Genetics 4BIO3 J.

1st SEM 2014-2015

CHROMOSOME MUTATIONS: VARIATION IN NUMBER AND ARRANGEMENT

INTRODUCTION
Mutations and resulting alleles affect phenotype and traits are passed according to Mendelian principles
Chromosome mutations or abberations change in total chromosome number, deletion or duplication of genes or chromosome segments,
rearrangement of genetic material within or among chromosomes
Chromosome aberrations are passed to offspring in predictable manner
Minor alterations in content or location can result to phenotypic variation

1 VARIATION IN CHROMOSOME NUMBER: TERMINOLOGY AND ORIGIN

Chromosome variation addition or loss of a chromosome to the addition of more
haploid sets of chromosomes
Aneuploidy gain or loss of one or more chromosomes but not a complete set
Monosomy loss of single chromosome from diploid genome
Trisomy gain of 1 chromosome
Euploidy complete haploid sets of chromosomes are present
Polyploidy more than 2 sets are present
Triploid with 3 sets of chromosomes
Tetraploidy - with 4 sets of chromosomes
Chromosomal variation
originates as random
error during gamete
production
Nondisjunction failure to
disjoin during segregation;
disrupts normal
chromosome distribution

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2 MONOSOMY AND TRISOMY RESULT IN VARIETY OF PHENOTYPIC EFFECTS

Monosomy

Trisomy

Loss of 1 chromosome; produces 2n-1

Monosomy for X chromosome (45, X Turner syndrome)
Monosomy for autosomes
Not usual in humans
Drosophila - chromosome IV flies develop more slower, reduced
body size, impaired viability; Chromosomes II and III lethal
Failure of survival can be due to:
If 1 of the genes is a lethal allele monosomy unmasks the
recessive lethal allele that is tolerated by heterozygotes
Single copy of recessive gene may be insufficient to provide lifesustaining function (haploinsufficiency)
Better tolerated in plants monosomy for autosomal chromosomes
(maize, tobacco, evening primrose, jimson weed)

Gain of 1 chromosome, 2n +1
Extra chromosome more viable individuals in both animal and plant
species
In animals only if chromosome is small
Addition of large autosome to diploid complement has severe
effects, usually lethal during development
In plants individuals are viable, altered phenotype
Jimson weed, Datura 24 diploid number; alteration in plants
capsule
Rice plant, Oryza sativa haploid number of 12

Down Syndrome: Trisomy 21

Discovered by Langdon Down
Trisomy of Chromosome 21 (47, 21+) found in 1 out of 800 births
Outward appearance of the individuals is very similar, bear striking resemblance to one
another prominent epicanthic fold in each eye and flat face and round head
Can also have protruding, furrowed tongue and short, broad hands
Retarded physical, psychomotor, and mental development
Poor muscle tone, life expectancy average of 50 years
Prone to respiratory disease and heart malformations; higher risk of leukemia
Death in older adults is due to Alzheimer disease
Critical region of chromosome 21 contains genes that are dosage sensitive - Down
syndrome critical region (DSCR)
Decreased risk of having cancer involving tumors due to presence of extra copy of
DSCR1 gene
DSCR1 gene encodes protein suppressing vascular endothelial growth factor (VEGF)

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1st SEM 2014-2015

Origin of Extra 21st Chromosome in Down Syndrome

Condition occurs through nondisjunction of chromosome 21
Failure of paired homologs to disjoin during in anaphase I or II leads
to n+1 gametes
Addition can be from mother or father (ovum source of 95% of
47,21+ cases) - derived from studies of age of mothers giving birth to
infants with Down Syndrome
Increase of the syndrome as age increases

Approaches to determine if child will have 47,21+

Amniocentesis - fetal cells obtained from amnion
Chorionic villus sampling (CVS) - fetal cells obtained from chorion
Noninvasive prenatal genetic diagnosis fetal cells and DNA are
derived directly from maternal circulation; requires only 10mL
maternal blood sample

Nondisjunctional event more likely to occur during oogenesis in women

over 35 years old
Women 30 or 40 years old produce ova that are significantly older and
have been arrested longer
Counselling informs prospective parents about the probability that their
child will be affected and educates them about Down Syndrome
Down Syndrome children known for affectionate, loving nature

