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The nucleosome: the fundamental unit of chromosomal packaging of DNA with histones Fig. 12.3 b DNA does not coil smoothly Base sequences dictate preferred nucleosome positions along DNA Spacing and structure affect gene function Models of higher level compaction seek to explain extreme compaction of chromosomes at mitosis Fig. 12.4 a Formation of 300 A fiber through supercoiling Models of higher level compaction seek to explain extreme compaction of chromosomes at mitosis Radial loop-scaffold model for higher levels of compaction Fig. 12.4 b Each loop contains 60-100 kb of DNA tethered by nonhistone scaffold proteins Radial loop-scaffold model continued Fig. 12.4 c A closer look at karyotypes: fully compacted metaphase chromosomes have unique, reproducible banding patterns Fig. 12.6 a Banding patterns are highly reproducible Not known what they represent A closer look at karyotypes Banding patterns help locate genes Fig. 12.6 b Polytene chromosomes are an invaluable tool for geneticists Fig. 12.15 c in situ hybridization of white gene to a single band (3C2) near the tip of the Drosophila X chromosome Polytene chromosomes are an invaluable tool for geneticists A closer look at karyotypes Banding patterns can be used to analyze chromosomal differences between species Can also be used to reveal cause of genetic disease Fig. 12.6 c e.g., Downs syndrome – 3 copies of chromosome 21 Specialized chromosomal elements ensure accurate replication and segregation of chromosomes There are many origins of replication Replication occurs in about 8 hours during S phase in actively dividing human cells DNA polymerase can assemble new DNA at a rate of about 50 nucleotides per second Many origins of replication are required to complete the task of copying the DNA in a genome In mammals, there are 10,000 origins of replication Origins of replication are scattered throughout the chromatin, 30 – 300 kb apart Structure of yeast origin of replication Autonomously replicating sequences (ARSs) in yeast consist of an A – T rich region ARSs permit replication of plasmids in yeast cells Fig. 12.11 b Telomeres preserve the integrity of linear chromosomes Telomeres are protective caps on eukaryotic chromosomes Fig. 12.8 Prevent fusion with other chromosomes Protect tips from degradation Solve the endreplication problem DNA polymerase cannot reconstruct 5’ end of a DNA strand Fig. 12.9 Fig. 12.10 Binding of telomerase to TTAGGG and addition of RNA extends the ends Segregation of condensed chromosomes depends on centromeres Centromeres appear as constrictions on chromosomes Contained within blocks of repetitive, noncoding sequences called satellite DNA Satellite DNA consists of short sequences 5-300 bases in length Centromeres have two functions Hold sister chromatids together Kinetochore – structure composed of DNA and protein that help power chromosome movement Centromere structure and function Fig. 12.11 a Structure of yeast centromere Fig. 12.11 b Studies using DNase identify decompacted regions Fig. 12.12 a Position effect variegation in Drosophila: moving a gene near heterochromatin prevents it expression Facultative heterochromatin Fig. 12.14 a Moving a gene near heterochromatin silences its activity in some cells and not others Comparing the mouse and human genomes The loss or gain of one or more chromosomes results in aneuploidy Autosomal aneuploidy is harmful to the organism Monosomy usually lethal Trisomies – highly deleterious Trisomy 18 – Edwards syndrome Trisomy 13 – Patau syndrome Trisomy 21 – Down syndrome Humans tolerate X chromosome aneuploidy because X inactivation compensates for dosage Fig. 13.27 Meiotic nondisjunction Failure of two sister chromatids to separate during meiotic anaphase Generates reciprocal trisomic and monosomic daughter cells Chromosome loss Produces one monosomic and one diploid daughter cell Fig. 13.28 a Mosaics – aneuploid and normal tissues that lie side-by-side Fig. 13.28 b Aneuploids give rise to aneuploid clones Gynandromorph in Drosophila results from female losing one X chromosome during first mitotic division after fertilization Fig. 13.29 Euploid individuals contain only complete sets of chromosomes Monoploid organisms contain a single copy of each chromosome and are usually infertile Monoploid plants have