BIOL 2416 Chapter 16: Chromosomal Changes

Chromosomal Mutations Changes in Chromosome number Chromosome structure Induced by Chemicals radiation Detected by Genetic analysis (linkage studies) Microscopic analysis Karyotyping Seen in 6/1000 of live births Contribute significantly to ½ of miscarriages Stillbirths Genetic disorders Seen in 11% of men with fertility problems Seen in 6% of people institutionalized with mental deficiencies

Changes in Chromosome Structure 4 kinds: Deletions Duplications Inversions re-attaching DNA in opposite orientation Translocation moving DNA piece from one chromosome to another Often studied using Drosophila polytene chromosomes Chromatid bundles produced by DNA replication without mitosis/meiosis cell division Tightly paired at centromeres Easy to see banding patterns All begin with a break in the DNA Leaves sticky ends not protected by telomeres Induced by: Heat or radiation (especially ionizing) Viruses Chemicals Transposable elements Errors in recombination (Xover)

Deletions Among most devastating mutations (cannot recover lost piece) Effect depends on actual deletion: AA mutates to Aa (still normal) Aa mutates to aa (abnormal) Loss of centromere means acentric chromosomal piece will be lost during cell division Detected by unpaired loops in karyotypes Common disorders: Cri-du-chat Syndrome (chromosome 5 piece deleted) cat’s cry, microcephaly; round face; hypertelorism; micrognathia; prominent nasal bridge; epicanthic folds; hypotonia; severe psychomotor retardation Prader-Willi Syndrome (paternal chromosome 15 piece deleted) developmental delay, cryptorchidism (small or undescended testes), hyperphagia obesity (never feel full – can’t quit eating), short stature, mild retardation Angelman Syndrome (maternal chromosome 15 piece deleted) seizures, severe mental retardation, inappropriate laughter, a characteristic face that is small with a large mouth and prominent chin, fair skin,hair and eyes

Duplications Can be: Probably result from unequal Xing over Tandem (adjacent) Reverse tandem (adjacent in opposite order) Terminal (at end of chromosome) Probably result from unequal Xing over Similar sequences elsewhere in chromosome) Also seen as unpaired loops Can result in multi-gene families (Hb alpha vs. beta) E.g. Drosophila bar eye shape allele (slit-like rather than oval) Resembles incompletely dominant mutation Small X-chromosome segment (16A) duplicated Female heterozygotes have kidney-shaped eyes (medium # of eye segments) Hemizygous males have slits (low # of eye segments)

Inversions Cut and paste back in opposite orientation Pericentric: include centromere Paracentric: exclude centromere Shows up as inversion loop Usually no lost DNA, but can cause problems if breakpoint falls in regulatory/gene region Xover of inverted region can compound problems: Can cause imbalance in number of genes in gametes - some deleted, some duplicated Sometimes acentric (no centromere) or dicentric (2 centromeres) pieces are formed

Translocations Change in location of a chromosome segment Intrachromosomal - within same chromosome Interchromosomal - between two chromosomes Called reciprocal if exchanged Can be balanced (even swap) or unbalanced Gametes can be affected Homozygous for translocation means altered gene linkage Nonreciprocal: often result in unbalanced duplications or deletions in gametes after segregation E.g. familial Down’s syndrome: long arm of #21 translocates to and travels with long arm of #14 or #15; one gamete has no copies of #21 while the other has two copies of #21; fusion of gamete with two copies of #21 with a normal gamete (one copy of #21) results in Down’s syndrome (< 5% of cases). Reciprocal: heterozygotes have trouble pairing homologues at metaphase (cross-like arrangements) Often see inviable gametes with duplications/deletions

Diseases caused by translocations Familial Down’s syndrome Cancer Reciprocal translocation involving #9 and #22: Philadelphia Chromosome AML, CML Proto-oncogene convereted to c-abl oncogene Reciprocal translocation involving #8 and #14 Burkitt’s Lymphoma infertility

Position effects Inversions or translocations may move gene(s) from transcribed euchromatin to untranscribed heterochromatin E.g. white eye locus in Drosophila Inversion moves w+ (red) gene from euchromatin on the X chromosome to heterochromatin (essentially becomes w (white) allele) Affected cells in hemizygous w+ males or w+/w females will show up as white; eyes will be red with white spots Or duplications may alter expression patterns of genes differently depending on where they are located E.g. Bar locus in Drosophila The greater the number of ADJACENT duplicated 16A regions within the Bar gene on a given chromosome, the lower the number of eye facets (3/1) The same number of duplicate 16A regions spread out evenly over two chromosomes results in more eye facets (2/2)

Fragile sites Narrowings or unstained chromosome areas (gaps) are prone to breakage Over 40 human fragile sites known E.g. Fragile X Syndrome Xq27.3 tends to break Causes retardation in 80% of fragile X males Only 33% of female heterozygote carriers show mild retardation Caused by tandem CGG repeats inside the FMR-1 gene at the fragile X site; disease caused by amplification above a threshold number of repeats Other triplet repeat diseases are myotonic dystrophy, spinobulbar muscular distrophy (Kennedy’s disease) and Huntington’s disease.

Changes in chromosome number Euploid = 1 complete set of chromosomes, or exact multiples of complete sets (e.g. 1n, 2n, etc) Monoploidy or polyploidy = change in numbers of whole sets of chromosomes Aneuploid = change in numbers of individual chromosomes, so chromosome number is no longer an exact multiple of the haploid set

Aneuploidy Autosomal aneuploidy not well tolerated in animals Can occur due to nondisjunction (disjoin = to separate, non = not happening) Already seen earlier with sex chromosomes Autosomal aneuploidy not well tolerated in animals E.g. trisomy 21 (non-familial Down’s syndrome): Higher risk of nondisjunction in moms over 35 Moderate mental retardation, short, epicanthal folds, short/broad hands, heart problems, higher chance of acute leukemia, GI problems, lower life expectancy E.g. trisomy 13 (Patau), trisomy 18 (Edwards)

Monoploidy and polyploidy Both are cases of euploidy (have complete sets of chromosomes) Monoploidy = 1n Rare in adult diploids because of recessive lethal mutations Although male bees, wasps and ants develop from unfertilized haploid eggs and are monoploid Polyploidy = 3n or more More common in plants due to self-fertilization Autoplyploid = all chromosomes sets from same species (e.g. seedless fruits) Allopolyploid = from different species Salmon is polyploid Almost all animals and plants have polyploid tissues/cells: e.g. endosperm and mammalian liver tissue Euploidy is lethal in most animals, but common in plants (has played role in speciation) Polyploidy results from Meiotic division without cytokinesis Nondisjunction of ALL chromosomes Fusion of e.g. diploid + haploid > polyploid