Chromosomal Arrangement

Variations in Chromosome Number and Arrangement Chromosomal mutations or aberrations Abnormal chromosomal number Gene deletion or duplication Chromosome rearrangements Aberrant (different from the norm) chromosomes are passed on in a Mendelian fashion (Independent assortment during Meiosis)

Terminology Euploid (Eu=True) – chromosomes present in complete haploid units Diploid Triploid Tetraploid Aneuploid – loss or gain of one or more chromosomes (2n+x, 2n-x) Alloploid – multiples of different genomes

Aneuploidy Commonly results from nondisjunction during meiosis Monosomy 2n-1 Trisomy 2n+1 Tetrasomy 2n+2, Pentasomy 2n+3….. Klinefelter (XXY) and Turner syndromes (X) are examples of Aneuploidy involving human sex chromosomes

Kleinfelter Syndrome Anatomical Characteristics

Turner Syndrome Characteristics

Nondisjunction

Aneuploidy - Monosomy 2n – 1 condition Monosomy involving autosomes may have severe phenotypic effects in animal species (but generally not plants) Monosomy for Drosophila chromosome 4 (only 5% of genome) gives live fly but small and with low viability Monosomy for chromosomes 2 and 3 lethal

Cri-du-Chat Syndrome Autosomal monosomy in humans not usually reported beyond birth (die quickly) Partial autosomal monosomy may survive Segmental deletions of chromosomes “Cry of cat” syndrome Loss of part of 5p arm (46, -5p) 1/50,000 births

Cri-du-Chat

Aneuploidy - Trisomy Trisomy (2n + 1) Meiotic issues Somewhat/slightly less severe than monosomy when involves autosome Large autosomes usually lethal in both Drosophila and humans Generally viable in plants Meiotic issues Anaphase has one going to one cell, two to the other

Trisomy Meiosis

Down Syndrome (Trisomy 21) Discovered in 1866 by John Langdon Down Now known to result from trisomy 21 (47 +21) Occurs at 21st position in karyotype Occurs one per 800 live births 75% due to nondisjunction in meiosis I Ovum is source of extra 21 in 95% of cases Maternal age Ova can be stalled in meiosis I for 20 or more years… Familial Down syndrome is the result of a translocation of a portion of chromosome 21

Down Syndrome – Trisomy 21

Maternal Age and Down Syndrome 1/1000 births when maternal age is 30 1/100 at age 40 1/50 at age 50

Aneuploidy - Patau Syndrome Trisomy 13 (47 +13) occurs at 13th position in karyotype 1/19,000 births Many problems; death commonly by 3 months Some parental age correlation but average age of parent is somewhat higher than for normal children No evidence yet for maternal or paternal probabilities as source of extra chromosome

Patau Syndrome

Warning, the next slide is graphic

                                                                                                                                                 A 37 2/7 week gestational age male infant with Patau syndrome demonstrating alobar holoprosencephaly with cyclopia. A) Facial features included sloping forehead with a proboscis superior to a single central palpebral fissure. B) Close-up of the fused eyelids and proboscis showing a single nostril. C) Polydactyly showing six digits. D) Posterior view of the brain showing indistinct gyri, fusion of the hemispheres, and occipital encephalocele.E) Transposition of the aorta (A), and hypoplastic pulmonary trunk (P). F) Trisomy 13 [47, XY, +13] (karyotype by Giemsa-banding). Chan et al. Diagnostic Pathology 2007 2:48   doi:10.1186/1746-1596-2-48

Aneuploidy - Edwards Syndrome Trisomy 18 (47 +18) Occurs at 18th position in karyotype Many problems, survival less than 4 months Occurs 1/8000 live births 80% female (in study of 143 cases) Average maternal age is high (nearly 35)

Edwards Syndrome

Viability in Human Aneuploidy (ex: 2n+x, 2n-x) Reduced viability (survival) of persons born with monosomic or trisomic autosomal conditions Significant percentage of spontaneously aborted fetuses are trisomic for an autosome (Carr study, 1971) Virtually all possibilities found Few monosomic autosomes found Most are usually terminated much earlier in development Some polyploid examples found

More From the Carr Study 15-20% of all pregnancies terminate by spontaneous abortion About 30% of these have chromosome abnormalities 0.20 x 0.30 = 0.06 so up to 6% of all pregnancies originate with an abnormal number of chromosomes in the zygote New data sets this rate as high as 1—30%

More Still… Highest percentage are aneuploid (2n +1, 2n-1) Most common is 45,X (would be Turner syndrome) 70% of these have maternal X Most involve failure during spermatogenesis

Turner Syndrome Monosomy X

Triplo X (XXX) Result of Nondisjunction taller than average typically causes no unusual physical features associated with an increased risk of learning disabilities delayed development of speech and language skills Seizures or kidney abnormalities occur in about 10 percent of affected females

XYY extra copy of the Y chromosome in each of a male's cells Result of non-disjunction This condition occurs in about 1 in 1,000 newborn boys taller than average typically causes no unusual physical features increased risk of learning disabilities and delayed development of speech and language skills. Delayed development of motor skills (such as sitting and walking), weak muscle tone (hypotonia), hand tremors or other involuntary movements (motor tics), and behavioral and emotional difficulties are also possible

