Winter Exam 3 Flashcards
Why do we need meiosis?
so the number of chromosome does not double through each generation
What stpes does meiosis consist of?
sigle round of dna replication and two cell divisions
Which part of meiosis is known as the reductinoal division phase?
Meiosis I
What is the genetic content during Telophase I?
haploid number of chromosomes (1n)
diploid amount of DNA (2c)
What is the genetic content of daughter cells at the end of meiosis?
4 haploid cells that are genetically different from each other and the precursor cell
What happens if there is Nondisjunction at Meiosis II?
Failure to separate sister chromatids
During what phase does genetic recombination occur?
Prophase I
What is the synaptonemal complex? During what phase is it observed?
ladder like protein w two lateral elements and one central element.
Only seen in Prophase 1
It keeps homologs physically linked
What proteins make up the ladder-like SC? What happens if there are mutations in these genes?
central rungs: SYCP1
side of ladder: SYCP2, SYCP3
Subfertility and/or infertility
What are the 4 subphases of Prophase I in order?
Lepotene
Zygotene
Pachytene
Diplotene
What happens in Lepotene (4)?
200-400 double stranded breaks - non-random
SPO11 (endonucleases)
pairing of homologs
formation of SC lateral parts
What happens in Zygotene ?
synapsis of homologs
lateral and central elements of SC join
most DSB repaired via non-crossover here
What happens in pachytene?
SC formation complete
ALL DSBs repaired- crossover: DNA exchange bw two non-sister chromatids
chiasmata bw non-sister chromatids
What happens in diplotene?
SC breakdown homologs separate (except chiasmata)
What is independent assortment?
homologous chromosomes randomly distributed during division I.
2^n possible gametes
(where n= haploid #)`
What is genetic recombination?
crossing over of reciprocal DNA in non-sister chromatids
scrambling of dna
So # possibilities are endless
What is a chiasma and whay is it important?
holds homologs together until anaphase I
proper segretgation
What is the dictyate stage?
the arrest of primary oocytes through prophase 1 (diplonema stage)
500X increase in size here
Describe how there is incomplete cytokinesis in spermatogenesis.
incomplete cytokineses
forms a syncytium
share resources
synchronize process
what is the prinicple of segregation?
alleles segregate
genes occur in pairs and only one is transmitted
(Contrasted blending theory)
what are the 3 mendellian laws
- segregation
- independent assortment
- dominance/recessive
What is an exception to indenpendent assortment?
genes located in the same proximity may assort together
What is autosomal dominnat characterized by?
vertical transmission no skipped generations equal gender proportions father to son possible heterozygosity less severe
What are some examples of autosomal dominant disoriders>
postaxial polydactylyl Huntingtons disease marfanss neurofibramotsis type 1 RB
What are characteristics of autosomal recessive?
horizontal transmission, skipped generation equal gender proportions father to son possible usually from mating heterozygotes
What are examples of autosomal recessive disorders?
sickle cell anemia
cystic fibrosis
Hurler syndrome (lysosomal storage)
Tyrosinase-negative albinism
What is tyrosinase-negative albinism?
mutation in tyrosinase gene
results in block of snthesis of melanin
What is consanguinity?
mating of closelyrelatied individuals
associated w high proportions of autosomal recessive diseases
Define penetrance
the probability a mutated gebotype will have the corresponding phenotypic expression
Reduced penetrance is <100%
What is an example of a disoreder with reduced penetrance?
hereditary RB (mutationin Rb gene) - 90% Inherited as an autosomal dominant trait So the 10% of non-penetrant people have a 50% chance of transmission 1/20,000 children-most common
Describe the mechanism of reduced penetrance in Retinoblastoma
- inherited mutated gene plus a…
- gene damaging event (so 2-hit)
This gene damage can occur in normal people too
What is Variable Expression?
the extent of expression of a particular disease phenotype (mild to severe)
can be environmental cause
(NOT penetrance, which is all or nothing)
What is an example of a variable expressive disease?
Neurofibromatosis (NF1)- common 1/3000
less severe:cafe au lait spots, benign growths, neurofibromas
more severe: thousands NFs, earning diasbilityes, HTN, scoliosis
fully penetrant, though
What does it mean when a disease is congenital?
When the disease is present at birth
What is Huntingtons disease?
delayed onset; 30-50 yrs loss of motor control, psych disorders 100% penetrant expansion of trinucleotide (CAG) in 5' translated region onset earlier when affected father
What is pleiotropy? What is an example of a pleiotropic gene?