Human Aneuploidy
Patau Syndrome (47, 13+)
Edwards Syndrome (47, 18+)
Survival of aneuploidy conditions, karyotype analysis of spontaneously
aborted foetuses:
1. Approximately 20 percent of all conceptions terminate in
spontaneous abortion

2. 30 percent of all spontaneously aborted foetuses have some form of

chromosomal imbalance (at least 6% of conceptions have abnormal
chromosome complement)
Gametes lacking a single chromosome are functionally impared to a
serious degree or embryo dies early in the development
Normal embryonic development requires precise diploid complement
of chromosomes to maintain equilibrium in genetic information
expression

Genetics 4BIO3 J.M

1st SEM 2014-2015

3 POLYPLOIDY (2 HAPLOID CHROMOSOME SETS) IS PREVALENT IN PLANTS

Polyploidy more than 2 multiples of haploid chromosome set

Naming based onset number (triploid, 3n)
Well known in lizards, amphibians, fishes, and plants
Odd numbers are not maintained in generations

Originate in 2 ways:
1. Addition of 1 or more extra chromosome set identical to normal haploid
complement autopolyploidy
2. Combination of chromosome sets from different species; due to
hybridization allopolyploidy

Autopolyploidy
Each additional set of chromosomes identical to parent species
Triploids represented as AAA; tetraploids AAAA
Autotriploids
Failure of all chromosomes to segregate during meiosis
If a diploid gametes is fertilized by haploid gamete zygote has 3 sets
of chromosomes; 2 sperm may fertilize an ovum

Autotetraploids theoretically more likely to be found

Produce balanced gametes when involved in sexual reproduction
If chromosomes have replicated but parent cell never divides and reenters
interphase double chromosome number
Tetraploid cells can be produced experimentally from diploid cells apply
cold or heat shock or apply colchicine

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Colchicine alkaloid derived from autumn crocus; interferes with
spindle formation replicated chromosomes cannot separate at
anaphase and migrate to poles
Autopolyploids larger than diploid relative
Increase is due to larger cell size rather than greater cell number can
have increased flower and fruits in plants
Important triploid plants Solanum, Winesap apples, bananas,
seedless watermelons, tiger lily Lilium tigrinum
Tetraploids alfafa, coffee peanuts, McIntosh apples

1st SEM 2014-2015

Gerald Fink create strains of S. cerevisiae with 1,2,3 or 4 copies of the

genome and examined expression levels of all genes during cell cycle
Using stringent standard ploidy increase
Gene expression either increased or decreased at least tenfold
Repressed when ploidy increases G1 cyclins
G1 cyclins facilitate cells movement through G1; if delayed, gene
expression is repressed
Stay in G1 phase cell grows larger before moving to S phase

Allopolyploidy
Hybridizing 2 closely related species
Haploid ovum from species with AA chromosome is fertilized by sperm
from species with BB set, results to AB chromosome set
Organism may be sterile inability to produce viable gametes
(especially when some or all a and b chromosomes are not
homologous and cannot synapse in meiosis)
If AB combination undergoes natural or induced chromosomal
doubling 2 copies of all a and b chromosomes will be present (results
to fertile AABB tetraploid)

Allotetraploid -polyploidy contains 4 haploid genomes from separate

species
Amphidiploid - describes allotetraploid; both original species are
known; plants like these are found in nature (success based on forming
balanced gametes)
Meiosis proceeds 2 homologs of each specific chromosome are
present
Amphidiploids from closely related species- can have homology
between a and b chromosomes
Rare in animals fertilization is species specific

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Amphidiploid example: cotton Gossypium
26 chromosome pairs : 13 large, 13 small

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Amphidiploid exhibit traits of both parental species

Ex. Wheat (2n=14; 4n=28) and Rye (2n=14)
Cross of tetraploid whet and diploid rye produced Triticale

4 VARIATION OCCURS IN CHROMOSOME COMPOSITION AND ARRANGEMENT

2 class of chromosome aberration delete, add, or rearrange
substantial portions of 1 or more chromosomes
Gene or chromosome part deletions and duplications
Rearrangement of genetic material in a chromosome segment transferred to another chromosome, translocations (gene locations
are altered within the genome)
Due to breaks along chromosome axis followed by loss or
rearrangement of genetic material
nd