Polyploidy in Plants Multiples of a genome 3n, 4n, 5n, etc. Relatively infrequent in animals Mostly in lizards, amphibians and fish Even numbers of sets generally more stable and therefore more common Types Autopolyploidy – multiples of the same genome Allopolyploidy - multiples of different genome

Autopolyploidy Each additional set of chromosomes is identical to the parent species Mole Salamander, Wheat, human liver, apples and bananas Origin Complete failure to segregate during meiosis (first or second division nondisjunction) Multiple sperm fertilize an egg Triploids created by crossing diploid with tetraploid Experimentally produced by cold or heat shock during meiosis

Mole Salamander

Experimentally Produced Tetraploids Colchicine inhibits microtubule polymerization by binding to tubulin, one of the main constituents of microtubules. Availability of tubulin is essential to mitosis, and therefore colchicine effectively functions as a "mitotic poison" or spindle poison

Allopolyploidy Multiples of different genomes Can occur through hybridization of two “closely” related species Allotetraploid an interspecific hybrid having a complete diploid chromosome set from each parent form —Also called Amphidiploid Cabbages and mustard

Allotetraploid Formation Gametes fuse DNA replication with subsequent cell division to form nonsterile hybrid Normal mitosis and meiosis

Endopolyploidy Only certain cells of an otherwise diploid organism are polyploid Some human liver cells are 4n, 8n or 16n Some apical region tissues of plant Gut lining of mosquitoes can be 16n Some tissues of insects in genus Gerris (water strider) Up to 2048 copies of genome (2n = 22 so some cells have 40,000+ chromosomes)

Chromosome Rearrangements Types Deletions Duplications Translocations Reciprocal Nonreciprocal Most involve one or more breaks in the DNA/chromosome Broken ends lack telomeres and can be “sticky” Can rejoin with other ends

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Consequences of Rearrangements Are heritable to daughter cells And if in germ line to subsequent generations Balanced translocations may not impact individual greatly But gamete production will create defective cells/zygotes with predictable frequency Gene dosage Pairing problems during meiosis

Deletions Deletions Terminal deletions remove end of chromosome Often a result of DNA damage involving strand breakage Intercalary deletions delete an interior portion Only portion retaining centromere will be maintained in daughter cells Synapsing with normal chromosome creates a deletion loop or compensation loop visible during meiosis Crossover between direct repeats can result in an internal deletion

Compensation Loop in a Polytene Chromosome Creates a partially hemizygous condition and results in a phenomenon called pseudodomince

Duplications Section of chromosome occurs more than once in a haploid equivalent (genome) Commonly arise from unequal crossing over Important evolutionary process 1970 Susomo Ohno – “Evolution by Gene Duplication” Gene duplication produces a reservoir of genes from which to evolve new ones Why reinvent the wheel from scratch?

Unequal Crossing Over

Position Effects Bar-eye phenotype in Drosophila

Gene Duplication and Evolution Yeast genome has about 5000 genes with about 55 duplicated regions that encode 376 pairs of duplicated genes Humans have 1077 duplicated blocks of genes, with 781 having 5 or more copies of the duplicated segment Make up nearly half of chromosomes 18 and 20

Chromosomal Inversions No loss of genetic information (nucleotides) Crossover between inverted repeats Segment is inverted 180 degrees in chromosome

Chromosomal Inversions Paracentric inversion does not involve centromere Pericentric inversion involves centromeric region

Inversions and Gametogenesis One member of homologous pair has inversion Normal pairing during meiosis not possible Inversion loop forms When no recombination (process by which genetic information is broken and rejoined) occurs, 50% of gametes have inversion But recombination can occur…

Inversions and Gametogenesis Can break genes May cause position effects Especially if transported to position near heterochromatin (white eye in Drosophila moved to near centromere) Major problems with recombination Meiosis/mitosis Acentric chromosomes – no centromere Dicentric chromosomes – two centromeres On the plus side… Inversions can stabilize a good combination of alleles by blocking crossovers that would separate them

Inversions and Recombination Many defective gametes can be produced

Translocations Reciprocal translocations result from crossover events between nonhomologous chromosomes Balanced translocation condition may result Semisterility (50%)

Familial Down Syndrome Robertsonian translocation or centric fusion Fusion of the Q arms of two acrocentric chromosomes (13,14, 15, 21 and 22) P arms lost (no centromeres)

Familial Down Syndrome Most of Q arm from chromosome 21 translocated to 14 (14/21 translocation) Fusion occurs at two rDNA regions on the chromosomes About 20% rDNA copies lost Carrier still normal

Fragile Sites There are some mutant/fragile sites on chromosomes where chromatin fails to become properly compacted Areas often subject to breakage Can be associated with mental retardation and cancer

Fragile X Syndrome 1/4000 males, 1/8000 females Dominant, not fully penetrant Folate-sensitive (water-soluble B vitamin that occurs naturally in food ) site on X chromosome Breakage more likely when cells grown under folate deficiency conditions FMR1 (fragile X mental retardation gene) many CGG tandem repeats 6-54 is normal, 55-200 is a carrier (and unstable– genetic anticipation), above 200 expresses syndrome Male offspring more likely to receive expanded locus than female offspring

Fragile X Chromosomes