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.