Inheritance and genetics

Question 1

Not all genetic information is carried on chromosomes in the nucleus, where else is it located?

Answer 1

There is also genes present on a mitochondrial chromosome and mutations on this piece of DNA may also cause disease.

Question 2

Why is taking a family history and drawing out a pedigree important?

Answer 2

• It helps predict the mode of inheritance of a disease.
• It enables you to calculate risk to other family members and offspring.
• It allows you to distinguish between disorders with similar clinical presentations.

Question 3

What do you need to consider when constructing a pedigree?

Answer 3

• start with the proband.
• include at least three generations where possible.
• information on both sides of the family important.
• age and when the clinical symptoms became apparent is important.
• as genetics mutations vary by population it is important to record ethnicity.
• if possible note cultural background, some give rise to consanguinity.
• dates/causes of deaths.
• if twins, mono or dizygotic.
• recurrent pregnancy losses (do we know if these involve chromosomal rearrangements?).
• any children that may have died.
• consanguinity.

Question 4

Difference between monozygotic and dizygotic twins?

Answer 4

Monozygotic - identical.

Dizygotic - non-identical.

Question 5

What do we mean by autosomal dominant (AD) inheritance?

Answer 5

• disease allele located on an autosome (chromo 1 - 22).
• trait is dominant, so only one copy of disease allele needed for individual to express phenotype.
• as autosomal both males and females affected and both can transmit the disorder to sons and daughters.
• therefore proportion of affected males in pop should be similar to affected females in pop.

Question 6

Autosomal dominant - what to look for on a pedigree?

Answer 6

• male to male transmission.
• (unless new mutation occurred) all affected individuals will have at least one parent who is affected.
• vertical transmission (affected individuals in every generation).

Question 7

Give some examples of autosomal dominant conditions?

Answer 7

• Achondroplasia.
• Huntington disease.
• Marfan syndrome.
• Myotonic dystrophy.
• Neurofibromatosis.

Question 8

When it comes to autosomal dominant inheritance what do you need to consider?

Answer 8

• Variable expression, incomplete penetrance and homozygosity.

Question 9

What is variable expression?

Answer 9

• This is when the degree of severity of a disorder varies. E.g. Neurofibromatosis type 1: some individuals only have cafe au lait patches on skin and some may have tumours. This is due to genes not acting in isolation but act against a background of many other genes (modifier genes - suceptibilty/protection) and variable environment.

Question 10

What is incomplete penetrance?

Answer 10

• When it comes to AD inheritance most affected people will have an affected parent if no new mutation has arisen and disease is 100% penetrant.
• Sometimes in pedigree it looks like disease has skipped a generation but may be someone who carries the disease allele but doesn’t show any symptoms = reduced penetrance. Usually expressed as a %.

Question 11

What happens if you are homozygous for an AD disorder?

Answer 11

• If homozygous for the disease allele (AD) then the individual may have a more severe phenotype e.g. Achondroplasia or there may be no difference between homozygotes and heterozygotes e.g. Huntington disease.

Question 12

What do we mean by autosomal recessive (AR) inheritance?

Answer 12

• disease allele recessive, need two copies to be affected.
• parents usually carriers of disease allele and unaffected. This gives rise to horizontal pattern of inheritance on pedigree, sibs tend to be affected.
• alleles present on autosomes.

Question 13

Give some examples of autosomal recessive conditions?

Answer 13

• Phenylketonuria (PKU).
• Cystic fibrosis (CF).
• Sickle cell anaemia.

Question 14

Things to consider when thinking about autosomal recessive disorders?

Answer 14

• Pseudodominance, compound heterozygote and double heterozygote.

Question 15

What is pseudodominant inheritance?

Answer 15

• When a pedigree resembles that of an AD disease despite the disorders actually having an AR cause. This may be caused by high incidence of carriers in the extended family due to an isolated community or assorted mating (e.g. Deaf individuals - same schools/socialise with each other may be more likely to get married etc).

