Genetics

Question 1

Causes of disease x 3

Answer 1

Genetic - Down syndrome, Huntington, Cystic Fibrosis etc

Multifactorial - Cleft lip, diabetes, Heart disease (due to a mix of genetic and environmental factors)

Environmental - Diet, Drugs, infection

Question 2

Definitions: 
Genotype 
Phenotype 
Allele 
Polymorphism 
Homozygous 
Heterozygous 
Hemizygous

Answer 2

Genotype - genetic makeup of an individual
Phenotype - appearance/physical characteristics (mix of environment and genes)
Allele - Alternative form of a gene
Polymorphism - DNA sequence variation
Homozygous - both alleles the same
Heterozygous - alleles at the locus are different
Hemizygous - only 1 allele present at the locus

Question 3

Classification of genetic diseases:

Answer 3

Chromosomal:
- change in the structure or number of chromosomes

Mendelian:
- disorder due to alteration in one gene - AD, AR, SD, SR

Non Mendelian:

• imprinting/epigenetics
• Mitochondria mutations
• Mosaicism

Question 4

Mitochondria DNA

Answer 4

Ring of DNA used to produce proteins for the mitochondria

Mitochondria are mostly from your mum as many more fir in the egg cell - hence condition will be passed on via women

Question 5

De novo mutation

Answer 5

A mutation that happens in the sperm or egg cell and can be passed on to offspring

Question 6

Translocation chromosome variation

Answer 6

Chromosome breaks and a portion reattaches to another chromosome.

Reciprocal = no genetic material lost - not effect parent but may effect offspring

Robertsonian = long arms of 2 chromosomes fuse to form 1, short arm is lost and hence there is a loss of genetic material

Question 7

Inversion chromosome variation

Answer 7

c/some breaks and a section joins reversed.
Paracentric doesn’t include the centromere
Pericentric does

Question 8

Deletion chromosome variation

Answer 8

Deletion of a single base to a large piece of chromosome during DNA replication.
Interstital = in middle of the chromosome
Terminal = on the end

Question 9

Duplication chromosome variation

Answer 9

Production of one or more copies of a gene, part or whole chromosomes.

Tandem = same way 
Inverted = added on in reverse

Question 10

Ring chromosome

Answer 10

When the ends of a c/some becomes deleted the ends may join to form a ring.

Question 11

Fragile site

Answer 11

Part of the chromosome that may break when exposed to partial replication stress.

Question 12

Autosomal recessive inheritance

Answer 12

Only shown in heterozygous state
Male and female affected in equal proportions
Uncommon in pedigree with few individuals affected

Question 13

To work out the risk factor of a baby having a genetic disease…

Answer 13

Chance carrier x chance carrier x risk of child affected if both carriers

Question 14

Definitions: 
Autosome 
Allelic heterogeneity 
Consanguinity 
Autozygosity 
Penetrance 
Expressivity 
Anticipation

Answer 14

1. Any chromosome other than the sex chromosomes
2. Situation where different mutations result in the same genetic condition
3. Reproductive union between 2 relatives
4. Homozygosity by descent - inheritance of same allele through two branches of the family
5. % of individuals with a specific genotype showing the expected phenotype
6. Refers to the range of phenotypes expressed by a specific genotype
7. Where by genetic disorder affects successive generations earlier and more serve - usually due to expansion of triplet repeat

Question 15

Autosomal Dominant inheritance

Answer 15

Male and female affected in equal proportions

In multiple generations and more common than recessive

Question 16

Somatic mosaicism

Answer 16

Genetic fault in some tissues of the body

E.g. cancer that develops only in some certain tissues.

Question 17

Gonadal mutation

Answer 17

Genetic fault present in gonadal tissue

As it is present in germ cells it develops into all cells and hence can be passed on.

Question 18

X linked inheritance

Answer 18

Usually only males affected

Not passed from males to males as X chromosome is responsible.

Question 19

Lyonization

Answer 19

Generally only 1 of 2 chromosomes active in each female cell as only one lot of product is needed. Which cell is activated can be switched .

Question 20

Mitochondria DNA

Answer 20

Mostly inherited from mother

Homoplasmy = a eukaryotic cell whose mitochondrial DNA copies are identical

Heteroplasmy = multiple copies of mtDNA in each cell, with only a proportion being affected by a mutation. Level of severity can vary.

Most Mt diseases are caused by DNA in the nucleus (85%)

Question 21

Variant

Answer 21

Nucleotide sequence of the gene varies of that from from the normal population

Question 22

Incidental/secondary findings

Answer 22

Additional findings concerning a patient that may or may not have potential health implications. They are discovered during the genetic test, but are beyond the aims of the original investigation.

E.g - non paternal discovery, risk of early onset of…

Important to have full conscientious before the investigation takes place

Question 23

Sequencing DNA - Sanger

Answer 23

Uses PCR to amplify regions of interest followed by sequencing of products. Useful for a single gene test.

