Genetic Disorders

Heritable genetic diseases

mutations are present in the germline

Numerical chromosome abnormalities

polyploidy - an extra set of chromosomes

aneuploidy - an extra or missing single chromosome

How do numerical chromosome abnormalities occur?

• occur during cell division in the female germline

• chromosomes line up during meiosis

• kinetochore won’t properly attach so both chromosomes are brought ot one side

• nondisjunction occurs

• other cell is unviable

Splice sight mutations

• mutation in the splice acceptor site

• affects the efficiency at which the spliceosome recognises that site

• extension of TT or GT repeats

• this results in an exon skipping resulting in wrong mRNA

Dominant mutations

• one copy is sufficient for a given disease phenotype

• can occur via haploinsufficiency

Dominant negative effect

• one copy is normal but the mutated copy interferes with the function of th enormal protein

• occurs in osteogenesis imperfecto

  • collagen gene mutations

  • normally form fibres

  • mutations interfere with the way collagen fibres pack leading to brittle bones

Mendelian Inheritance

• the presence of mutation in a single gene is sufficient for disease manifestation

• a single gene is responsible for one phenotype

Locus Heterogeneity

• deviation from Mendelian Inheritance

• one phenotype can be caused by mutations in any one of a number of genes

Outcomes of Locus Heterogeneity

• hearing loss

• because mutations occur in two different genes, children always inherit one normal gene - phenotypic rescue

Incomplete penetrance

• observed in dominant modes of inheritance

• the mutation is or should be present but it is not leading to the disease (even though it should since it is dominant)

• although these mutations should cause disease, there are other factors that influence (genetic background, environment) whether the disease is manifested or not

X mosaicism

• males have one X and one Y chromosome

• females have two but that is two many

• one of the X chromosome is inactivated - random (around 200 cell stage embryo)

• randomness can lead to deviations in whats expected from Mendelian patter

• embryos have the same heterozygous state

• manifesting heterozygote - shouldn’t normally express the disorder but because of x inactivation it does

Mitochondrial Inheritance

• inheritance is matrolineal

  • mitochondria are only inherited from mother

• sperm delivers its nuclear genetical material but the mitochondria remain behind

• mitochondria don’t enter the egg cell

Heteroplasmy effect

• cells have different ratios of the mutated mitochondria

• small amount of mitochondrial go into each early egg precursor

  • widely differing ratios of mutated mitochondria in fully develop egg cells

  • due to bottleneck effect we get different ratios

  • results in siblings having differing severities of the disease

• because process is random, it is difficult to predict ratios in mitochondrial diseases

• another effect is that it can lead to different ratios of mutated mitochondria in different organ and tissue types

• they have different thresholds (e.g some have a low threshold - smaller amount of mitochondria to cause an adverse phenotype)

• high energy use tissues and organs will be the most frequently affected

• brain and skeletal muscle have low phenotypic expression

Complex traits

• several genes contribute in an additive fashion to determine an end phenotypic outcome

• Mendel studies focused on binary traits (exist in one form or another)

• for most traits we observe a continuous distribution

The polygenic/infinitesimal model

• additive to the phenotypic outcome

• each allele has a smaller effect but you need to inherit several to manifest the disease

Polygenic threshold model

• account for the fact that the disease is either expressed or not

• it is only when a certain disease threshold hold is breached that the disease is manifest

The Carter effect

• some complex genetic diseases also display sex dimorphism, an explanation for these might be provided by polygenic threshold model

• when females do present within the family, there is a higher number of risk alleles within that family

Heritability

• population specific parameter

• the phenotypic variation in a given population that is due to variation in genetic factors within the population

Estimation of heritability

• determined by twin studies

• monozygotic twins which you can pair with dizygotic twins

• compare rates of phenotypic correlation for a certain cancer

• dizygotic provide a good control for the environment

• if high correlation from mono - high contribution from genetic factors

• correlation in mono never reaches 100%

  • tells us that environment plays a significant role

Liability Threshold model

• incorporates environmental factors

• genetic and environmental factors can contribute to complex disease manifestations

• Heritability = Vg / Vp

Estimates from twin studies according to Falconer’s Formula

Heritability (broad sense) = 2(CR mz - CR dz)

Interactions between genetic variants in broad sense heritability

• Dominance Interaction - interaction within a locus

• Epistasis - interaction between loci

• one variant can influence whether one variant is phenotypically expressed

Somatic mutations in non cancerous disease

• understanding is poor as they are difficult to detect because there are in small amounts

• modern sequencing approaches have helped sequencing

• we can predict the earlier the mutation occurs the more likely it will have an adverse phenotypic effect

