MCG - Basics of Genetic Inheritance

Question 1

Describe the basic idea of how DNA is packed within the cell.

Answer 1

Genes are the discrete units of inheritance, and are distributed across the chromosomes.

Chromosomes are composed of DNA wound around beads of protein (histones). The DNA and protein is referred to as chromatin.

Each unit of a histone with DNA wrapped around it is called a nucleosome, and they themselves can be coiled around each other, which can be packed closely and compressed until you end up with about 4 metres of DNA which has been compressed to fit in a eukaryotic nucleus, which is about 5 microns in diameter..

Question 2

Describe the human karyotype.

Answer 2

We have 46 chromosomes (23 from each parent). There are 22 pairs of autosomes & one pair of sex chromosomes.

This is assessed by staining chromosomes from
metaphase spreads. We use metaphase because that is when the chromosome condense enough for the microscope to be able to see them.

G - banding (stained with Giemsa) creates alternating light and dark (heavy) bands; the pattern is characteristic for each chromosome pair.

Cytogenetics is the study of the genetic component of a cell through the visualisation and analysis of chromosomes.

Question 3

Describe the centromere and its role in mitosis.

Answer 3

The centromere is the constriction near the centre of the chromosome. The centromere is the point of DNA to which the kinetochore is bound, which is a complex of proteins that binds the mitotic spindle.

The mitotic spindle is the network of protein fibres that spreads from pole to pole. It grabs the kinetochores which, in turn, are attached to the centromeres.

And during the anaphase stage of mitosis, the mitotic spindle separates the duplicated chromosomes, so that you end up with two cells with the equivalent amount of DNA in each one.

Question 4

What are the three types of human chromosomes based on size?

Answer 4

Metacentric: centromere is in the middle of chromosome

Submetacentric: centromere towards end of chromosome (short arm is referred to a p arm, and long arm as q arm)

Acrocentric: centromere is far closer to one end than the other

Question 5

Why do chromosomes replicate?

Answer 5

① - For development, growth, and replacing lost cells (wound healing etc).

MITOSIS: leads to production of two cells, with the same number of chromosomes as the parent

② - For transmission of genetic information to offspring.

MEIOSIS: reduces the genetic content by half, so that sexual reproduction occurs without doubling of the genetic content. Plus, introduces variation owing to the recombination between homologous chromosomes.

Question 6

What is the difference in the end result of mitosis and meiosis?

Answer 6

The difference in meiotic cell division is that after the chromosomes are duplicated, the homologous chromosomes form pairs and exchange genetic material.

So, at the end of meiosis, the amount of genetic material has been halved, and genetic variation has been introduced.

MITOSIS: one round of DNA replication, one round of chromosomal segregation
- two daughter cells, 46 chromosomes each (genetically identical).

MEIOSIS: one round of DNA replication, recombination, two rounds of chromosomal segregation
- four daughter cells, 23 chromosomes each (genetically variable)

Question 7

How much of the Y chromosome confers maleness?

Answer 7

Two chromosomal abnormalities suggest that a small region at the end of the short arm of the Y is all that is needed to confer maleness:

(1) Some human males are 46, XX (the normal karyotype for a female) - attached to one of the X chromosomes is a short region from the p end of the Y.
(2) Some human females are 46, XY (the normal karyotype for a male). In this case, a small region near the long end of the Y chromosome is missing.

Question 8

What is the only part of the X and Y chromosomes that are exchanged between them?

Answer 8

Either end of the Y chromosome are composed of sequences that have equivalents in the X chromosomes. These are referred to as the pseudo autosomal regions. Because they share homology with parts of the X chromosome, they are what result in the X and Y forming pairs and exchanging genetic material during meiosis. Those are the only regions exchanged between the X and Y.

The rest of the Y chromosome has a region called the MSY (male-specific region of the Y). It is in this region that the SRY (sex determining region of the Y) can be found.

Question 9

What is the significance of the SRY gene?

Answer 9

SRY is a gene that encodes a protein that acts as a testis determining factor (TDF).

SRY is the only region of the Y required for male development.

Question 10

Define aneuploidy, and how one can arise.

Answer 10

It is a karyotype with an irregular number of chromosomes.

Trisomies and monosomies are examples of aneuploidy.

EUPLOIDY: the complete chromosome set
ANEIPLOIDY: one or more individual chromosomes present at an extra copy (or are missing).

