chapter 3 covered normal cell division and chromosomal segregation things don’t always go smoothly...

• 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

Chromosome Aberrations

Listing: 4301 (CRN 49684); 6301 (CRN 49685)Instructor: David A. RayTime: MWF 10 – 10:50 AMRoom: 021 BiologyA 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 :1.Basic genome structure2.Concepts in genome analysis3.Genome change over time

Genomes and Genome EvolutionCourse Announcement: Spring 2015

…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


Chromosome Aberrations• 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

Chromosome Aberrations• 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

Chromosome Aberrations• 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)• http://highered.mheducation.com/sites/dl/free/

0072835125/126997/animation41.html


• 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• https://www.youtube.com/

watch?v=THAjvn1cdDM• Pericentric inversions – the

centromere is part of the inversion• https://www.youtube.com/

watch?v=QXU7XojaEOs• 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• https://www.youtube.com/watch?v=MLDCJ2gUC84


• 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• https://www.youtube.com/watch?

v=vbGw4VanNjk


• Robertsonian translocations are a mechanism of chromosomal evolution

• Muntjac chromosomes


Muntiacus gongshanensis2n=8F,9M

Muntiacus reevesi2n=46

~4.5 my

• 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

– https://www.youtube.com/watch?v=8FGYzZOZxMw


• Chromosome diversity and organism complexity• A misunderstanding of what evolutionary theory predicts• http://www.drdino.com/possum-redwood-tree-and-kidney-bean-

our-ancestors/

• What’s wrong with this argument?


http://www.drdino.com/possum-redwood-tree-and-kidney-bean-our-ancestors/

http://www.drdino.com/possum-redwood-tree-and-kidney-bean-our-ancestors/

• 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:• 1.

http://genetics.thetech.org/original_news/news124 - “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?


• 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

Transposition

“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.

• 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

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

Transposition

Transposon w/ transposase gene

Pol II transcription

Transposase

Translation

Donor

Target

• 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

Transposition

Pol III transcription

Reverse transcription and insertion

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

Transposition

exon 1 SINE

intron

exon 2

SINE transcription can extend past the normal stop signal

Reverse transcription creates DNA copies of both the SINE and exon 2

DNA copy of transcript

Reinsertion occurs elsewhere in the genome

SINE exon 2

chapter 3 covered normal cell division and chromosomal segregation things don’t always go smoothly...

Documents

abnormal chromosome

seensex chromosome aneuploidy

process of failed chromosome

human genome

gene dosage changes

gene dosage imbalances

genome analysisgenome

appearance of chromosomes