• location dependent

• mental health is influenced by somatic mutations

  • mutations we pick up along the way can influence our phenotypic expression

Key features of cancerous cells

1. the ability to replicate indefinitely

2. the ability to evade apoptosis

Examples of early drivers of cancers

1. Mutations that inactivate DNA repair pathways

2. mutations that increase the rate of cell divisions and therefore DNA replication

Cancer stem cells

• can replicate themselves or differentiate into a different tissue type

• naturally hardwired into them is disability one of the hallmarks of a cancer cell

• if they undergo a mutation, it will accelerate the mutation rate it is then referred to as a cancer stem cell

• has the ability to self renew indefinitely naturally

• picks up a mutation that confers other basic cancer property

How to target cancer stem cells

• chemotherapeutic agent that has cytotoxic effect kills the tumour cells but not the cancer cell

  • because the ability to replicate indefinitely

• repopulation of tumour

• target cancer cell to prevent tumour from reforming

Oncogenes

• genes that become activated in some way and drive tumour formation

• only one copy of the gene needs ot be mutated (dominant mutation)

• usually occur in cases with no family history (sporadic)

The philadelphia chromosome and Leukaemia

• translocation netween chromosome 9 and 22

• break points are lcoated within two important genes

• chromosome 9 - able gene, chromosome 22 - bcr gene

• after translocation is philadelphia chromosome that contains a fusion of the abl and bcr gene

ABL gene

• regulates haematopoietic cell division

• turn on in which it will promote the proliferation in the haematopoietic compartment

How does Abl and BCR fusion impact Abl

• locks Abl activity into on position - uncontrolled proliferation within the haematopoietic cell compartment leading to promotion of tumour creation

MYCN amplification and neuroblastoma

• within gene promoters where a gene is amplified

• Macan gene amplified leading to cancer

• function: transcription factor binding to heterodimer interacting with Max (TF)

• binds to E box driving transcription of neural pre cursor cells

• turns on genes that will drive the proliferation iwhtin this neural precursor compartment

• when amplifed: over activation of E box and over production of genes, over proliferation - tumours

• occurs in neural crest compartment

• go on to form sympathetic nervous system e.g neuroblastoma

Tumour supressor genes

• dont undergo any gain of function mutation

• inactivated by mutation

• display a family history and not sporadic

• need to occur in both copies of the gene

Knudsons two hit hypothesis

• tumour formation in the retina

• in you inherit one copy that is going to be present in all cells of the offspring

• you only need to inactivate one copy in any one of those cells, which is more likely than having to inherit two copies

• cancer is quite unlikely

Breast cancer and Fanconi’s anaemia

• if you inherit one copy your risk jumps a lot

• genes play a role in DNA damage repair

How do BRCA1 and BRCA2 play a role in DNA damage repair?

• repair double strand breaks: a bit of the DNA goes missing e.g ionizing radiation

• BRCA 1 senses break and recruits a BRCA2 RAD51 complex

NON HOMOLGOUS INJOINING

• stitch back together two chromosomal ends, error prone

HOMOLOGOUS

• error free recombination

• resection of one of the stands of these chromosomal ends

• enzymes come along and digesting away one of the strands on both broken chromosomal ends

• those generated single stranded regions will search cell for sequence homology

• polymerase comes along and uses that SS region as a primer and extends

Fanconi’s anaemia

• congenital condition associated with bone marrow failure, developmental abnormalities present at birth and increased risk of leukaemia

• biallelic mutations in any one of several genes can cause FA

• biallelic mutations in BRCA2 can also cause FA

• mutations can occur in different timeframes which can lead to one of the two diseases to occur (Breast cancer or FA)

Difference in phenotypes of Breast Cancer and FA

BREAST CANCER

• inherit one normal copy of BRCA2 and one defected copy

• both copies need to be inactivated - normal phenotype

• only when second copy is inactivated that leads to defective

FA

• both copies are inherited

• present from single cell zygote stage

• present during embryonic development

• symptoms observed from birth

Von Hippel-Lindau Syndrome

• mutation in Von Hippal Lindau gene

• two copies leads to tumours occuring on vasculatur

• with one copy you still get these other phenotype (vision impairments, poor motor skills)

VHL pathway defect

NORMAL

• VHL protein forms an interation with HIF alpha

• HIF alpha is a protein involved in transcription

• VHL usually binds to it and tags it with ubiquitin (degradation)

  HYPOXIC

• VHL modified and nitrosilated and can no longer bind

• free to interact with another TF and forms a hetero dimer and interacts with promoters to activate expression of certain growth genes

• e.g vascular endothelial growth factor of EGF driving proliferation and angiogenesis

• it occurs constituvely with no regulation in blood vessel precursor cell - high potential of tumour formation