Chromosome aberrations II

Autosomal aneuploids & polyploidies

Dr. Thomas Hiscox
School of Biological Sciences, Monash University

References:
Klug et al – Chapter 6 (11 ed) or Chap 8 (12 Ed) & Chap 24 (12 Ed)

Some figures taken from:

Brooker et al Chap 8
Saunders and Bowman Chap 13
Previous lecture review

• Karyotyping used to identify

chromosome abnormalities
• FISH
• QF-PCR
• qPCR and / or NGS
• Aneuploidy – a change from the
normal number of chromosomes
• Gene dosage responsible for abnormal
phenotypes
Aneuploidy the result of abnormal meiosis
1 1’
a
If individual was
Homologous chromosomes
heterozygous Aa
called 1 and 1’

MI Normal Non-disjunction at meiosis I Non-disjunction at meiosis II

a a
a

MII

a a a a a a

A A a a Aa Aa O O A A aa O
resulting gametes
Common sex aneuploidies
Karyotype Name Sex Viable Fertile
47, XXX Triple X F Yes Yes
45, X Turner F Yes No
47, XYY Double Y M Yes Yes
47, XXY Klinefelter M Yes No

Alteration in sex chromosome number DOES NOT necessarily make

the individuals sterile
Outline for today

1. Autosomal aneuploidies
1. Monosomy
2. Trisomy

2. Polyploidies
1. Autopolyploidy
2. Allopolyploidy
3. Somatic polyploidy
Autosomal aneuploidies

• Arise due to errors in meiosis

• Monosomy – one chromosomal homolog missing

• Trisomy – extra chromosome

• Normally not well tolerated

• Compared to sex aneuploids (Triple X, Turner)

• Why?

https://pbs.twimg.com/media/Dd_WI0iV4AAKT58.jpg
Non-disjunction of autosomes
1 1’
a
If individual was
Homologous chromosomes
heterozygous Aa
called 1 and 1’

MI Normal Non-disjunction at meiosis I Non-disjunction at meiosis II

a a
a

MII

a a a a a a

A A a a Aa Aa O O A A aa O
resulting gametes
PollEv

Why are autosomal

aneuploidies so badly tolerated
in humans?
Monosomies (2n – 1)

• Autosomal monosomies are not tolerated in humans

• Exception Turner syndrome (but that’s a sex aneuploid which is tolerated better due
to X-inactivation)

• In humans, monosomic foetuses die in utero

• Generally better tolerated in the plant kingdom
• Monosomic tobacco & Jimson weed have been isolated

• Tend to be less viable and often sterile

Monosomies unmask recessive alleles

• Lethal alleles can be tolerated in

the host, if an intact non-lethal
homolog available
• Similar to X-linked inherited traits
being more common in males
Haploinsufficiency
• Generally both alleles are expressed
• The resultant proteins (from both alleles are
required for normal function)

• Haploinsufficiency
• When a single copy of an allele is NOT sufficient to
perform biological function

• Example:
• DiGeorge Syndrome (22q11.2 deletion syndrome)

• TBX1 mutations
Trisomies (2n + 1)
• Accumulation of an additional chromosome

• Generally better tolerated in humans than monosomy

• i.e: trisomies more likely to survive (0.3% live births)

• Survivability increased if trisomy is in small chromosome

• Trisomy in all chromosomes occur, but only 3 survive

• Trisomy accounts for 35% spontaneous abortions
Trisomy in plants
• Trisomic plants viable, but
infertile

• Typically associated with

phenotypic differences

• Trisomics of Jimson weed

(Datura)
• Diploid number 24
• Trisomy of each chromosome results Brooker 3
in a different capsule phenotype Fig. 8.16
Down Syndrome (Trisomy 21 or 47, 21+)
• Occurs in 1/800 live births
• Phenotypically variable
• Commonly presents with:
• Short stature

• Mental retardation

• Epicanthic fold (give eye characteristic

almond-shape)

• Heart and nervous system abnormalities

• Life expectancy not common beyond 60s Klug Fig 6.3

Down Syndrome Critical Region (DSCR)

• A hypothetical region on chromosome 21 thought to be involved in

the phenotypes observed
• 21q22.2 = DSCR

• In a mouse DS model, identified candidate genes

1. DYRK – reproduces dosage-sensitive learning defects in Drosophila and mice

2. DSCAAM – reproduces heart and nervous system defects

 Maternal age effect and Down syndrome
• Prevalence of Down Syndrome
births increases with maternal
age (at conception)

• Ovum the source of extra Chr 21 in 95%

• Most ND events occur at anaphase I

• Paternal age appears

unimportant

Klug Fig 6.4

Why is DS more common in older mothers?

• In human females, meiosis starts in the foetus, but stops at diplotene

(prophase I)

• Meiosis only continues upon ovulation

• Therefore women in the late 30s early 40s produce eggs that are older (been arrested
in prophase I) for longer

• Spindle fibres less effective at older ages?

 Gametogenesis in Humans

20 oocyte arrested at
Ovulation metaphase II

After fertilization

10 oocyte arrested at diplotene → from development to sexual maturity

Patau syndrome (Trisomy 13 or 47, 13+)

• 1/15000 live births

• A higher proportion die in utero

• Risk increases with maternal

age

• Poor prognosis
• Few survive beyond 1 year

• Survivors affected with severe learning

difficulties, psychomotor difficulties,
cardiac abnormalities Klug Fig 6.5
Edward’s syndrome (Trisomy 18 or 47, 18+)

• 1/8000 live births

• Most foetuses result in spontaneous

abortion

• Few (5-10%) survive beyond 1 year

• Common phenotypes:
• Failure to thrive, microcephaly skull
deformities, born with clenched hands
Many of the common trisomies are spontaneously
lost in pregnancy
Even though individuals with trisomy 21 (Down syndrome) can live long
lives, 80% do not successfully come to term.

