DDT - Genetics

What is autosomal dominant

A pattern of inheritance where only one allele is required for the disorder / trait to be present.

What is autosomal recessive

A pattern of inheritance where two copies of a mutated gene, one from each parent, are required for the disorder to manifest in offspring. This means that the trait is expressed only when both alleles are present.

What is x-linked recessive

Genetic conditions associated with mutations in genes on the X chromosome. A male carrying such a mutation will be affected, because he carries only one X chromosome. A female carrying a mutation in one gene, with a normal gene on the other X chromosome, is generally unaffected.

What is co-dominant in terms of genetics

A pattern of inheritance where both alleles in a heterozygote are fully expressed, resulting in offspring with a phenotype that is a combination of both traits. This occurs without one allele being dominant over the other.

What is germline mosaicism?

Germline mosaicism is a genetic condition where some of an individual's germ cells (sperm or eggs) carry a mutation, while others do not. This can lead to offspring inheriting genetic disorders even if the parent does not show symptoms.

What is somatic mosaicism?

Somatic mosaicism is a condition where an individual has two or more genetically different cell lines within their body, resulting from mutations that occur after fertilization.

What is a nonsense mutation?

Where a stop codon is prematurely present due to amino acid change

What is a missense mutation?

Replacement of one amino acid to another in a protein

What is a splicing mutation?

Where exon to intron sequences are changed, leading to either partial or complete loss of exons, leading to shortening of proteins

What is a frameshift mutation?

A genetic mutation caused by the insertion or deletion of nucleotides in a DNA sequence, altering the reading frame of the genetic code. Also splicing mutations can cause this to occur as well.

Changes in the promoters will lead to?

1. Change to a protein sequence?

2. No change to protein sequence

3. Change in splicing region

4. Change in protein expression

5. No change in the gene at all

1. Change to a protein sequence?

2. No change to protein sequence

3. Change in splicing region

4. Change in protein expression

5. No change in the gene at all

Loss of control during transcription or will need to use an alternative promoter during transcription

If a single base pair change occurs in an exon it will cause?

1. Change to protein sequence

2. No change to protein sequence

3. Change in splicing region

4. Change in protein expression

5. No change in the gene at all

1. Change to protein sequence

2. No change to protein sequence

3. Change in splicing region

4. Change in protein expression

5. No change in the gene at all

This occurs as it will either change or remove exons, insert or remove stop codons and alter splicing sites as well as affecting the open reading frame.

If a single base pair change occurs in an intron it will cause?

1. Change to protein sequence

2. No change to protein sequence

3. Change in splicing region

4. Change in protein expression

5. No change in the gene at all

1. Change to protein sequence

2. No change to protein sequence

3. Change in splicing region

4. Change in protein expression

5. No change in the gene at all

This will occur as it will alter the splicing site

What is gain of function?

Changes in gene function, affecting protein production, may become active and enhanced to work in other ways. It is dominant when it comes to inheritance

What is loss of function?

Loss of function is where gene function is either reduced, or completely inactive, even if proteins are produced. This is typically recessive in terms of inheritance

What is an inborn error of metabolism

A rare genetic disorder where the body is unable to break down food, due to a lack of enzymes /
A heterogeneous disorder where metabolic pathways are inactive, and carbohydrates, fatty acids and proteins are either not stored or broken down effectively

If enzyme c was missing what would occur to the other parts in the pathway?

There would be no production of D as there is no enzyme to convert C to D. There would be a build up C and E as it cannot be converted to anything else, and A and B would possibly build up as well if the path is reversible. Also there would be no negative feedback loop either

If the OTC enzyme has a loss of function mutation, what would build up as a result of this?

Carbamoyl phosphate would build up as it would not be converted into citrulline

Which loss of function mutation would have a greater malignancy, and cause more damage to the body:
NAGS (Converts ammonia, which is incredibly toxic) or ASS (Converts citrulline, which is not found to be toxic)

NAGS would be far more dangerous, as it will cause a build up of ammonia, leading to hyperammonaemia, leading to coma and possible death. The ASS enzyme is still important, but a LOF is far less impactful than NAGS.

2 patients are showing mutations linked to the CPS1 enzyme, vital for the urea cycle. One patient has 1 nonsense and 1 missense mutation, while another patient has 2 nonsense mutations. Which patient has the more severe symptoms?

The 2 nonsense mutations are far more severe than the other patient, as no enzyme is produced at all. This leads to a build up of ammonia, and can lead to death. The 1 missense and 1 nonsense patient is still going to produce enzymes, but will have less activity than a useless person, but it will not result a risk to life. This would have a similar result for any pathway in the body.

What is the Guthrie test (neonatal screening), amniocentesis and also chorionic villus biopsy and how it’s performed.

1. Guthrie test is a prick to the baby’s heel post birth to collect blood, to test for 9 serious diseases. Developed in 1959 and mid 60’s was used common for newborn screening

2. Amniocentesis is the collection of amniotic fluids post week 15, since it is filled with foetal keratinocytes (Skin cells)

3. Chorioni villus biopsy is only used if it is to be believed if there is a possible miscarriage, or cause serious harm to the baby, like abnormal chromosomes and chromosome counts. Takes tissue from the placenta

Methods of detecting genetic diseases

Ideograms / Karyotype that show images of chromosomes, to detect mutations
FISH (fluorescent in situ hybridisation) that uses fluorescent labelled DNA to detect mutations as well, using stains and counterstains to highlight different locus or chromosomes
PCR and sanger test make up the entire genome
ARMS based PCR detects specific mutations you’re looking for quickly
Next gen massively parallel sequencing screen DNA using PCR and making daughter strand extend by a nucleotide at a time

Small scale, fast results would require which type of genetic testing method?

Next generation would be the fastest method to use, as it can give results in seconds. However, if time is not a constraint, either FISH or Karyotype would be the next best option

When would PCR and sanger testing be the best choice?

When time is not an issue, and when you want incredibly in depth answers, to detect abnormalities that no other test can detect (The gold standard of genetic sequencing)

Using the image below who you need to test if the genetic disorder for child II.2 (Male) has a genetic disease that fits either of these diseases:

X-linked recessive
Autosomal Recessive

You would need to test the I.3 for X-linked recessive as they are carriers, and cannot be affected by the disease. Male to male transmission is also not possible with this, so you would not need to test the male.
For autosomal recessive, both parents would be tested (I.3 and I.4), since 2 recessive alleles are needed

What is gene therapy?

Giving someone medical care by altering / modifying their genes

Give a few examples of gene therapy

Haematopoietic stem cell gene therapy - Can treat immunodeficiency diseases
Immunotherapy for cancer - Modifying patient T cells to attack cancer cells
The liver - Can help it to not be affected by viruses, as well as help to treat other diseases
These are just a few examples, there are much more to pick from

What are some treatments for those who have inborn errors of metabolism, like phenylketonuria?

With phenylketonuria, there must be strict phenylalanine intake whilst adolescent and brain still developing (Maybe even further beyond)
Giving patient tyrosine as supplement which is highly deficient in those affected by phenylalanine