Question 16

What is a compound heterozygote?

Answer 16

• Individual who has different mutations in the same gene but different mutations on the paternal and maternal chromosomes - since carrying two mutations within the gene = affected.

Question 17

What is a double heterozygote?

Answer 17

• Individual who is a carrier for 2 separate recessive conditions (they wouldn’t be affected by either of them).

Question 18

What do we mean by x-linked recessive inheritance?

Answer 18

• mutation of gene on X chromosome.
• males hemizygous for x-linked genes (only one x) then any male with one copy on an x-linked recessive disease allele will be affected.
• females usually not affected, normal allele will compensate.
• males have to transmit x to daughters so all of their daughters will be carriers and sons unaffected as they pass their y.
• carrier female, can pass defective allele to sons and daughters, sons will be affected females will be carriers.

Question 19

When would a woman be affected by an x-linked recessive condition?

Answer 19

• if they have two copies of disease allele (all sons affected and daughters carriers). This would occur if they had an affected father and a carrier mother.
• when suffering from chromosomal disorder turners (45,X). Single x carries the disease allele then affected.
• individual chromosomally male (XY) but phenotypically female because suffering from androgen insensitivity. No good x to compensate.
• skewed x inactivation, the good x is silenced to a higher degree than the one carrying the mutation therefore a carrier female may show symptoms.

Question 20

Give some examples of x-linked recessive conditions?

Answer 20

• Dunchenne muscular dystrophy (DMD).

- Haemophilia A.

Question 21

What do we mean by x-linked dominant inheritance?

Answer 21

• only one copy of disease allele on X chromosome required to be affected.
• both males and females affected (males may be more severely affected because only carry one copy of genes on x).
• some x-linked dominant disorders lethal in males.
• on pedigree may look AD but with x-linked dominant you can’t get male to make transmission.

Question 22

Give some examples of x-linked dominant disorders?

Answer 22

• Vitamin D resistant rickets.

- Rett syndrome (lethal in males).

Question 23

What do we mean by Y- linked inheritance?

Answer 23

• vertical pattern of inheritance.
• only males affected.
• all sons of affected male will present with disorder.
• females not affected and don’t act as carriers.

Question 24

How many genes does the Y chromosome contain and what are they involved in?

Answer 24

• Around 50.
• Spermatogenesis (production or development of mature sperm): mutations can cause infertility.
• So y-linked disorders weren’t usually passed on as can’t have kids however now with assisted reproductive techniques can be passed on (e.g. ICSI).

Question 25

What is ICSI?

Answer 25

• Intracytoplasmic sperm injection - can take sperm that weren’t mature enough to cause pregnancy naturally and inject into egg. - creates a pregnancy that can now pass on y-linked disorders.

Question 26

What do we mean by mitochondrial inheritance?

Answer 26

• mitochondria contain one small circular chromosome containing 37 genes.
• both males and females can be affected.
• mitochondria only ever inherited from the mother, pedigree will always show inheritance through the female line.
• vertical pattern inheritance.
• never passed on from affected males.

Question 27

What are the difficulties with predicting accurate risks in mitochondrial disorders?

Answer 27

• There is a wide range of phenotypic variability because mitochondrial chromosome is present in multiple copies and the severity of disease depends on how many mitochondrial chromosomes carry the mutation and which ones are past on.

Question 28

Give some examples of mitochondrial disorders and what are the symptoms?

Answer 28

• Leber hereditary optic neuropathy (LHON) - sudden onset of severe visual loss in young adults.
• Mitochondrial encephalopathy, lactic acidosis and stroke like episodes (MELAS) - siezures, dementia and stroke like symptoms.

Question 29

Name all modes of inheritance, both common and others.

Answer 29

• Common: autosomal dominant, autosomal recessive and x-linked recessive.
• Others: x-linked dominant, mitochondrial and y-linked.

