Chapter 8: Chromosome Variation

Chromosome Mutations include rearrangements, Aneuploids, and Polyploids

● Chromosome Morphology : Position of the centromere on the chromosome; 4 types:

○ Metacentric ○ Submetacentric ○ Telocentric ○ Acrocentric

● Karyotyping: complete set of chromosomes possessed by an organism

○ the chromosomes are prepared from actively dividing cells (blood or bone marrow cells) halted in metaphase

○ arranged acording to size: in decending order

● Banding: helps distinguish chromosomes that are similar in shape and size; each chromosome has its own “signature” made apparent by staining

○ G bands (a): Giesma stain, rich in adenine-thymine (A-T) base pairs

○ Q bands (b): quinacrine mustard ○ C bands (c): centrometric heterochromatin ○ R bands (d): rich in cytosine-guanine base

pairs ○ ***See human male karyotpe photo***

Chromosomes Rearrangments Alter Chromosome Structure● 3 Categories of Chromosme mutations :

○ Rearrangements: alters structutre ■ rearrangments often occur when double stranded breaks occur within the

strands of the DNA molecule, and are incorrectly put back together in the body’s effort to repair

○ Aneuploidy: alters number of chromsomes ○ Polyploidy: one or more complete sets are added (3n, 4n, 5n +)

● Four types of chromosomal rearragements ○ Duplication: a segment of the chromosome is

duplicated ○ Deletion: segment deleted○ Inversion: segment rotated 180 degrees○ Translocation: segment moves from one

chromosome to a nonhomologous chromsome, or to another place on the same chromsome

Chromosome Duplication:● Tandem duplication: a duplicated chromosome region is directly adjacent to the original

segment

○● Displaced duplication: the duplicated segment is some distance from the original

segment either on the same chromosome or on a different one ○ Compared to the normal chromosome in the picture above, a displaced

duplication example would be AB·CDEFGEF.● Reverse duplication: the sequence of the duplicated segment is inverted relative to the

sequence of the original segment ○ Example: AB·CDEFFEG

● Homozygous for duplication: person carries the duplication on both homologous chromosomes

● Heterozygous for duplication: carries duplication of one of the homologous chromosomes

○ causes problems at Prophase I of meiosis: the chromosomes are two different lengths and can't pair up correctly, causing the chromosome with the duplication to form a loop that compensates for the difference in length

○ the appearance of this loop in meiosis enables us to detect duplications

● Duplications can affect phenotypes○ In fruit flies, the Bar region determines the shape of the

eyes. ■ Normal flies have 1 Bar region each and have

round eyes ■ Heterozygous flies have 1 Bar region on one

homolog and 2 duplicated Bar regions (bar mutation) on the other ○ In humans: (see power point example

Unequal Crossover leads to Duplications and Deletions● during crossover, duplicated regions of

chromosomes misalign

Unbalanced Gene Dosage● Chromosome region duplication effects

phenotypes because protein production is directly related to the number of copies of the corresponding gene

● developmental processes require the interaction of multiple proteins, if one protein increases and one stays the same due to improper gene dosage, problems occur

● Segmental Duplications: numerous duplicated sequences in human genome greater than 1000 base pairs in length

● Duplications provide one way for new genes to evolve

○ the original copy can provide the function essential for survival, while the duplicated gene copy is free to mutate

○ eventually the duplicated copy can aquire a mutation that is beneficial to the organism

Chromosome Deletion● Deletions: loss of a chromosomal

segment ● Large deletions are easily

detected because chromosome is noticeably shorter

● during pairing in Prophase I of meiosis, normal chromosome loops out the deleted region of the other chromosome to compensate for length difference

Effects of Deletions● Most people homozygous for chromosomes with deleted regions are lethal all copies of

any essential genes are missing in the deleted regions ● The deletion can also include the centromere, keepign the chromsome from segregating

in mitosis and meiosis ● For those heterozygous for a deletion:

○ Imbalances in gene produce: loss of protein product ○ Pseudodominance: expression of a normally recessive gene if the dominant

gene is deleted (b/c the dominant is not there to mask the recessive) ○ Haploinsufficiency: a single gene is not sufficient to produce a wild type

phenotype

Effects of Deletions/Duplications in Humans

Chromosome Inversion● Inversion: Segment is inverted/turned 180 degrees; 2 break points are necissary ● if a chromosome originally had segments AB·CDEFG, then chromosome AB·CFEDG

represents an inversion that includes segments DEF.● depends on the involvement of the centromere in the inversion

