Human Genetic Mutations What is a mutation Mutations

Human Genetic Mutations

What is a mutation? • Mutations are changes made to an organism’s genetic material. • These changes may be due to errors in replication, errors during transcription , radiation, viruses and many other things. • Mutations can occur within a specific gene (small scale), as well as to the chromosome as a whole (large scale).

Are mutations always bad? • Favorable mutations present organisms with an advantage over others and ensure their survival. These mutations will accumulate in a population. • Less favorable mutations are removed from the gene pool through natural selection. – Organisms with these mutations will not survive.

Gene Mutations • Small scale: one gene is affected • Any change to the DNA sequence of a gene: Nucleotides/Bases may be added, missing, or changed

Causes of Mutations • spontaneous • occur during DNA replication • Caused by MUTAGENS • physical, ex: radiation from UV rays, X-rays or extreme heat • or chemical (molecules that misplace base pairs or disrupt the helical shape of DNA).

Gene Mutations: 2 Types Point Mutation Frameshift Mutation

Point Mutation- One Base Change • One base (A, T, C, or G) is substituted for another • Example: Sickle-cell anemia • 3 Possible Consequences: – nonsense mutations: code for a stop, which can translate the protein – missense mutations: code for a different amino acid – silent mutations: code for the same amino acid

What does it look like? Normal THE BIG RED DOG RAN OUT. Missense THE BIG RAD DOG RAN OUT. Nonsense THE BIG RED. Frameshift (1 bp deletion) Frameshift (1 bp insertion) Frameshift (3 bp deletion) Triplet repeat expansion THE BGR EDD OGR ANO…. THE BIG RED DOO GRA NOU THE BIG DOG RAN OUT. THE BIG BIG BIG RED DOG RAN OUT.

Example: Sickle Cell Anemia Normal Red Blood Cell Sickle Red Blood Cell • Red blood cells shaped like a disc • Hemoglobin (protien) carries oxygen to all parts of the body • Red blood cells form an abnormal crescent shape • Hemoglobin (protein) is abnormally shaped • don't move easily through your blood vessels • form clumps and get stuck in the blood vessels

Sickle Cell Anemia Sickle cell anemia Image Credit: http: //explore. ecb. org/ Blood smear (normal) Image Credit: http: //lifesci. rutgers. edu/~babiarz/

Mutations: Substitutions Normal gene GGTCTCCTCACGCCA ↓ CCAGAGGAGUGCGGU Codons ↓ Pro-Glu-Cys-Gly Amino acids Substitution mutation GGTCACCTCACGCCA ↓ CCAGUGGAGUGCGGU ↓ Pro-Arg-Glu-Cys-Gly Substitutions will only affect a single codon Their effects may not be serious unless they affect an amino acid that is essential for the structure and function of the finished protein molecule (e. g. sickle cell anemia) © 2010 Paul Billiet ODWS

Mutations: Inversion mutations, also, only affect a small part of the gene Normal gene GGTCTCCTCACGCCA ↓ CCAGAGGAGUGCGGU Codons ↓ Pro-Glu-Cys-Gly Amino acids © 2010 Paul Billiet ODWS Inversion mutation GGTCCTCTCACGCCA ↓ CCAGGAGAGUGCGGU ↓ Pro-Gly-Glu-Cys-Gly

Mutations: Additions A frame shift mutation Normal gene GGTCTCCTCACGCCA ↓ CCAGAGGAGUGCGGU Codons ↓ Pro-Glu-Cys-Gly Amino acids © 2010 Paul Billiet ODWS Addition mutation GGTGCTCCTCACGCCA ↓ CCACGAGGAGUGCGGU ↓ Pro-Arg-Gly-Val-Arg

Mutations: Deletions A frame shift mutation Normal gene GGTCTCCTCACGCCA ↓ CCAGAGGAGUGCGGU Codons ↓ Pro-Glu-Cys-Gly Amino acids © 2010 Paul Billiet ODWS Deletion mutation GGTC/CCTCACGCCA ↓ CCAGGGAGUGCGGU ↓ Pro-Gly-Ser-Ala-Val

The genetic code is degenerate A mutation might not have a negative effect on the phenotype Changes in the third base of a codon often have no effect. This is called wobble © 2010 Paul Billiet ODWS

Frameshift Mutation- More than one base is affected • One or more bases (A, T, C, or G) are added or deleted • Causes: Cystic Fibrosis • Caused by: – Insertion: adding a base – Deletion: removing a base

Example: Cystic Fibrosis (CF) • What is it? – Autosomal, recessive disorder • Symptoms – Thick mucus in the lungs and digestive track – Constant lung infections and impaired digestion

Cystic Fibrosis (CF) • Who gets it? – Anyone – Most common in Caucasians • Prevalence – 1 in ~3, 000 Americans has CF – 1 in 23 white Americans carries the mutant allele!

