Learning Assessment 8: Chromosomal Abnormalities

How does a duplication or deletion alter a characteristic?

"Unbalanced gene dosage"- interaction of various gene products ex) If three wild-type chromosomes interact, the gene products will be shared equally. If B gene, for ex, is duplicated, there is twice as much of that protein product and there will be an altered phenotype developed in the individual

A genotype that has XXYY (2n+2) will have ___ barrbodies.

1

Three main categories of changes in the chromosome

1) Chromosome rearrangement- duplication, deletions, translocations, inversions 2) Aneuploidy- gain or loss of one chromosome for a particular chromosome type 3) Polyploidy- involves one or more complete sets of chromosomes

Types of chromosomal rearrangements

1) Duplications 2) Deletions 3) Translocations 4) Inversions

Three types of translocations

1) Reciprocal- a switch of genes between two chromosomes 2) Nonreciprocal- no exchange, chromosome gives genes to another chromosome, but nothing in return 3) Robertsonian- fusion of Q arms of two non-homologous chromosomes; creates one huge metacentric chromosome

Unbalanced gametes can result when a reciprocal translocation is inherited or de novo, just as they can form from a Robertsonian translocation. The four possibilities are

1) transmitting two normal copies of the two involved chromosomes 2) transmitting two abnormal copies, with no effect on the phenotype of an offspring unless a vital gene is disrupted 3 and 4) transmitting either translocated chromosome, which introduces extra or missing genetic material and likely would affect the phenotype

A genotype that has XXXYY will have ___ barrbodies

2

If nondisjunction occurs in meiosis II, we will end up with

2 normal gametes, 2 abnormal gametes subject to aneuploidy

A MoM value above ___ means that the level of the biomarker is twice as high or twice as low as the average in a normal pregnancy.

2.0

If nondisjunction occurs in meiosis I, we will end up with

4 abnormal gametes (aneuploidies)

An example of translocation

Acute promyelocytic leukemia- involves reciprocal translocation between chromosome 15 and 17. PML (15) gene and RARA (17) gene end up fusing into a PML-RARa protein. Normal RARa protein controls differentiation and PML blocks cell growth and stimulates apoptosis. When fused together into a protein, this blood cancer will occur.

___ mutations and abnormalities impact individual chromosomes

Aneuploidy

___ refers to an extra or missing chromosome

Aneuploidy

An easy assay in order to determine whether a nondisjunction event occured in an individual with regards to the sex chromosome is to look for the ___.

Barr bodies (number of barr bodies is equal to the number of supernumerary X chromosomes; any beyond one we will have a barr body)

How can a female have two copies of all the genes present on the X chromosome? (its so big) With regards to the Y, where there is not that much (we can live without a Y chromosome, all females don't have them)

Barr bodies! One copy of the X is inherited in the female is randomly inactivated in each of the somatic cells. It could be the paternal or maternal X that is inactivated. But all the subsequent daughter cells will have their X inactivated on paternal or maternal side of cells. The inactivated chromosome condenses into a barr body. Consequence- females are mosaics ex) calico cat. The allele that causes red fur color is on one X and black fur color is on other X; the black allele is on the fathers X chromosome, and condensed into a barr body. Mothers is not condensed and expressed as red fur allele.

Why are the most frequently seen extra autosomes in newborns chromosomes 21, 18, and 13?

Because these chromosomes carry many fewer protein-encoding genes than the other autosomes, compared to their total amount of DNA.

___ is slightly less accurate than ___.

CVS; amniocentesis

Why is trisomy 21 less devastating?

Chromosome 21 is a lot smaller than chromosome 1; they decrease by size

___ happen when there is a double strand break occur in two positions along the length of the chromosome. Both nucleotide strands have a break. DNA repair pathways will try to fix it. Sometimes they will fix it but the pathways reinsert the segment in the improper order. The consequence is that the linkage group will change, leading to the alteration of gene function and regulation.

