Genetics Lecture 25, 10/31; Chapter 15 DNA repair and mutation

DNA repair and mutation
Looking specifically at alterations to the chemical composition of DNA

• (1:45) Mutation is the basis of genetic study. Mutate a gene and the determine the phenotype
• Certain organisms are easier to mutate, for example: bacteria, fungi, yeast, viruses and fruit flies. THey have shorter lifespans.

(4:35) How mutations arise.

• Two models for how bacterial mutations arise
• Spontaneous: mutation occurs at any given time
• Adaptive: cell will mutate in response to environmental pressure
• EX. Antibiotic resistance: the cell will mutate in response to the presence of the antibiotic.
• 1943 - Luria and Delbruck set out to test the two models. They set up a number of cultures of e. coli. Sensitive to infection with the T1 phage. Prior to starting the counted the total number of cells. They then exposed the cells to phage. Following exposure they counted number of survivors.
  
• Survivors are cells witha mutation that allowed them to survive infection.
• start with small # of cells and grow them.
  
• Spontaneous mutation could occur at any time.
• if it happens ealy 1 cell picks up a mutation and divides. All cells from this cell have the mutation. High percentage of cells with a mutation
• if it happens late you get orginal cell with the mutation and a few rounds of cell division and a small percentage of resistant cells.
• in the experiment they looked at 10 cultures. SPontaneous model would propose that there would be variety in the number of resistant cells in the cultures. In the adaptive model mutation is the result of environmental pressure. THis suggests that with a number of different cultures, if all cells are exposed to phage at the same time then each culture should have mutation occuring at the same time. Each culrue should have about the same number of reistant cells - adaptive model
• found that 10 cultures had a wide variety of resistant cultures. Indicates the mutation is spontaneous. Reffered to as the fluctuation test.
  
• Additional work has been down to show that mutation is primarily spontaneous. There are rare occasions when mutation is adaptive.

(23:00) How to classify mutations

Spontaneous vs. induced.

• Spontaneous mutation arises naturally in a spontaneous fashion. No exposure that led to the mutation.
• Induced mutation: some envionmental exposure leads to a mutation. EX: Smoke two packs a day and you develop a mutation --> lung cancer.

(27:10) Somatic mutations vs gametic mutations

• somatic mutations arise in somatic cells. A somatic cell mutation typically leads to a small population of cells with that mutation.
• Gametic mutations - mutations in gametes. A gametic mutation in a gamete involved in a fertilization, that offspring will have that mutation in every cell.

(32:20) Broad categories of mutation

• morphological mutation. A mutation which alters the structure of a all organisms.
• Nutritional mutation: Lack the ability to synthesize an amino acid vitamin or a mutation that prevents you from breaking down some compound.
• Behavioural mutation: any mutation which alters the behaviour of an organism. EX. Fruitflies - beating of wings is important in mating. A mutation that impacts the ability of a fruit fly to Beat its wings will have behavioral consequences.
• (38:00) Regulatroy mutations: mutations in genes which produce proteins that regulate the expression of other genes. Alter the way the regulated gene is expressed.
• (40:10) Lethal Mutation: any mutation which kills an organism
• Conditional mutation: only seen under certain conditions.
• EX temperature sensitive mutation: a mutation that is scene at a particular temperature.
  

Genetics Lecture 24, 10/29; Large Mutations in Chromosome Structure

Side Note:
Trisomy - 3 copies of one chromosome.
Triploidy - instead of 46 you have 69 chromosomes because you have extra copies of every chromosome

(1:00) Large mutations in Chromosome structure

Deletion: removal of a substantial (as in a whole gene) portion of a chromosome.

• Two Categories of Deletion:
  
• Terminal Deletion: delete from the end of a chromosome
• Intercalary deletion: an internal deletion within the structure of a chromosome
• Cri - du - chat syndrome: a deletion of a small portion of a chromosome results in a substantial effect (baby cries like cat)
• In any deletion, if it is large enough, it will result in death of the organism.

(6:45) Gene Duplication Mutation: a portion of a chromosome copied. Could be anywhere from a single locus to multiple locus, caused by unequal crossover during meiosis.

• Gene redundancy/amplification: deals particularly with essential genes example rRNA gene.
• An organism will have multiple copies of the rRNA gene. rRNA is represented by 0.3 to 0.4% of all genes in an organism. Drosophila has 130 copies of the rRNA gene. If you delete one you have other copies to fill this role. If only a single copy is present of an essential gene, mutation will most likely result in death. In Drosophila, a mutation which decreases the number of copies of the gene still equals poor development and reduced viability. The larger the number of mutated genes the greater the severity.
• (13:25) Gene duplication can lead to phenotypic effects for the cell. Bar eyed phenotype in Drosophila (X-linked dominant mutation)
• heterozygous females and hemizygous males (mutant X chromosome) have one version of the phenotype.
  
• homozygous females have a more severe version of the phenotype.
• in 1930's it was deteremined that all flies have one copy of a particular region of the X chromosome. Your are wild type of you have one copy. The Bar eyed phenotype has two copies of this region. The homozygous females a.k.a. Double bar eyed (the most severe) have 3 copies of this region.
  