Cause of Cystic Fibrosis (CF) • The “CFTR” gene is mutated – 3 base pairs are deleted • Mutant protein is missing an amino acid and cannot fold correctly vs

Chromosomal Mutations • Any change in the structure or number of chromosomes • Large scale: Affect many genes

5 Types 1. 2. 3. 4. 5. Deletion Duplication Inversion Translocation Non. Disjunction

Chromosomal Deletion One or more genes are removed Causes: Wolf-Hirschhorn syndrome (severe mental retardation) cri du chat syndrome (mewing sounds, mental retardation)

Deletions • Examples of disorders caused by deletions: – Prader-Willi Syndrome • Deletion of the long arm on chromosome 15 • Characterized by compulsive eating

Chromosomal Duplication A segment of genes is copied twice and added to the chromosome Causes: Charcot–Marie–Tooth disease (high arched foot, claw feet, confined to a wheelchair)

Chromosomal Inversion a segment of genes flip end-to-end on the chromosome Causes: Four-Ring Syndrome (cleft palate, club feet, testes don’t descend)

Chromosomal Translocation Material is swapped with another chromosome Causes: Burkitt’s Lymphoma (cancer of the lymph nodes, in children)

Nondisjunction • Chromosomes FAIL TO SEPARATE during meiosis

Nondisjunction • Produces gametes (and therefore a baby) with one missing chromosome or one extra chromosome

Chromosomal Mutations • Most chromosomal mutations are harmful or lethal • If the fetus survives: Tend to cause wide-spread abnormalities • Example: Down Syndrome

Trisomy 21 - Down Syndrome

Down Syndrome • Cause: Nondisjunction of chromosome 21 “TRISOMY 21”

Disease-Associated Mutations Alter Protein Functional protein Nonfunctional or missing protein

Are all mutations harmful? • Sequence changes or variants can be – Silent (no change in product): Polymorphism • We have thousands of these – Manifesting (changing RNA or protein product): Mutation We all carry 7 -10 gene mutations Can lead to VARIATION

Polymorphism • A change in DNA sequence that is not disease causing • Occurs usually in greater than 1% of population • Usually does not change an amino acid sequence or produces a significant change (ie: valine for isoleucine) • Can produce codominance or changes in coloration or appearance

Variations: Co-dominant expression Definition: alleles that are both expressed when they occur in the heterozygous state. Example: ABO blood group antigens

ABO blood typing: co-dominant alleles A/- -/- B/- AB AB A/- BB B/- BB BB

Variations: New Mutations • Occur at a rate of 10 -4 to 10 -7 per locus per cell division • “Hot spots” occur: CG pairs (8. 5 x higher rate) • More easily seen in a very large gene • Paternal age effects ( remember why? )

Autosomal dominant: new mutation often as heterozygous dd dd dd Dd dd dd dd

Achondroplasia • Autosomal dominant • 1/26000: most common genetic dwarfism • 80% new mutations • Features – upper arms and thighs are short – lumbar lordosis (lower spine curves out) – large head – intact intellect – Mutation in FGFR 3: activating mutation

Effects of homozygosity dd dd dd DD dd dd Dd

Homozygosity for some dominant traits is lethal http: //www. echt. chm. msu. edu/courseware/block. II/Pathology/382131. jpeg Homozygosity for achondroplasia causes very severe phenotype

Autosomal Dominant and variable expression • Pleiotropy: one gene, many effects on different systems • Random chance • Modifier genes

Marfan Syndrome: variable expression • Skeletal findingsdisproportionate long bone growth • Tall Stature • Eyes- dislocated lenses • Heart-dilation of aortic arch http: //medgen. genetics. utah. edu /

Familial Retinoblastoma: a recessive state in the cell inherited as AD trait http: //www. people. virginia. edu/~rjh 9 u/retblst. html http: //www. retinoblastoma. com/Images/CT%20 Scan. jpg

KEY POINT #2 Mutation of a gene = Mutant protein Dysfunctional proteins cause the symptoms of the disorder

Testing for mutations • Ultrasound • Amniocentesis • Blood draw • Direct to Consumer testing (DTC)

Genetic Screening - Amniocentesis

Unusual Human Mutations • Progeria

Epidermodysplasia Verruciformis

Ectrodactyly

Proteus syndrome

Trimethylaminuria