Chapter 16 - Variations in Chromosome Structure and Function : • Chromosome structure • Deletion, duplication, inversion, translocation • Chromosome number • Aneuploidy, monoploidy, and polyploidy.
Chapter 16 - Variations in Chromosome Structure and Function:
• 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.
Chromosomal structure mutations:
1. Deletion
2. Duplication
3. Inversion - changing orientation of a DNA segment
4. Translocation - moving a DNA segment
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.
Fig. 16.2
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
Fig. 16.6, Drosophila Bar and double-Bar results from duplications caused by unequal crossing-over (Bridges & Müller 1930s).
Unequal crossing-over produces Bar mutants in Drosophila.
Multi-gene families - result from duplications:
Hemoglobins (Hb)
• Genes for the -chain are clustered on one chromosome, and genes for the -chain occur on another chromosome.
• Each Hb gene contains multiple ORFs; adults and embyros also use different hemoglobins genes.
• Adult and embryonic hemoglobins on same chromosomes share similar sequences that arose by duplication.
• and hemoglobins also are similar; gene duplication followed by sequence divergence.
• Different Hb genes contribute to different isoforms with different biochemical properties (e.g., fetal vs. adult hemoglobin).
Linkage map of human hemoglobins
In humans, 8 genes total on 2 different linkage groups:-chain: , 1, 2-chain: , G, A, ,
In birds, 7 genes total on 2 different linkage groups: -chain: , D, A -chain: , , H, A
•The -chain genes are ordered in the sequence they are expressed.
Vijay G. Sankaran and Stuart H. Orkin Cold Spring Harb Perspect Med 2013; doi: 10.1101/cshperspect.a011643
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.
Fig. 16.7
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.
Fig. 16.8, 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)
Fig. 16.9, 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)
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).
Fig. 16.10
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):
• Alternate segregation, ~50%: 4 complete chromosomes, each cell possesses each chromosome with all the genes (viable).
• Adjacent 1 segregation, ~50%: each cell possesses one chromosome with a duplication and deletion (usually inviable).
• Adjacent 2 segregation, rare: each cell possesses one chromosome with a duplication and deletion (usually inviable).
Fig. 16.11, Meiosis in translocation heterozygotes with no cross-over.
Variation in chromosome number:
Organism with one complete set of chromosomes is said to be euploid (applies to haploid and diploid organisms).
Aneuploidy = variation in the number of individual chromosomes (but not the total number of sets of chromosomes).
Nondisjunction during meiosis I or II (Chapter 12) aneuploidy.
Fig. 12.18
Variation in chromosome number:
• Aneuploidy not generally well-tolerated in animals; primarily detected after spontaneous abortion.
• Four main types of aneuploidy:
Nullisomy = loss of one homologous chromosome pair.
Monosomy = loss of a single chromosome.
Trisomy = one extra chromosome.
Tetrasomy = one extra chromosome pair.
• Sex chromosome aneuploidy occurs more often than autosome aneuploidy (inactivation of X compensates).
• e.g., autosomal trisomy accounts for ~1/2 of fetal deaths.
Fig. 16.11, Examples of aneuploidy.
Variation in chromosome number:
Down Syndrome (trisomy-21, OMIM-190685):
• Occurs in 1/286 conceptions and 1/699 live births.
• Probability of non-disjunction trisomy-21 occurring varies with age of ovaries and testes.
• Trisomy-21 also occurs by Robertsonian translocation joins long arm of chromosome 21 with long arm of chromosome 14 or 15.
• Familial down syndrome arises when carrier parents (heterozygotes) mate with normal parents.
• 1/2 gametes are inviable.
• 1/3 of live offspring are trisomy-21; 1/3 are carrier heterozygotes, and 1/3 are normal.
Fig. 16.18
21
14
21
14
Fig. 16.19,Segregation patterns for familial trisomy-21
Trisomy
Inviable
Inviable
Inviable
Carrier
Normal
Relationship between age of mother and risk of trisomy-21:
Age Risk of trisomy-21
16-26 7.7/10,000
27-34 4/10,000
35-39 ~3/1000
40-44 1/100
45-47 ~3/100
Trisomy-13 - Patau Syndrome
2/10,000 live births
Trisomy-18 - Edwards Syndrome
2.5/10,000 live births
Fig. 16.22Variation in chromosome number:
Changes in complete sets of chromosomes:
Monoploidy = one of each chromosome (no homologous pair)
Polyploidy = more than one pair of each chromosome.
Variation in chromosome number:
Monoploidy and polyploidy:
• Result from either (1) meiotic division without cell division or (2) non-disjunction for all chromosomes.
• Lethal in most animals.
• Monoploidy is rare in adult diploid species because recessive lethal mutations are expressed.
• Polyploidy tolerated in plants because of self-fertilization; plays an important role in plant speciation and diversification.
• Two lineages of plants become reproductively isolated following genome duplication, can lead to instantaneous speciation.
• Odd- and even-numbered polyploids;
Even-numbered polyploids are more likely to be fertile because of potential for equal segregation during meiosis.
Odd-numbered polyploids have unpaired chromosomes and usually are sterile. Most seedless fruits are triploid.