Chromosome Aberrations

Name: Chromosome Aberrations
Uploaded: 2017-08-29T06:56:02+00:00
Duration: PTM23S24
Channel: Eustace West
Description: Chromosome Aberrations

Chromosome Aberrations
Chapter 3 covered normal cell division and chromosomal segregation Things don’t always go smoothly Nondisjunction is the process of failed chromosome and sister chromatid segregation, which can result in abnormal chromosome numbers and abnormal chromosome morphology The normal ‘complete set’ number of chromosomes in any individual of a species is the euploid number If that number is not accurate for a given cell, it is considered an aneuploidy Aneuploid cells and organisms typically have a reduced survival rate

Genomes and Genome Evolution Course Announcement: Spring 2015
Listing: 4301 (CRN 49684); 6301 (CRN 49685) Instructor: David A. Ray Time: MWF 10 – 10:50 AM Room: 021 Biology A lecture and interactive course that aims to clarify what genomes are, how they are investigated and what has been and can be learned from them. Topics will include : Basic genome structure Concepts in genome analysis Genome change over time …there are people who have concerns that are quite reasonable, and they are frightened of things they don't understand. --Thomas R. Cech (discussing the human genome) What more powerful form of study of mankind could there be than to read our own instruction book? -- Francis S. Collins

Announcements Exam review sessions – TBA
Sunday and Monday evening No homework this week – no corresponding chapter in the Sapling system

Nondisjunction has different effect depending on when it takes place Normal meiosis

Nondisjunction in meiosis I Meiosis I

Nondisjunction in meiosis II Meiosis II

Karyotype – the number and appearance of chromosomes in the nucleus of a eukaryotic cell Nondisjunction generally results in abnormal karyotypes

Gene dosage is the main impact of aneuploidy Increased or decreased numbers of genes means increased or decreased amounts of gene products – disrupting the chemical balance of the cell Plants tend to handle gene dosage imbalances better than animals Datura stramonium is a weed with 2n=24 12 phenotypically distinct lineages were identified in 1913, one for each chromosome that could be impacted

Gene dosage is the main impact of aneuploidy a – trisomic (chromosomes 3 and 5) Arabidopsis thaliana b – tetrasomic (chromosome 4) wings from Drosophila melanogaster c – trisomic (chromosome 16) mouse embryo

Humans are very sensitive to gene dosage changes and aneuploidy is typically lethal Autosomal trisomy of 13, 18, and 21 are the only ones seen in surviving infants No autosomal monosomies are seen Sex chromosome aneuploidy is more tolerated and several forms of trisomy are observed along with one type of monosomy >50% of human conceptions are spontaneously aborted in the first trimester >50% of those are the result of chromosomal aneuploidy

Trisomics typically exhibit reduced fertility because of problems in meiosis The extra chromosome results in improper pairing and segregation Two synapsis scenarios are possible – neither results in proper segregation at anaphase I If fertilization occurs with the aneuploid gamete, the offspring is usually inviable Semisterility, some significant proportion of the progeny is inviable

Mitotic nondisjunction in somatic cells results in daughter cells that are 2n+1 or 2n-1 They usually do not survive and are limited in number If they do survive and the nondisjunction occurs early in embryogenesis, mosaicism can result 25-30% of Turner syndrome cases are mosaics – some cells are 2n=45, some are 2n=46, some are 2n=47

Uniparental disomy - when both chromosomes of a pair in the offspring were derived from a single parent Scenario 1 - rare Nondisjunction for the same chromosome occurs in sperm and egg One gamete with neither copy unites with the other gamete with both copies Scenario 2 – more common Nondisjunction occurs in one parent, gamete is n+1 Union with normal gamete produces trisomic zygote In trisomy rescue, one copy of the trisomic chromosome is ejected during mitosis of early development If the two retained copies are from the same parent  uniparental disomy

Polyploidy – the presence of three or more complete sets of chromosomes in an organism’s nucleus Autopolyploidy – duplication of chromosome sets within a species Allopolyploidy – combining chromosome sets from different species Tolerated much more readily in plants Commercial cotton is the result of allopolyploidy

Commercial cotton is the result of allopolyploidy

Three mechanisms of autopolyploidization Multiple fertilization of one egg by multiple pollen grains Meiotic nondisjunction leading to diploid rather than haploid gametes Mitotic nondisjunction in sex stem cells

Allopolyploid hybrids are often viable but infertile Chromosome pairs sets are not homologous and cannot synapse properly in meiosis Chromosome nondisjunction can resolve this problem, the doubled chromosomes have homologs for pairing during synapsis  hybrid is fertile

