Mutations When Good DNA Goes Bad (This is your last set of notes, all material is subject to your final exam)

Mutations Hollywood’s images of mutation

Mutations Actual Mutations in fruit flies

What is a mutation? A mutation is any change in a cell’s DNA A mutation can occur in an individual gene - results in a single changed protein - Ex: cystic fibros - a mutation in the protein that makes a type of ion channel in the cell membrane - bacterial resistance to antibiotics is an example of a beneficial gene mutation

What is a mutation? continued A mutation can occur in a chromosome - a chromosome contains many genes - chromosomal mutations affect many proteins Examples: Down Syndrome Edward’s Syndrome Patau Syndrome Syndrome is a collection of symptoms – many things wrong

What Causes Mutations? Mutations do not have to be bad Can be caused by mutagens- a physical or chemical cause of mutation. Examples: UV light, radiation, drugs, and benzene. Mutagens are often also carcinogens – anything that causes cancer Can be natural, random events. - mutations occur in approximately 1/100,000 DNA replications Mutations do not have to be bad (think evolution)

Mutation Types Gene Mutation Chromosomal Mutation Point Mutation Frameshift Mutation Chromosomal Mutation Non-disjunction Deletion Inversion Duplication Translocation

Gene Mutation – point mutation Mutations can occur in genes point mutation – one base substituted for another impacts one codon and one amino acid Normal: the fat cat ate the rat Point Mutation: the fat car ate the rat Normal: ACG TTT CCC GGG CCC Mutation: ACG TAT CCC GGG CCC The 2nd codon and the 2nd amino acid would be different in the mutation -

Gene Mutation - frameshift Mutations can occur in genes frameshift mutation – a nucleotide is either inserted or deleted in a gene Insertion Deletion This causes the codons to shift their position in the reading frame from the point of the mutation onward for the rest of the protein This can be very damaging to the gene

Gene Mutation - frameshift Frameshift mutation – deletion the fat cat ate the rat (nomal) the ftc ata tet her at (mutation) remember, bases still need to go in 3s, so they shift Every codon from deleted “a” will be different This could potentially cause every amino acid to be different from that point onward

Gene Mutation - frameshift Frameshift mutation – insertion the fat cat ate the rat (normal) the faa tca tat eth era t (mutation) remember, bases still need to go in 3s, so they shift This could potentially cause every amino acid to be different from that point onward

Chromosomal mutation Chromosomal mutations can occur when there is an error in meiosis (reproduction) or chromosomes are damaged chromosomes hold many genes – this type of mutation has huge impact! can result in extra copies of entire chromosomes can be changes to parts of chromosomes

Chromosomal mutation A few Examples of chromosomal mutations (nondisjunction mutations) Down Syndrome “trisomy 21” Turner Syndrome Klinefelter Syndrome Triple X syndrome (trisomy X)

Chromosomal mutation Examples of chromosomal mutations Down Syndrome “trisomy 21” About 95 percent of the time, Down syndrome is caused by trisomy 21 the child has three copies of chromosome 21 (instead of the usual two copies) in all cells. Down syndrome is a chromosomal condition that is associated with intellectual disability, a characteristic facial appearance, and weak muscle tone (hypotonia) in infancy. All affected individuals experience cognitive delays, but the intellectual disability is usually mild to moderate.

Chromosomal mutation 2. Turner Syndrome (females only) Turner syndrome is related to the X chromosome: usually a X chromosome is missing or altered People typically have two sex chromosomes in each cell: Normal females have two X chromosomes males have one X chromosome and one Y The missing genetic material affects development before and after birth. Short stature, puberty does not happen, 30% of those with Turner syndrome have extra folds of skin on the neck, a low hairline at the back of the neck, skeletal abnormalities, or kidney problems. 1/3 to ½ with Turner syndrome are born with a heart defect (

Chromosomal mutation 3. Klinefelter Syndrome (males) Normal males have XY, Klinefelter males have XXY (nondisjunction) Considered genetically male, symptoms may not appear until onset of puberty Diminished functionality of gonads (testes) Males could be sterile (can not reproduce)

