Biochemistry 6 Flashcards
Cytogenetics
the study of chromosomes and chromosomal abnormalities
Some diseases are caused by
Microscopically observable alterations in chromosomes. Could involve the presence of extra chromosomes or the loss of chromosomes. Or, structural alterations of chromosomes (loss, gain or movement of segments of chromosomes).
What is the leading known cause of intellectually disability and pregnancy loss?
chromosomal abnormalities
Chromosomal rearrangements are responsible for?
several human cancers.
CML and Burkitt lymphoma.
Karyogram
ordered display of 23 pairs of human chromosomes in a typical somatic cell: 22 pairs of autosomes and 1 pair of sex chromosomes
Chromosomes can be stained with various?
Stains, so that a banding pattern can be seen. The bands reflect normal differences in chromosome structure or composition
Autosomal chromosomes (1-22) are arranged from?
largest to smallest
Sex chromosomes are in the
lower right corner
Chromosomes have a p and q?
p = small arm (p for petite)
q= long arm
Each arm can be described by region and?
band number (region before band)
14q13
chromosome 14, long arm (q), region one, band 3
Acrocentric
centromere is high up
Cells with a complete set of chromosomes are termed
euploid
monoploid
diploid
triploid
tetraploid
1n
2n
3n
4n
The gain of one or more entire chromosome set is termed
polyploidy
Triploidy
cells that contain three copies (3n) of each chromosome (69 total). It usually occurs as a result of dispermy (the fertilization of an ovum by two sperm cels), and is common at conception.
The vast majority of polyploidy are
lost prenatally (about 1 in 10,000 live births). These babies have multiple birth defects of the heart and central nervous system, and they do not survive.
Aneuploidy
indicates a deviation from the euploid (normal) number of chromosomes, is the term used to describe the loss or gain of specific chromosomes.
Aneuploidy is the?
gain or loss of a SINGLE chromsomome
Two major types of aneuploidy are observed
trisomy (three copies of each chromosome) and monosomy (one copy of a specific chromosome)
Monoploidy
is the loss of an entire chromosome set
(leaving only 23 chromosomes), which is never seen in humans (except in gamete formation).
Monosomies and trisomies are usually caused by
nondisjunction (the failure of the two members of the chromosome pair to disjoin or separate) during either meiosis I or meiosis II (production of the
gametes). May or not be viable for life.
1st mitotic division non-disjunction is more
serious because you won’t get any normal diploid cells
All autosomal monosomies are
lethal
Only a monosomy of the X chromosome is viable:
Turner Syndrome
If the gamete produces a zygote, the resulting fetus will?
manifest the chromosomal abnormality
Nondisjunction can occur in the
gametes of both men and women
nondisjunction definition
when a homologous pair
of chromosomes fails to separate during
anaphase.
Three trisomies compatible with live birth (survival to term)
13, 18, 21 (smallest number of genes). This does not mean that all children with these trisomies survive, only that some do.
Why Trisomies 13, 18 and 21?
-fewer genes
-advanced maternal age (more than 35) is the primary risk factor
Trisomy 21 indicated as
47, XY + 21 or 47, XX + 21
Trisomy 21 constitutes approximately 1 of every
700 live births
Trisomy 21 is the most
commonly seen form of trisomy that is compatible with live birth (likely due to its smallest chromosome size)
Flourescence In Situ Hybridization (FISH) Analysis of Trisomy 21
-A fluorescence probe against a specific DNA sequence binds to the chromosome
-Chromosome 21 is red
Down syndrome characteristics
-Variable expressivity
-Standardized IQ between 40 and 60
-Almond eyes, flat nasal bridge, protruding tongue
-GI obstruction
-Single palmar crease - a single transverse line across the palm
Trisomy 21
Approximately 95% of people with Down Syndrome.
Results from three copies of chromosome 21.
Three copies of chromosome 21
Robertsonian translocation
About 3% of people with Down Syndrome. Results from a Robertsonian translocation. This increases the risk of having more than one child with trisomy 21. One is part of the derivative chromosomes - 45 chromosomes.
