Biochemistry 4 Flashcards
We have known for more than _____ years about the different sex contribution in males XY and females XX
50 years
Labeled as “sex chromosomes” but it is really?
genes (some in autosomes) that determine sex.
Development is very sensitive to an?
Imbalance in the number of genes. Normally, each gene is present in 2 copies.
Several human genetic ________ are the results of gene deletion or gene duplication
deficiencies
Males contain only one X chromosome. How to accommodate the numerical difference in X-linked genes?
- X linked genes work twice as hard in males
- X linked genes work half as hard in females
- One copy of each X-linked gene is inactivated in females
A mechanism must exist for __________ compensation, otherwise?
dosage compensation, otherwise women would have twice the product for almost any gene on the X chromsome.
Lyon Hypothesis
one of the two female X chromosomes is inactivated in every somatic cell
Lyon hypothesis happens
early in female embryonic development, random process with one exception, permanent inactivation
Females are mosaics which means?
two different populations of cells, with either paternal OR maternal X chromosome inactivated
Anhidrotic ectodermal dysplasia
Abnormal development of structures like nails, hair, or sweat glands. Males show absence of sweat glands.
Why do heterozygous females display random patterns with and without sweat glands?
random inactivation
Lyon hypothesis has proven to be accurate by the presence of?
Barr bodies, dense mass of chromatin in interphase of somatic cells that is not observed in healthy males (but may be found in males with chromosomal abnormalities)
The number of Barr bodies in a somatic cell is?
one less than then number of X chromosomes
X inactivation starts at the? Contains which gene?
XIC (X inactivation center). Contains XIST gene.
What escapes inactivation?
XIST
XIST can only be expressed from the?
Inactive X chromosome: it can only be detected in healthy females
XIST _______coats the inactive X chromosome
RNA
What helps to ensure long-term stability of the inactivation?
High methylation of DNA and histone hypoacetylation.
If the Barr body represents an inactive X chromosome, why would having extra fewer or inactive chromosomes (triple X) represent any problem?
X-activation is incomplete. Small percentage of genes on the X chromosome escape inactivation, meaning they are still expressed and can disrupt normal development,
About ______ of all genes on the X chromosome escape inactivation and remain active in all copies. What genes does this include?
15%. XIST gene and PAR1 and PAR2 regions (pseudoautosomal regions) behave like autosomal genes (are not sexed linked).
Lack of or excess gene expression leads to?
An affected individual
Healthy = ______ active + _______ inactive X (XIST, PAR1, PAR2)
100% active X
15% inactive X (is ACTIVE)
Affected = XO = _______ active X
100% (excess) (ALL ACTIVE)
Affected XXX = _______ active X + ____ inactive X + ____ inactive X
100% active X
15% inactive X (ACTIVE)
15% inactive X (ACTIVE)
Sex Linked genes are those genes located on the
X or Y chromosomes
Relatively few genes (and no vital genes) are located on the?
human Y chromosome
Some housekeeping genes located on the Y chromosome have what mechanism?
Inactivation-escaping homolog on the X chromosome.
Females Homozygous for the non-mutated allele are:
Heterozygous for non-mutated alle are:
X1X1
X1X2
Females homozygous for diseased allele
X2X2
In females, X linked recessive genes have a pattern of inheritance like?
autosomes, although mosaicism is possible in some heterozygotes
Males hemizygous for X chromosome
X1 (non-mutated) or X2 (disease). In males, it behaves like a dominant gene.
X linked recessive diseases are more common in?
males than females
X-linked recessive inheritance pedigree
- trait is much more frequent in males than females (all males)
- NOT male to son transmission.
- The disease can skip generations with carrier females.
X1X2 (carrier female) + X1Y (healthy male)
Most common mating
2nd possible mating: normal female (X1X1) + affected male (X2Y)
Daughters: 100% unaffected carriers
Sons: 100% healthy
3rd possible mating: carrier female + affected male
-Rare occurence
-Daughters 50% affected and 50% unaffected carriers
-Sons: 50% healthy and 50% affected
-NOT male to son transmission
X-linked recessive diseases
- Hemophilia A (factor VIII deficiency)
- Hemophilia B (factor IX deficiency)
- G6PD deficiency
- OTC deficiency
- Lesch-Nyhan syndrome
- Red-green colorblindness
- Duchenne Muscular dystrophy / Becker muscular dystrophy
GLORD H
Red-green color blindness
Rare among females, affects a small percentage of males. In many cases it is the result of aberrant recombination of homologous chromosomes in meiosis.