Time consuming and expensive, but very accurate

Question 24

NGS - next generation sequencing

Answer 24

Massively parallel sequencing
Low cost per gene
Very fast

But less accurate and a huge about of raw data

Question 25

Interpretation

Answer 25

Genes vary from Normal — variant of unknown significance — pathogenic variant If the variant is unknown we can compare it to a healthy control population, check it against the healthy family members. If a.a change is significant e.g charge polarity etc then we can predict the variation will be pathogenic.

Question 26

Wild type variant

Answer 26

The normal variant

Question 27

RNA sequencing

Answer 27

Can be used to analyse transcriptome and hence detect if a variant produces a non functioning protein and hence the severity of its impact.

Question 28

Ideogram:

Answer 28

Diagram showing expected chromosome banding after G staining

Question 29

How to produce a karyotype?

Answer 29

Take your sample e.g blood Add PHA to culture medium to increase cell division Incubate at 37C for 48 hours Add colcemid - inhibit metaphase and this is when c/some are most clear Add a hypotonic solution to make the chromosomes swell Spread cells on to a slide G stain the chromosomes to get banding

Question 30

Karyotype

Answer 30

Arranges chromosomes in pairs 1 — 22 | Longest to shortest with X and Y at the end

Question 31

Numerical chromosome abnormalities:

Answer 31

Trisomy - gain of a whole chromosome (47, XX, +21) Monosomy - loss of a whole chromosome Polyploidy - gain of a whole set of chromsomes

Question 32

Structural abnormalities

Answer 32

Translocation Inversion Duplication Deletion

Question 33

How do numerical chromosome abnormalities occur?

Answer 33

Non-disjunction can lead to gametes witch are monosomic or trisomic for a certain chromosome.

Question 34

Common numerical chromosome conditions:

Answer 34

Down syndrome (+21) - facial features, LD, heart and digestive problems Edwards syndrome (+18) - small head unable to walk - only 10% survive first year Note many numerical chromosome babies do no survive to birth

Question 35

Deletion on 15q leads to...

Answer 35

Prayer will I or Angelman

Question 36

How does F.I.S.H work?

Answer 36

DNA is labelled with fluorescent probes which are hybridised to the chromosome. They attach to the target gene or section and hence if fluorescent then it shows the presence of that DNA fragments. E.g when used for +21 each cell will have 3 fluorescent chromosomes showing presence of Down Syndrome Also used to locate broken part of chromosome origin

Question 37

Microarrays benefits?

Answer 37

Genetic testing technique that allows higher resolution and hence the detection of small deletions up to 1 Mb. Much higher than microscopy.

Question 38

Cytogenetics?

Answer 38

The study of inheritance in relation to the structure and function of chromosomes.

Question 39

Constitutional vs acquired abnormalities...

Answer 39

Constitutional = occur at gametogenesis, affects all cells of the body, heritable. Acquired = changes occur during life, restricted to malignant tissue, not heritable

Question 40

How do c/some abnormalities cause cancer?

Answer 40

They can cause cancer via: Fusion - breakpoints occur within the two genes involved, fusion creates a hybrid which gives rise to a chimaeric protein. Deregulation = juxtaposition of a gene to a regulating gene altered regulation can lead to an increased level of transcription.

Question 41

Different types of variants:

Answer 41

Deletion - removal of nucleotide if not a multiple of three then it will result in a frame shift Splice site variant - affects the accurate removal of intron/exons Non-sense variant - substitution producing a stop codon, leading to a truncated protein Mis-sense variant - single base substitution may not result in anew a.a due to the degenerate nature of the code. Expansion of tri-nucleotide repeat - There are sections of the genetic code where everyone has a certain number/ range of repeats but once a threshold is reached then the repeat becomes pathogenic.

Question 42

Examples of diseases with an expansion of a tri-nucleotide repeat:

Answer 42

Huntington’s disease - CAG | Fragile X - CGG

Question 43

Heterogeneity meaning?

Answer 43

The state of being heterozygous

Question 44

Diagnostic genetic test:

Answer 44

Patient has signs suggesting a disease, a genetic test will be used to confirm diagnosis.

Question 45

Predictive testing...

Answer 45

Testing health at risk family members for a familial variant

Question 46

Carrier testing

Answer 46

For x linked and autosomal recessive disorders carrier testing can be used to see if you are a carrier

Question 47

Pre-natal test

Answer 47

Genetic test using placenta or amniotic fluid sample. Only done when there is a chance of a sever pathogenic variant as 1-2% chance of miscarriage.

Question 48

PGD - Pre implantation gents diagnosis

Answer 48

Make an embryo Extract DNA - test for the genetic variant Implant healthy embryos into the uterus

Question 49

Normal variant Pathogenic variant Benign variant Allele of undetermined significance

Answer 49

Normal = age tic info which is present in 95% of the population Pathogenic = variant that causes the disease Benign = variant found in less than 5% of the population - rare - doesn’t cause pathogenic effects Allele of undetermined significance = not enough information to determine if the variant is benign of pathogenic.

Question 50

What is multifactorial inheritance?

Answer 50

Diseases due to an combination of genetic and environmental factors. They are the most common types of diseases. Risk greatest for 1st degree relatives then falls rapidly.

