Lecture 1 - Genetics And Inheritance

Question 1

Inherited traits are controlled by what?

Answer 1

Genes

Question 2

What is genome?

Answer 2

This contains all the info needed to construct a living organism.

Question 3

Mutations in genotype causes what type of diseases?

Answer 3

1. Monogenic Disorders - Sickle cell disease, Cystic Fibrosis
2. Polygenic Disorders - T2D, Schizophrenia and Rheumatoid Arthritis

Question 4

Genotype also determines whether you are resistant to diseases and example of this is?

Answer 4

Individuals who lack CCR5 (chemokine receptor) are immune to HIV-1 as this is how HIV-1 usually acts to cause an infection.

Question 5

Genotype also controls the response to drugs:

1. Mutant type of CYP450 - slow metabolisers
2. Polymorphism in CYP450 - fast metabolisers
3. Breast Cancer (those who OE HER2)

Answer 5

CYP450 is used to metabolise 25% of drugs. This is important for converting codeine to morphine allowing to act as a pain killer.

1. Individuals who have a mutant type of CYP450 are slow metabolisers so codeine can’t be metabolised to morphine. Hence, another drug has to be given —> PERSONALISED MEDICINE.
2. However, individuals with a polymorphism in CYP450 are fast metabolisers so intake of codeine can lead to respiratory depression and death.
3. Some cases of breast cancer (30%) are due to OE of HER2 —> this promotes high cell division. Herceptin can be given to these individuals as this blocks HER2 action. However, this is ineffective in the other 70% cases.

Question 6

How does human genome fit inside nucleus?

How is accessed for transcription and translation?

Answer 6

Human Genome - 1.8m
Nucleus - 5µm

1. DNA is wrapped around histone proteins (chromatin) and this is highly condensed and compact to form nucleosomes. This then condenses to form chromosomes which are highly compact allowing it to fit inside nucleus.
2. In its compact shape, RNA polymerase cannot access DNA for transcription and translation. Hence, in transcription, the section of DNA required is unravelled and is made accessible for mRNA synthesis.

Question 7

Features of Human Genome:

1) How many chromosomes are present and what type?
2) Nomenclature for females
3) Nomenclature for males
4) Are genes on Y chromosome essential?

Answer 7

1. 46 Chromosomes (22 pairs of autosomes and 1 pair of sex chromosomes)
2. 46, XX - Female
3. 46, XY - Male
4. Genes on Y chromosomes is not essential as females don’t have a Y chromosome.

Question 8

What is Cytogenetics and how is Cytogenetics performed?

Answer 8

Cytogenetics = is studying genetic component of cell by visualising and analysis chromosomes.

In Cytogenetics, you use chromosomes in metaphase stage as these are visible.
They are then stained with Giemsa (causes G-bands where chromosomes have unique light and dark bands).

Question 9

How are chromosomes classified?

Answer 9

Chromosomes are characterised by:

1. Size
2. Patterns of G-bands
3. Position of Centromere

Question 10

What is a centromere and what are the different types of centromeres?

Answer 10

Centromere is a constriction in chromosomes. Kinetochore proteins binds to centromere. This is associated to mitotic spindle in cell division allowing separation of chromatids.

The three different types of centromeres:

• Metacentric e.g. Chrom 3
• Submetacentric e.g. Chrom 17
• Acrocentric e.g. Chrom 21

Centromeres splits chromosomes into short (p) arm and long (q) arm.

Question 11

Why do Chromosomes replicate?

Answer 11

1) To replace cells lost (with wound healing) and for cell growth and development.

Mitosis - allows production of 2 identical daughter cells which are identical to parent (diploid)

2) To pass genetic informations to offspring.

Meiosis - produces 4 daughter cells identical to each other (haploid) but not to parent (diploid). This allows zygote to be diploid when gamete fusion occurs. Also have genetic variation due to chromosome recombination.

Question 12

Differences between Mitosis and Meiosis:

Answer 12

Mitosis:

• 1 round of DNA replication
• 1 round of chromosomal segregation
• 1 cell (diploid) —> 2 cells (diploid)

Meiosis:

• 1 round of DNA replication
• 2 rounds of chromosomal segregation and recombination)
• 1 cell (diploid) —> 4 cells (haploid)

Sperm cells make 4 daughter cells but oocytes don’t. They produce only 1 functional egg cell and the other three are lost.

