Lecture 4

Question 1

what are mutations

Answer 1

“Mutations are changes in the genetic material of a cell (or virus)” Campbell et al. (2005) pp328
“A mutation is any heritable alteration in the genetic material” Russell (2006) pp5
Heritable: transmitted from parent to offspring
Genetics focuses on heritable mutations
but not all mutations are heritable e.g., cancer is caused by mutations but these arise in the soma,
not the germ line

Question 2

what is spontaneous mutation

Answer 2

Evolution requires genetic differences, generated by sex (recombination) and by SPONTANEOUS mutation
Very low rate of spontaneous mutation (NOT zero), e.g., for human germ line ~ 3 new mutations per 108 base pairs per generation
~ 100-200 new mutations in each human child (6 billion bps, diploid)
But there are lots of people……
~100 million births a year
~ 20 billion (20,000,000,000) new mutations per year in world population

Question 3

what 2 things increases mutation rate

Answer 3

increasing amount of DNA damage

decreased rate of repair

Question 4

describe induced mutation

Answer 4

Can dramatically increase the mutation rate to >1000 fold spontaneous rate using Chemical mutagens or radiation
ALL mutagens damage DNA: causing mutation
ALL mutagens can cause cancer

Question 5

what is Karyotyping

Answer 5

Chromosome Painting
Specific chromosomes can be labelled by fluorescing multiple DNA sequences that are specific to a single chromosome.
Used to -
• Count the number of chromosomes
• Look for structural changes in
chromosomes
• Abnormal results may be due to a
genetic syndrome or condition, such as:
Down syndrome
Klinefelters syndrome (XXY) Trisomy 18
Turner syndrome (XO)

Question 6

how does UV light cause mutations and how does this link with skin ca

Answer 6

UV-light causes Thymine dimers (T-T)
Leads to Frame-Shift Mutations if not repaired

In bright sunlight, EACH skin cell suffers 50-100 new T-T Dimers every SECOND. Overwhelms repair machinery
main types of skin ca are
- basal/squamous cell carcinomas which are slow-growing, easy to treat, and account for 62000 cases each year
- malignant melanoma, is dangerous and fast growing, spreads very quickly, 3000 cases a year

Question 7

describe Xeroderma pigmentosum

Answer 7

Mutations in genes for Excision Repair Machinery =extreme sensitivity to UV light
Exposure causes basal cell carcinoma, metastatic malignant melanoma, squamous cell carcinoma
Inherited, autosomal recessive
XP affects ~1/250,000

photosensitivity, exposure to light causes intense pigmentation, extreme freckling, skin ca
also hypersensitivity to UV, X rays and intercalating chemicals

Many of the genes related to Xeroderma pigmentosum are part of a DNA-repair process known as nucleotide excision repair (NER).
Up to 30 different gene products are involved in nucleotide-excision repair
Mutation of any one of seven of XPA-XPE genes can cause the disease

Question 8

What effects do mutations have on genes?

Answer 8

Most random mutations affect UNIMPORTANT regions:
- between genes
- between exons
MOST mutations are silent (even if homozygous)
UNLESS they affect the protein coding part of genes or their expression

Question 9

what are insertions and deltetions

Answer 9

insertions and deletions are additions or losses of nucleotide pairs in a gene. these mutations have a disastrous effect on the protein more often than substitutions do. insertion or deletion of nucleotides may alter the reading frame, producing a frameshift mutation

Question 10

what are substitutions

Answer 10

a nucleotide pair substitution replaces one nucleotide and its partner with another pair of nucleotides
silent mutations have no effect on the amino acid produced by a codon because of redundancy in the genetic code
missense mutations still code for an amino acid but not the correct amino acid
nonsense mutations change an amino acid codon into a stop codon, nearly always leading to a nonfunctional protein

Question 11

describe albinism

Answer 11

The mutant tyrosinase enzyme is unable to convert tyrosine into the pigment melanin. As a result melanin is absent from skin, hair and eye retinas. It has a frequency of about 1 in 17000 births.

Four Oculocutaneous Albinism Genes:
OCA1: tyrosinase enzyme
mutants have severe albinism
OCA2: PProtein(tyrosinase‘helper’) mutants have mild albinism
OCA3: tyrosine-related gene (very rare) mutants have weak albinism
OCA4: SLC45A2 Protein (tyrosinase helper) mutants have mild albinism

Several other albinism-like syndromes are described (Hermansky-Pudlak Syndrome)

Question 12

describe the Molecular basis of alkaptonuria

Answer 12

First human ‘Mendelian’ Disorder
Archibald Garrod (1908)
Gene on chromosome 3 encodes homogentisate 1,2-dioxygenase
Mutants can’t convert Homogentisic Acid to Maleylacetoacetic Acid
Homogentisic Acid is black and in mutants is expelled with the urine

Question 13

describe the Molecular Basis of Phenylketonuria

Answer 13

Phenylketonuria
- High Phenylpyruvic acid
- Progressive brain dysfunction
Mutation
- Phenylalanine hydroxylase gene
- Recessive condition
Treatment
- Phenylpyruvic acid birth test 
- Low phenylalanine diet

Question 14

Cystic Fibrosis is the most common single-gene disorder in Europeans - Why?

Answer 14

Carriers MAY have higher survival to Cholera

Question 15

describe the cystic fibrosis mutation

Answer 15

Most Genetic conditions have mutations that are specific to one family (or families related by descent)
However, 75% of CF mutations are a three base pair deletion of the 508th amino acid phenylalanine (F508)
Tests have been developed that allow us to diagnose the F508 mutation The other 25% of CF mutations are family specific but can be diagnosed The F508 mutation probably arose in Europe about 50,000 years ago

Question 16

describe sickle cell anaemia

Answer 16

Normally, the majority of adult hemoglobin (HbA) is composed of four protein chains, two α and two β globin chains arranged into a heterotetramer. Mutation causes production of abnormal red blood cells (In sickle-cell disease, the mutation is specific to β globin).
these amino acids are on the outside of the haemoglobin molecule when it takes up it’s tertiary and quaternary shapes.
glutamic acid is a hydrophilic amino acid. it interacts with water molecules, helping to make the hb molecule less soluble.
valine is a hydrophobic amino aicd. it does not interact with water molecules, making the haemoglobin molecule less soluble.
The haemoglobin molecules of HbS/HbS homozygotes undergo a change in shape that distorts the morphology of the red blood cells, and causes a severe, life-threatening form of anaemia called sickle-cell anaemia.
Persons heterozygous HbA/HbS for this allele have a much less severe form of anaemia called sickle-cell trait.
Because the disease phenotype of HbA/HbS heterozygotes is more similar to but not identical to the HbA/HbA homozygote, the HbA allele is said to be incompletely dominant to the HbS allele.
Also exhibits Pleiotrophy
The presence of a single functional allele gives a phenotype that is not normal but less severe than that of the non-functional homozygote. This occurs when the functional allele is not haplo-sufficient. The terms haplo-insufficiency and incomplete dominance are typically applied to diseases like sickle cell anaemia.