Question 30

What is a proband?

Answer 30

• First affected family member who seeks medical attention for a genetic disorder.

Question 31

What is a consultand?

Answer 31

• The individual (not necessarily affected) who presents for genetic counselling and through whom a family with an inherited disorder comes to medical attention.

Question 32

Explain the inheritance pattern of PKU and why patients are affected?

Answer 32

• PKU is autosomal recessive, occurs from mutations in the gene that encodes the enzyme phenylalanine hydroxylase (PAH). The person cannot properly manufacture PAH so they cannot break down the amino acid phenylalanine which is an essential building block of dietary proteins. They accumulate high levels of phenylalanine in their urine and blood and this buildup eventually causes mental retardation and behavioural abnormalities (gene involved on chromosome 12).

Question 33

What is the gene involved in cystic fibrosis?

Answer 33

CFTR gene.

Question 34

What is the gene involved in sickle cell anaemia?

Answer 34

HBB gene.

Question 35

What is the gene involved in Huntington disease?

Answer 35

HTT gene.

Question 36

What is the gene involved in myotonic dystrophy?

Answer 36

DMPK gene.

Question 37

What is the gene involved in familial hypercholesterolemia?

Answer 37

LDLR gene.

Question 38

What is the gene involved in neurofibromatosis?

Answer 38

NF1 gene.

Question 39

Give some examples of diseases that often show incomplete penetrance?

Answer 39

• Huntington disease, breast cancer and retinoblastoma.

Question 40

Give an example of a condition that always shows complete penetrance?

Answer 40

• Inheritance of a specific point mutation in the fibroblast growth factor receptor 3 gene (FGFR3) always results in achondroplasia (this disorder is characterised by abnormal bone growth and dwarfism).

Question 41

Give an example of anticipation (type of variable expressivity)?

Answer 41

• Huntington disease may have an earlier onset with more severe symptoms in subsequent generations. All to do with number of CAG repeats present increasing.

Question 42

What is holoprosencephaly?

Answer 42

• Condition in which the embryonic forebrain does not correctly divide into 2 lobes.

Question 43

Variable phenotypes a can be caused by a number of factors, some of which are …

Answer 43

• Modifier genes.
• Environmental factors.
• Allelic variation.
• Complex genetic and environmental interactions.

Question 44

What are the symbols for female, male and a person of unknown sex?

Answer 44

• Female = circle.
• Male = square.
• .Person of unknown sex = triangle.

Question 45

What is the symbol for someone who is deceased?

Answer 45

• The symbol for that individual (e.g. Female = circle) with a diagonal line through it.

Question 46

What is the symbol for someone who is adopted?

Answer 46

• The symbol for that individual (e.g. Female = circle) with square brackets around it.

Question 47

Which test can be used to determine the genotype of an individual?

Answer 47

• Polymerase Chain Reaction.

Question 48

What is the CCR5 gene and what does it encode?

Answer 48

• It’s a gene located on chromosome 3 and it encodes a cytokine receptor that HIV1 uses in conjunction with CD4 to infect T Cells. There are individuals who are resistant to HIV1 infection as a result of a common 32bp deletion in both copies of the CCR5 gene. This deletion results in early termination of translation producing non-functional protein. Individuals who inherit 1 allele with the 32bp deletion have partial resistance to HIV1 infection.

Question 49

On a gel what is the marker/ladder used for? And which fragments are closest to bottom of the gel?

Answer 49

• Marker/ladder = reference used to determine size.
• The smaller fragments move faster as they are lighter and so reach the bottom of the gel before the bigger/heavier fragments.

Question 50

What will you see on a gel if you have a homozygous/heterozygous individual?

Answer 50

• homozygous individual: will only see one band.

- heterozygous individual: will show two bands at different sizes.

Question 51

What is the HWE?

Answer 51

• p(2) + 2pq + q(2).
• p(2) = frequency of WT homozygote.
• 2pq = frequency of heterozygote.
• q(2) = frequency of minor allele homozygote.

