Gene Mutation: Origins and Repair Processes

Gene Mutation: Origins and Repair Processes
We will not cover much of repair processes, as already covered in Mol Bio. Only need to know what we covered in class
finish-up chapter 10, move on to chapter 11
H.J. Muller Demonstrates that X-rays are mutagenic (1927)
Developed a mating scheme that allowed one to find recessive lethal mutations.

Looked in males for mutations as they are hemizygous for all genes on the X-chromosome.

Looked for an absence or reduction of grandsons in the F2 generation

CIB is a balancer chromosome:
C: indicates that this chromosome cannot yield progeny that have undergone recombination
I: recessive lethal
B: dominant eye marker;B/+ have small eyes
w: recessive allele; w/w flies have white eyes
12-1
Chromosome Mutations
Reciprocal translocation
Chapter 11
Questions and answers you should understand
Basic problems
5, 6, 14

Genome can be altered by large scale alterations to chromosome structure or changes in the copy number of chromosomes
Organisms with multiples of the basic chromosome set are called euploids
Polyploids are individual organisms in which there are more than two chromosome sets. Common in plants, not in animals
Aneuploids have a chromosome number that differs from the normal number for the species by a small number of chromsomes
Meiosis I
The problem with Trisomy
One cell will receive two chromosomes
and the other will receive just one. Only showing one chromosome. So for each chromosome, will either receive just one or two. It is unlikely the gamete will always receive two or one of each, so sterile.
Aneuploidy: Chromosome number is abnormal

Can be caused by non-disjunction during meiosis or mitosis.

A failure of the process of chromosome segregation of homologous chromosomes or chromatids during meiosis.
Non-disjunction Meiosis I
meiotic products with n+1 have two different copies of chromosome 1
Non-disjunction Meiosis II
meiotic products with n+1 have two of the “same” copies of chromosome 1
Human chromosome condition in which individual has 44 autosomes and a single X chromosome (XO).

Turner syndrome-female with many abnormalities.

Most monosomic chromosome complements are lethal in utero and so that is why there are not diseases associated with this condition.
Monosomics (2n-1)
Karyotype from individual with Turner syndrome.
Trisomics (2n+1)

Human condition in which individual has 44 autosomes,
two X chromosomes and a Y (XXY)

Klinefelter syndrome-male with many abnormalities
XYY Karyotype
XXY Karyotype
The Concrete Boot: The creeper who can't go straight. Reisen wants a favour from reformed break-in specialist Spider Scott, and the sadistic underworld boss has a forceful way of asking for favours. Add the lure of twenty thousand quid and an enticing lady, plus as much danger as he can handle, and the rogue chromosome in the XYY Man's genetic make-up that makes him a natural criminal starts itching like crazy.
Misconceptions:
Trisomic (2n+1)
Down syndrome- Trisomy of chromosome 21 (most frequently observed).
Rare forms caused by translocations (discuss later)
Incidence of Down’s syndrome increases with maternal age.
Human female meiocytes are arrested at diplotene stage of meiosis I (tetrad stage). Meiosis resumes at menstruation.

It is thought that the association between chromosomes are more likely to breakdown over time.
Gene Balance
Why do we see abnormalities with aneuploids and monsomics in nature more frequently than with polyploids?
In animals autosomal aneuploids that survive are trisomics and monosomics of small
chromosomes. Thus fewer genes have aberrant dosage.
Gene Dosage and Gene Balance: In euploids the ratio of genes on any chromosome to that of any other chromosome is 1:1, with the exception of the sex chromosomes.
Gene dosage influences the amount of transcript produced from a gene, and thus the amount of protein.
Normal physiology depends on the proper ratio of gene products. If the relative dosage of genes changes by removal or addition of a chromosome, this results in physiological imbalances in all of the processes for which there are genes on that chromosome.
Dosage compensation-Sex chromosomes
In humans the Y chromosome appears to be a degenerate X in which there are very few functional genes, but the X contains many genes important for basic functions in the cell.
In humans, X chromosomes are akin to being aneuploid, in that females have two X-chromosomes and males have one.

But it has been found that the amount of transcript for genes on the X is similar between males and females. This is called dosage compensation.
What is the mechanism? In humans one of the X chromosomes in females is inactivated.
Changes in chromosome structure
Often called rearrangements.

If a chromosome segment is lost: deletion
If a chromosome segment is added: duplication
If a chromosome segment is moved to a different chromosome: translocation
Inversion: A chromosomal mutation consisting of the removal of a chromosomal segment, its rotation 180°, and its reinsertion in the same location
Inversions that have breakpoints in genes
Inversions

Paracentric: Centromere is outside the inversion
Pericentric: Centromere is within the inversion
Paracentric Inversion
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Paracentric
Inversion
Dicentric
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Pericentric
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Duplication and deletion
on both arms
Balanced/Reciprocal Translocation
1/2 of the meiotic products are non-functional
Translocation Behavior
Complementation:
The production of a wild type phenotype when two different mutations are combined in a diploid.
A scientist has identified two new alleles she calls a1 and b1.
a1 and b1are recessive alleles.
Both a1/ a1 and b1 / b1 mice have no fur.
She wants to figure out if a1 and b1 are alleles of the same gene.

a1/ a1 X b1 / b1
All progeny have fur. Therefore a1 and b1 complement.
This indicates that a1 and b1 are alleles of different genes (99.9% of the time).

More on complementation

Her labmate finds another recessive allele, c1.
The phenotype for homozygous c1/c1 mice is that they have no fur.

He tests if c1complements a1 and b1
c1/c1 X a1/a1 : all progeny have fur
c1/c1 X b1/b1 : no progeny have fur

He concludes that c1 complements a, but not b.
Therefore, c1 and b1 are alleles of the same gene (99.9% of time).
c1 and b1 are in the same complementation group.
Deletion Mapping
pn (prune): only deletion 264-38 fails to complement
fa (facet): all but 258-11 and 258-14 fail to complement
Using genomic approaches to identify deletions and duplications
microarray/ DNA Chip
DNA from mutant Cy5
DNA from wild type Cy3
A. Mutant has a deletion (chr. 1)
B. Mutant has a duplication
(chr 4)
Cy5/Cy3=1
normal chromosome
Cy5/Cy3=.5
deletion
Cy5/Cy3=2
duplication
Cy5/Cy3=15
tandem duplication
Fate of human implanted embryos