Question 13

Summary of Mitosis:

Answer 13

Diploid parent undergoes chromosomal replication in prophase. This causes cell to have sister chromatid pairs.

In metaphase, sister chromatid pairs align in equatorial plane.

In anaphase and telophase, sister chromatids separate and 2 identical daughter cells are generated.

Question 14

Summary of Meiosis:

Answer 14

Diploid parent undergoes chromosome replication in prophase. This causes cells to have homologous chromosome pairs (1 mother and 1 father) which undergo recombination. This allows exchange of genetic information.

In metaphase, homologous pairs line up in equatorial region.

In anaphase, homologous pairs separate.

Another round of chromosome segregation occurs and then sister chromatids separate. This causes formation of 4 haploid identical daughter cells.

Question 15

How much of Y chromosome confers maleness?

Answer 15

Chromosomal abnormalities show that a small region on P arm of Y chromosome confers maleness:

• some males have 46, XX - found that one X chromosome has a small region of Y chromosome
• some females are 46, XY - found that short arm of Y chromosome is missing a small region —> causes female phenotype.

This was found to be the SRY gene - this encodes for a protein which acts as a TESTES DETERMINING FACTOR which causes male development.

Question 16

What is an aneuploidy?

Answer 16

Irregular no. of chromosomes. These individuals are said to have an abnormal karyotype.

Question 17

What are the consequences of an abnormal karyotype?

Answer 17

Can lead to spontaneous abortions (50% are due to trisomies). Some can lead to live births if trisomy occurs in short chromosomes.

Trisomies in long chromosomes (e.g. chromosome 1) is fatal and will impact development.

Question 18

What are the causes of aneuploidies:

Answer 18

1. Non-disjunction (failure of homologous chromosomes to segregate properly in meiosis)
2. Age - Ova are as old as mother as all females are born with all the oocytes they will need in their lifetime. Unlike males where spermatogenesis is continuous.

Ova at birth are found in the meiosis I stage. After ovulation, they arrest in meiosis II.

Question 19

Trisomy 21 or Down Syndrome - 47, XX or XY +21

Answer 19

• Retarded Growth and Development
• Mental Retardation (delay in mental and social skills)
• Single Crease on hand (Simian crease)
• Cardiac Abnormalities
• Increased risk of Leukaemia (WBC cancer)

Question 20

Trisomy 13 or Patau Syndrome - 47, XX or XY +13

Answer 20

• Heart Defects
• Incomplete brain development
• Infant only survives for 130 days

Question 21

Trisomy 18 or Edward’s Syndrome - 47, XX or XY +18

Answer 21

• Heart defects
• Intestines protrude outside body
• 95% die before born
• Rest usually die in 1yr of life

Question 22

Examples of abnormalities in Sex Chromosomes:

Answer 22

• Klinefelter Syndrome
• Turner Syndrome
• Super-male Syndrome

Question 23

Klinefelter Syndrome - 47, XXY

Answer 23

• appear normal
• infertile
• small testes

Question 24

Turner Syndrome - 45, X (monosomy)

Answer 24

• Short stature and amenorrhoea
• Infertile —> not born with egg cells
• No adolescent growth spurt

Question 25

Super-male Syndrome - 47, XYY

Answer 25

- Asymptomatic - Increased growth velocity (taller than average) - Inaccurately stereotypes as being violent criminals

Question 26

When is it necessary to determine karyotype? When should amniocentesis be done?

Answer 26

If foetus is at risk of developing chromosomal abnormalities then karyotype has to be determined. Amniocentesis is only done if offspring is at high risk of developing aneuploidies. This procedure is non-invasive and has a low risk of miscarriage.

Question 27

How to do amniocentesis?

Answer 27

1) Inject needle into amniotic sack to obtain foetal cells 2) Analyse chromosome 13, 18, 21 using qPCR (95% accuracy) 3) Karyotype is looked at for further accuracy (100%) No. of amniocentesis tests increase with age as more likely to get trisomy if have baby later in life.

Question 28

What is Mendelian Inheritance?

Answer 28

- simple genetic characters depend on genotype at a single locus - diseases caused by this can lead to monogenic disorders, such as SCA and CF

Question 29

What is Mendelian’s Law?