Sticky ends produced at points of breakage, can rejoin other broken

ends
If breakage and rejoining do not established can be inherited
Heterozygous for aberration aberration found in 1 homolog but not
the other; unusual pairing are formed during synapsis
If no loss or gain of genetic material heterozygous aberrations has
no effect on phenotype; offsprings can be carriers of certain aberrations

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5 DELETION IS A MISSING REGION OF A CHROMOSOME

Chromosomes break in 1 or more places and portions can be lost
Deletion (deficiency) missing piece
Terminal deletion - occur at near one end
Intercalary deletion - within chromosome interior
Formation of deletion (compensation loop)

Chromosome portion retaining the centromere is usually maintained

when cell divides ; Segment without centromere lost in progeny cells
following mitosis or meiosis
If small part of a chromosome is deleted organism can survive
Large deletion lethal

Cri du Chat Syndrome in Humans

Deletion of small terminal portion of Chromosome 5 (46, -5p)

Case of partial monosomy but region of missing is too small considered as
segmental deletion
Reported by Jerome LeJeune
May exhibit anatomic malformations gastrointestinal and cardiac complication,
mentally retarded, abnormal development of glottis and larynx (leads to eerie
cry)

Not inherited; results from sporadic loss of chromosomal materials in gametes

Longer deletions greater impact on physical, psychomotor, and mental skill
levels
Portion of the chromosome missing contains TERT gene
TERT encodes telomerase reverse transcriptase; essential for telomere
maintenance during DNA replication

Genetics 4BIO3 J.M

1st SEM 2014-2015

6 DUPLICATION IS REPEATED SEGMENT OF A CHROMOSOME

Duplication part of the gene (locus, chromosome piece) is present
more than once
Heterozygous pairing can produce compensation loops
May result of unequal crossing between synapsed chromosomes or
through replication error
3 aspects of duplications
1. Result in gene redundancy
2. May produce phenotypic variation
3. Important source of genetic variability during evolution

Gene Amplification Ribosomal RNA Genes

Presence of abundant rRNA supports protein synthesis

More metabolically active higher demand for rRNA
Single copy of gene encoding rRNA is inadequate in many cells
rDNA genome encoding specific RNA sequences
Gene amplification is used

In oocytes normal amplification of rDNA insufficient to provide adequate rRNA amounts

needed to construct ribosomes
rDNA genes - found in chromosome area nucleolar organizer region (NOR)

The Bar Mutation in Drosophila

Duplications can cause phenotypic variation
might appear to be caused by simple gene
mutation
Bar-eye phenotype of Drosophila
Phenotype inherited same like dominant Xlinked mutation

Normal wild-type females 800 facets in each eye

Heterozygous female 350 facets
Homozygous females 70 facets
Female with fewer facets double Bar

Polytene X chromosome of Bar flies contain specific

banding patterns 1 copy of the region designated
as 16A is present on both X chromosomes;
duplicated in Bar flies; tripled in double Bar flies

Genetics 4BIO3 J.M

1st SEM 2014-2015

7 INVERSIONS REARRANGE LINEAR GENE SEQUENCE

Inversion chromosome segment is turned 180degrees within a
chromosome ; does not involve loss of genetic information; only
rearranges linear gene sequence
Requires breaks at 2 points along chromosome length and
reinsertion of inverted segment

Inverted segment can be short, long and may or may not include a
centromere
Paracentric inversion -centromere not part of rearranged chromosome
segment
Pericentric inversion centromere is part of inverted segment

Consequences of Inversions during gamete Formation

Normal linear synapsis during meiosis not possible
if only 1 member of homologous pair has inverted
segment
Inversion heterozygotes organisms with 1 inverted
chromosome and a noninverted homolog
Formation of inversion loop aids in pairing between
inversion heterozygotes in meiosis
If no crossing over in inverted segment of the
inversion loop homologs segregate; normal and
inverted chromatids
If crossing over happens abnormal chromatids
In crossing over of paracentric inversion
1 recombinant dicentric chromatid (2
centromeres)
1 recombinant acentric chromatid (lacks
chromatid)
Both contain duplications and deletions of chromosome
segments

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1.
2.
3.
4.
5.

