By Dibya Ranjan Dalei Adm no- 9PBG/16

Chromosomal abberations

A chromosome anomaly, abnormality, aberration, or mutation is a missing, extra, or irregular portion of chromosomal DNA. 

It can be from an a typical number of chromosomes or a structural abnormality in one or more chromosomes.

Chromosome structure

• Deletion, duplication, inversion, translocation

Chromosome number

• Aneuploidy, monoploidy, and polyploidy.

Chromosomal mutations:

• Arise spontaneously or can be induced by chemicals or radiation.

• Major contributors to human miscarriage, stillbirths, and genetic disorders.

• ~1/2 of spontaneous abortions result from chromosomal mutations.

• Visible (microscope) mutations occur in 6/1,000 live births.

• ~11% of men with fertility problems and 6% of men with mental deficiencies possess chromosomal mutations.

Structural chromosomal abberations

Studying chromosomal structural mutations:

Polytene chromosomes

• Occur in insects, commonly in flies (e.g., Drosophila).

• Chromatid bundles that result from repeated cycles of chromosome duplication without cell division.

• Duplicated homologous chromosomes are tightly paired and joined at the centromeres.

• Chromatids are easily visible under the microscope, and banding patterns corresponding to ~30 kb of DNA can be identified.

Chromosomal structural mutations - deletion:• Begins with a chromosome break.

• Ends at the break point are ‘sticky’, not protected by telomeres.

• Induced by heat, radiation, viruses, chemicals, transposable elements, and recombination errors.

• No reversion; DNA is missing.

• Cytological effects of large deletions are visible in polytene chromosomes.

Chromosomal structure mutations - effects of deletions:

• Deletion of one allele of a homozygous wild type normal.

• Deletion of heterozygote normal or mutant (possibly lethal).

• Pseudodominance deletion of the dominant allele of a heterozygote results in phenotype of recessive allele.

• Deletion of centromere typically results in chromosome loss(usually lethal; no known living human has a complete autosome deleted).

• Human diseases:

• Cri-du-chat syndrome (OMIM-123450)

• Deletion of part of chromosome 5; 1/50,000 births• Crying babies sound like cats; mental disability

• Prager-Willi syndrome (OMIM-176270)• Deletion of part of chromosome 15; 1/10,000-25,000• Weak infants, feeding problems as infants, eat to death

by age 5 or 6 if not treated; mental disability

Deletion mapping:

• Used to map positions of genes on a chromosome; e.g., detailed physical maps of Drosophila polytene chromosomes.

Fig. 16.3, Deletion mapping used to determine physical locations of Drosophila genes by Demerec & Hoover (1936).

Chromosomal structure mutations - duplication:• Duplication = doubling of chromosome segments.

• Tandem, reverse tandem, and tandem terminal duplications are three types of chromosome duplications.

• Duplications result in un-paired loops visible cytologically.

Fig. 16.5

Drosophila Bar and double-Bar results from duplications caused by unequal crossing-over (Bridges & Müller 1930s).

Unequal crossing-over produces Bar mutants in Drosophila.

Chromosomal structural mutations - inversion:

• Chromosome segment excises and reintegrates in opposite orientation.

• Two types of inversions:

• Pericentric = include the centromere• Paracentric = do not include the centromere

• Generally do not result in lost DNA.

Chromosomal structure mutations - inversion:

• Linked genes often are inverted together, so gene order typically remains the same.

• Homozygous: ADCBEFGH no developmental problemsADCBEFGH

• Heterozygote: ABCDEFGH unequal-crossingADCBEFGH

• Gamete formation differs, depending on whether it is a paracentric inversion or a pericentric inversion.

Unequal crossing-over w/paracentric inversion:(inversion does not include the centromere)

Results:

1 normal chromosome

2 deletion chromosomes(inviable)

1 inversion chromosome(all genes present; viable)

Unequal crossing-over w/pericentric inversion:(inversion includes the centromere)

Results:

1 normal chromosome

2 deletion/duplication chromosomes(inviable)

1 inversion chromosome(all genes present; viable)

A

B

A

B

b

a

b

a

A

B

b

a

A

B

b

a

A

a

b

B

Non-recombinant Recombinant

Heterozygote

Viable GametesAll genes present

Inviable GametesGenes missing

Chromosomal inversions suppress recombination in heterozygotes!

Chromosomal Structural Mutations - Translocation:• Change in location of chromosome segment; no DNA is lost or

gained. May change expression = position effect.

• Intrachomosomal• Interchromosomal

• Reciprocal - segments are exchanged.• Non-reciprocal - no two-way exchange.

• Several human tumors are associated with chromosome translocations; myelogenous leukemia (OMIM-151410) and Burkitt lymphoma (OMIM-113970).