Chromosome inversions

___ is when one or more chromosomes shatters

Chromothripsis q

___ is the classical area of genetics that links chromosome variations to specific traits, including illnesses

Cytogenetics

___ is when part of a chromosome is missing

Deletion

___ and ___ mutations are missing and extra DNA sequences, respectively. They are types of copy number variants (CNVs)

Deletion; duplication

___ is caused by having too many copies of chromosome 21.

Down syndrome

___ is when part of a chromosome is presented twice

Duplication

Turner's syndrome (XO)

Females; no second copy of the X chromosome. No Y chromosome to prevent female development, so will be female. Consequence of only having one X results in under-developed ovaries and inability to have kids.

___ of chromosomes consists mostly of highly repetitive DNA sequences, whereas ___ has many protein-encoding sequences.

Heterochromatin; euchromatin

Should an aneuploidy result, sometimes we can have a cell attempt to correct that aneuploidy (it can recognize that cell is monosomic or trisomic). How?

If monosomy occurs, sometimes replication of the chromosome can happen; if trisomy occurs, the cell can lose or discard one member of the chromosome set

How do you count barr bodies

In humans with more than one X chromosome, the number of Barr bodies visible at interphase is always one fewer than the total number of X chromosomes

___ is when a segment of chromosome is reversed

Inversion

___ is a chromosome with identical arms

Isochromosome

Problem with having homologs from one parent? (ex) if monosomy is fixed

It can be helpful because now we have the right number of copies, but now it is homozygous and having two copies of the same allele can cause detrimental affects (some homozygous alleles can be lethal). Another problem is imprinting; several hundred genes are silenced when passed from one parent; the expression of a gene can be lost

A man with ___ is underdeveloped sexually.

Klinefelter syndrome

Why do females tend to have aneuploidy?

Males go through many rounds of DNA synthesis and replication through their lifetime, while female DNA synthesis happens while we are still in utero. The first meiotic division does not occur until ovulation. Within womb we have replicated all our chromosomes and they are halted (under meiotic arrest). As women age, we need proteins to maintain our replicated chromosomes.

Klinefelter syndrome (XXY)

Males; have a copy of that male Y chromosome to suppress female development but also have another additional X chromosome. Consequence is they tend to be a little taller than normal males.

___ are biochemicals whose levels in the blood fall within a certain range in a pregnant woman carrying a fetus with the normal number of chromosomes, but may lie outside that range in fetuses whose cells have an extra copy of a certain chromosome.

Maternal serum markers

___ is when one chromosome is absent

Monosomy

Nondisjunction events have these consequences:

Monosomy- loss of one member of the homologous pair is almost always lethal Trisomy- one additional member of an homologous pair is also almost always lethal

Sex chromosome aneuploidy

Most common type of aneuploidy; includes Klinefelter and Turner's syndrome. Causes of changes in phenotype is in regards to gene-leakage from the X chromosome. In Turner's. even though in females one X chromosome is gone, there is a little leakage that occurs from the inactivated copy, and that leakage is important for normal female development and fertile development. In Klinefelter's, one of the Xs is going to be inactivated and the leakage is associated with a growth factor, making them grow up slightly more normal.

uniparental disomy

Offspring receives 2 copies of a chromosome from 1 parent and no copies from the other parent.

How does Trisomy 21 of Down Syndrome occur?

Overexpression of genes on chromosome 21. This can happen due to the pairs of chromosomes fail to separate properly in an error, known as nondisjunction. Robertsonian translocation causes chromosome rearrangement as well. Therefore down syndrome is present when the karyotype displays 2 complete copies of chromosome 21 and 1 copy of a Robertsonian translocation 14:21.

___ mutations and abnormalities impact entire sets of chromosomes

Polyploidy

___ refers to extra chromosome sets

Polyploidy

___ is a chromosome that forms a ring due to deletions in telomeres, which cause ends to adhere

Ring chromosome

In a ___, the short arms of two different acrocentric chromosomes break, leaving sticky ends on the two long arms that join, forming a single, large chromosome with two long arms. The tiny short arms are lost, but their DNA sequences are repeated elsewhere in the genome, so the loss does not cause symptoms.

Robertsonian translocation

___ makes males, males and suppresses female development.

Sex determining region (SRY) Y gene

A triploid can be due to:

The formation of a diploid gamete, such as when a normal haploid sperm fertilizes a diploid oocyte. Most triploids result from fertilization of an oocyte by two sperm.