○ Paracentric inversion: centromere not included ○ Pericentric inversion: includes the centromere

■ ex: AB·CDEFG to ADC·BEFG● Those with inversions have neither lost nor

gained genetic material, just the order has changed

● Many genes are regulated in a position dependent manner; change that position and the gene can’t function

○ known as the Position Effect

● Inversions in Meiosis:○ Individuals homozygous: no problems arise during meiosis○ Individuals heterozygous:

■ homologous sequences align only if the two chromosomes form an inversion loop (a)

■ reduced recombination in genes located in the inverted region, as gametes formed result in nonviable offspring

■ abnormal gametes formed in a pericentric inversion because of single crossover

○ if a heterozygous cross over occurs in paracentric inversion:■ The crossover occurs in the inversion loop between the two inner chromatids■ This forms a chromosome with 2 centromeres (dicentric) and one

chromosome with no centromere (acentric fragment), and is as a result lost. ● This is because in anaphase the centromeres are pulled in opposite

directions. This forms a dicentric bridge on the dicentric chromosome. The bridge eventually breaks.

■ the inner chromatids in the gametes are abnormal, with one chromatid with two copies of some genes and the other with none

● the one with non is non viable■ the outer chromatids (not participating in cross over) are non recombinants

○ If a heterozygous cross over occurs in Pericentric Inversion

■ There are no dicentric bridges or acentric fragments, but, two of the chromatids have too many copies of some genes and none of others

■ Results in: ● one normal non recombinant gamete (ABCDEFGHI)● one nonrecombinant gamete with paricentric inversion (ABCFEDGHI)● two nonviable recombinant gametes

○ to find the first one, look at the alleles that are inverted (in this case, CDE)

○ one gamete will have the alleles before the inversion twice: one before the inversion section and one after (ABEDCBA)

○ the other gamete will have the alleles after the inversion twice: one before the inversion section and one after (GFCDEFG)

Concept Check 1● A Dicentric Chromosome is produced when crossing over takes place in an individual

heterozygous for which type of chromosome rearrangement?○ Paracentric inversion

Chromosome Translocations (TQ: What kind of Rearrangement is it?)

● Translocation: movement of genetic material between non homologous chromosomes or within the same chromosome

○ Differes from crossing over becasue in crossing over there is an exchange of genetic material between homologous chromsomes

● Genetic information is the same, but the order has changed, affecting phenotype○ physical linkage between genes that were unlinked on separate chromosomes

before, causing a new gene expression or position effect. Could become under controll of new regulatory sequences.

○ the break that happens during a translocation can disrupt the gene’s function ● Three Types of Translocation:

● Nonreciprocal translocation: genetic material moves from one chromosome to another without any reciprocal exchange; transfer

○ ex: AB·CDEFG and MN·OPQRS → AB·CDG and MN·OPEFQRS● Reciprocal Translocation: two-way exchange of segments between the

chromosomes ○ ex: AB·CDEFG and MN·OPQRS → AB·CDQRS and MN·OPEFG

● Robertsonian Translocation: short arm of one acrocentric chromosome is exchanged with the long arm of another, creating a large metacentric chromosome and a fragment chromosome that fails to segregate (is lost)

Translocation in Meiosis (Don’t need to know process in detail, know why gametes are viable and why some are not)

Non viable gametes depending on the separation will determine if gametes are viable or not

○

Translocation in Evolution● During evolution, two ape chromosomes came to form one human chromosome through

robetsonian translocation

○ this is why humans have 46 instead of 48: we’ve lost a homologous pair due to translocation

○ all the grey spots are homologous areas (DNA similar)

○

Concept check 3What is the outcome of a Robertsonian translocation?

