The Revision Questions

Explain the difference between genotype and phenotype (Define both and explain the relationship between them)

A genotype is the organisms genetic makeup

A phenotype is the observable characteristics of an organism

The relationship between the two is that the genotype provides the instructions for the phenotype

Explain the inheritance of an X-linked disorder if the father (or mother) is the carrier

If the disorder is X-linked and the father is the carrier then all the daughters will be carriers and all the sons will be unaffected.

The daughters will get one X chromosome from their father and 1 Normal X chromosome from their mother. Whereas the sons will receive 1 Normal X chromosome from their mother and a Y chromosome from their father, meaning they are unaffected

Using examples, Explain the difference between expressivity and penetrance

Penetrance refers to whether a trait is expressed at all. In polydactyly, an individual may carry the dominant allele but show no extra digits, demonstrating incomplete penetrance.

Expressivity refers to the degree or severity of the phenotype. In polydactyly, affected individuals may show variation ranging from a small skin tag to fully formed extra fingers, demonstrating variable expressivity.

Therefore, penetrance describes presence or absence of the trait, whereas expressivity describes the extent of its expression.

Briefly describe the process of meiosis and note the key differences with mitosis

Meiosis is a type of cell division that produces gametes. One diploid parent cell undergoes 2 divisions after a single round of DNA replication, forming 4 genetically different haploid cells. Whereas mitosis produces 2 diploid cells that are genetically identical. Crossing over and independent assortment occur in meiosis but does not in mitosis. meiosis also occurs in germ cells whereas mitosis occurs in somatic cells

Briefly explain what is meant by heritability and how heritability is estimated

Heritability is the proportion of variation in a trait in a population that is due to genetic differences (rather than environmental factors).

It is estimated by comparing how similar related individuals are for a trait (Twin studies)

What is meant by gene dosage? Give one example of how gene dosage is altered in neurodevelopmental disorders

Gene dosage = Number of copies of a gene present in a cell, and how this affects the amount of protein produced

Example: Down Syndrome, individuals have 3 copies of chromosome 21 rather than 2. This means that more protein is produced than normal, which contributes to the cognitive and developmental features of the condition.

Briefly explain the key steps in turning a gene into a protein

1. Transcription

• DNA sequence of a gene is copied into mRNA in the nucleus

• RNA polymerase build the mRNA strand

2. Translation

• mRNA travels to the ribosome in the cytoplasm

• Transfer RNA (tRNA) brings amino acids to the ribosome

• The ribosome reads the mRNA in sets of 3 bases (Codons)

• Each codon specifies a specific amino acid

3. Protein Folding

• The chain of amino acids (polypeptide) folds into a functional protein

Explain briefly what occurs during crossing over and how this process is related to neurodevelopmental disorders

Crossing over occurs during prophase

Homologous chromosomes pair up and DNA segments are exchanged between matching chromosomes, creating new combinations of alleles. This increases genetic variation in offspring.

Crossing over can go wrong, leading to chromosomal rearrangements such as deletions and duplications. For instance, DS is due to the duplication of chromosome 21.

Give 2 examples of specific single-nucleotide mutation types - define the change, the effect on the protein and the likely consequences

Missense Mutation: A single base change that changes one amino acid in the protein, which may change the amino acids function and effect enzyme activity.

Nonsense Mutation - A single base mutation that converts a codon for an amino acid into a stop codon. This means that translation stops early, producing a shortened protein

Briefly describe neurulation and one way in which an error in neurulation can alter the developing brain

Neurulation - Is an early embryonic process where the neural plate folds inwards to form the neural tube. This is the precursor of the brain and the spinal cord

Error example:

If the rostral neural tube fails to close, it results in anencephaly, where much of the brain fails to develop properly. This drastically alters brain formation

Explain briefly two different mechanisms that migrating neurons and axons use the find their way to their correct place in the developing nervous system

Chemical guidance cues: Growing axons and migrating neurons detect gradients of signalling molecules in their environment. These cues either attract or repel them, guiding them toward their correct target

Contact Guidance along cellular scaffolds- Neurons attach and travel along radial glial fibres or along existing axon tracts. This provides a pathway that directs them to the appropriate location

What determines if a synapse is kept and consolidated or pruned ? How might where the synapse is on a neuron influence this?

Depends on its activity and usefulness within a neural circuit. If a synapse is used often and helps the neuron fire, it is kept and strengthened. If it is rarely used, it is weakened and pruned away.

The synapses closer to the cell body have a bigger effect on the neuron and are more likely to be kept. The synapses further out on the dendrites have less effect and are more likely to be pruned unless they are very active

Briefly explain what “regressive growth” means in terms of neural development

Regressive growth is when the developing nervous system first makes more neurons and connections than needed, and then removes the extra ones by apoptosis (cell death) and synaptic pruning. This helps the brain refine and organise its final structure

How does the thickness of the cortex change after middle childhood. Give one reason why this change takes place

After middle childhood, the cortex becomes thinner due to synaptic pruning. The unused connections between neurons are removed making the brain more efficient

Why is plasticity increased in childhood and why is it useful for an adult brain to have less plasticity than a child’s brain?

Increased in childhood because the brain is still developing. The neurons and synapses can change, form and be removed in response to experience.

If adults brains had too much plasticity, it might constantly overwrite important learned abilities

Describe Experience Independent plasticity

Brain development that happens automatically without needing specific experiences.