many uses Visualize recessive traits directly Introduction of mutations into individual cells Select for desirable phenotpyes (herbicide resistance) Hormone treatment to grow selected cells Fig. 13.30 Treatment with colchicine converts back to diploid plants that express desired phenotypes Fig. 13.30 c Polyploidy has accompanied the evolution of many cultivated plants 1 out of 3 flowering plants are polyploid Polyploid often increases size and vigor Often selected for agricultural cultivation Tetraploids - alfalfa, coffee, peanuts Octaploid - strawberries Fig. 13.31 Fig. 13.32 Triploids are almost always sterile Result from union of monoploid and diploid gametes Meiosis produces unbalanced gametes Tetraploids are often source of new species Failure of chromosomes to separate into two daughter cells during mitosis in diploid Cross between tetraploid and diploid creates triploids – new species, autopolyploids 13.33 a Fig. 13.33 b Maintenance of tetraploid species depends on the production of gametes with balanced sets of chromosomes Bivalents- pairs of synapsed homologous chromosomes that ensure balanced gametes Fig. 13.33 c Some polyploids have agriculturally desirable traits derived from two species Amphidiploids created by chromosome doubling in germ cells e.g., wheat – cross between tetraploid wheat and diploid rye produce hybrids with desirable traits Fig. 13.34 Deletions remove genetic material from genome Fig. 13.2 Phenotypic consequences of heterozygosity Homozygosity for deletion is often but not always lethal Heterozygosity for deletion is often detrimental Fig. 13.3 Mapping distances affected in deletion heterozygotes Recombination between homologues can only occur if both carry copies of the gene Deletion loop formed if heterozygous for deletion Genes within the loop cannot be separated by recombination Fig. 13.4 a Deletion loops in polytene chromosomes Fig. 13.4 b Deletions in heterozygotes can uncover genes Pseudodominance shows a deletion has removed a particular gene Fig. 13.5 Deletions can be used to locate genes Fig. 13.6 Deletions to assign genes to bands on Drosophila polytene chromosomes Complementation tests Deletion heterozygote reveals chromosomal location of mutant gene Deletions to locate genes at the molecular level Fig. 13.7 a Labeled probe hybridizes to wild-type chromosome but not to deletion chromosome Molecular mapping of deletion breakpoints by Southern blotting Fig. 13.7 b, c Duplications add material to the genome Fig. 13.8 a,b Duplication loops form when chromosomes pair in duplication heterozygotes In prophase I, the duplication loop can assume different configurations that maximize the pairing of related regions Fig. 13.8 c Duplications can affect phenotype Novel phenotypes More gene copies Genes next to duplication displaced to new environment altering expression Fig. 13.9 Unequal crossing over between duplications increases or decreases gene copy number Fig. 13.10 The effects of duplications and deletions on phenotpye Heterozygosity creates imbalance in gene product altering phenotypes (some lethal) Genes may be placed in new location that modify expression Deletions and duplications drive evolution of the genome Inversions reorganize the DNA sequence of a chromosome 180° rotation of chromosomal regions after double-stranded break Rare crossover between related genes on a chromosome Fig. 13.11a,b An inversion can affect phenotype if it disrupts a gene Fig. 13.11 c Inversion heterozygotes reduce the number of recombinant progeny Inversion loop in heterozygote forms alignment of homologous regions Fig. 13.12 Gametes produced from pericentric and paracentric inversions are imbalanced Fig. 13.13 Pericentric inversion (cont’d) Paracentric inversion (cont’d) Fig. 13.13 cont’d Balancer chromosomes help preserve linkage Fig. D.6 Balancers carry multiple, overlapping inversions Most contain a dominant marker and recessive lethal mutation that prevents survival of homozygotes Useful in genetic manipulations and mutant screens Translocations attach one part of a chromosome to another Translocation – part of one chromosome becomes attached to nonhomologous chromosome Reciprocal translocationexchange between nonhomologous chromosomes Robertsonian translocations can reshape genomes Reciprocal exchange between acrocentric chromosomes generate large