How translocation affects the products of meiotic segregation:

Gamete formation differs for homozygotes and heterozygotes:

Homozygotes: translocations lead to altered gene linkage.

• If duplications/deletions are unbalanced, offspring may be inviable.

• Homozygous reciprocal translocations “normal” gametes.

Heterozygotes: must pair normal chromosomes (N) with translocated chromosomes (T); heterozygotes are “semi-sterile”.

Segregation occurs in three different ways (if the effects of crossing-over are ignored):

1. Alternate segregation, ~50%: 4 complete chromosomes, each cell possesses each chromosome with all the genes (viable).

2. Adjacent 1 segregation, ~50%: each cell possesses one chromosome with a duplication and deletion (usually inviable).

3. Adjacent 2 segregation, rare: each cell possesses one chromosome with a duplication and deletion (usually inviable).

Meiosis in translocation heterozygotes with no cross-over.

What Are Mutations? The sudden heritable changes in the

characteristics of an organism is referred to as mutation.

Changes in the nucleotide sequence of DNA

May occur in somatic cells (aren’t passed to offspring)

May occur in gametes (eggs & sperm) and be passed to offspring

Are Mutations Helpful or Harmful?

Mutations happen regularly Almost all mutations are neutral Chemicals & UV radiation cause

mutations Many mutations are repaired by

enzymes Some type of skin cancers and leukemia

result from somatic mutations Some mutations may improve an

organism’s survival (beneficial)

Mutations are quantified in two ways:

• Mutation rate = probability of a particular type of mutation per unit time (or generation).

• Mutation frequency = number of times a particular mutation occurs in a population of cells or individuals.

Terminology describing mutations in protein coding sequences:

Nonsynonymous/missense mutation

Base pair substitution results in substitution of a different amino acid.

Nonsense mutation

Base pair substitution results in a stop codon (and shorter polypeptide).

Neutral nonsynonymous mutation

Base pair substitution results in substitution of an amino acid with similar chemical properties (protein function is not altered).

Synonymous/silent mutation

Base pair substitution results in the same amino acid.

Frameshift mutations:

Deletions or insertions (not divisible by 3) result in translation of incorrect amino acids, stops codons (shorter polypeptides), or read-through of stop codons (longer polypeptides).

Types of Mutations(A) point mutations:

1. Base pair deletions and insertions

2. Base pair substitutions.

1. Transitions

• Convert a purine-pyrimidine to the other purine-pyrimidine.

• 4 types of transitions; A G and T C

2. Transversions

• Convert a purine-pyrimidine to a pyrimidine-purine.

• 8 types of transversions; A T, G C, A C, and G T

Types of base pair substitutions and mutations.

Types of base pair substitutions and mutations.

(B) Based upon Direction of mutation:-1. Forward mutation

Mutation changes wild type (ancestral) to mutant (derived).

2. Reverse mutation (back mutation)

Mutation changes mutant (derived) to wild type (ancestral).

3. Suppressor mutation

Occur at sites different from the original mutation and mask or compensate for the initial mutation without reversing it.

• Intragenic suppressors occur on the same codon;e.g., nearby addition restores a deletion

• Intergenic suppressors occur on a different gene.

(C) Based upon Cause of mutation:-1. Spontaneous mutations :

• Spontaneous mutations can occur at any point of the cell cycle.• Mutation rate = ~10-4 to 10-6 mutations/gene/generation• Rates vary by lineage, and many spontaneous errors are repaired.Spontaneous chemical changes

i. Depurination

Common; A or G are removed and replaced with a random base.

ii. Deamination

Amino group is removed from a base (C U); if not replaced U pairs with A in next round of replication (CG TA).

Prokaryote DNA contains small amounts of 5MC; deamination of 5MC produces T (CG TA).

Regions with high levels of 5MC are mutation hot spots.

Deamination.

2. Induced mutations Induced due to a treatment with physical or chemical mutagens.

(D) Based upon Dominance relationship 1. Dominant mutation 2. Recessive mutation 3. Co-dominant mutation 4. Incompletely dominant mutation(E) Based on tissue of origin

1.Somatic/ Bud mutation 2.Germinal(F) Based on effect on survival

1. Lethal- All individuals are killed 2. Sublethal- Most of the individuals are killed 3. subvital- Some of the individuals are killed 4. vital- Dont affect survival 5. supervital- Increases survivality

(G) Based on type of trait affected;- 1. Visible or Morphological mutations 2. Biochemical mutations(E) Based on quantum of Morphological effect;- 1. Macro mutations- produce large enough changes 2. Micro mutations- Short legged changes in the

phenotype(F) Cytological basis:- 1. Chromosomal- Structural or numerical abberations 2. Gene mutations- Alterations in base sequences of

a gene 3. Cytoplasmic- Changes in mitochondria or

chloroplast DNA

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