Question 52

Genotyping was carried out on 788 individuals. The majority of people had two normal copies of CCR5 = 647 (CCR5/CCR5). There were 134 heterozygous individuals (CCR5/ccr5) and 7 homozygous individuals (ccr5/ccr5). Calculate the allele frequencies.

Answer 52

• For genes on autosomes each individual carries 2 copies of the gene, so for 788 individuals this = 1576 alleles.
• next count the number of alleles in homozygotes and heterozygotes and then you divide this by the total number of alleles to get the allele frequency.
• number of CCR5 alleles = 647 x 2 = 1294 (from first group) plus 134 (from second group) = 1428.
• number of ccr5 alleles = 134 (from second group) plus 7x2 = 14 (from third group) = 148.
• therefore the allele frequency of CCR5 = 1428/1576 = 0.906.
• the allele frequency of ccr5 = 148/1576 = 0.094.
• the frequency of the WT is usually higher.

Question 53

Explain the Hardy-Weinberg Equilibrium.

Answer 53

In a large randomly mating population with no disturbance from outside influence the relative proportions of different genotypes remain constant from one generation to another.

Question 54

For CCR5, the WT allele = CCR5 (p) and mutant allele = ccr5 (q).

• p = 0.906 and q = 0.094 (these are the allele frequencies in a population). Population = 788.
• how many individuals in this population have each of the three possible genotypes?

Answer 54

To predict the number of individuals with a certain genotype in a population: multiple the allele frequency by the number of individuals on that population.

• p(2) x 788 = 0.906 x 0.906 x 788 = 646.82
• 2pq x 788 = 2 x 0.906 x 0.094 x 788 = 134.22
• q(2) x 788 = 0.094 x 0.094 x 788 = 6.96

Question 55

Name some assumptions made by the Hardy-Weinberg Equilibrium?

Answer 55

• population large: number of children produced by individuals with different genotypes will balance out so that the gene frequencies remain stable. If it’s a small population one allele could be transmitted to a large number of children by chance and could result in a marked change in allele frequency from one population to the next.
• Matings are random with respect to locus.
• No consanguinity.
• Assumes that allele frequency remains constant over time: no appreciable rate of new mutation (if particular locus has a high mutation rate there will be a steady increase of mutant alleles in population).
• Assumes no selection against or for a particular genotype.
• Assumes no significant immigration from a population with very different allele frequencies (this will lead to gradual change in allele frequency known as gene flow).

Question 56

Disturbing Hardy-Weinberg Equilibrium is known as what?

Answer 56

• Random Genetic Drift.

Question 57

Matings can be random and non-random, what do each of these mean?

Answer 57

• Random mating: the selection of a partner regardless of that persons genotype.
• Non-random: assortative mating and consanguinity are 2 examples of this. Assortative = tendency of humans to choose partners who share particular characteristics e.g. AR deafness, may have went to same support group. Consanguinity = marriage between blood relatives, a wide spread consanguinity in population will lead to a relative increase in the frequency of affected homozygotes and a relative decrease in the frequency of heterozygotes.

Question 58

For AR conditions HWE allows us to estimate the number of people in which we expect to be carriers of a disorder in a population. If given the information that PKU affects 1/4500 people and the population we are looking at contains 1000 people, how would we do this?

Answer 58

• this number gives us the frequency of q(2) since the affected individual must carry two copies of the minor allele. From this we can take the square root to give us the frequency of q (the minor allele) which = 0.015. Since p+q= 1 by knowing the frequency of q we can work out the frequency of p. P = 1 - 0.015 = 0.985.
• we can then use these two allele frequencies to calculate the expected frequency of heterozygotes using the HWE (remember heterozygotes are represented by 2 x p x q).
• 2pq = 2 x 0.985 x 0.015 = 0.030.
• 0.030 x 1000 = 30 people will be carriers.