GENE MUTATIONGenetics

By: Jaycris C. Agnes

The genetic code is the set of rules by which information encoded within

genetic material (DNA or mRNA sequences) is translated into proteins

 (amino acid sequences) by living cells.

Genetic Code

• Introduction:

• The Codons in mRNA are nucleotide bases, “read” in blocks of three.

• There are 64 codons, 61 of these base triplets correspond to specific amino acids. Three other serve as signal to stop translation.

Codons

A gene mutation is defined as an alteration in the sequence of nucleotides in DNA a polymer of nucleotides joined together.

Gene Mutation

• During protein synthesis, DNA is transcribed into RNA and then translated to produce proteins.

• Altering nucleotide sequences most often results in nonfunctioning proteins.

• Mutations cause changes in the genetic code that lead to genetic variation and the potential to develop disease. 

Kinds of Gene Mutation

Point mutations are the most common type of gene mutation. Also called a base-pair substitution, this type of mutation changes a single nucleotide base pair. Point mutations can be categorized into three types:

1. Point Mutation

SILENTMISSENS

E

NONSENSE

SILENT MUTATION

Although a change in the DNA sequence occurs, this type of mutation does not change the protein that is to be produced.

MISSENSE MUTATION

TYPES OF MISSENSE MUTATION

Conservative

Non-conservative

Result in an amino acid change. However, the properties of the amino acid remain the same (e.g., hydrophobic, hydrophilic, etc).

Result in an amino acid change that has different properties than the wild type. The protein may lose its function, which can result in a disease in the organism.

DNA sequence Amino acid sequence Type of mutation

ATG CAG GTG ACC TCA GTG M Q V T S V None

ATG CAG CTG ACC TCA GTG M Q L T S V Conservative

ATG CCG GTG ACC TCA GTG M P V T S VNon-conservative

Conservative vs. Non-conservative

Non-conservative Mutation Diseases

• Sickle Cell Anemia (loss-of-function)

Sequence for normal hemoglobin

ATG GTG CAC CTG ACT CCT GAG GAG AAG TCT GCC GTT ACT

START Val His Leu Thr Pro Glu Glu Lys Ser Ala Val Thr

Sequence for Sickle Cell Anemia

ATG GTG CAC CTG ACT CCT GTG GAG AAG TCT GCC GTT ACT

START Val His Leu Thr Pro Val Glu Lys Ser Ala Val Thr

• Cancer

Valine Glutamic Acid

Mutation changing a valine to glutamic acid in the braf gene; this leads to an activation of the RAF protein which causes unlimited proliferative signalling in cancer cells.

All cancers derive from single cells that have acquired the characteristics of continually dividing in an unrestrained manner and invading surrounding tissues.

•What is cancer?

Human melanoma cell undergoing cell division

Credit: Paul Smith & Rachel Errington, Wellcome Images

• Cancer cells behave in this abnormal manner because of changes in the DNA sequence of key genes, which are known as cancer genes. Therefore all cancers are genetic diseases.

•What is cancer?

Oncogene(gain-of-function)

Cancer

Ras

Genes which normally function to PROMOTE cell growth/division in a controlled manner

Tumour suppressor gene (loss-of-function)

TS

Cancer

These genes normally function to PREVENT cell growth/division

•Importance of somatic DNA changes in human cancer

Somatic

Inherited

Both

Only 5 –10% of cancer cases have a clear hereditary component, e.g. BRCA1 and BRCA2 in breast cancer

Even in those cases where susceptibility is clearly inherited, somatic changes are required for cancer to develop

NONSENSE MUTATION

2. Frameshift Mutation

3. Repeat Expansion Mutation

END.

1. Causes thick, sticky mucus and very salty sweat.

2. Bacteria colonize in the mucus causing infections.

3. Eventually fatal.

• Cause by Deletion of a base in Phenylalanine in chromosome number 7. X-Linked recessive.

•Cystic Fibrosis

1. Myotonic dystrophy is a chronic, slowly progressing, highly variable, inherited multisystemic disease.

2. It is characterized by wasting of the muscles (muscular dystrophy), cataracts, heart conduction defects, endocrine changes, and myotonia.

•Myotonic DystrophyCaused by trinucleotide repeat of CUG (Leucine).

X-linked Dominant.

• Large, protruding ears (one or both)

• Long face (vertical maxillary excess)

• High-arched palate (related to the above)

• Hyperextensible finger joints• Hyperextensible ('Double-jointed')

thumbs• Flat feet• Soft skin• Postpubescent macroorchidism (La

rge testes in men after puberty) • Hypotonia (low muscle tone)• single palm crease (crease goes

across entire palm)

•Fragile X SyndromeCaused by trinucleotide repeat of CGG(Arginine) in X- Chromosome. X-linked Dominant.

• Autism/ ADHD/ Mental Retardation.• Strabismus (lazy eye)• Obsessive-Compulsive Disorder (OCD) [some]

• Speech may be cluttered or nervous.• Stereotypic movements (e.g., hand-flapping) and atypical social development, particularly shyness, limited eye contact, memory problems, and difficulty with face encoding.

People inflicted by FXS have:

•Fragile X Syndrome

• Afflicted person suffered from severe anemia.

Caused by Nonsense mutation of CAG(glutamine) to UAG (STOP). Autosomal Recessive.

•B-Thalassemia