___ is when two chromosomes join long arms or exchange parts

Translocation

___ is when there is one chromosome extra

Trisomy

Three different cases where live births of non-disjunction of autosomes are

Trisomy 13 (Patau syndrome) Trisomy 18 (Edward syndrome) Trisomy 21 (Down's syndrome)

An imbalance with regard to expression of genes present on the sex chromosomes is less damaging than an imbalance with regards to the autosomes in human development because?

We have a mechanism in place to deal with dosage compensation. This dosage compensation is called "random X-inactivation" or the formation of bar bodies.

The 24 human chromosome types are numbered from largest to smallest- 1 to 22. The other two chromosomes are the ___

X and Y

Phenotype of Turner's syndrome female will have ___ genotype and ___ barrbodies.

XO (2n-1) or 45, X (45 chromosomes instead of 46; X is the type of chromosome we are missing); zero

Phenotype of "seemingly normal" female can have a genotype of ___ and ___ barrbodies.

XXX (2n+1); 2

A Klinefelter syndrome abnormal male will have a genotype of ___ and ___ barrbodies.

XXY (2n+1); 1

A barr body is

a condensed X chromosome that is inactive

Two-thirds of all triploids result from the fertilization of ___.

a haploid oocyte by two haploid sperm

Aneuploidy is caused by

a nondisjunction event that can occur during mitosis or meiosis- nondisjunction is the failure of homologous chromosomes to properly segregate, which happens during anaphase of meiosis 1 or 2. If we have a nondisjunction event, then both copies of the chromosome diploid wind up in the same cell. Other daughter cell won't have any of this chromosome. There will still be 22 other pairs of somatic chromosomes in that cell. But it is (2n-1) because the cells are diploid but missing one copy of a homologous pair. The other cell will be trisomic (2n+1); they are still diploid but will have one additional member of one chromosome pair. All 4 gametes will become abnormal.

A chromosome is ___ if it pinches off only a small amount of material toward one end

acrocentric

The first fetal karyotype was constructed using ___. In this procedure, a doctor removes a small sample of amniotic fluid from the uterus with a needle passed through the woman's abdominal wall.

amniocentesis

The two traditional technologies that provide images of chromosomes from a fetus are ___ and ___. The images are organized into karyotypes that show the normal 46 chromosomes or abnormal conditions, such as extra or missing chromosomes, inverted chromosomes, or chromosomes that have exchanged parts.

amniocentesis; chorionic villus sampling (CVS)

Cells missing a single chromosome or having an extra chromosome are ___, which means "not good set". Rarely, aneuploids can have more than one missing or extra chromosome, indicating abnormal meiosis in a parent.

aneuploid

The ___ of a gene having duplications can change the phenotype expressed ex) an extra bar of gene can change genotype to heterozygous, affecting its phenotype

bar region

The ___ is the largest constriction of a chromosome. it is where spindle fibers attach when the cell divides. A chromosome without one is no longer a chromosome. It vanishes from the cell as soon as division begins because there is no way to attach to the spindle.

centromere

chromosome rearrangement

change in chromosome structure

During the 10th through 12th weeks of pregnancy, ___ obtains cells from the chorionic villi, which are fingerlike structures that develop into the placenta. A karyotype is prepared directly from the collected cells, rather than first culturing them, as in amniocentesis. Results are ready in a few days.

chorionic villus sampling

Occasionally, a chromosomal aberration occurs only in a cell of the embryo, or only in a chorionic villus cell. This results in ___.

chromosomal mosaicism

The condition when the karyotype of a villus cell differs from that of an embryo cell is known as

chromosomal mosaicism

The condition when the karyotype of a villus cell differs from that of an embryo cell is known as ___.

chromosomal mosaicism

Increased risk of aneuploidy is due to ___ and ___

cohesin; shugoshin protein

A technique called ___ is used to detect very small CNVs, which are also termed ___ and ___. The technique compares the abundance of copies of a particular CNV in the same amount of DNA from two people- one with a medical condition, one healthy.