Allopolyploid hybrids can occur naturally or via human manipulation Hybrid vigor – more rapid growth, increased productivity, improved resistance to disease is typical of allopolyploids Fruit and flowers sizes are typically increased in polyploids Fertility is often decreased, particularly in odd-numbered polyploids >50% of flowering plants are derived from polyploid ancestors Allopolyploids are reproductively isolated from parent species  ‘overnight’ speciation Reduced natural selection on duplicated copies of genes

Mutations may cause the loss or gain of chromosome segments, yielding severe abnormalities via gene dosage Broken chromosomes can adhere to the broken ends or termini of other chromosomes Acentric (lacking a centromere) chromosomes are lost during cell division Partial chromosome deletions are sometimes large enough to be seen through a microscope Terminal deletion  results from single break point Cri-du-chat syndrome – 5p deletion high-pitched cat-like cry mental retardation delayed development distinctive facial features small head size (microcephaly) widely-spaced eyes (hypertelorism) low birth weight and weak muscle tone (hypotonia) in infancy

Interstitial deletion  results from two break points on a single chromosome WAGR syndrome  severity depends on the extent of the deleted region Chromosome 11p13 deletion Increased incidence (45-60%) of Wilms’ tumor Aniridia Genitourinary problems Mental retardation

Unequal crossover or nonhomologous recombination Most often occurs in repetitive regions of a genome Caused by misalignment during recombination Results in partial duplication on one homolog and partial deletion on the other Individuals with these conditions are partial duplication heterozygotes and partial deletion heterozygotes

Williams-Beuren syndrome Normal presence of duplicated PMS gene on chromosome 7 Partial deletion products have 17 missing genes Partial duplication products have 17 extra genes Hemizygotes for partial deletion exhibit Williams-Beuren syndrome ‘elfin’ featurs Developmental delays Cardiovascular problems, particularly aortic stenosis Increase socialbility but a tendency toward phobias and anxiety

Microdeletions and microduplications are smaller and not easily detected FISH (fluorescent in situ hybridization)

Chromosome breakage can be repaired but may lead to: Inversions – repair in the wrong orientation Translocations – reattachement to the wrong chromosome or place on the right chromosome Depending on conditions, there may be no phenotypic consequences Disrupted genes

Inversions – repair in the wrong orientation Paracentric inversions – the centromere is not involved Pericentric inversions – the centromere is part of the inversion Inversion heterozygotes – individuals with one normal and one inverted homolog

Meiotic consequences of inversions vary Synapsis b/t inverted and normal homolog results in an inversion loop Problems arise when a crossover occurs within the loop Paracentric inversion crossover results in dicentric and acentric chromosomes Two normal and two abnormal gametes Dicentric chromosome is pulled in opposite directions and parts are lost Acentric chromosome is lost

Meiotic consequences of inversions vary Synapsis b/t inverted and normal homolog results in an inversion loop Pericentric inversion crossover results in deletion and duplication products Two normal and two abnormal gametes The probability of crossover is proportional to the size of the loop/inversion Fertility is impacted if inversions are very large

Announcements Exam review sessions – Sunday and Monday 5pm – 6 pm – here Exam material will include – Everything from when I started to what I get through today

Translocation heterozygotes harbor one normal and one translocated copy Like inversions, phenotype may be unaffected if no genes are disrupted Also like inversions, fertility problems if there are segregation abnormalities

Translocation types Unbalanced – an unreciprocated translocation Reciprocal balanced – two nonhomologs switch places Robertsonian – aka chromosome fusion

Meiotic consequences Reciprocal balanced No chromosome has a fully homologous partner Cross-like structure forms at synapsis  two outcomes are possible

Meiotic consequences Robertsonian translocation Occurs with acrocentric chromosomes (13,14, 15, 21, 22) Carriers have one chromosome fusion while the other homologs remain separate Carriers are normal but have an increased risk of trisomic offspring Robertsonian fusion of 14 and 21 increases risk of Down syndrome offspring

Meiotic consequences Multiple patterns are possible

Robertsonian translocations are a mechanism of chromosomal evolution Muntjac chromosomes Muntiacus reevesi 2n=46 ~4.5 my Muntiacus gongshanensis 2n=8F,9M

A Robertsonian translocation in the human lineage African apes – n=24 Humans – n=23 Where did the extra chromosome go?