Disorder Proportion undergoing

spontaneous pregnancy
loss (%)

Trisomy 13 95
Trisomy 18 95
Trisomy 21 80
Monosomy X 98

Emery’s Table 18.3

Outline for today

1. Autosomal aneuploidies
1. Monosomy
2. Trisomy

2. Polyploidies
1. Autopolyploidy
2. Allopolyploidy
3. Somatic polyploidy
Polyploidies

• Term used to describe instances where more than 2, complete sets

of the genome are available

Diploidy Triploidy Tetraploidy

Polyploidy in evolution

?
Amphioxus
Most primitive chordate
http://www.devbio.biology.gatech.edu/wp-content/uploads/2015/03/amphioxus-
wholemoust-fabian-2.jpg

https://optimumcondition.com/wp-content/uploads/2016/10/human-body.jpg
Polyploidies

• Stable polyploidy un-common in

animals
1. Reproduction of polyploid leads to
aneuploidy
2. Interferes with gene dosage

• But polyploidy is seen in fish,

lizards and amphibians
• Batura toad(Bufotes baturnae)
http://www.nature-images.eu/species/amphibians/images/bufo-
baturae/720x480/3.jpg

• Much more stable in plants

Autopolyploidy
• More than 2 sets of chromosomes all derived from one ancestral
species

• Can happen naturally if:

1. Fusion of non-diploid gametes
2. The cell re-enters interphase after prophase I (mitosis) in early
embryonic development

• Can also be induced experimentally using colchicine

• Tolerated in plants and of important commercial significance

Formation of autopolyploids

rmal me s s

rmal me s s n d s nc n

er l sa n

l d y e

er l sa n
Err r n m ss

r l d
e ra l d
Experimentally induced polyploidy

Diploid Tetraploid

Early Prophase Metaphase Cell re-enters interphase

Colchicine added Colchicine removed

Common plant polyploidies

https://aliquotthesciencespot.files.wordpress.com/2017/11/bananaanatomy1.jpg

https://miro.medium.com/max/800/1*bchbRnDjd1rqbKKRjAGxQg.png
 Chromosome complement in gametes must be balanced

Diploid Triploid

Saunders Fig 3.10 Brooker Fig 8.21

New species by autopolyploidy
Once r d ced, an a e ra l d s an “ ns an ” new s ec es

Diploid (2n) Triploid (3n) Tetraploid (4n)

Viable Viable viable
Fertile Sterile Fertile

Diploid X Tetraploid = Triploid

So tetraploid is reproductively isolated from its diploid ancestor

 Allopolyploidy
• Generation of a polyploid
individual from the fertilisation of
two closely related but different
species

• Progeny will be fertile if:

1. The progeny has a diploid number of
chromosomes AND

2. There is sufficient similarity between

genes for synapsis to occur

Brooker Fig 8.27

Allopolyploidy cont’d

• Inter-species hybrid
• Often done to create progeny with the most desirable characteristics of both parents

• The hybrid has one set of chromosomes from each parent (e.g. AB)

• Allopolyploidy is tolerated well in plant species, used frequently in

commercial crops
• Rarer in mammals and other animals
Mules

Donkey (jack) X Horse (mare)

Donkey = 62 chromosomes
Horse = 64 chromosomes

Mule = 63 chromosomes (infertile)

Jones & Johnsen (1985)
Equine Vet Sci, 5: 87-90
Creation of allopolyploids

• Interspecies hybrids can be

made fertile if made polyploidic

• Use colchicine to arrest mitosis

during embryogenesis, then
remove

• Generates a fertile amphidiploid

(or an allotetraploid)

Klug Fig 6.8

Successful allotetraploids - Triticale

Wheat Rye
Tetraploid
X Diploid
28 Chr 14 Chr

Infertile hybrid, colchicine added

Triticale
Diploid
42 Chr
Endopolyploidy (somatic polyploidy)

• The situation where certain cells within a diploid organism become

polyploidic
• A type of tissue mosaicism

• Can happen by:

1. Cells entering the mitotic cycle (prophase), without progressing through the other
stages – re-enter interphase

2. The cell can progress through the normal steps of mitosis, except that a single
nuclear membrane will form over all DNA during telophase
 Endopolyploidy in humans
• Humans liver cells can be
polyploidic
• 3n, 4n or 8n

• Sometimes chromosomes remain

attached – called polytene chromosomes

• Unclear why polyploidy happens

• Produce high levels of gene products?

• To generate larger cells?

Brooker Fig 8.19

Summary

• Autosomal aneuploidies
• Not tolerated well in mammals (or animals in general – exceptions?)
• Monosomy of autosomes – not seen, why?
• Trisomies
• Downs & Patau
• Maternal age effect – error in gametogenesis
• Polyploidies
• Allopolyploidy versus Autopolyploidy
• Commercial significance
Questions you should be able to answer

1. How does autotriploidy arise and are autotriploids fertile or sterile?

Questions you should be able to answer

2. How does meiosis occur in autopolyploids?