WEEK 6 CHROMOSOME ABBERATIONS Flashcards
What do autosomal aneuploidies arise from?
- Errors in MEIOSIS –> Monosomy (one chromosomal homologue missing) and trisomy (extra chromosome)
Why are autosomal aneuploidies generally not well tolerated compared to sex aneuplodies?
-Autosomes have more genes so gene dosage compensatory
In humans, what happens to autosomal monosomic foetuses?
- They die in utero
Where are autosomal monosomies better tolerated (which type of organisms)?
- Plant kingdom
e. g. Monosomic tobacco and Jimson Weed –> but less viable and often sterile
What do autosomal monosomies unmask?
- Recessive alleles
- Lethal alleles can be tolerated in the host IF an intact, non lethal homologue is available.
In what condition can lethal alleles be tolerated in the host for autosomal monosomies?
- If an intact, non lethal homologue is available
What is haploinsufficiency and an example?
- When a single copy of an allele is not sufficient to perform the biological function
- DiGeorge Syndrome (22q11.2 deletion)
What is the concentration of the protein indirectly associated with?
- The gene number
What is the formula for a trisomy?
-2n +1
What are trisomies?
- The accumulation of an additional chromosome
Do trisomy in all chromosomes occur?
- Yes BUT only 3 survive –> 35% of spontaneous abortions
Is the survivability increased if the trisomy is in a small chromosome?
- YES
Are trisomic plants viable and fertile?
- They are viable but NOT fertile (infertile)
What is the genotypic formula for Down Syndrome (Trisomy 21)?
- 47, (XX or XY), +21
What is the DSCR?
-The Down Syndrome Critical Region –> hypothetical region on chr.21 THOUGHT to be involved in the phenotype observed –> 21q22.2 = DSCR
Which two candidate genes were identified in the mouse DS model?
- DYRK–> reproduces DOSAGE SENSITIVE learning defects in Drosophila and mice
- DSCAAM–> reproduces heart and Nervous System defects
What is the relationship between maternal age and Down Syndrome prevalence?
- Prevalence of DS births INCREASES with maternal age at conception
- IN 95% of cases, the ovum is the source of extra Chr.21
- Most ND events occur at anaphase I
- PATERNAL AGE HAS NOTHING TO DO WITH IT!
WHY IS DS MORE COMMON IN OLDER MOTHERS?
- In human FEMALES–> meiosis starts in foetus but STOPS at Diplotene (Prophase I)
- Meiosis only continues upon OVULATION (So women in late 30s/early 40s make eggs that are older “been arrested at prophase I’ for longer)
- Also may be that spindle fibres are LESS EFFECTIVE at older ages
What occurs in Pauau syndrome?
TRISOMY 13 –> 47, +13
1/5000 live births (higher proportion DIE in utero)
-Risk INCREASES with maternal age
-Few survive beyond 1 yr
-Survivors–> Severe learning difficulties, psychomotor difficulties, cardiac abnormalities
What occurs in Edwards Syndrome?
TRISOMY 18–> 47, +18
- 1/8000 live births
- MOST foetuses result in SPONTANEOUS ABORTION
- Few survive BEYOND 1 YR
- Common phenotypes–> Failure to thrive, microcephaly scull (small) deformities, born with clenched hands
Does paternal age play a role in Down syndrome?
- NO
An individual has diploid somatic (“body”) cells with 2n = 20 chromosomes. At the end of mitosis in somatic cells, each daughter cell would have ____ chromosomes. In germline cells, at the end of meiosis I, each daughter cell would have_____ chromosomes. At the end of meiosis II, each daughter cell would have ____ chromosomes.
- 2n=20
- 1n=10
- 1n=10
If non-disjunction of chromosome 21 occurred at anaphase I of meiosis, the two chromosome 21s present in a gamete would be ______?
- Genetically different
What does meiosis allow for?
- The generation of genetic variation among offspring
- The generation of new combinations of alleles on the same chromosome
- The transmission of equivalent genetic information from generation to generation
- The genetic contribution of two individual parents to each offspring
The human autosomal trisomies that can result in live births are trisomies for which three autosomes?
Autosomes 13, 18 and 21
What best describes human sex determination?
- Individuals with a Y chromosome are male
Nondisjunction in the first meiotic division in a male human could result at fertilization in which two syndromes?
- turner syndrome and kleinfelter syndrome
Of the four common human sex chromosome aneuploidies, which two are fertile?