Genes that effect multiple organ systems/tissues
ex: Marfan’s: eye, bones, CV
mutant fibrillin-1 gene
What is heterogeneity? Name an example of a disease?
mutations at two or more distinct loci can produce same/similar phenotypes
ex: Osteogenesis imperfecta
100% penetrant, but variable expression
mutation pro-a-1 or pro-a-2 collagen gene
How does a person with a new mutation influence that persons offspring?
Genes at that loci of the germ cells will remain unchanged and will be normal
However the offspring has a 50% higher risk of getting an autosomal dominant disease
What is germline mosaicism?
presence of more than one genetically distinct cell line in the germline but not in somatic cells
(Parent carries mutation in his/her germline but does not express the disease in somatic cells)
How does germline mosacism occur? When is it likely to be seen
During embryological developement of the parent, there was a mutation that affected all/part of the germline but none of the somatic cells
Most likely to be seen when two autosoal dominant offspring have disease when there is no previous family history
For what diseases is geermline mosaicism possible?
achondroplasia
neurofibromatosis 1
duchenne dystrophy
hemophilia A
What is genomic imprinting? Example?
The differential activation of genes depending on the parent from which the gene was inheritied
ex: deletion of 3-4 Mb on long arm of chrom15
When inherited from dad: PWS
when inherited from mom: Angelman’s
What is X inactivation (Lyonization) ?
1 X chromosome in every somatic cell at the 16-64 cell stage of XX females is randomly and permanently inactivated in that cell and in all its clonal descendents.
2 distinct populations of cells: one with an active paternally derived X chromosome and the other with an active maternally-derived X chromosome.
What is dosage compensation
The effect of X-inactivation leading to the equalization of gene products in males and females
What are characteristics of X-linked Dominant inheritance?
Twice as many females affected as males
-because they carry 2x the amount of X chromes
No father to son transmission
All daughters of affected fathers are diseased
Vertical transmission
Depends on affected parent’s gender
What is the most comomn cause of inherited mental retardation in males?
Fragile X syndrome
What is Fragile X Syndrome?
X chrom. w/o folic acid breaks 80% pen in males, 30% in females (X-inactivation) CGG repeats (230-1000) in 5' untranslated region Males with the pre-mutation (50-230 repeats) cannot transmit to their daughters, but # of repeats is expanded when passed through the daughters. Result is grandsons and great-grandsons of males with pre-mutation are more likely to be affected.
What is anticipation?
Wheen more recent generations express more severe forms of a disease
What are the 4 main characteristics of X-linked recessive diseases?
- Horizontal transmission with skipped generations
- Mostly males affected
- Occurence/recurrence is 25% overall (0% girls)
- NO father to son transmission
From whom is mitochondrial DNA inherited? Why?
From mothers. Sperm do not have mitochondria in their head
Referred to as pseduo sex linked
What are some exapmles of mitochondirally inherited DNA? (pseudo-sex-linked)
Leber hereditary optic neuropathy
Kearns-Sayre disease
Pearson Syndrome
When can you use karyotyping?
metaphase cells light microscope gender ploidy large scale >4million bp
When can you use FISH?
interphase or metaphase
fluorescence microscope
fluorescent labeled DNA probes
What chromosomes is aneuploidy most common?
13, 16, 18, 21, 22
What is trisomy and how does it occur?
presence of an extra chromosome
nondisjunction during gametogenesis
(50% of spontaneous abortions)
(also from Robertsonian tranlocation, mosacism)
Trisomy 21 can lead to the overexpression of which genes?
SOD1-overexpress causes high H2O2 COL6A1-heart defects ETS2-hypotonia DYRK-mental retardation APP-Alzheimer's
What is the triple screen for Down’s syndrome?
Screen for Downs Syndrome:
maternal age risk
ultrasound
maternal serum testing
What are some methods to obtain a prenatal sample of cells
amniocentesis
chorionic villi sampling
percutaneous umbilical blood sampling
What is a Robertsonian translocation?
reciprocal translocation of homologous chromosomes.
Acrocentric centromere
Often long arms join together and short arms join together but arent viable
Besides trisomy 21, what are some other common autosomal aneupoloidy syndromes?
Patau syndrome (trisomy 13) Edwards Syndrome (trisomy 18)
What are the two classes of multifactorial traits?
continuous (quantitative)
discontinuous (dichotomous)
What are characteristics of continuous traits?
