Genetics science (pretty much pure genetics not clinical)

Question 1

If a mutation is passed on by autosomal dominant inheritance what are the chances that a kid will be affected if one of their parents are ?

Answer 1

50%

Question 2

Appreciate this

Answer 2

Question 3

What is a missence mutation ?

Answer 3

It is a point mutation in which a single nucleotide change results in a codon that codes for a different amino acid.

Question 4

What is meant by wild type?

Answer 4

Wild type (WT) refers to the phenotype of the typical form of a species as it occurs in nature. Originally, the wild type was conceptualized as a product of the standard “normal” allele at a locus, in contrast to that produced by a non-standard, “mutant” allele.

Question 5

Give an overview of what is meant by frameshift mutations

Answer 5

In a frameshift mutation, one or more bases are inserted or deleted. Because the DNA coding sequence in is based upon a series of triplet sequences or codons – deletions or insertions can be ‘in-frame’ or ‘out-of-frame’. An in-frame deletion must involve at least 3 DNA bases (it may be more and is usually multiple of 3) removes an entire codon and so may lead to the deletion of an amino acid from a protein e.g.

a. In-frame deletion

Wild-type sequence [part of the human antithrombin gene]

Glu Leu Ser Lys Ala Asn
5’- GAA CTG TCC AAG GCC AAT

Mutant Sequence: in-frame 3bp [CTG] deletion

Glu Ser Lys Ala Asn
5’- GAA TCC AAG GCC AAT

Deletion of the CTG codon removes the leucine amino acid but does not change the reading frame and the other amino acids remain unchanged. However, whilst the reading frame is maintained, in-frame deletions give risk to a protein that lacks one or more amino acids. This frequently disturbs the tertiary structure of the protein and as a result it either fails to be secreted to if it does, it is rapidly removed from the circulation.
Of course a 3bp deletion could remove part of one codon and part of the next and give rise to an out-of frame deletion. Similarly a 3bp insertion could occur between the nucleotides of a codon leading to an out-of frame insertion.

Question 6

Explain more specifically now what is meant by a deletion (in frame) mutation ?

Answer 6

An in-frame deletion must involve at least 3 DNA bases (it may be more and is usually multiple of 3) removes an entire codon and so may lead to the deletion of an amino acid from a protein e.g.

a. In-frame deletion

Wild-type sequence [part of the human antithrombin gene]

Glu Leu Ser Lys Ala Asn
5’- GAA CTG TCC AAG GCC AAT

Mutant Sequence: in-frame 3bp [CTG] deletion

Glu Ser Lys Ala Asn
5’- GAA TCC AAG GCC AAT

Deletion of the CTG codon removes the leucine amino acid but does not change the reading frame and the other amino acids remain unchanged. However, whilst the reading frame is maintained, in-frame deletions give risk to a protein that lacks one or more amino acids. This frequently disturbs the tertiary structure of the protein and as a result it either fails to be secreted to if it does, it is rapidly removed from the circulation.
Of course a 3bp deletion could remove part of one codon and part of the next and give rise to an out-of frame deletion. Similarly a 3bp insertion could occur between the nucleotides of a codon leading to an out-of frame insertion.

Question 7

Explain more specifically what is meant by a deletion frameshift (out of frame) mutation ?

Answer 7

Out-of-frame deletion

Mutant Sequence: in-frame 2bp out-of-frame deletion

In contrast an out-of-frame deletion changes the reading frame and gives rise to an amino acid sequence which following the deletion is completely different from the native sequence.

Wild type sequence

Glu Leu Ser Lys Ala Asn
5’- GAA CTG TCC AAG GCC AAT

In this sequence if we delete the CT in the CTG that encodes leucine then this changes the reading frame and the corresponding amino amino acid sequence

Glu Val Gln Gly Gln …
5’- GAA GTC CAA GGC CAA T..

Similar changes to the reading frame are seen with in-frame insertions (multiples of 3bp) or out-of frame insertions (more or less that 3bp but never multiples of 3bp).

Question 8

What is meant by a non-sense mutation ?

Answer 8

Nonsense mutations arise from single bp substitutions and which cause the creation of a premature stop codon. In the example below the C→A [TGC→TGA] mutation changes the Cys to a Stop codon.

Normal sequence
Ser
5’- ATG CTG TGC

Mutant sequence
Stop
5’- ATG CTG TGA

Some out-of-frame deletions or insertions may give rise to the creation of a premature stop codon downstream of the insertion/deletion.

Question 9

Explain what is meant by splice mutations ?

Answer 9

Splice Mutations: Specific nucleotide sequences at the splice sites guide the correct splicing of DNA. If a mutation alters one of these signals, then part of or the whole intron may not be removed and remains as part of the final RNA molecule. The translation of this sequence alters the sequence of the protein product.

Some frameshift mutations can be partially corrected due to transcriptional stuttering and/or ribosomal slippage and this leads to the production of some normal protein.

Question 10

What is meant when it is said tuberous sclerosis shows genetic heterogeneity ?

Answer 10

The mutation may be in TSC1 or TSC2

Question 11

Define penetrance

Answer 11

Penetrance is defined as the percentage of individuals with a given genotype who exhibit the phenotype associated with that genotype.

Question 12

What is meant if it is said ‘‘disease expression is variable’’?

Answer 12

Different people are affected differently by the disease – even within the same family

Question 13

Appreciate this pic of normal keratin filament assembly - applies to the pics for the explanations of some definitions in other flashcards

Answer 13

Question 14

What is meant by Haploinsufficiency?

Answer 14

Haploinsufficiency is the phenomenon where a diploid organism has only a single functional copy of a gene (with the other copy inactivated by mutation) and the single functional copy of the gene does not produce enough gene product (typically a protein) to bring about a wild-type condition, leading to an abnormal or diseased state. It is responsible for some but not all autosomal dominant disorders. Haploinsufficiency is therefore an example of incomplete or partial dominance

i.e. only one copy of working - reduced protein production

Question 15

Explain what is meant by dominant negative mutations in genes ?

Answer 15

Dominant negative mutations (also called antimorphic mutations) have an altered gene product that acts antagonistically to the wild-typeallele. These mutations usually result in an altered molecular function (often inactive) and are characterized by a dominant or semi-dominantphenotype.

i.e. expression of abnormal protein interferes with normal protein

Question 16

Explain what is meant by Gain of function mutations in genes

Answer 16

A type of mutation in which the altered gene product possesses a new molecularfunction or a new pattern of gene expression. Gain-of-function mutations are almost always Dominant or Semidominant.

i.e. Mutant protein gains a new function, affecting cell processes

Question 17

Explain what is meant by recessive disease?

Answer 17

Recessive genetic disorders (RGD) result from inheriting two defective recessive alleles of a gene, one from each parent.

i.e. Autosomal recessive - 2 faulty copies of gene produce no protein

Question 18

If a child’s parents are both carriers for a autosomal recessive disease what are the chances of the child being affected by the disease ? (by affected this means affected not carrying it)

Answer 18

1 in 4 risk of an affected child if parents carriers

Question 19

Appreciate the point in the pic

Answer 19

Question 20

Appreciate the pic for the risk of developing a disease

Answer 20