A Robertsonian translocation in the human lineage Human chromosome 2 = ancestral ape chromosomes 12+13 Predictions, if this is true, then…

Predictions, if this is true, then… Telomeric DNA? Ijdo JW, Baldini A, Ward DC, Reeders ST, Wells RA, Origin of human chromosome 2: an ancestral telomere-telomere fusion. Proc Natl Acad Sci U S A 1991 Oct 15;88(20):9051-5 Centromeric DNA? Avarello R, Pedicini A, Caiulo A, Zuffardi O, Fraccaro M, Evidence for an ancestral alphoid domain on the long arm of human chromosome 2. Hum Genet 1992 May;89(2):247-9

Chromosome diversity and organism complexity A misunderstanding of what evolutionary theory predicts What’s wrong with this argument?

Chromosome diversity and organism complexity 1. “The theory of evolution teaches that living things are becoming more complex as time progresses.” No, it predicts that organisms will adapt over time to become more effective at reproducing. If becoming less complex accomplishes that task, so be it. 2. “… it would seem logical … that organisms with least number of chromosomes were the first ones to evolve and those with the most chromosomes are the end result of millions of years of evolution experimenting to increase complexity in living organisms.” No. Chromosome number has no relationship to organisms complexity. Split your textbook into 50 individual books. Does it change the amount of information? Two examples to illustrate this point

Chromosome diversity and organism complexity Two examples: “The 44 Chromosome Man And What He Reveals About Our Genetic Past”. A balanced translocation of chromosomes 14 and 15 yields a chromosome number of 44, not 46. According to Kent’s argument, he should now be flying around and echolocating to catch insects. What happens to the information in 20 books if you decide to combine them into a single volume?

Chromosome diversity and organism complexity Two examples: 2. Which bat? The lesser horseshoe bat (Rhinolophus hipposideros) has 56 chromosomes but the short-tailed fruit bat (Carollia perspicillata) only has 20. Does that mean that the fruit bat is actually an ear of corn or that the horseshoe bat is really a silkworm in disguise? Is one bat “more complex” than the other?

Transposition Transposable Genetic Elements are DNA sequences that the ability to move and/or copy themselves in a genome Mobilize via processes called transposition or retrotransposition Powerful agents of genomic change and instability “A substantial proportion of … eutherian-specific CNEs arose from sequence inserted by transposable elements, pointing to transposons as a major creative force in the evolution of mammalian gene regulation.” - Mikkelson et al., 2007.

Transposition Transposable Genetic Elements are DNA sequences that the ability to move and/or copy themselves in a genome Mobilize via processes called transposition or retrotransposition Powerful agents of genomic change and instability Vary in length, sequence composition, copy number and mechanism of mobilization

Transposon w/ transposase gene
Transposition Transposable Elements Two major classes of TEs Class II – DNA transposons Replicative (copy-and-paste) and non-replicative (cut-and-paste) transposition Encode a gene for transposase, the enzyme responsible for transposition Target Donor Transposon w/ transposase gene Pol II transcription Translation Transposase

Reverse transcription and insertion
Transposition Transposable Elements Two major classes of TEs Class I – retrotransposons Replicative (copy-and-paste) Mobilize via an RNA intermediate and that RNA intermediate is reverse transcribed back to DNA as part of the mobilization mechanism Reverse transcription and insertion Pol III transcription

Transposition

Transposition Transposable Elements LINE and SINE elements in humans
>50% of the human genome is derived from TEs. Most of this mass is from Long INterspersed Elements and Short INterspersed Elements LINEs are autonomous – encode many of the enzymes required for their mobilization ~850,000 copies

Transposition Transposable Elements LINE and SINE elements in humans
>50% of the human genome is derived from TEs. Most of this mass is from Long INterspersed Elements and Short INterspersed Elements SINEs are nonautonomous – rely on other TEs (LINEs) for the enzymes required to mobilize ~1 million copies

Transposition Transposable Elements
LINE-1 and Alu are the most common LINEs and SINEs, respectively in the human genome Both are associated with a variety of human structural variants and functional mutations A LINE-1 insertion into the factor VIII gene is responsible for some cases of hemophilia Some cases of Duchenne muscular distrophy Alu insertions are confirmed to be the cause of at least 25 human diseases

Transposition Transposable Elements Exon shuffling
SINE exon 2 intron SINE exon 2 DNA copy of transcript SINE transcription can extend past the normal stop signal Reverse transcription creates DNA copies of both the SINE and exon 2 Reinsertion occurs elsewhere in the genome

Chromosome Aberrations

Similar presentations

Presentation on theme: "Chromosome Aberrations"— Presentation transcript:

Similar presentations

About project

Feedback

Log in

Auth with social network:

Chromosome Aberrations

Similar presentations

Presentation on theme: "Chromosome Aberrations"— Presentation transcript:

Similar presentations

About project

Feedback