Transcript Document

Chapter 16 - Variations in Chromosome Structure and Function:
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Chromosome structure
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Deletion, duplication, inversion, translocation
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Focus of Cytogenetics
Chromosome number
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Aneuploidy, monoploidy, and polyploidy.
Chromosomal mutations:
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Arise spontaneously or can be induced by chemicals or radiation.
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Major contributors to human miscarriage, stillbirths, and genetic
disorders.
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~1/2 of spontaneous abortions result from chromosomal
mutations.
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Visible (microscope) mutations occur in 6/1,000 live births.
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~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
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Occur in insects, commonly in flies (e.g., Drosophila).
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Chromatid bundles that result from repeated cycles of chromosome
duplication without cell division.
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Duplicated homologous chromosomes are tightly paired and joined
at the centromeres.
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Chromatids are easily visible under the microscope, and banding
patterns corresponding to ~30 kb of DNA can be identified.
Chromosomal structural mutations - deletion:
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Begins with a chromosome break.
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Ends at the break point are ‘sticky’, not protected by telomeres.
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Induced by heat, radiation, viruses, chemicals, transposable
elements, and recombination errors.
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No reversion; DNA is missing.
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Cytological effects of large deletions are visible in polytene
chromosomes.
Fig. 16.2
Chromosomal structure mutations - effects of deletions:
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Deletion of one allele of a homozygous wild type  normal.
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Deletion of heterozygote  normal or mutant (possibly lethal).
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Pseudodominance  deletion of the dominant allele of a
heterozygote results in phenotype of recessive allele.
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Deletion of centromere  typically results in chromosome loss
(usually lethal; no known living human has a complete autosome
deleted).
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Human diseases:
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Cri-du-chat syndrome (OMIM-123450)
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Deletion of part of chromosome 5; 1/50,000 births
Crying babies sound like cats; mental disability
Prager-Willi syndrome (OMIM-176270)
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Deletion of part of chromosome 15; 1/10,000-25,000
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Weak infants, feeding problems as infants, eat to death
by age 5 or 6 if not treated; mental disability
Deletion mapping:
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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:
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Duplication = doubling of chromosome segments.
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Tandem, reverse tandem, and tandem terminal duplications are
three types of chromosome duplications.
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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)
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Genes for the -chain are clustered on one chromosome, and genes
for the -chain occur on another chromosome.
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Each Hb gene contains multiple ORFs; adults and embyros also use
different hemoglobins genes.
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Adult and embryonic hemoglobins on same chromosomes share
similar sequences that arose by duplication, further maintained by
gene conversion.
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 and  hemoglobins also are similar; gene duplication followed by
sequence divergence.
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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:
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Chromosome segment excises and reintegrates in opposite
orientation.
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Two types of inversions:
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Pericentric = include the centromere
Paracentric = do not include the centromere
Generally do not result in lost DNA.
Fig. 16.7
Chromosomal structure mutations - inversion:
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Linked genes often are inverted together, so gene order typically
remains the same.
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Homozygous:
ADCBEFGH
ADCBEFGH
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Heterozygote:
ABCDEFGH
ADCBEFGH
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Gamete formation differs, depending on whether it is a paracentric
inversion or a pericentric inversion.
 no developmental problems
 unequal-crossing
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:
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Change in location of chromosome segment; no DNA is lost or
gained. May change expression = position effect.
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Intrachomosomal
Interchromosomal
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Reciprocal - segments are exchanged.
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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.
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If duplications/deletions are unbalanced, offspring may be
inviable.
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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).
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:
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Aneuploidy not generally well-tolerated in animals; primarily
detected after spontaneous abortion.
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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.
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Sex chromosome aneuploidy occurs more often than autosome
aneuploidy (inactivation of X compensates).
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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):
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Occurs in 1/286 conceptions and 1/699 live births.
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Probability of non-disjunction trisomy-21 occurring varies with
age of ovaries and testes.
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Trisomy-21 also occurs by Robertsonian translocation  joins
long arm of chromosome 21 with long arm of chromosome 14
or 15.
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Familial down syndrome arises when carrier parents
(heterozygotes) mate with normal parents.
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1/2 gametes are inviable.
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1/3 of live offspring are trisomy-21; 1/3 are carrier
heterozygotes, and 1/3 are normal.
Fig. 16.18
14
21
14
21
Trisomy
Inviable
Inviable
Fig. 16.19,
Segregation patterns for
familial trisomy-21
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
Variation 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.
Fig. 16.22
Variation in chromosome number:
Monoploidy and polyploidy:
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Result from either (1) meiotic division without cell division or (2)
non-disjunction for all chromosomes.
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Lethal in most animals.
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Monoploidy is rare in adult diploid species because recessive lethal
mutations are expressed.
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Polyploidy tolerated in plants because of self-fertilization; plays an
important role in plant speciation and diversification.
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Two lineages of plants become reproductively isolated following
genome duplication, can lead to instantaneous speciation.
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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.