

-more diseases attributed to mutations in single genes

-diff mutation in 1 gene+ diff diseases in same gene (heterogenety)

e.g mutation in FGFR-3

An example:

Mutations in FGFR-3

P250R – Muenke’s syndrome

G308R – Achondroplasia

(dwarfism)

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mutations and disease (many genes 1 disease)

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e.g

Xeroderma pigmentosum (XP)

‘Children of the Night’

• Mutations in 8 different genes that all function in DNA-damage repair lead to XP (8 variants)

• Individuals are hypersensitive to sunlight and often develop carcinomas

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what is penetrance

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-The frequency with which a person manifests the gene that they possess

-Not all dominant mutations display 100% penetrance

-Penetrance is determined via genetic and environmental factors

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what is expressivity

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Variation in the severity of the symptoms caused by a mutation

For example, in sickle cell anaemia (which is always caused by the same mutation) symptoms range from very severe to extremely mild

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what's a phenocopy

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• An environmental modification that mimics a genetic disease

• The classic example of this is confusing genetic deafness with deafness caused by Rubella during pregnancy

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what is mosaicism

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• Not all the cells in the body are genetically identical

• Two or more populations of cells with different genotypes

• In the germline or somatic

• Caused by mutations – different genes

– different diseases

• Often confused with X-inactivation

• An example of true mosaicism is mild Klinefelter’s syndrome (46/47 XY/XXY)`

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other factors which affect genetic conditions

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• Environmental: The expression of genetic conditions can be influenced by environmental conditions e.g: phenylketonuria, a disease that once diagnosed is treatable via provision of a low phenylalanine diet

• Anticipation:Severity appears to increase with each generation, commonly due to trinucleotide repeats (e.g. Fragile X, CGG, X chromosome, & Huntington’s)

Genomic Impriting:he expression of a gene depends of the parent from which the gene is inherited. The imprinted (inherited) allele is silenced (epigenetic: DNA methylation, histone modification), expression from non-imprinted allel

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point mutation diseases

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Substitutions (missense)

• All cases of Sickle cell anaemia are caused by the same mutation in β-globin

• The mutation leads to a glutamic acid (E) being replaced by a valine (V) instead at position 6 in the protein

E6V

Nonsense mutations

• Duchenne muscular dystrophy is often caused by nonsense mutations in the dystrophin gene

• Lysine (K) > unknown/unspecified (X) i.e. stop codon

K1524X

nsertion mutations

Familial Hypercholesterolemia (FH) results in elevated levels of blood lipids. A genetic study was carried out on a large consanguineous Pakistani family with a history of FH and a common insertion mutation was identified.

c.2416_2417InsG

Deletion mutations

Around 80% of cystic fibrosis patients in Western Europe harbour a deletion mutation that deletes the phenylalanine (F) residue at position 508 in the protein.

ΔF508

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What type of tests are carried out?

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• Newborn screening

• Diagnostic testing

• Carrier testing

(test for parents if carry one copy of mutation,

that in 2 copies causes a disorder)

• Prenatal testing

• Preimplantation genetic diagnosis

• Predictive and presymptomatic testing

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what is a complex disease

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a on- monogenic disease e.g

Cancer

Asthma

Migraine

Diabetes (I and II)

Arthritis

MS

Hypertension

Cardiovascular disease

Obesity

Crohn’s disease

Schizophrenia

Autism

Alzheimer's

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what is heritability ?

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• Heritability is defined as a number between 0 and 1, as the number increases, so does the amount that phenotype is influenced by genetics

• High heritability does not necessarily mean the phenotype is solely determined by genetics (e.g. height in humans), environment and chance has an effect too

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what is concordance

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• Concordance is the probability (%) that twins (identical or non-identical) will both have the disease, given that one of the pair has the disease
• The difference between the percentage concordance in dizygotic twins compared with monozygotic twins can be used as an estimate of heritability
• Concordance studies have also shed light onto the genetic component of several psychiatric and behavioural disorders
• Autism in particular seems to be strongly influenced by genetic factors.