- Triple X
- Double Y
Of the four common human sex chromosome aneuploidies, which two are fertile?
SRY
Which of the following is the karyotype of a human male with an extra copy of chromosome 18?
47 XY, + 18
In humans, normal sex chromosome number imbalance is corrected by dosage compensation which:
- down regulates gene expression on one of the X chromosome in females
Which of the following karyotypes would create cells with two Barr bodies? 47, XXY 47, XXX 48, XXXX 46, XX
47, XXX
The type of chromosome rearrangement where there are two breaks in a chromosome and the internal region rotates 180o is called a(n) ________, whereas the type where a segment of one chromosome becomes attached to a different chromosome is called a(n) _______.
.
INVERSION, TRANSLOCATION
What do reciprocal translocations occur between?
- Any two non homologous chromosomes
A mother heterozygous for a small deletion on one of her chromosomes wants to have a child with a male with a normal chromosome distribution. What is the likelihood that the child will be heterozygous for the same small deletion?
50%
Which of the following translocations would be most likely to have no consequence to the host?
Reciprocal translocations
An inversion where the centromere is inside the inverted region is called _____ inversion, whereas one where the centromere is outside the inverted region is called _______.
- Pericentric
- Paracentric
A single crossover has occurred within the inversion loop of a person heterozygous for a pericentric inversion. What is the proportion of normal versus abnormal gametes?
50% normal
50% abnormal
The main type of mutagen that causes chromosome rearrangements is:
Radiation
- A person is a carrier for a large paracentric inversion, what proportion of her gametes will be unbalanced, assuming that a crossover will occur within the inversion loop?
- In this individual, unbalanced gametes are a result of the formation of a(n)__________ bridge while the _____
chromosomal fragment would be lost during meiosis.
- Dicentric bridge
2. Acentric
Human adult haemoglobin consists of four subunits, two alpha subunits and 2 beta subunits. These two subunits share a high degree of similarity between each other. What is the most likely reason these two genes have evolved?
Duplication
If you saw this karyotype for chromosomes 1 and 2 in humans what type of chromosomal rearrangement does it indicate?
1, der(1), 2, der(2)
Reciprocal translocation
A heterozygote for a translocation will produce how many balanced gametes during meiosis if the chromosomes segregate via the alternate pattern?
100% balanced
The structure formed when the chromosomes concerned align at meiosis in a heterozygote for a Robertsonian translocation is a:
trivalent
What are polyploidies?
-Term used to describe instances where MORE THAN 2 COMPLETE SETS of the genome are available
Why are STABLE polyploidies un-common in animals?
- Reproduction of a polyploid leads to aneuploidy
- It interferes with GENE DOSAGE
Which species are polyploidies much more stable in?
-Polyploidies are much more stable in PLANTS! Also seen in FISH, LIZARDS AND AMPHIBIANS (Batura Toad)
WHAT IS AUTOPOLYPLOIDY?
-More than 2 sets of chromosomes all derived from one ancestral species
How can auto polyploidy happen nautrally?
- Fusion of NON-DIPLOID gametes
2. Cell RE-ENTERS interphase after prophase I (mitosis) in early embryonic development
How formation of autopolyploids be induced experimentally?
-Colchicine (inhibits chromosome segregation in mitosis)
What is ALLOPOLYPLOIDY?
-Generation of a polyploid individual from the fertilisation of two closely related but different species
What are two reasons as to when the progeny of allopolyploids will be fertile?
THE PROGENY WILL BE FERTILE IF:
- Progeny has DIPLOID number of chromosomes AND
- There is sufficient similarity between genes for synapsis to occur
Why is Allopolyploidy done?
To create progeny with the most desirable characteristics from each parent (one whole set of chromosomes from each) –> AB
What is an example of a successful allotetraploid?
- Triticale (hybrid of wheat and rye)
28chr * 14chr= 42 chr
What process is an advantage in commercial plant growing?
- Autopolyploidy
What is the process that is thought to have contributed to our evolution from an Amphioxus (Primitive chordate) to a complex human?
- Multiple stages of polyploidy
What are examples (2) of common plant polyploidies?
- Bananas (got rid of the black and yuck seeds)–> but now can not plant banana naturally
- and Strawberries (made them much larger 8n)
Can there be new species by autopolyploidy?-
YES
- e.g. Salmon
- Tetraploid is both viable and fertile –> isolated from its diploid ancestor
Is a Diploid organism viable and fertile in context of autopolyploidy?
