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 ) Deletion of part of chromosome 5; 1/50,000 births Crying babies sound like cats; mental disability Prager-Willi syndrome (OMIM ) 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: /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 problems ADCBEFGH Heterozygote:ABCDEFGH  unequal-crossing ADCBEFGH 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)

Figure 1. Chromosome inversions that distinguish humans and chimpanzees inferred from a comparison of their genomic sequences [3]. Kirkpatrick M (2010) How and Why Chromosome Inversions Evolve. PLoS Biol 8(9): e doi: /journal.pbio

A B A B b a b a A B b a A B b a A a b B Non-recombinantRecombinant Heterozygote Viable Gametes All genes present Inviable Gametes Genes missing Chromosomal inversions suppress recombination in heterozygotes!

Example showing how chromosomal rearrangements contribute to speciation in Anopheles gambiae. Avril Coghlan, Evan E. Eichler, Stephen G. Oliver, Andrew H. Paterson, Lincoln Stein. Chromosome evolution in eukaryotes: a multi-kingdom perspective. Trends in Genetics, Volume 21, Issue 12, (2005), 673 –

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 ) and Burkitt lymphoma (OMIM ). Fig

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 , 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

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 , Examples of aneuploidy.

Variation in chromosome number: Down Syndrome (trisomy-21, OMIM ): 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 Fig , Segregation patterns for familial trisomy-21 Trisomy Inviable Carrier Normal

Relationship between age of mother and risk of trisomy-21: AgeRisk of trisomy /10, /10, ~3/ / ~3/100

Trisomy-13 - Patau Syndrome 2/10,000 live births Trisomy-18 - Edwards Syndrome 2.5/10,000 live births

Fig 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.

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.

Viable Self-fertile

Most seedless fruits are triploid.