Aneuploidies are caused by non-disjunction: The failure of homologous chromosomes to separate properly during meiosis.

Question 11

What is the significance of finding out if a foetus has an aneuploidy?

Answer 11

Aneuploidy is responsible for 50% of spontaneous abortions, and 50% of those are trisomies.

Live births do arise from certain trisomies (such as of chromosome 21).

Question 12

What does having Trisomy 21 or Down’s Syndrome imply for an individual?

Answer 12

It leads to retarded growth and development, and delayed mental and social skills (mental retardation).

Some common complications are cardiac abnormalities, and increased incidence of acute leukaemia.

Doctors are able to determine babies with down syndrome by looking for the Simian crease,which is a singly crease spanning the width of the palm.

Question 13

What does having Trisomy 18 or Edward’s Syndrome imply for an individual?

Answer 13

It results in numerous abnormalities, including heart defects and intestines protruding outside the body.

About 95% of affected indivduals die in utero.

Of the liveborn infants, only 50% live to 2 months, and only 5–10% will survive their first year of life.

Question 14

What does having Trisomy 13 or Patau Syndrome imply for an individual?

Answer 14

Common abnormalities include:

• heart defects,
• incomplete brain development

The mean survival in trisomy 13 syndrome patients is ca. 130 days.

Question 15

What occurs when there is a trisomy in larger chromosomes, such as chromosome 1?

Answer 15

If you were to consider a trisomy of chromosome 1 or 2, they are far bigger than chromosome 13, 18 or 21, so they cause far more developmental abnormalities such that the pregnancy no longer proceeds.

Question 16

What are some sex chromosomal abnormalities?

Answer 16

47, XXY - Klinefelter Syndrome:

• can appear normal
• diagnosis is usually made late during adult life at the investigation of infertility (5% of males in fertility clinics)
• small testes (limited development of secondary sexual characteristics)

45, X - Turner Syndrome (a monosomy)

• diagnosis sometimes made late during adult life at the investigation of short stature or amenorrhoea
• no adolescent growth spurt.
• ova degenerate in utero (infertile)
• limited development of secondary sexual characteristics

47, XYY - XYY syndrome

• asymptomatic
• increased growth velocity, above average height
• stereotype of XYY boys and men as violent criminals is false (no overrepresentation of XYY males in nationwide chromosome surveys of prisons)

Question 17

When is it necessary to determine karyotype?

Answer 17

It is important because it enables foetal diagnosis of chromosome abnormalities.

Amniocentesis is usually carried out during weeks 15- 20 of pregnancy. It is only offered when the combined test in the 1st trimester indicates a significant risk a baby will develop a serious condition or abnormality (esp. Down syndrome). This is because the procedure is invasive and has a small associated risk of miscarriage (1%).

Question 18

What are the simplified steps of amniocentesis?

Answer 18

1. The foetal cells are isolated.
2. The first test of Q-PCR (counts number of chromosomes 13, 18 and 21) is given to parents within 2 days, but it is not definitive.
3. The cells are grown in culture medium.
4. The second karyotype test after growing the cells in culture for two weeks to do a metaphase spread is definitive.

Question 19

Why is the nondisjunction as an age-related issue seen in females more?

Answer 19

The majority of aneuploid conceptions are attributable to non-disjunction during oogenesis (a low % is attributable to nondisjunction during spermatogenesis).

Sperm production is maintained throughout the lifetime of males (puberty onwards).

In contrast, oogenesis is largely complete at birth, suspended in meiosis I, and resumes once a follicle releases its oocyte into the fallopian tube, then arrests at meiosis II (the 2nd division is only completed once an egg is fertilized).

The ova are as old as the mother.

Question 20

Define Mendelian inheritance.

Answer 20

The simplest genetic characters are those that depend on the genotype at a single locus.

Diseases caused by these factors are referred to as monogenic disorders (single mutation in single gene). They display Mendelian inheritance patterns.

Mendel’s laws:

• every individual possesses a pair of alleles for a given trait, one of which is passed on to its offspring
• genes for different traits assort independently of each other (unless they are linked)

Question 21

What are the modes of inheritance for monogenic disorders?

Answer 21

① Autosomal recessive

② Autosomal dominant

③ X-linked recessive

④ X-linked dominant

Question 22

Give an example of an autosomal recessive disorder.

Answer 22

CYSTIC FIBROSIS

It is a mutation in the CFTR on chromosome 7 (cystic fibrosis transmembrane conductance regulator).