comparative genomic hybridization (CGH); microdeletions; microduplications

Changing the number of copies of a gene due to deletion and duplication can create ___; having more than just one copy of a particular gene; having duplicates

copy number variants (CNVs)

A reciprocal translocation carrier can have symptoms if one of the two breakpoints lies in a gene, disrupting its function. However, a reciprocal translocation that arises ___ in a sperm or oocyte can affect health if fertilization occurs and development proceeds, because the resulting individual would have extra or missing genetic material.

de novo (from the beginning)

Y is always inherited by the ___ while the X is always inherited by the

father; mother

A technique called ___ introduced the ability to highlight individual genes; it is more targeted than conventional chromosome staining because it uses DNA probes. The probes are attached to molecules that fluoresce when illuminated, producing a flash of color precisely where the probe binds to a complementary DNA sequence among the chromosomes in a patient's sample.

fluorescence in situ hybridization (FISH)

Whats the problem with having additional copies of a gene?

gene dosage

A newer approach, ___, is being used to study down syndrome at the cellular level. Genome editing cuts double-stranded DNA at a specific site on a chromosome and allows insertion of a specific DNA sequence.

genome editing

Centromeres lie within vast stretches of ___. The arms of the chromosome extend outward from the centromere. Gradually, with increasing distance from the centromere, the DNA includes more protein-encoding sequences.

heterochromatin

Tightly wound, highly repetitive ___ forms the centromere (the largest constriction) and the telomeres (the tips) of chromosomes. Elsewhere, lighter-staining euchromatin includes many protein-encoding genes. The centromere divides this chromosome into a short arm and a long arm.

heterochromatin

Females are ___ XX and males are ___ XY

homogametic; heterogametic

A translocation event is responsible for creating

human chromosome number 2

An ___ shows chromosome arms (p is short and q is long) and numbered regions, called bands, and subbands. The numbers assigned to bands and subbands increase with distance from the centromere.

ideogram

Aneuploidies in offspring increases with ___; likelihood that a nondisjunction will occur in her gametes as women gets older

increasing maternal age

A rare type of translocation is an ___, in which part of one chromosome inserts into a nonhomologous chromosome. Symptoms may result if the inserted DNA disrupts a vital gene or if crucial DNA sequences are lost or present in excess.

insertional translocation

Homologous chromosomes recognize each other by their sequence similarity. So when an inversion occurs, an ___ can occur in order for the sequences to align with the pattern they recognize. Crossing over can lead to duplications and deletions in the subsequent chromosomes.

inversion loop

An ___ is the result of another meiotic error that leads to unbalanced genetic material; it is a chromosome that has identical arms. It forms when, during division, the centromeres part in the wrong plane.

isochromosome

A mutation is considered a chromosomal abberation if

it is large enough to be seen with a light microscope using stains and/or fluorescent probes to highlight missing, extra, or moved genetic material

The standard chromosome chart is called the ___; it displays chromosomes in pairs by size and by physical landmarks that appear during mitotic metaphase, when DNA coils tightly, enabling it to be visualized.

karyotype

The ___ is a set of genes that are inherited as a group; that is, during cell division they act and move as a unit rather than independently.

linkage group

Inversions with devastating effects can be traced to meiosis, when a crossover occurs between the inverted chromosome segment and the noninverted homolog. To allow genes to align, the inverted chromosome forms a ___. When crossovers occur within the loop, some areas are duplicated and some deleted in the resulting recombinant chromosomes.

loop

X and Y act as pairing partners and normally segregate during

meiosis I

Nondisjunction occurs when

members of a chromosome pair fail to separate

A chromosome is ___ if the centromere divides it into two arms of approximately equal length

metacentric

Most children born with a chromosome number other than 46 have an extra chromosome (a trisomy) rather than a missing one (a ___)

monosomy

The majority of the Y chromosome is ___; about 95% of it does not recombine with the X chromosome. Although there is some similarity in the telomeres, (pseudoautosomal region- sequence shared between the X and Y that lets them recognize one another as pairing partners during meiosis)

non-recombining

The meiotic error that causes aneuploidy is called ___.