Gaussian distribution
Additive locus model
Genetic background can be expressed differently in different environments
What are characteristics of discontinuous traits?
NOT a Gaussian distribution
either present or absent
Threshold model
Who is more susceptible to a discontinuous disease?
First degree relatives
If disease is more common is certain sex, then relatives of the opposite sex are at higher risk
How much more common is pyloric stenosis in males
5X more common in males
What type of couple will have a higher risk of producing a baby with pyloric stenosis: 1) couple in which the male had stenosis in infancy or 2) couple in which the female had stenosis in infancy
Couple in which the female had pyloric stenosis in infancy
What are the probabilities of getting congenital hip displasia in men and women?
Women are 9X more likely
What is the risk of getting cleft lip in the general population?
1/1000
What is the formula for risk of recurrence?
recurrence risk = root (occurrence risk)
What is heritability?
the degree of genetic factors for a certain trait
H = 2( Cmz - Cdz ) , where C is concordance
(0-1 range)
What is the cause of neural tube defects?
and spina bifida anencephaly?
failure of neural tube to close durin early development
List exapmles of multifactorial diseases
cardiovascular disease cancer DM Alzheimers obesity alcoholism psych disorders
What is an inborn error of metabolism?
genetically determined biochemical disorder in which a specific enzyme defect causes a clinically significalnt block or alteration in a metabolic pathway
What is phenocopy?
overlap of symptoms bw disorders
What are some causes of pathogeneses of metabolic disorders?
Deficiency of compound
Toxic compound
Abnormal localization
What organ systems are more likely to be effected by metabolic disoreders?
hepatic and neurologic, though any system can be effected
What are some early signs and symptoms of genetic disorders?
energy defectis
toxic products-> poor feeding, vomiting, failure to thrive, lethargy, dev delay
What are some later signs of genetic disorders?
toxin accumulation leading to cell damage ataxia seizures lethargy coma neurologic damage
What are the most likely causes of acute neonate demise?
tyrosinemias oranic acidemias urea cycle defects fatty acid oxidation defects glactosemia
What are some amino acides that can lead to metabolism defefcts?
phenylalanine
tyrosine
BCAA (val, leu, ile)
What is alkaptonuria (AKU) ?
Deficiency in HGO causes HGA deposition
Black Urine disease (homogentisic acid excrete)
abnormal pigmentation, arthritis
autosomal recessive (Slovakian bad)
What is Classic Phenylketonuria (PKU) ?
mutation in PAH (phenylalanine hydroxylase) Most common a.a. metabolism disorder Brain and neuro damage Worse if mother had untreated PKU Turkish descent is more common
What is Hereditary tyrosinemia type 1 (HT1) ?
Deficiency in FAH (fumarylaceoacetate hydrolase)
Accumulation of substrate
can lead to liver, kidney and neural problems
What is Maple Syrup Urine Disease (MSUD) ?
Deficiency in any protein component (BCKAD)
syrup scented urine,
neuro probems
What is Galactosemia?
Most common monogenic disorder of carb metab.
Failure to convert galactose to glucose
Mutation in GALT
same missense mutation in 6th exon
poor suckling, failure to thrive, vomiting, diahrrea, jaundice
cataracts can be observed
also caused by galactokinase and UDG-4 deficiencies
What types of tissues do glycogen disorders effect most?
liver
skeletal muscle
What is the most common source of energy for skeletal and cardiac muscle during fasting?
fatty acid oxidation
Provides ketone bodies instead of glucose
Describe congenital adrenal hyperplasia
mutation in CYP21A2 (cyt P450)
which is expressed in adrenal cortex
Usually from gene conversions
What are MPS disorders?
Inability to degrade glycosaminoglycans
10 different enzymes cause 6 distinct disorders
ex: Hurler, Hunter, Sanfilippo
Most autosomal recessive except Hunter and Fabry (X linked)
What are sphingolipidoses?
lipid storage diseases
ex: Tay Sachs and Gaucher
What is the result of Tay Sachs?
accumulation of GM2 gangliosides in neurons
no treatment available
What is the cause of Gaucher and describe the different types?
Deficiency in glucocerebrosidase leading to accumulation of glucosylceramide
Type 1: visceromegaly, skeletal diseases
Type 2: most severe; death in 2 years
Type 3: Intermediate phenotype
Cerezyme is recombinant glucocerebrosidase
How is X-linked adrenoleukodystrophy (ALD) different than other x-linked diseases
about 50% of female carriers have less severe form
What lab values are needed for a triple screen ?