C: normal wild-type allele encodes functional CFTR
c: mutant allele lacking 508th codon

There are over 500 mutant alleles, CFTRΔ508 is by far the most common in northern Europe (70-80% of mutant alleles).

Question 23

How does the CFTR gene maintain a free flowing mucus layer?

Answer 23

The mRNA is going to be made in the nucleus, and exported into the cytosol. It will be translated by ribosome, and because CFTR is a membrane protein, it will be entering the endoplasmic reticulum and going through to the Golgi. There, the glycosylated CFTR is packaged into vesciles and sent to the plasma membrane, where it is inserted into the membrane where it can exert its functions.

The CFTR protein is a pump that drives chloride ions outside of the cell into the outside environment. This is very useful in the lung, as you are constantly and bringing in bacteria from the outside. The bacteria are swept away by a layer of mucous that is outside the epithelial layer of the lung. The mucous is runny as, when the chloride ions are being pumped out, water exits the cell by osmosis. This means the mucous layer becomes mobile and can move the bacteria away.

Question 24

What happens to the maintenance of the mucus free flow in the mutant CFTRΔ580 gene?

Answer 24

Missing the amino acid means that the protein does not fold properly in the ER. The proteins then aggregate and become toxic to the cell, and so are degraded by proteases in the ER.

The mutant CFTRΔ508 does not exit the endoplasmic reticulum.

There is thus a loss if Cl- gradient, and the mucus becomes thicker, leading to lung infections, and blockage of the ducts in the pancreas and the intestines.

The lifespan of the individual is reduces, and less than ~50% reach their 40th birthday.

Question 25

How can you identify an autosomal recessive disorder in a pedigree?

Answer 25

• the trait is rare
• the trait often skins generations (hidden in heterozygous carriers)
• it affects males and females equally
• the trait is transmitted by either sex

Question 26

Give an example of an autosomal dominant disorder.

Answer 26

HUNTINGTON’S DISEASE

It is a neurodegenerative disease; it causes a gradual cognitive decline, effectively fatal.

It is caused by mutations at the HD locus.

The normal HD has ca. 28 repeats of the CAG codon (polyglutamine tract). The mutant HD has > 36 repeats of CAG codon.

This causes aggregation of the protein, cytotoxicity, resulting in neuronal cell death.

This explains why a heterozygous individual develops HD, because the mutant polypeptide will aggregate regardless of presence of wild-type protein.

The number of these alleles in the population is explained by the slow accumulation of the HD aggregates until diagnosis – by the time it is identified, the individuals have already reproduced and has children.

The disease doesn’t appear until well into adulthood (as the accumulation of HD aggregates is slow).

Question 27

How can you identify an autosomal dominant disorder in a pedigree?

Answer 27

• the trait is frequent in the pedigree
• people are affected in each generation
• the trait affects males and females equally
• the trait is transmitted by either sex

Question 28

Give an example of an X-linked recessive disorder.

Answer 28

Haemophilia A

It is a mutation in the gene for blood clotting factor VIII on X chromosome.

Question 29

How can you identify an X-linked recessive disorder in a pedigree?

Answer 29

• it will occur most frequently in males (as the only have one copy of X)
• it cannot be passed from father to son (as they only give Y)
• all daughters of affected fathers are carriers (as they have to inherit X from father)

Question 30

What are polygenic characteristics?

Answer 30

They are characteristics controlled by genes at more than one locus (most human characeristics).

These traits are either:

• discontinuous (its there or it isn’t) – e.g. type II diabetes mellitus
• continuous – e.g. height

Question 31

What are multifactorial traits?

Answer 31

They are traits which are influenced by the environment.

Question 32

Give examples of some disorders showing multifactoral inheritance.

Answer 32

• cardiovascular disease
• diabetes mellitus
• obesity
• mental illness

Question 33

How do we assess the contribution made by genetics vs. environment for a given disorder?

Answer 33

When genetics makes a clear contribution, the frequency of disease concordance increases alongside the degree of genetic similarity between individuals.
To understand this best we use twin studies.

Twin studies:
Monozygotic (identical) twins are genetically identical.
Dizygotic twins (non-identical) are not genetically identical.

Disorders occurring more frequently in both members of MZ twin pairs than in both members of DZ twin pairs must be influenced by genetics.

A disorder principally controlled by environment will occur with a similar frequency in both types of twins.