- YES
- Viable and fertile
Is a Triploid (Diploid * Tetraploid) organism viable and fertile in context of autopolyploidy?
- Viable BUT not fertile (STERILE)
Is a tetraploid organism viable and fertile in context of autopolyploidy?
- YES
- Viable and Fertile
What is endopolyploidy?
-Situation where certain cells within diploid organism become polyploidic (type of tissue mosaicism–> In cancers, solid tumours, leukemias)
What is endopolyploidy alsk known as?
- Somatic polyploidy
How can endopolyploidy (AKA Somatic Polyploidy) occur? (2 reasons)
- Cells RE-ENTERING mitotic cycle (prophase) WITHOUT progressing through the other stages (thus re entering interphase)
- Cell can progress through the NORMAL steps of mitosis except that a single nuclear membrane will form over ALL DNA during telophase
What is an example of endopolyploidy in humans?
- Human LIVER cells –> 3n, 4n or 8n
- Chromosomes can still remain attached “polytene chromosomes”
Why can polyploidy occur? (2 possibilities)
- Producing high levels of gene products
- To generate larger cells
- (these are both POSSIBILTIES but not definite)
Why are variations in autosome number not tolerated?
- Unmasks recessive alleles and haploinsufficiency
- Same as polyploidies –> not tolerated in most animals
- Can be tolerated in plants (commercial importance)
What are 3 things that the fragile regions in chromosomes can do?
- Break off (and sometimes rejoin to another chromosome)
- Invert
- Duplicate
What can changes in chromosome structure lead to in phenotypes?
- Varied phenotypes
- Sometimes NOTHING happens (if they are all balanced)
- Sometimes disease can occur
What are chromosome fragile sites and are they prone to spontaneous break?
- Tiny gaps or ‘pinches’ that tend to break
- They are usually NOT prone to spontaneous breaks unless other factors influence chromosomal instability
What are the 4 (with an extra one) main types of chromosomal abberations?
- Deletions
- Duplications
- Inversions
- Translocations (reciprocal or non-reciprocal)
- There are also ring chromosomes, but we don’t count them as we hardly see them
What occurs in a chromosomal deletion?
- Chromosome breaks in one or more places –> chromosome portion is lost
What are the two types of chromosomal deletions?
- Terminal deletion (on the end)
2. Intercalalry deletion (aka interstitial deletion) –> portion in the middle is lost and forms a loop
In meiosis or mitosis with deletion chromosomes, why does a deletion loop form?
- Bc. partial chromosomes can’t pair properly
- the deletion loop (compensation loop) forms and this allows synapsis to occur
What is an example of a disorder with a partial monosomy and what are the symptoms?
- Cri Du chat syndrome
- Partial deletion of Chr.5 46, 5p-
- Anatomical deformities in glottis and larynx
- Mental retardation
- Generally NORMAL life expectancy
What occurs in a duplication event?
- Portion of the chromosome is duplicated
What are duplications produced as a result of with an example?
- Uneven crossing over OR errors in DNA replication
- There is a HIGH degree of phenotypic variation (not always bad thing as long as overall genes are BALANCED)
- e.g. of gene duplication (like in alpha and beta subunits of Hb)
Is there a high degree of phenotypic variation in duplications?
- YES
- this is not always a bad thing
What are the two positive effects of duplication?
- Gene redundancy
2. Evolution
What is an example of how gene redundancy is useful from a duplication event?
- Ribosomes are required in high numbers in metabolically active cells
- Having MULTIPLE copies of the rRNA gene allows for SIGNIFICANT numbers to be generated
How did gene duplication contribute positively to gene duplication?
- Paralogous genes arose from genetic duplication event
What is an example of a negative effect of gene duplication?
MECP2 DUPLICATION SYNDROME: Duplication of a region on X, q-arm
-X linked inheritance
Symptoms: Profound intellectual disability
- Hypotonia
- Predisposition to infections
- Epileptic seizures
What are the two types of inversions and what do these involve?
- Paracentric inversion–> Centromere is OUTSIDE the inverted region
- Pericentric inversion –> Centromere is INSIDE the inverted region
In general, what happens in gene inversions?
- The gene order is reversed!
How do inversions arise and are the genes in balance?
- Unusual looping of chromosome
- Genes are IN BALANCE! So MINIMAL EFFECT ON INDIVIDUAL–>BUT consequences for offspring IF inversion interferes with the expression of other genes like ONCOGENES
If there is a HOMOZYGOTE for two chromosomes that exhibit an inversion, what would happen?