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Classical studies used to investigate the genetic contribution to a disease

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1. family studies
2. adoption studies

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alleles shared between families

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1st degree

50%

Parent/Child, sibling

2nd degree

25%

Grandparent/Grandchild, Aunt or Uncle/Niece or Nephew

3rd degree

12.5%

Cousins, great grandparent/great grandchild

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Fisher’s theory

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• stated that traits were controlled by large numbers of different genes, which individually still obeyed Mendel’s laws of segregation

• But most diseases are discontinuous in distribution, right?

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‘liability threshold’ determines disease state of an individual

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• When alleles push the distribution towards the liability threshold they are termed ‘risk alleles’ or susceptibility alleles

• This model is supported by studies on the congenital disorder pyloric stenosis
• Not all alleles are additive, some are dominant, some display epistasis (modifier genes), others are protective

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familial breast cancer allele

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BRCA1

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how are susceptibility alleles identified

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using

Parametric analysis

A type of linkage analysis that uses LOD scores (>LOD >linkage)

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Non-parametric analysis

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A type of linkage analysis that analyses co-inheritance

The premise is that alleles which predisposed an ancestor to a disease will be inherited by affected family members at a frequency greater than expected

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what is transformation

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• Transformation arises when a cell acquires mutations that allow it to evade the checkpoint mechanisms of the cell cycle

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what triggers cell transformation ?

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oncogenes

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• Proto-oncogenes control key processes in cell growth including:

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• Growth factors (PDGF)

• Growth factor receptors (EGFR)

• Growth factor signalling (RAS)

• Transcription factors (MYC)

• Cyclins (Cyclin D1)

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how do proto-oncogenes become activated

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• Proto-oncogenes become activated oncogenes via a gain-of-function event:

• Activation by amplification

• Activation by mutation

• Activation by chromosomal rearrangement

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tumour suppressors

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-supress cell transformation

-negativelly reduce cell growth

• ome of the major tumour-suppressor genes are involved in G1-phase checkpoint control (pRb and p53)

• Mutations in tumour suppressor genes are generally recessive

- In other words, both alleles must be mutated in order for the gene to stop functioning (Knudson’s 2-hit hypothesis)

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how many divisions do normal cells undergo before dying

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50

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what causes cells to die

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shortening of telomeres

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what enzyme is reactivated in cancerous cells

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telomerase

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what gene therapy

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• This can be approached in two ways:

• Somatic gene therapy

• Germline gene therapy

• Somatic gene therapy will only ever influence the individual

Germline gene therapy will influence future generations and is currently illegal in most countries

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Transgene delivery

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• Delivered either:

  
  

  • in vivo (within the body)

  • ex vivo (outside of the body)

• Which to use, is dictated by the nature of the disease

  
  

  • e.g. blood disorders are amenable to an ex vivo approach

• Many diseases are not suited to ex vivo therapy due to tissue cell type and location

• In vivo gene therapy attempts to directly deliver the transgene to the site of disease

• However, even single gene disorders such as cystic fibrosis can affect a surprising number of tissue types. Which tissue type should be targeted?

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mostly used widely used vehicles

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virusese.g-

• Adenoviruses e.g. common cold

• Herpesviruses e.g. cold sores

• Retroviruses e.g. HIV

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comparison of gene therapy

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what disorders best suit gene therapy

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single gene recessive disorder

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Adenovirus gene therapy

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Head and neck cancer

• Some success using an oncolytic virus (specifically targets cancer cells): Onyx-15 (modified adenovirus)

• p53-deficient tumour cells

• 7 of 12 patients had induced necrosis (dead tissue) in the tumour

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Retrovirus gene therapy

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SCID-XI

X-linked severe combined immunodeficiency (X-SCID)

• A disorder affecting reduction of blood cells: NK and T cells

• 10 affected children were given retrovirus-based gene therapy in 2000

• Cured 8 of the children, however…

By 2007, 4 of those 8 children had developed leukaemia!