E.G. Forming basic neurons and early brain structures

Describe experience dependent plasticity

Brain changes that occur because of unique individual experiences

E.G. Playing an instrument

Describe experience expectant plasticity

Brain development that expects certain common experiences (seeing, hearing or touching) to occur, this is necessary for normal development

What is one brain change that takes place during aging and why does it occur ?

Gradual loss of neurons and synapses in the hippocampus and prefrontal cortex

This occurs due to cell stress, reduced plasticity and slower repair mechanisms

Briefly explain the role of chaperones in protein folding

They help other proteins fold into correct 3D shape. They prevent misfolding and clumping by temporarily binding to the protein as it folds ensuring it reaches its proper functional form

Explain what loss of function effect and “gain of function” effects are in protein

Loss of function - The protein loses its normal activity or is missing entirely. Cannot perform its usual roles in the cell. E.G. a mutated enzyme that no longer works

Gain of Function - The protein gains a new or abnormal activity, which can disrupt normal cell processes. E.G Protein that is always on causes uncontrolled cell growth

Briefly, but completely, describe the genetic change/mutation that causes full mutation Fragile X Syndrome

An increase in the number of CGG trinucleotide repeat in the FMR1 gene on the X chromosome. In the full mutation there are more than 200 repeats. This causes hypermethylation of the promoter region, causing gene silencing. Leading to reduced or absent FMR1 protein

Causing FXS

If a woman carries the fragile X premutation, what percentage of her sons will have
fragile X? What percentage of her daughters? If the father is the carrier of the
premutation, what percentage of his sons will have fragile X? What will we see in his daughters?

Woman:

50% of her sons have FXS

Daughters are likely to have the premutation (each daughter has a 50% chance of inheriting it)

Father:

0 Sons with have FXS

daughter will be carriers

What is genetic responsibility and how does it relate specifically to FXS

It is the idea that individuals have a duty to understand, manage, and communicate genetic information that could affect their own health or health of relatives.

For FXS, this disorder is X-linked and can passed silently through premutation.

Explain two roles FMRP can play in the cell using its ability to bind to RNA

Regulating protein production (translation control)

• slows down or temporarily blocks translation so proteins are made at the right time and place

transporting mRNA to specific locations

• carries certain mRNA from the cell body to dendrites and synapses

• local protein synthesis

• Essential for synapse development and plasticity

Explain how missing FMRP interacts with mitochondrial function

Missing FMRP disrupts regulation of proteins involved in energy metabolism, leading to abnormal mitochondrial function and reduced ATP production in neurons, which contributes to FXS

Explain one way in which missing FMRP results in altered synaptic plasticity

FMRP’s function is in controlling protein production at synapses, without It, too many proteins are made at the synapse and therefore, this changes the shape and function of dendritic spines. So neurons cannot adjust, learning and memory are impaired

How is the brain itself physically different in FXS and how might this change be the result of changes to synaptic function

• dendritic spines are often longer and thinner

• subtle differences in regions like the hippocampus and cortex

This is because too many synaptic proteins are made and the synapses weaken, disrupting plasticity.

Describe one neuropathological change that occurs in FXTAS and identify a symptom of the disease that is associated with that change

Abnormal clumps of protein and RNA that build up inside the nucleus of neurons and astrocytes. They interfere with normal cell function and contribute to cell dysfunction and degeneration.

This damage is associated with symptoms such as intention tremor and ataxia

Explain the theory around how increased FMR1 mRNA may be toxic inside the nucleus

Individuals with FXTAS have a premutation in the FMR1 gene, this increases transcription.

Produces abnormally high levels of FMR1 mRNA, so accumulates in the nucleus

Sequesters RNA-binding proteins

Protein synthesis is not regulated

protein aggregation and neuronal dysfunction occur

What is the relationship between CGG expansion length and FMR1 mRNA levels in premutation carriers? Does repeat length matter for the penetrance of FXTAS and, if so, how?

The longer the CGG repeat = Higher FMR1 mRNA

the protein FMRP is slightly reduced = too much abnormal mRNA

Longer repeats = higher risk of FXTAS (higher penetrance)

What are the symptoms on which FXTAS is diagnosed

• Intention tremor

• Poor balance

• Poor coordination

Symptoms typically observed after the age of 50

More severe in males

Diagnosis made through clinical, radiological findings and molecular testing

What disorder is FXTAS often misdiagnosed as? Why might this mistake happen in the clinic?

Parkinsons

Due to the similarity of symptoms such as tremors and balance problems

Explain the circumstances under which a person could experience FXTAS and full-mutation FXS at the same time

If mosaicism occurs.

• A person has both full mutation and premutation FMR1 alleles in different cells

• Some cells cause FXS

• Some cells can lead to FXTAS later in life

Briefly explain two key differences between FXTAS and PD

FXTAS is caused by a genetic change (CGG repeat expansion in the FMR1 gene)

PD is not caused by degeneration of dopamine producing neurons in the substantia nigra

FXTAS causes intention tremor

PD causes resting tremor

Describe one piece of evidence that supports the idea that PD could be a “prion-like” disorder

Misfolded a-synuclein in PD can spread between neurons and induce normal a-synuclein to misfold, demonstating prion like propagation similar to that seen in Creutzfeldt-Jakob disease

What are the hallmark motor symptoms of PD and in what order are they typically experienced

first:

Tremors

Bradykinesia

There are 6 stages of PD

Briefly explain 2 key differences between PD and Dementia with Lewy Bodies