Answer 29

- all individuals have pair of alleles for a given trait. One is passed to offspring. - Alleles of different traits segregate/assort independently

Question 30

What is non-Mendelian inheritance?

Answer 30

If genes are mutated on X chromosome then females show a different trait to males. This is not autosomal but is X-linked.

Question 31

Modes of monogenic inheritance:

Answer 31

1. Autosomal recessive - CF 2. Autosomal dominant - HD 3. X-linked recessive - Haemophilia A 4. X-linked dominant 5. Mitochondrial diseases

Question 32

Autosomal Recessive - CFTR: Locus? Alleles? Most common mutant type? Pedigree? (Autosomal/ X-linked/ recessive/ dominant)

Answer 32

Locus: Chromosome 7 Allele: C - wild type CFTR c - mutant type Most common form is missing a.a on 508th codon (∆F508). CC - normal Cc - Heterozygotes (normal/carriers) cc - CF Heterozygotes are normal as presence of dominant allele masks the phenotype of recessive allele. If both parents are heterozygotes, chances of child having CF is 1 in 4 chances. This is an autosomal recessive disorder - autosomal as both males and females are equally affected. Recessive as trait skips generation.

Question 33

Pathophysiology of CFTR:

Answer 33

CFTR is a Cl- channel which is synthesised in ER and packaged into vesicles and taken to Golgi. This is then expressed on PM to allow Cl- export and H2O follows via osmosis. This keeps mucus mobile and fluid-like allowing it to trap bacteria in airways. Mutation in CFTR e.g. CFTR∆F508. This is synthesises in ER but is misfolded so is degraded by the ER quality control systems. Hence, this is not expressed on PM —> [Cl] is high inside so H2O enters cell via osmosis. This causes mucus to be thick so can’t trap bacteria and leads to infections. This can also b locks ducts in pancreas and intestines.

Question 34

Autosomal Dominant: Huntington’s Disease ``` Type of disease? Symptoms? Causes? Normal vs. Mutant? Pedigree? ```

Answer 34

- Neurodegenerative disease - Gradual cognitive decline - caused by mutation in HD locus - Normal HD has 28 repeats of CAG codon (Gln) —> forms a polyglutamine tract - mutant HD has more than 36 repeats of CAG codon; this causes: 1. Expansion of polyglutamine tract 2. Aggregation of protein as it is misfolded 3. Precipitation in neural tissues - neuronal cell death (neurons don’t regenerate) Autosomal dominant as presence of mutant allele will lead to symptoms (aggregation of proteins still occurs). However, this only appears in adulthood as it takes time for mutant HD to aggregate/ accumulate. Trait is seen in every generation and affects both males and females equally.

Question 35

X-linked Recessive: Haemophilia A ``` Is it Mendelian? Where is the mutation found? What does the gene encode for? Normal mother X Haemophiliac father? Carrier mother X normal father? Is it more frequent in males or females? ```

Answer 35

- not Mendelian characteristics - gene is on X chromosome - son obtains X from mother and Y from father. If mother is affected, then all sons will be affected. - this is a mutation in gene encoding blood clotting factor VIII - If normal mother mates with a haemophiliac father: - all females are carriers - can’t be passed from father to son - if mother is carrier and father is normal: - half the sons will have disease - half the daughters will be carriers - more frequent in males than females

Question 36

What are polygenic disorders? Does it follow mendelian’s law? Two types of traits? What is a multifactorial disease and give examples?

Answer 36

- this is controlled by more than one locus (i.e. more than one gene) - not follow mendelian’s law - Traits are either continuous or discontinuous: - Discontinuous - T2D - Continous - Height Multifactorial - if influenced by environ and genetics (i.e. more than one factor) e.g. T2D, CVD, obesity and mental illnesses.

Question 37

How do we assess the contribution made by genetic vs. environment for a given disorder:

Answer 37

Done through twin studies where monozygotic (identical) or dizygotic (non-identical) twins are used. Monozygotic - same egg divides so genetically identical. Dizygotic - 2 ovum are fertilised by 2 sperm at same time so not identical. You can tell if a disease is inherited or environment by looking at prevalence of a disease in MZs and DZs (concordance). If disease is more prevalent in MZs then disease is inherited i.e. if have high concordance in MZ than DZ then there is a genetic factor involved as MZs have same genome to each other.