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Chapter 16 - Variations in Chromosome Structure and Function: • • Chromosome structure • Deletion, duplication, inversion, translocation • Focus of Cytogenetics 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, further maintained by gene conversion. • 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 ADCBEFGH • Heterozygote: ABCDEFGH ADCBEFGH • 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: • 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): 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: • 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 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: • 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.