Mosaicism and down syndrome
Approximately 2% of people with Down Syndrome.
Results from some cells having three copies of Chr. 21 and some cells have two copies of Chr. 21. This can result in a later diagnosis if the typical features of Down syndrome are not apparent. You can kick out the extra X chromosome and that cell becomes euploid.
At some point an extra
Chromosome 21 and can be kicked out. All the cells are euploid while the others are triploid. Phenotype is different - can be mild or normal range of down syndrome.
The risk of producing a child with Down syndrome is much higher for a
45 year old woman than a 25 year old woman
However, the common belief that most children with down syndrome are born to
an older women is incorrect.
There are a lot more 25 year old women having
children than there
are 45 year old women having
children. This results in more Down syndrome conceptions in women under age 35 than over age 35.
Women under the age of 35 have
80% of the babies with Down syndrome.
Mothers of infants with Down syndrome have an
average age of
28 years
Trisomy 18 (Edward Syndrome)
Trisomy 18 is the most common chromosomal abnormality among still borns, so the incidence rate is lower
Trisomy 18 occurs primarily as a result of
non-junction
What is not seen in Edward Syndrome?
Robertsonian translocations because chromosome 18 is not acrocentric.
Trisomy 13 is what syndrome
Patau syndrome
Trisomy 13 has post-natal survival rates similar to that of
Edward syndrome
Origin of extra chromosome 13
- 95% of cases are due to nondisjunction in the
mother’s gametes. - About 5% of trisomy 13 is a result of Robertsonian translocation.
Robertsonian translocation definition
Abnormalities of the sex chromosomes are tolerated more than?
abnormalities of the autosomes
1.X-inactivation (most genes on the X chromosome)
- incomplete x inactivation
incomplete x inactivation
some genes such as the ones on pseudoautosomal regions (PAR), Xinactivation center (XIC) and X-inactive specific transcript (Xist) are NOT inactivated.
In a normal female: one copy of most genes on the ____ chromosome are __________ but two copies of genes in the what are expressed?
One X gene is expressed, two copies of PAR1/PAR2 are expressed
In a normal male, one copy of
PAR1/2 expressed from X-chromosome and one copy of PAR1/2 expressed from Y-chromosome
In an individual who has a sex chromosome abnormality
Either increased or decreased gene dosage of PARs
Monosomy for the X chromosome
Turner syndrome, 45X or 45X0
In Turner syndrome, there is only
one X chromosome, so an individual has only one copy of the PAR1 and PAR2 genes, and is lacking a second copy.
Turner syndrome & PAR gene
Therefore, they have only 50% of the PAR gene products compared to a normal individual. There are many variant forms with partial X chromosomes and mosaicism.
turner syndrome treatment
includes growth hormone and estrogen therapy.
Turner syndrome characteristic features
infertile, ovaries do not develop properly
Klinefelter Syndrome
47XXY. Assigned male at birth.
In this case, the individual will have one Barr body (inactivated X) but is gaining an extra active copy of all
the pseudoautosomal genes on the extra X chromosome, resulting in having an excess of those gene products. They have three copies of PAR, while a typical person only has two.
Klinefelter syndrome characteristics
do not make sperm, come to the doctor for infertility problems
Klinefelter characteristic phenotype is so
phenotype is so subtle
In males, the X and Y chromosomes?
Pair and undergo recombination during the generation of gametes. To pair, there must be regions of homology.
The homologous regions, termed the pseudoautosomal regions (PAR1 and PAR2), are at the
tips of both arms of X and Y and include about 2.5 million base pairs of DNA.
Errors during recombination can lead to
XX males and XY females
SRY gene is translocated to the?
X chromosome during meiosis inappropriately to produce an XY female.
Just proximal to the pseudoautosomal region 1 (PAR1) is a gene called
SRY (sex-determining region on the Y) that is involved in male sexual development.
