Chapter 9 – Chromosomal Variation

Chromosome Morphology• Metacentric

– Centromere is centrally located; arms equal length• “p” and “q” – “p” is smaller when there is a size difference

• Submetacentric– Centromere is off center

• Acrocentric– Centromere is close to one end– p arm has satellites (knobs on stalks)

• Telocentric– Centromere is at one end– Not present in humans

Karyotype

• Complete set of chromosomes arranged in homologous pairs

• Sample is from an actively dividing cell– Chemical inhibits spindle

assembly formation• Cell can not complete

mitosis

– Hypotonic solution swells cell

• Allows chromosomes to spread out

– Dropped on slide and stained

Staining • G banding

– Giemsa stain; most common– Stains A-T rich regions

• C banding– Stains centromeric heterochromatin and portions of

chromosomes with large sections of heterochromatin• 1, 9, 16, Y

• R banding– Stains G-C rich regions– Gives opposite banding pattern of G banding

• Q banding– UV light is used– Same pattern as G banding

Staining

Types of chromosome mutations

• Chromosomal rearrangement– Structure is altered

• Aneuploidy– Abnormal number of chromosomes– Missing one or more/having one or more extra

• Polyploidy– 1 or more additional sets of chromosomes

Chromosome rearrangements

• 4 types– Duplications

– Deletions

– Inversions

– Translocations

Duplications• Section of chromosome is

doubled

• Tandem– Repeated segment is right

after the original

• Displaced– Repeated segment is

located elsewhere on chromosome, or on a different chromosome

• Reverse– Sequence is inverted from

the original sequence

Duplications• Heterozygotes

– During paring of homologous chromosomes, duplicated region loops out

– Offspring receive two copies of involved genes from parent with duplication, and a third copy of the other parent

• Partial trisomy for all involved genes

• Alters gene dosage

Gene dosage

Deletions• Loss of a portion of

chromosome

• Large deletions can be seen cytogenetically; microdeletions by FISH

• If the deleted region includes the centromere, entire chromosome will be lost

• Usually lethal in homozygous form

• Heterozygotes – Normal chromosome must

loop out during pairing– Partial monosomy for all

involved genes

Deletions - heterozygotes• Affects gene dosage

• Pseudodominance– Expression of mutant/recessive phenotype

due to loss of normal/dominant copy

• Haploinsufficiency – Both copies of the gene are needed to

manufacture adequate amount of gene product

• One gene doesn’t produce enough for a normal phenotype

Inversions• Two breaks in chromosome, then flipped and

reinserted

• Paracentric inversion– Both breaks occur in one arm

• Pericentric inversion– Breaks on both arms; centromere is involved– Can change morphology by altering centromere position

• Effects– Disruption of a gene – no functional product– Position effect

• Change in gene position can affect gene expression

Inversion loops• Chromosomes have to

loop when pairing

• Paracentric inversion loops

– If crossing over occurs within loop:

– Creates a dicentric chromosome and an acentric chromosome

• Acentric is lost• Dicentric forms a dicentric

bridge, and breaks• Nonviable recombinant

gametes

Paracentric inversion loop

Inversion loops

• Pericentric inversion loops

– Crossing over within loop creates recombinant chromosomes with duplications and deletions

• nonviable

Pericentric inversion loops

Translocations• Rearranges genetic material

to another part of the same chromosome; or nonhomologous chromosome

• Nonreciprocal– Segment moves from one

chromosome to another

• Reciprocal– Exchange between two

chromosomes

• Effects– Loss of gene function –

break– Position effect– Creation of a

fusion/abnormal protein

Robertsonian translocation• Between two

acrocentric chromosomes– 13, 14, 15, 21, 22

• 2 q arms are joined at a common centromere– Forms a metacentric

chromosome if two chromosomes are same size

• Small fragment is usually lost– Tends to be acentric

Translocations

• Translocated chromosome is named after the chromosome that is the origin of the centromere

• Heterozygotes have one normal copy of a chromosome, and one translocated one– During meiosis, all 4 chromosomes will

associate– Can segregate 1 of 3 ways

Translocation segregation

• Alternate– Both normals go to one

pole; both translocated go to the other

• Balanced; viable

• Adjacent 1– Each pole gets one normal,

and the opposite translocated

– Partial monosomies/partial trisomies

• inviable

• Adjacent 2– Each pole gets both the

normal and translocated of the same chromosome

– Inviable; rare

Translocation segregation

Fragile sites

• Under certain conditions/culturing techniques, chromosomes develop breaks/restrictions at particular locations

• Now routinely tested for by FISH analysis

Aneuploidy

• Abnormal number of chromosomes– Caused by:

• Loss of chromosome during cell division; random error or loss of centromere; nondisjunction

• Robertsonian translocation

• Types– Nullisomy 2n – 2 – missing both members of a

homologous pair– Monosomy 2n – 1 – missing one chromosome– Trisomy 2n + 1 – one extra chromosome– Tetrasomy – 2n + 2 – two extra chromosomes of the

same type/homologous

Aneuploidy

• Alters phenotype dramatically– Often lethal if constitutional

• Can see elaborate abnormalities in tumor cells – X inactivation in mammals takes care of extra Xs, so

not as severe

• Down syndrome– Primary

• 3 free copies of #21– Familial

• Extra copy due to translocation– Can be involved in Robertsonian translocation– Parent can have 45 chromosomes, but have normal phenotype

since all genetic material is present

Uniparental Disomy• Both chromosomes of a homologous pair

from the same parent

• Probably originated from a trisomy– One chromosome is lost early in development

• Recessive diseases– One carrier parent and one normal parent can

have an affected child

Mosaicism

• Nondisjunction in later development can cause “patchiness” – normal cells and abnormal cells

• Approximately 50% of Turner syndrome can be mosaics– 45, XO/46, XX

Polyploidy• Extra sets of chromosomes

– Triploid – 3n; tetraploid – 4n

• Common in plants – more tolerant of extra sets of chromosomes

• Autopolyploidy– Extra set is from same species

• Error in cell division

– Extra chromosome caused pairing problems; especially with odd numbers

• 3n usually sterile; produce small seeds– Bananas; “seedless” watermelon

Polyploidy

• Allopolyploidy– Hybridization between two species– AABBCC x GGHHII– F1 generation ABCGHI – not homologous

• Gametes are inviable, but may be able to reproduce asexually

– Nondisjunction error can lead 2x, which could then reproduce sexually