CS262 Discussion Section 4

Agenda for today

Brief coverage of mutations. Discussion of material related to HMMs (on

the blackboard)

Mutation

A mutation is a permanent change in the DNA sequence.

It can have profound consequences It can severely compromise an organism’s fitness

if the change occurs in a vital position in the DNA sequence. A single nucleotide change causes the disease sickle-

cell anemia. Note: We will not discuss the molecular

mechanisms responsible for the creation of mutations.

http://www.defiers.com/sc.jpg

Somatic vs Germ line cell lineages

Somatic vs Germ line mutations

A mutation that occurs in the germ line, is passed on to the next generation.

A mutation in a somatic cell is not transmitted to the organism’s offspring. But it may have unfortunate consequences for the

individual in whom it occurs (such as cancer) In tracking the genetic changes that

accumulate during evolution, we concentrate on events that occur in the germ line.

Classification of mutations according to the length of the DNA sequence affected

Point mutation A single nucleotide is

affected

Segmental mutation

Several adjacent nucleotides are affected.

Classification of mutations according to the effect on the DNA molecule

1. Substitution: The replacement of one nucleotide by another

TCTCGCATGGTAGGT

AGAGCGTACCATCCA

5’-

-5’

-3’

3’-

TCTCGCATGGTAGAT

AGAGCGTACCATCTA

5’-

-5’

-3’

3’-

Classification of mutations according to the effect on the DNA molecule

Substitution mutations in protein-coding regions are classified according to their effect on the protein synthesized. Synonymous: No change in the amino-acid

specified. Most of them are silent. (no changes detected at the

amino acid level) A synonymous mutation may not always be silent.

Non-synonymous: Change in the amino-acid.

Non-synonymous (amino-acid altering) mutations could be either Missense mutation: changes the affected codon

into a codon that specifies a different amino acid from the one previously encoded.

Nonsense mutation: changes a sense codon into a termination codon, thus prematurely ending the translation process and ultimately resulting in the production of a truncated protein.

Classification of mutations according to the effect on the DNA molecule 2. Deletion: A block of one or more nucleotide

pairs is lost from a DNA molecule.

TCTCGCATGGTAGGT

AGAGCGTACCATCCA

5’-

-5’

-3’

3’-

TCTCTGGTAGGT

AGAGACCATCCA

5’-

-5’

-3’

3’-

Classification of mutations according to the effect on the DNA molecule 3. Insertion: The addition of one or more

nucleotide pairs.

TCTCGCATGGTAGGT

AGAGCGTACCATCCA

5’-

-5’

-3’

3’-

TCTCAAGCATGGTAGGT

AGAGTTGCAACCATCCA

5’-

-5’

-3’

3’-

Indels

Deletions and insertions are collectively referred to as indels, because when two sequences are compared, it is impossible to tell whether a deletion has occurred in one, or an insertion has occurred in the other.

In a coding region, an indel that is not a multiple of 3 nucleotides causes a frameshift mutation.

Frameshift mutation

Shift in the reading frame: The coding sequence downstream of the gap will be read in the wrong phase. Indels may not only introduce numerous amino

acid changes… … but may also obliterate the termination

codon… …or bring into phase a new stop codon, resulting

in a protein of abnormal length.

Classification of mutations according to the effect on the DNA molecule Inversion: 180 degree rotation of a segment

of the DNA molecule.

TCTCGCATGGTAGGT

AGAGCGTACCATCCA

5’-

-5’

-3’

3’-

TCTTACCATGCGGGT

AGAATGGTACGCCCA

5’-

-5’

-3’

3’-

Site of inversion

Classification of mutations according to the effect on the DNA molecule 5. Recombination: The exchange of a

sequence with another.

5’-AACT-3’

5’-CACG-3’

3’-TTGA-5’

3’-GTGC-5’

5’-AACG-3’

3’-TTGC-5’

5’-CACT-3’3’-GTGA-5’

Spatial distribution of mutations

Mutations do not occur randomly throughout the genome. Some regions are more prone to mutate than others (hotspots of mutation).

One such hotspot is the dinucleotide 5’-CG-3’ (also called CPG) in which cytosine is frequently methylated in many animal genomes, changing it to 5’-TG’-3’