One metacentric chromosome and one chromosome with two very short arms ***TQ: Know these examples during a test ***

8.3 Aneuploidy is an Increase or decrease in the number of individual chromsomes ● Variations in copy number

○ Aneuploidy: change in # of individual chromosomes○ Polyploidy: change in # of chromosome sets

● Causes of Aneuploidy:○ deletion of centromere during mitosis and meiosis (-1 in gametes)

■ spindle fibers have nothign to attach to in a acentric chromosome, doesn’t get pulled to a gamete

○ result of Robertsonian translocation; the small arm chromosome is lost (-1 in gametes)

○ Nondisjunction during meiosis and mitosis (-1 or +1 in gametes)■ Nondisjunction: sister chromatids in meiosis or mitosis or homologous

chromosomes in meiosis fail to separate■ Nondisjunction can occur at Meiosis 1 and not Meiosis II or the other way

around

●● Types of Aneuploidy (n=haploid # of chromosomes)

○ Nullisomy: loss of both members of a homologous pair of chromosomes (2n-2)■ in humans: 44 chromosomes

○ Monosomy: loss of a single chromsome (2n - 1) ■ 45 chromosomes

○ Trisomy: gain of a single chromsome (2n + 1) ■ 47 chromosomes

○ Tetrasomy: gain of both members of a homologous pair (2n + 2) ■ *not any 2 random chromosomes■ 48 chromosomes

Concept Check 3A diploid organism has 2n = 36 chromosomes. How many chromosomes will be found in a trisomic member of this species?

2n = 36; 36 + 1 = 37

Effects of Aneuploidy● Plants: Jimson weed

○ can cause different ○ Each mutant is trisomic for a different chromosome pair

○● Humans:

○ Humans have a higher percentage of spontaneous abortion (miscarriages) and most are due to aneuploidy

○ In humans, aneuplody happens more often in sex chromosomes than in autosomes because if you have an extra X chromosome, it will not effect gene dosage, as it will become a barr body. An extra Y chromsome isn’t much of a problem either because they are small (don’t carry a lot of genetic information) and the genetic information the do carry isn’t necessary for viable life.

○ sex-chromosomes aneuploids■ Turner Syndrome: XO (-1 X chromosome) ■ Klinefelter syndrome: XXY (+1 X chromosome)

○ Autosomal aneuploids■ Trisomy 21: Down syndrome

● Chromosome 21 is smaller, so extra copies of this is not as detrimental is not lethal

● increases with mother’s birth age ● Primary down syndrome: 75% random nondisjunction in egg

formation; extra chromosome 21

○ non hereditary

○ ● Familial Down Syndrome: extra copy of part of chromosome 21 is

attached to another chromosome; total # of chromosomes is stil 46

○ same phenotype of Primary downs, but is hereditary ○ Robertsonian translocation: long arm of 21 and short of 1

change places producing chromosome with long arms of 14 and 21 and one chromosome with short arms of 21 and 14, which is lost.

○ Translocation Carrier: (see karyotype w/ blue circles) 45 chromosomes but does not have down syndrome

■ received 2 long arms of 14 and 21 from robertsonian translocation; sufficient amount of DNA to function properly. The subsequent 14/21 short armed chromosome, with little DNA, is lost

■ increased chance of having a child with down syndrome

○ Affected w/ Familial Downs: 46 chromosomes; inherited the 14/21 long arm chromosome, both chromosome 21 and one 14

● Translocation Carrier Gametes: ○ A carrier parent has 1 copy of 21, 1 copy of 14, 1 copy of

14/21○ carriers: inherited 14/21 from mom, normal 14 and 21 from

dad○ normal: inherited 14 and 21 from mom and dad○ downs: inherited 21 and 14/21 from mom, and 14 and 21

from dad ○ lethal: monosomy or trisomy combinations

■ Trisomy 18: Edward Syndrome, 1/8000 live bitths ■ Trisomy 13: Patau syndrome 1/15000 live births■ Trisomy 8: 1/25000-1/50000 live births ■ Why is there a drastic decrease in frequency of this trisomic syndrome

from chromosome 18 to chromosome 8?