• (19:15) Gene duplication could serve as a resovoir for new genes to be produced
• if you have a single copy of an essential gene mutation has a potentially devastating effect.
• if yoy have MULTIPLE copies of a gene you can make one copy and make a new gene with a new function and still have copies of the original gene.
• Evidence that supports this:
• If you compare genes with very different functions there is a relatively high degree of sequence similarity.
• Families of genes. Groups of genes within an organism which are highly similar (80-90% similar) and share similar functions. EX. aminoacyl tRNA synthases: enzymes which link amino acids to tRNA molecules. EACH cell has 20 different forms of this enzyme 1 per unique amino acid.

(26:30) Inversion: a region of chromosome flipped 180 degrees, reordering the genes

• pericentric inversion: the centerosome region is included in the region
• paracentric inversion: the centrosome is not involved
• Two effects of inversion:
• an in version can fuction to prevent synapsis during meiosis
• position effect: being near a region of heterochromatin can change the expression of a gene. If the inversion does this (changes the position relative to heterochromatin) it can be expressed.

(30:50) Translocation: a region of a chromosome moving to an entirely different region of the genome

• major impact is position effect: moving genes closer or farther away from regions of heterochromatin.
  

Genetics Lecture 23, 10/27 - Chapter 8: Chromosomal mutations, non disjunction, monosomy, trisomy

Chromosome Mutation: anytime you have a cell with an abnormal # of chromosomes. Typically this is the loss or gain of one chromosome.

• Monosomy: loss of one chromosome
• Trisomy: gain of a chromosome . . . 3 copies of a chromosome
• QUES: How does this happen? ANS: non-disjunction event during meiosis.
  
• Non-disjunction event explained: during anaphase when a chromosome pair is supposed to separate it fails to do so. Because of this you produce gametes which are not haploid. Your gametes are either diploid or empty for that particular chromosome.
• When you fertilize a diploid gamete you produce a trisomy. If a gamete without a copy of a chromosome is fertilized you will get a monosomy.
• Anueploidy - a condition of having one extra or one less copy of a single chromosome.
• Euploidy - condition where a cell has a complete extra haploid complement of chromosomes. EVERY CHROMOSOME
• Triploid - has 3 complements of chromosomes
• tetraploid - 4 haploid complements of chromosomes
• Result - broad phenotypic changes.

(13:05) Genetic mutations more in depth

• Monosomy: a condition of having one copy of a particular chromosome.
  
• Partial Monosomy: Cri-du-chat syndrome (cry of the cat)--> deletion of a large portion of the P arm on chromsome 5. Referred to as 46, -5p
• Anatomic abnormalities in the cardiac region as well as the gastrointestinal tract and mental retardation.
  
• Abnormal development of the glotis and the larynx. When these baby's cry they sound like cats.
• There is a correlation between the size of the deletion and the severity of the disease. The larger the deletion the worse the disease.
• (20:00) Trisomy: (more prevelant/common) presence of an extra copy.
• Trisomy 21 = Down Syndrome.
• series of syptoms associated with down syndrome
• affected individual - 6-8 of the traits
  
• affected individuals have a tendancy to look like each other.
• Traits: epicanthic fold over the corner of the eye. Flat face. Round head. Short. Some form of mental retardation. Short life span (avg into 50's)
• Typically the non-disjunction is in the ovum (95%). Correlation between occurency and the age of the mother at conception.
• If mom is 30 it is 1 in 1000.
• If mom is 40 it is 1 in 100
• If mom is 45 it is 1 in 50
• 35% of all births to a Mom above 40 result in Down Syndrome.
• (28:20) Why is there such a strong correlation between age of the mother and frequency of Down Syndrome?
• Females are born with all of their eggs - the eggs are with the mother since birth. Meiosis II happens during menstrul cycle and fertilization.
  
• (32:55) Trisomy 13 - Patau syndrome
• Infant is not mentally alert. High chance of being deaf. Clef Palate.
  
• Typically death occurs by 3 months.
• Upon autopsy you see a high degree of organ system malformation.
  
• Average age of the parents of Patau syndrome is 32.
• (36:45) Trisomy 18 - Edwards Syndrome
• smaller than average, elongated skull, congenital dislocation of the hip.
• Life expectancy is 4 months
• majority of affected infants are female.
• average age of parents of Edwards syndrome is 34.7

• Technically you can have a trisomy or a monosomy of any chromosome. It depends on which chromosome has a non-disjunction event. Embryos with these arrangments lead to early miscarrage.
• 15-20% of all conceptions end in miscarriage. Could be as high as 50% (mother doesn't even know she was pregnant)
• Of miscarriages, 30% have a chromosomal abnormality.
• 6% of all conceptions have a chromosomal abnormality.

• Post implantation (refers to time when it occurs). What happens: there is a system set up in which the embryo is, in effect, screened for abnormalities. If an abnormality is found your body will attempt to trigger a miscarriage. WHY? Basic answer is, conserve energy. Historically, there was a high mortality rate for women during birth - body wants to preserve itself.
  

• Miscarriages are on the rise. WHY?
• People are delaying having children till later in life.
• Home pregnancy tests - people are finding out they are pregnant sooner. (Schau's Theory)