Chromosomal mutation 4. Triple X syndrome (trisomy X) (females) Females may be taller than average, this chromosomal change typically causes no unusual physical features. Most females with triple X syndrome have normal sexual development and are able to conceive children. Triple X syndrome is associated with: increased risk of learning disabilities & delayed development of speech and language skills. Delayed development of motor skills (sitting & walking) and weak muscle tone (hypotonia) behavioral and emotional difficulties possible characteristics vary widely among affected girls and women Seizures&kidney abnormalities occur in 10% of those affected

Nondisjunction Non-dis-junction (junction is a joining, so disjunction would be separating) a type of chromosomal mutation that occurs during meiosis (reproduction) Occurs when a tetrad fails to split in meiosis I or chromatids fail to split in meiosis II

Nondisjunction(note the labeled nondisjunctions…the tetrads are supposed to pull apart)

Nondisjunction some gametes (sex cells) receive an extra copy of a chromosome called trisomy – the zygote produced from this gamete will have 3 copies of the chromosome after fertilization Trisomy-21 (on the 21st chromosome) causes Down Syndrome Nondisjunction causes other gametes to receive no copies of a chromosome called monosomy –the zygote (early embryo) produced from this gamete will have only one copy of the chromosome after fertilization monosomy is usually lethal

Deletion A portion of a chromosome is lost Deletions are responsible for many syndromes: Cri du Chat – infant sounds like cat, feeding problems, severe cognative issues, behavioral issues Wolf-Hirschhorn syndrome – mental retardation, seizures, poor muscle tone, cleft lip & palate Wolf-Hirschorn=deletion on the upper arm of chromosome 4. Mental retardation, microcephaly (small head),seizures,poor muscle tone, cleft lip and cleft palate Cri du chat - name comes from the cry of the infant, Sound like a meowing cat. 1/3 lose the cry by age 2. Symptoms include feeding problems, severe cognitve problems, behavioral problems (hyperactivity, tantrums aggression, repetetive movements), heart problems, microcephaly,

Inversion A segment of a chromosome will reverse end to end Many are not harmful as long as there is no extra DNA or missing DNA

Duplication a segment of a chromosome is duplicated producing extra copies of genes-on a chromosome Pallister-Killian Syndrome – mental retardation, epilepsy, visual impairment, deafness, heart defects, uneven pigment in skin can also lead to new genetic combinations - potential force for evolution Pallister-Killian =mental retardation, epilepsy, visual impairment, deafness, heart defects, areas with little pigment and other areas with too much pigment

Translocation In genetics, a chromosome translocation is a chromosome abnormality caused by the rearrangement of parts between nonhomologous chromosomes Balanced (usually not harmful) Unbalanced(usually harmful)

Diagnosis A karyotype is produced to examine an individual’s chromosomes A karyotype is a picture of a a person’s chromosomes as homologous pairs Allows many chromosomal mutations to be seen

Producing a Karyotype for an embryo Fluid is taken from the womb by amniocentesis (see next slide) The fluid contains cells from the embryo the cells are grown in a tissue culture and induced to undergo mitosis they are treated making them easier to see and photographed in metaphase. pictures of homologous chromosomes are matched up and examined for mutations The # of chromosomes in a human cell was not determined until 1956. It required a mistake in 1952 in which cells were accidently placed in a hypotonic solution allowed chromosomes to swell to the point of greater visibility. It was still not possible to distinguish homologous pairs. Not until the 70’s was it possible to stain them to produce banding making distinguishing homologues

Amniocentesis Any pregnant woman who: Will be 35 years or older at time of delivery (chromosomal abnormalities increase with a woman's age) Has a history of a previous fetus or child with a birth defect Has a family history of certain birth defects Has an abnormal genetic test (such as MSAFP) or abnormal sonographic results from this pregnancy

Normal Karyotypes