Question 51

How do you identify that a condition has a genetic component?

Answer 51

Family studies Twin studies Adoption studies

Question 52

How do family studies work when looking for multifactorial inheritance?

Answer 52

Compare the incidence of a disease amongst the family of an affected individual with the general population. In the family the condition risk will be dramatically higher - genetic And will vary depending on the degree of the genetic relationship The risk will vary depending on the number of the family affected.

Question 53

How do twin studies work when looking at multifactorial inheritance?

Answer 53

Compare genetically identical monozygotic twins with genetically non identical twins. The concordance rate is the % of twin pairs studied that both have the condition. If genetic component you would expect the concordance rate to be higher in monozygotic than dizygotic twins. Further showed genetic if still high risk even when monozygotic twins reared apart.

Question 54

Adoption studies:

Answer 54

Adopted children with a parent with a multifactorial condition still have a high risk of developing the disease. But the condition rate will still be higher in family’s where child has not be adopted also showing environmental factors play a role.

Question 55

Heritability

Answer 55

The portion of the causes for a disease that is due to genetic factors rather than the environment. Expressed as a % or between 1 and 0 Calculated from concordance rate in MZ

Question 56

The liability model: What does it show? What is liability?

Answer 56

The factors that influence the development of a multifactorial condition, genetic and environmental can be considered as a single entity known a liability. The liabilities for an individual form a continuous normal distribution curve The curve for relatives is shifted to the tight. A threshold exists above which a normal phenotype exists. Past threshold is known as the population incidence.

Question 57

How to know that part of the condition Is environmental?

Answer 57

Take a sample of patients and scope the whole genome for differences between their genes. Look for a SNP etc that is more common in the disease population. I presume not everyone with the gene will have the condition and hence there must be an environmental factor to the condition.

Question 58

Environmental factors that can affect multifactorial inheritance?

Answer 58

Drugs, alcohol, maternal infections — prenatal Obesity — Type 2 diabetes Pill, obesity, breast feeding — breast cancer Smoking — lung cancer Drugs — schizophrenia

Question 59

What is eugenics?

Answer 59

The study of how to arrange reproduction in a population to increase occurrence of heritable characteristics regarded as desirable. Positive eugenics = characteristics you want to increase Negative eugenics = stop breeding

Question 60

Genetic counselling =

Answer 60

The process by which patients or relatives at a risk of a genetic disorder that may be hereditable are advised on the consequences, probability of transmitting and the ways it may be prevented.

Question 61

What is directive vs non directive genetic counselling?

Answer 61

Direct = family may not fully understand consequences, may expect to be told what to do, you may feel you have a duty to reduce disease frequency. Non-direct = family may have extensive personal experience, decisions are personal to them, your aim is to help the individual. Non-directive, non judgemental counselling is what you aim to do

Question 62

What is a screening test?

Answer 62

Process of identifying people with an increased chance of a condition. Note someone who is screened positive may not have or develop the condition.

Question 63

What is a diagnostic test?

Answer 63

Confirms whether the condition is present or not. May have screened positive before.

Question 64

When does the foetus have full moral status?

Answer 64

After 24 weeks.

Question 65

What is an invasive prenatal test?

Answer 65

Diagnostic test for prenatal conditions 2 types include, chronic villus sampling and amniocentesis. CVS - at 10 weeks Needles and/or probes are inserted into the uterus and the fluid collected is tested. 05-1% of a miscarriage. amniocentesis = from 14 weeks

Question 66

What is NIPT?

Answer 66

Non-invasive pre-natal testing Circulating in the mother blood stream is foetal DNA from the placenta. Therefore you can take the mothers blood and analyse the foetal DNA with in. Therefore you can check or prenatal conditions such as extra chromosome 21 material.

Question 67

Positives and benefits of NIPT?

Answer 67

Less invasive prenatal tests and hence less miscarriages. If the risk is 1/150 results in 91% confirmed diagnosis Issues: False positive may lead to termination of a “healthy” foetus There may be an increased number of terminations May lead to eugenics (social pressures of family and society)

Question 68

What is PGD?

Answer 68

Pre-implantation genetic diagnosis Eggs fertilised in vitro, embryos develop. A few cells are then tested for genetic conditions and if non are found embryo can be planted into mother.

Question 69

How Is PGD regulated?

Answer 69

It is regulated by human fertilisation and embryology authority Also have to be licensed for IVF and PGD Risk of serious condition > 10% Female partner under 40 years No living unaffected child = expensive 12,000 and up to 3 cycles for the couple

Question 70

Altering the germ line, example and ethical issues...

Answer 70

The germ line cells result in sperm and eggs cells. Alter the germ line and it will be passed on. E.g mitochondria replacement therapy The Mitochondria contains 37 genes. Take the mothers egg and fathers sperm, just before they fuse transfer them to a new eggs cell with working mitochondria — forms a reconstructed zygote. Nuclear DNA still intact, but are you sure the mitochondria genes are only involved in the mitochondria???

Question 71

Why should altering the germ line not take place?

Answer 71

Genetic enhancement Eugenics Safety for future generations