AFP
HCG
UE
At what gestation is MSAFP done?
16 weeks - 2nd trimester
When is AFP likely to go up? down?
When the fetus has an open neural tube defect
Spina bifida: MSAFP will be elevated
Down’s syndrome: MSAFP will be somewhat low
What types of diseases is the triple screen used for?
Down’s
Trisomy 18
Neural Tube Defects (NTDs)
What is the quad test?
triple screen + inhibin A
performed in 2nd trimester
What lab values would you see for inhibin A with a fetus with Down’s syndrome?
Increased inhibin A levels
What are commonly tested markers in the first trimester?
free B-hCG
total B-hCG
PAPP-A (pregnancy associated plasma protein A)
What is low PAPP-A levels indicative of?
Down’s syndrome or Trisomy 18
Which marker is the only one to be useful in the 1st and 2nd trimester?
B-hCG
What type of ultrasound scan might be useful to identiy higher risks for Down’s and Trisomey 18?
Nuchal translucency
What test is used to detect neural tube defects?
AFP
What will an amniocentesis provide?
cells for growth
FISH analysis
amniotic fluid
When is diagnostic testing used?
for a symptomatic person
e.g. hemochromatosis
When is predictive testing used?
people with a family history of disease
Presymptomatic: ex Huntingtons
Predispositional: Breast cancer
What is included in a partial panel for cystic fibrosis?
87 different mutation tests
Delta F508 is most common mutation
For hemochromatosis, which gene mutations can detect most of the cases?
C282Y
H63D
Which of the steps of cancer (initiation, promotion, progression) is modifiable?
promotion
What is the difference bw a chromosome and a chromatid?
When two DNA molecules of duplicated chromosomes are joined together, each molecule is a chromatid/
(When unduplicated, each is a chromosome)
What happens during each phase of mitosis?
prophase: chromatin condenses
prometaphase: nuclear envelope breaks down
metaphase: sister chromatids align at center
anaphase: chromatids migrate opposite
telophase: nuclear envelope forms
During what phase of prophase 1 does pairing of homologs occur?
leptotene
During what phase of prophase 1 does synapsis occur?
zygotene
During what phase of prophase 1 does crossing over occur?
pachytene
When does the second meiotic division of an oocyte take place?
after fertilization
What phase do secondary oocytes remain in until further stimulation?
Metaphase 2
Even when risk is higher for older women to have Downs children, why are most Downs babies born to women younger than 35 years?
Most women who have babies are less than 35 years
How does having a baby affected with Down syndrome affect a woman’s risk for having another affected baby in a subsequent pregnancy?
Risk increases
Theoretically nondisjunction should be random
But risk increases to 1/100
List different ways a triploid cell can come about?
2 sperm fertilize 1 egg (2/3 cases)
diploid egg and 1 sperm (1/3 cases)
(possible to have diploid sperm but rare)
What is the cause of tetraploidy?
Mitotic failure
Chromosomes segregate into 1 daughter cell
n=92
How many chromosomes are in a karyotype of a Robertsonian tranlocation person?
45
What is the phenotype of a Robertsonian translocation person?
normal and abnormal
physical appearance normal
but repro is affected
Which Robertsonian translocation can lead to Downs ?
t(14:21) / 21
-There are 46 chromosomes but still a trisomy
/How might mosaic Downs arise
Somatic: mitotic nondisjunction (some 46, some 47)
Meiotic: Trisomic egg (47)
-Anaphase lag can lead to trisomy rescue
- rest of cell shave 47 tho
What is the genotype for Kleinfelter syndrome?
47 XXY
nondisjunction during Meiosis 1 so sperm is XY OR
nondisjunction during egg Meiosis 2 so egg is XX
What is the genotype for Turner Syndrome?
45 X
Mosacism or nondisjunction
What is the mutation in Alkaptouria (AKU)?
What is another name for the disease?
mutated HGO leads to HGA deposition
Black Urine disease
What is the mutation in Classic Phenylketonuria (PKU)?
Mutated PAH (phenylalanine hydroxylase)
What is the mutation in Hereditary tyrosinemia 1?
FAH (fumarylacetoacetate hydrolase)
What is the mutation in Maple Syrup Urine Disease?
BCKAD (branched chain ketoacid dehydrogenases)
What is the mutation in Galactosemia? M
mutated GALT
(OR galactokinase or UDG4E deg
What is the most common disorder for fatty acid oxidation?
MCAD (medium chain acyl coenzyme A dehydrogenase)