During anaphase, acentric chromatid moves randomly to 1 pole or other may be lost
Dicentric chromatid is pulled in 2 directions
Polarized movement produces dicentric bridges
Dicentric chromatid breaks at some point a part goes to each gamete during meiosis I
Gametes with recombinant chromatid are deficient in genetic material

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Offspring bearing crossover gametes inviable and

not recovered
Inversion suppresses crossing over
In heterozygotes inversion has effect of
suppressing recovery of crossover products
Can be inherited

Evolutionary Advantages of Inversions

Since crossover recovery in products is suppressed in inversion
heterozygotes groups of specific alleles at adjacent loci within
inversions can be preserved from generations
If alleles confer survival advantage beneficial

Example: set of alleles ABcDef is more adaptive than AbCdeF or abcdEF

Effective gametes contain favourable set of gametes
Same principle applied using balancer chromosomes contain inversions

8 TRANSLOCATIONS ALTER LOCATION OF CHROMOSOMAL SEGMENTS IN THE GENOME

Translocations movement of chromosomal segment to a new
location in the genome; does not directly alter individual viability
Reciprocal translocation exchange of segments between 2
nonhomologous chromosomes (2 nonhomologous chromosome arms
come close to each other to facilitate exchange)
If includes internal chromosome segments 4 breaks
Consequence like inversions; genetic information is not lost or
gained; rearrangement only
Synapsis of translocation heterozygote - pairing results in crosslike
configuration
Genetically unbalanced due to unusual alignment
Does not necessarily result to aberrant gametes

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2 possible segregation patterns leading to gamete formaton
Centromere 1 migrates randomly toward 1 pole of spindle during
anaphase I; travels along with either centromere 3 or centromere 4
Centromere 2 moves to other pole with either centromere 3 or
centromere 4
1,4 combination not involved in translocation
2,3 combination with translocated chromosomes; with complete
complement of genetic information
1,3 and 2,4 have duplicated and deleted segments
Meiotic products are unbalanced; participation in fertilization results to lethality
Semisterility 50% of the parents progeny that are heterozygous for reciprocal
translocation survive

Translocations in Humans: Familial Down Syndrome

Beaks at extreme ends of short arms of 2 nonhomologous acrocentric chromosomes

Small segments are lost; larger segments fuse at centromeric region
Produces large submetacentric or metacentric chromosomes
Robertsonian translocation

Parents contain 14/21, D/G translocation one parent has majority of G-group
chromosome 21 translocated to 1 end of the D-group chromosome 14
Individual - phenotypically normal even having only 45 chromosomes
In meiosis of the individuals gametes has 2 copies of chromosome 21 (offspring will
have down syndrome)
Other offspring can have standard diploid genome (normal) or balanced translocation
(normal)

1st SEM 2014-2015

Genetics 4BIO3 J.M

1st SEM 2014-2015

9 FAGILE SITES IN HUMAN CHROMOSOMES ARE SUSCEPTIBLE TO BREAKAGE

Fragile sites susceptible to chromosome breakage when cultured in
absence of certain chemicals (folic acid); failed are of a chromosome to
stain

Cause of fragility unknown

May indicate regions where chromatin is not tightly coiled

Fragile-X Syndrome (Martin-Bell Syndrome)

Individuals bearing folate-sensitive site on X-chromosome

Most common form of inherited mental retardation
Affects 1 of 4000 males, 1 of 8000 females
Females carry only 1 fragile X chromosome can be affected;
dominant trait
Affected males long, narrow faces with protruding chins, enlarge
ears, increased testicular size
FMR-1 can be responsible for the syndrome
Trinucleotide repeats sequence of 3 nucleotides repeated many
times

In FMR- 1 CGG sequence is repeated in an untranslated are adjacent to

coding sequence of the gene (upstream region)
Repeats vary
High number correlates with expression of fragile-X syndrome
6-54 repeats normal
55-230 repeats carriers
230+ repeats expression of the syndrome
Normal product of the gene RNA-binding protein (FMRP) expressed in
the brain
Genetic anticipation number of repeats increase in future generation