Duchenne muscular dystrophy (DMD) gene mutation and symptoms are?
gene mutated: dystrophin
symptoms: Gowers sign, progressive weakness and muscle loss
Most mutations leading to DMD are?
deletions that produce complete absence of the protein.
Becker muscular dsytrophy
mutation that results in a milder form of muscular dystrophy, where the protein is partially active
Dystrophin is necessary to maintain?
structural integrity of the cell’s cytoskeleton
Only 8-10% of female heterozygous carriers exhibit muscle weakness due to ?
random X-inactivation
Since X-inactivation is random, it is possible that, by random chance, most X chromosomes carrying the non-mutated allele are?
Inactivated. Such females are termed manifesting heterozygote or manifesting carrier. Female heterozygous for an X linked recessive disorder with mild manifestation of the disease, as a result of random X inactivated. So, by chance, the good X chromosome is inactivated more than the bad. Females have a mixed pattern of random x inactivation.
X-linked dominant inheritnace
- Trait is much more frequent in females than males
- Vertical transmission
- NOT male to son transmission.
- Affected males cannot transmit the diseases to sons, but TRANSMIT 100% OF THE DISEASE TO DAUGHTERS
X linked dominant diseases are
- hypophosphatemic rickets
- fragile x
- alport syndrome
- rhett syndrome
Hypophosphatemic rickets gene and symptoms
gene: PHEX
symptoms: bone deformities, joint pain, poor bone growth, short stature
fragile X syndrome gene and symptoms
gene: FMR1
symptoms: intellectual disabilities, distinctive facial features, anticipation due to trinucleotide repeat expansion, reduced penetrance in females (this is the one that is NOT more frequent in females).
The X chromosome is NOT fragile, although it looks like that in certain culture media.
Alport syndrome gene and symptoms
gene: COL4A5
symptoms: loss of kidney function (hematuria, proteinuria), hearing, and vision loss
Rhett syndrom gene and symptoms
gene: MECP2
symptoms: regression in motor, verbal and cognitive abilities, ataxia, growth failure and hand-wringing, mostly in females - usually lethal in males
Sex-influenced means
Autosomal trait expressed more frequently in one sex than another. (in the autosome). The trait is modified by the sex of the individual.
Sex influenced trait
male patterned baldness (autosomal dominant in males and autosomal recessive in females)
Other sex-influenced trait
gout (multifactorial) and hereditary hemochromatosis
Sex-limited trait
Autosomal trait expressed ONLY in one sex. Due to anatomical but not genetical differences. Example: uterine defects or sperm mobility problems. Although not manifested, it can be transmitted to the next generation.
Not all RNA and proteins produced in a cell are encoded by nuclear DNA. ______ contains 37 genes, mostly required for oxidative phosphorylation.
mtDNA
mtDNA is considered a remnant of?
when mitochondria were bacteria
There are ________ of mitochondria per cell and multiple mtDNA copies per mitchondria
hundreds
Replicative segregation
No tight control of segregation, random distribution of mtDNA between daughter and mitochondria, random distribution of mitochondria between daughter cells
Homoplasmy and heteroplasmy
High rate of mutations in mtDNA. Mitochondria can be heterogenous in their mtDNA and a cell can also be heterogenous.
Heteroplasmy
daughter cell received a mixed population of mitochondria, with and without mutated mtDNA
Homoplasmy
daughter cell received a pure population of mitochondria, all with non-mutated or mutated mtDNA
The more mitochondria with the mutation,, the?
more severe the disease expression
Mitochondrial disease can show?
considerable variability because of heteroplasmy
all mtDNA is inherited from the?
mother
(about 200 mitochondria per sperm cell vs. 200,000 mitochondria per egg cell)
About 200 mitochondria per _________ vs. 200,000 mitochondria per ________
sperm cell
egg cell
Non-mendelian inheritance - both males and females can be? But only females can?
affected, but only females can transmit the disease to their offspring
______ percentage of the offspring from the affected female will manifest the mitochondrial disease
100%
Mitochondrial Diseases
- CPEO
- Kearns-Sayre Syndrome
- Leigh syndrome
- LHON syndrome
- MERRF
- MELAS
- Pearson syndrome
K(1)L(2)M(2)P(2) – actually CPEO