metacentric chromosome and small chromosome Tiny chromosome may be lost from organism Fig. 13.16 A closer look at karyotypes Banding patterns can be used to analyze chromosomal differences between species Can also be used to reveal cause of genetic disease Fig. 12.6 c e.g., Downs syndrome – 3 copies of chromosome 21 Chronic myelogenous leukemia Fig. 13.17 Heterozygosity for translocations diminishes fertility and results in pseudolinkage Fig. 13.18 a.b Three possible segregation patterns in a translocation heterozygote from the cruciform configuration Fig. 13.18 c Pseudolinkage –genes near breakpoints act as if linked Semisterility results from translocation heterozygotes < 50% of gametes arise from alternate segregation and are viable Fig. 13.18 d Translocation Down syndrome translocation of chromosome 21 is small and thus produces viable gamete, but with phenotypic consequence Fig. 13.19 Transposable elements move from place to place in the genome Any segment of DNA that evolves ability to move from one place to another in genome Selfish DNA carrying only information to selfperpetuate Most are 50 – 10,000 bp in length Present hundreds of thousands of times in a genome ~ 7% of human genome are transposable elements Retroposons generate an RNA that encodes a reverse transciptase-like enzyme Two types Poly-A tail at 3’ end of RNA-like DNA strand Long terminal repeat (LTRs) oriented in same direction on either end of element Fig. 13.23 a Fig. 13.23 b The process of LTR transposition Fig. 13.23 LINEs and SINEs in humans LINEs- Long INterspersed Elements Likely source of retroviruses L1 family in humans, 6-7 kb in length Encode reverse transcriptase-like enzyme >20,000 copies in human genome SINEs-Short INterspersed Elements appear to have evolved from cellular RNA species, usually tRNAs Depend on availability of reverse transcriptase produced elsewhere Alu family in humans, 300 bp in length >500,000 copies in human genome Creation of LINE and SINE families Fig. 21.18 Transposons encode transposase enzymes that catalyze events of transposition Fig. 13.24 a TEs can generate chromosomal rearrangements and relocate genes Fig. 13.26 TEs can generate mutations in adjacent genes spontaneous mutations in white gene of Drosophila Fig. 13.25 Genomes often contain defective copies of transposable elements Many TEs sustain deletions during transposition or repair If promoter needed for transcription is deleted, TE can not transpose again Nonautonomous elements – need activity of intact copies of same TE for movement Autonomous elements – move by themselves Most SINEs and LINEs in human genome are defective P elements in Drosophila M strains of Drosophila have no P elements (most lab strains) P strains have many copies of P elements Hybrid dysgenesis – defects including sterility, mutation, and chromosomal breakage from crosses between P males and M females Promotes movement of P elements to new positions P-element transposons are critical tools in molecular genetics Hybrid dysgenesis Males from Drosophila strains carrying P elements crossed to females that lack P elements P element becomes highly mobile in germ line of F1 hybrids Chromosome breakage reduces fertility in hybrids Progeny of F1 flies carry many new mutations induced by P element insertion Eggs produced by P female have repressor protein that prevents transposition Repressor coded for by alternatively spliced P element mRNA Fig. D.7 Transformation: the introduction of cloned DNA into flies P-elements used as vectors Insert fly DNA into intact P element and then into plasmid Inject into embryos from M strain mothers Cross to P males Fig. D.8a Figure D.9 Transformation in plants by T-DNA Bacterium Agrobacterium tumefaciens is agent of transformation Fig. B.10 a Transfer of T-DNA into genome of wounded plant Antibiotic resistance markers engineered into plasmids provide selection Cells expressing the GUS reporter gene stain blue Transformation by Transposon Tagging Transposon tagging using transposable elements from Corn and Arabidobsis Insertional mutagenesis allows generation of mutants Transposon or T-DNA sequence can be used to identify and clone gene of interest PCR can be used to find plants carrying a mutated gene of interest Fig. B.11 a-c Fig. B.11 d,e PCR can be used to find worms carrying a mutated gene of interest Fig. C.10