Mutations Reading • Handout • Recommended web sites Learning objectives • Understand the causes and effects of DNA mutations • Be able to distinguish between germline and somatic mutations • Know the most common small and large scale mutations Mutation: A T C Change in number Change in arrangement A A C Change in sequence A change in the genetic material (DNA) A change in the number, arrangement or sequence of nucleotides in a gene Changes can be on a small or big scale Classification of mutations Classification according to: 1) Type of the cell: somatic or germline mutation 2) level of change: chromosomal or DNA sequence big 3) Effect on the protein (phenotype): misense / non sense / silent / frame shift 4) The cause of mutation: spontaneous or Induced Hereditary (germline) vs acquired (somatic) Hereditary (germline): occurs in sperm, ovum or zygot. mutation affects all body cells can be transmitted to offspring. Hereditary (germline) V.s acquired (somatic) Acquired (somatic): occurs in somatic cells Normal somatic cells mutation mutation affect group of cells cannot be transmitted to offspring. Abnormal cell population e.g cancer cells Normal cell population Chromosomal mutations A) Change in number: Aneuploidy: loss or gain of whole chromosomes Chromosomal mutation B) Change in arrangement: Change in DNA sequence Classified according to: A) Chemical nature of base changed: purines A pyrimidine Transversion C Transition Transition G T Transversion B) Effect in the protein: mutation in exons Substitution (point mutation): silent / missense / nonsense Frame-shift: deletion / insertion a) Silent mutation: Change in DNA sequence does not cause change in amino acids U to C AUGGCU AUGGCC Met- Ala Met- Ala b) Misense mutation: changes the amino acid AUGGCU Met- Ala A to U UUGGCC Leu- Ala c) Nonsense mutation: • Change in DNA sequence leads to formation of stop codon. • Leads to the formation of incomplete protein Template Mutation: G A Template Frame-shift mutation: Insertion or deletion of 1-2 nucleotides causes change in the entire protein sequence. Template Insertion of G Template Mutations : Induced Spontaneous Mutations: Spontaneous • Spontaneous mutation Changes that occur during normal genetic and metabolic functions in the cell 1.Mistakes during DNA replication 2.Base modifications caused by hydrolytic reactions Mutations: Induced • Induced mutation Changes that occur as a result of exposure to environmental agents (mutagens) 1.Ionizing radiation 2.Chemicals 3.Ultraviolet light (UV-light) The importance of DNA repair Xeroderma pigmentosa • Genetic disease caused by a lack of enzymes for nucleotide repair • Patients are extremely sensitive to sunlight • The disorder leads to different forms of cancer Genetic disorders Learning objectives • Understand the difference between dominant and recessive mutations • Know the main groups of genetic disorders with examples from each group • Be able to understand the pattern of inheritance for single gene disorders What is a genetic disorder? • An illness caused by abnormalities in genes or chromosomes • The disorders can be grouped into 4: 1. Single gene 2. Chromosomal 3. Mitochondrial 4. Multifactorial 1. Single gene disorders • Is caused by a mutation in a single gene • Recessive inheritance: Two copies of the gene must be mutated in order for the disease to occur • Dominant inheritance: Mutation in one copy of the gene is sufficient to cause the disease Dominant and recessive mutations 1. Single gene disorders: Autosomal dominant Examples: • Huntington’s disease • Neurofibromatosis • Achondroplasia • Polycystic kidney disease 1. Single gene disorders: Autosomal recessive Examples • Cystic fibrosis • Albinism • Phenylketonuria (PKU) • Sickle cell disease • Tay-Sachs disease 1. Single gene disorders: X-linked dominant 1. Single gene disorders: X-linked dominant cont. Examples: • Rett syndrome • Incontinentia Pigmenti type 2 • Aicardi Syndrome 1. Single gene disorders: X-linked recessive 1. Single gene disorders: X-linked recessive cont. 1. Single gene disorders: X-linked recessive cont. Examples: • Hemophilia A • Duchenne muscular dystrophy • Lesch-Nyhan syndrome • Male pattern baldness • Color blindness 1. Single gene disorders: Y-linked • Are caused by mutations on the Y chromosome • Every son of an affected father will be affected • Female offspring of affected fathers are never affected Example: • Male infertility 2. Chromosomal disorders Is caused by: • Chromosomal mutations • Numerical abnormalities: gain of a chromosome (trisomy) loss of a chromosome (monosomy) Chromosomal deletion syndromes • Cri du chat syndrome (5p deletion) • Wolf-Hirschorn syndrome (4p deletion) Chromosomal insertion: Fragile X syndrome • Multiple insertions of three nucleotides (CGG) creates a fragile X chromosome Trisomy 21; Down syndrome • Is caused by an extra copy of chromosome 21 XXY trisomy; Klinefelter syndrome • Is caused by the presence of an extra copy of the X chromosome X Monosomy; Turner syndrome • Is caused by the presence of only one copy of the X chromosome 3. Mitochondrial disorders • Is caused by mutation in mitochondrial DNA Examples: • Kearns-Sayre syndrome • Myoclonus epilepsy • Mitochondrial encephalomyopathy 3. Mitochondrial disorders cont. 4. Multifactorial disorders • Mutations in several genes in combination with lifestyle and environmental factors Examples: • Heart disease • Diabetes • Asthma • Cancer Recommended links • http://www2.estrellamountain.edu/facult y/farabee/biobk/BioBookhumgen.html • http://learn.genetics.utah.edu/content/di sorders/whataregd/ Tutorial Questions • A questions sheet about Mutations and Genetic disorders is available on Moodle