nondisjunction

The basis of ___ is that chorionic villus cells descend from the fertilized ___, so their chromosomes should be identical to those of the embryo and fetus.

ovum

Two types of inversions are distinguished by the position of the centromere relative to the inverted section. A ___ is when the inverted section does not include the centromere. A ___ inversion includes the centromere within the loop.

paracentric; pericentric

The MoM; multiples of the median, indicates how far individual results deviate from the normal range of concentration for each marker for ___

personal statistics (race, diabetes, twin pregnancy)

Deletion and duplication occurs during ___.

prophase 1 of meiosis 1

Shugoshin Protein

protects centromere; makes sure dissociation of the homologous chromosomes occurs at the proper time during anaphase I to allow homologs to separate from one another; but cohesin remains intact protected by the shugoshin so that the sister chromatids segregate with one another during anaphase I and don't segregate apart from one other until anaphase II when the centromere and shugoshin is broken down.

The long arm of a chromosome is designated ___; and the short arm is designated ___

q; p (for "petite")

A ___ ___, who has 45 chromosomes, may not have symptoms. However, they would produce unbalanced gametes- sperm or oocytes with too many or too few genes that can lead to spontaneous abortion or birth defects.

reciprocal translocation

In a ___, the second major type of translocation, two different chromosomes exchange parts. If the chromosome exchange does not break any genes, then a person who has both translocated chromosomes is healthy and a translocation carrier. He or she has the normal amount of genetic material, but it is rearranged.

reciprocal translocation

During monosomy, both homologs if fixed will have ___, while in trisomy, the homologs ___.

same DNA sequence; can be recombined or the same

5 human chromosomes have bloblike ends, called ___, that extend from a thinner, stalklike bridge from the rest of the chromosome. The stalk regions do not bind stains well. The stalks carry many copies of genes encoding ribosomal RNA and ribosomal proteins. These areas coalesce to form the ___; a structure in the nucleus where ribosomal building blocks are produced.

satellites; nucleolus

Using a FISH probe is a little like a ___ finding the word "hippopotamus" in a book compared to pulling out all words that have the letters h, p, and o.

search engine

If nondisjunction occurs during meiosis,

some gametes may have an extra copy of some genes

Atypical chromosomes account for at least 50 percent of ___, yet only 0.65 percent of newborns have them. Most embryos and fetuses with atypical chromosomes stop developing before birth.

spontaneous abortions

Most autosomal aneuploids (with a missing or extra non-sex chromosome) are ___.

spontaneously aborted

A chromosome is ___ if the centromere establishes one long arm and one short arm

submetacentric

The chromosome parts that lie between protein-rich areas and the telomeres are termed ___. These areas extend from 8,000 to 300,000 bases inward towards the centromere from the telomeres. They include some protein-encoding genes and therefore bridge the gene-rich regions and the telomere repeats.

subtelomeres

___ are chromosome tips. In humans, each of them repeats the sequence TTAGGG. In most cell types, each shorten with each mitotic cell division.

telomeres

A ___ mutation is movement of genetic material between nonhomologous chromosomes. These chromosomes don't contain the same genes; we are changing the linkage group within the genome. *A translocation can occur during recombination in prophase 1 of meiosis; crossing over is a type of translocation (but not a mutation because we're exchanging between homologous chromosomes during recombination)

translocation

In a ___, different (nonhomologous) chromosomes exchange or combine parts. These can be inherited because they can be present in carriers, who have the normal amount of genetic material, but it is rearranged. It can affect the phenotype if it breaks a gene or leads to duplications or deletions in the chromosomes of offspring.

translocation

___ is a condition when females have an extra X chromosome in each of her cells. The only symptoms are tall stature and menstrual irregularities.

triplo-X

An individual whose cells have three copies of each chromosome is a ___

triploid (3N, like the way a diploid is 2N)

A karyotype with one extra chromosome is called a ___.

trisomy

The most common autosomal aneuploid among liveborns is ___, because this chromosome has the fewest genes.

trisomy 21

Inheriting two chromosomes or chromosome segments from one parent is called ___.

uniparental disomy (UPD) ("two bodies from one parent")