■ Most cases of down syndrome and aneuploy is caused by maternal disjunction, and the chances of that increases as the mother’s age increases

○ Uniparental Disomy: both chromosomes are inherited from the same parent■ Starts off as a trisomy, with 2 chromosomes from one parent and one

from the other ■ If one of the chromosomes is lost, the embryo can survive (most

autosomal trisomies don’t); by chance the two remaining chromosomes may be from one parent resulting in the uniparental disomy

■ originalte as a trisomy but one chromosome is lost early in development and the remaining 2 chromosomes are from one parent

○ Mosaicism: type of nondisjunction where patches of tissues have different chromosome constitutions

8.4 Polyploidy is the Presence of More than Two Sets of Chromosomes● Polyploidy: organism possesses more than two set of chromosomes (triploids-3n,

tetraploids-4n, pentaploid- 5n)● Autopolyploidy: all chromosome sets are from a single species ● Allopolyploidy: chromosome sets are from 2 or more species

Autopolypoloidy (via nondisjunction)

●● Mitosis:

○ A 2n cell (2n=4) replicates chromsomes (4 chromsomes), they separate in anaphase (8 chromosomes) but the cell doesn’t divide due to nondisjunction

○ Product: cell with 8 chromosomes, or 4n ● Meiosis

○ A diploid 2n cell (2n = 4) replicates its chromosomes (4 chromsomes) but undergoes nondisjunction, faling to produce 2 1n gammetes like meiosis 1 should. It forms 2, 2n gametes with Meiosis II, those gametes interact wit ha healthy 2n, and form 3n triploid zygotes (autotriploid)

○ Product: ■ 2 gametes that are 2n like parents fusing with a normal gamete 1n

■ producing 3n triploid gamete ● Autopolyploids are often sterile

Autotriploid during Meiosis

●● With normal 2n cells, there 2 chromosomes for a homologous pair align and separate.

But with autotriploids, there are 3 chromosomes that are homologous.● The 3 homologous chromosomes have options in mieosis I:

○ two chromosomes pair and the other segregates randomly■ gamete 1: 2 chromosomes■ gamete 2: 1 chromosme

○ All three pair and all three segregate randomly■ gamete 1: 2 chromsomes ■ gamete 2: 1 chromsome

○ None pair and all three move to the same cell ■ Gamete 1: 3 chromsomes ■ Gamete 2: no chromsomes

● NO matter which combination, the result is unbalanced gametes because numbers of copies of chromsomes varies (2 copies of chromosome 1, 3 copies of chromsome 2, no copies of chromsome 4…)

● When these unbalanced gametes fuse with nomormal 2n gametes, the difference in number creates unbalanced gene dosage that is lethal.

● Triploids do not produce viable offspring ● Triploid Bananas, watermelons are bred on purpose and are seedless

Allopolyploidy (hybridization between species)

●

● Alloploidy: results from hybridization of two species● The F1 generation hybrid of 1n and 1n gametes (a 2n gamete) is sterile because if it

tried to fuse with a normal gamete, it would contribute unbalanced gametes and they would die.

○ The product with ABCGHI is still considered diploid beacuse it has the same number of chromosomes as the diploid parents.

■ Parent 1 = 2n, and Parent 2= 2n ■ F1 is 1n, and F1 is 1n ■ F1 gametes fuse, and produce a 2n cell, but it is only diploid because it

contains the same amount of chromosomes as the parent cells, although the chromosmes are not homologous pairs and it is functionally haploid

■ However, the F1 hybrid can undergo mitotic chromosome duplication, doubling the number of each chromsome, and becoming functionally diploid becasue every chromsome has one and only one other homologous partner, which is exactly what is needed so successfully undergo meiosis. it will produce balanced gametes that have one of each chromosome, and is 1n

● The significance of Polyploidy○ polyploid cells are physically larger than diploid cells

○ Plants are polyploids more often the animials ■ animals are less likely to breed with different species

○ Evolution: may give rise to new species

Concept Check 5 (look at worked problem in book)

23.5 Changes in Chromosome Number and STructure are often Associated with Cancer ● Chromosomal instability is a general feature of cancer cells

○ cause by various delations, inversions, translocations ○ Example: a reciprocal translocation between chromsome 9 and 22 causese

chronic myelogenous leukemia○ Aneuploidy

● Chronic Myelogenous Leukemia○ forms ne Philadelphia chromsome that becomes hyperactive protein; gene

overexpression in a position where it’s not normaly expressed ● Burkitt Lymphoma

○ translocation causes increased proliferation