- Meiosis would continue normally
- Genes would pair up during prophase as normal
If there is a homozygote for an inversion, will that inversion be passed onto the offspring?
- YES
If there is a HETEROZYGOTE for an inversion, what will happen if there is no crossover event?
- Inversion loop forms to allow genes to pair during prophase
- 50% will have inverted chromosome and 50% will have normal chromosome
If there is a HETEROZYGOTE for a PERICENTRIC inversion, what will happen if there IS A crossover event?
- 50% of NORMAL gametes (one inverted BUT balanced)
- 50% of ABNORMAL GAMETES (carrying deletions–> BUT NOT BALANCED –> infertility
If there is a HETEROZYGOTE for a PARACENTRIC inversion, what will happen if there IS A crossover event?
- Gametes produced : ½ normal; ½ ABNORMAL
- Acentric fragment (with no centromere) can get lost –> CANNOT ATTACH to the spindle
- Dicentric chromosome forms DICENTRIC BRIDGE –> fragment is lost
What are dicentric chromosomes?
- Chromosome breaks during separation fragment lost
- Leads to 2 normal gametes 1 with BALANCED INVERSION
- There are 2 deletion chromosomes (if fused with normal gamete foetus it is NOT VIABLE)
WHEN DO RING CHROMOSOMES FORM?
- When breaks occur on both arms and the ends re-join
- Effects are SEVERE –> ring chromosome 14 syndrome (very unstable and lost in early stages of meiosis)
In general, what are translocations?
- The transfer of genetic materials from one location to another
- If occurs within the SAME homologous pair: Intrachromosomal
- If occurs between NON-HOMOLOGOUS pairs: Interchromosomal
What is a reciprocal translocation?
Exchange of genetic material WITH replacement
What is a non-reciprocal translocation?
Exchangqe of genetic material with NO REPLACEMENT
What are the two origins of translocations?
- Chromosomal break and re-joining
2. Abnormal crossing over
If there is an individual that is homozygous for a translocation, does meiosis continue normally?
- YES
If there is an individual that is heterozygous for a translocation, does meiosis continue normally?
- NO
- Pair via a translocation cross –> “quadrivalent” (4 sister pairs of chromatids)
What is the result of alternate segregation?
- 2 normal gametes
- 2 gametes with a balanced translocation (100% balanced)
What is the result of Adjacent-1 segregation?
- 100% of gametes are UNBALANCED
What happens when an unbalanced gamete (from adjacent segregation) fuses with a normal gamete?
- Zygote will be unviable
- Thus REDUCED fertility in heterozygotes –> recurrent miscarriages
What is the result of adjacent-2 segregation?
-All 4 gametes unbalanced (100%)
Is adjacent-1 segregation of adjacent-2 segregation more rare?
- Adj-2 segregation is more rare
What does Der(1) mean?
- Based on the position of the centromere
- Der(1) means derivative of chromosome 1–> centromere comes from chromosome 1 (Based on the centromere location) while the other part comes from chromosome 2.
What are Roberstonian Transloactions and an example?
-Breaks can occur on the P arms of acrocentric chromosomes –>Reduces the chromosome number by 2
-P-arms lost and TWO q arms FUSE (Only tolerated IF P-arms contain NON ESSENTIAL (redundant) genes)
E.g. Familial Down Syndrome
What is familial down syndrome?
- Heritable form of Down Syndrome –> 3% of Down Syndrome Births
- Robertsonian Translocation b/w Chr. 14 and 21
What two things can inversions and translocations promote in evolution?
- Speciation if spread through population
- Reproductive isolation
If there is a normal gamete with normal gamete mating what is the fertility of the offspring?
- Fertile
If there is a normal gamete with translocation gamete mating what is the fertility of the offspring?
- Reduced fertility
If there is a translocation gamete mating with a translocation gamete what is the fertility from the offspring?
- Fertile
What is chronic Myelogenous Leukemia (CML)?
- Translocation between chr.9 and chr. 22 Philadelphia chromosome
- Translocation creates CHIMERIC protein BCR-ABL
What does chimeric mean (in terms of chimeric protein)
- fusion proteins
- proteins created through the joining of two or more genes that originally coded for separate proteins
What is AML (Acute Myeloid Leukemia)?
- Symptoms similar to CML BUT caused by t(18:21) Causes chimeric protein RUNX1-RUNX1T1 (ETO)
- Also caused by inv(16), or t(15:17)