The SRY gene produces a transcription factor which controls the expression of other
Genes that initiate the male phenotype in the early embryo. Those genes support male gonad (testes) development and suppress the development of female reproductive
structures.
translocation
Interchange of genetic material between NON-homologous chromosomes. Most common chromosomal aberrations seen.
Translation can be broken down into two groups
- Reciprocal translocation
- Robertsonian translocation
Reciprocal translocation
can be balanced (no genes deleted or duplicated) or unbalanced (genes
deleted or duplicated). Do not change chromosome number, just change location.
Robertsonian translocations
fusion between two acrocentric chromosomes
Reciprocal translocation occurs in two steps
- Chromosomal breaks on two homologous chromosomes at the same time
- The broken chromosomes exchange the material that was broken off.
The resulting spliced chromosomes are called derivative chromosomes.
Called chromosome 4 because it has the
centromere from chromosome 4.
For example, the individual below (zygote) has a balanced reciprocal translocation between
chromosomes 3 and 6, i.e. a part of chromosome 6 is now on chromosome 3 and a part of 3 is now on
6.
This person typically does NOT exhibit a phenotype because there is no deletion or duplication of
genetic materials. “Perfectly fine” until they want to have children.
However, the offspring of this individual are at high risk for chromosomal abnormality syndromes that
can include both duplications of chromosomal regions and deletions of chromosomal regions. This happens when gametes are made.
Possible gametes after translocation
Can have missing 6 - extra 3, can be missing 3 - extra 6, etc. You are worried about the next generation. 2/6 or 1/3 are viable.
Robertsonian Translocations are chromosomes
13, 14, 15, 21, 22 (involve only acrocentric chromosomes)
Robertsonian Translocation
The translocation involves the loss of the short arms of two acrocentric chromsomes and the fusion of the long arms at the centromere.
Robertsonian Translocation individuals are phenotypically
normal because the short arms of acrocentrics contain redundant genetic material (rRNA genes) that also exist elsewhere in the genome. They do have one fewer chromosome in total. They will be 45, XX or 45, XY
Robertsonian how many are viable
3/6 or 1/2
Chromosomal deletion
loss of genetic material caused by chromosomal break, can be severe due to loss of large amounts of genetic material
Mosaicism karyotype is
46 chromosomes
Cri du chat syndrome
(Cry of the cat)
-Deletion of the distal, short arm of chromosome 5: 46, XX (del5p) or 46, XY, del(5p)
-Characterized by the distinctive cry of the child, intellectual disability (average IQ about 35),
microcephaly, and characteristic facial features (wide-set eyes, low-set ears, small chin).
Ring chromosomes
Deletions sometimes occur at both tips of a chromosome. The
remaining chromosome ends can then fuse, forming a ring chromosome. This is rare
The karyotype of a female with a ring X chromosome is
46 X, rX which results in Turner Syndrome
Ring chromosomes are often lost resulting in
monosomy for the chromosome in at least some cells (mosaicism or the ring chromosome may be seen)
Common ring chromosomes
14 and 22
Isochromosome
A chromosome can divide along the axis perpendicular to its usual axis of division. The result is an isochromosome, a chromosome that has two copies of one arm and no copies of the other.
Isochromosomes of most autosomes are
lethal
Most isochromosomes observed in live births involve the
X chromosome, and babies with isochromosome usually have features of Turner syndrome
Isochromosome 18q
which produces an extra copy of the long arm of
chromosome 18, has been observed in infants with Edwards syndrome phenotype
Uniparental disomy
one parent contributed two copies of a chromosome and
the other parent contributed no copies (i.e., the
inheritance of two copies from the mother and
none from the father means that the offspring
receives no active paternal genes in the
imprinted region).
Causes of uniparental disomy
- Union of a gamete that has two copies of a
specific chromosome with a gamete that
contains no copies of that chromosome. - Trisomic conception can lose one of the
extra chromosomes (Mitotic errors in the early embryo, such as chromosome loss with subsequent
duplication of the homologous chromosome.)
