Genetics Flashcards
Streak ovaries in turners syndrome. Means what histology app
Ovaries are composed of only connective tissue
There are no developing follicles
What is cause of follicle less streak ovaries in turners syndrome
Loss of paternal chr X
Loss of all ovarian follicles by age 2
Ovaries develop normally in fetal life but by 2 they loose their follicles
Turner girls are infertile have amenorrhoea
No menses or breast
Only pubic hair are present
Most common cardiac abnormality with turners
Bicuspid aortic valve
Therapeutic radiation used in cancer treatment causes what effects
- free radical damage— cell as well as DNA damage
— DOUBLE stranded DNA BREAKS
SINGLE STRAND BREAKS ARE NOT EFFECTIVE BECAUSE THEY ARE EASILY REPAIRED BY POLYMERASE
Which nucleosides undergo dna methylation
Only cytoside and adenine
Point mutation in beta globin gene
With change of glutamic acid to valine at 6th position
What dz
Sickle cell disease
Examples of missense mutation
Sickle cell glu A - valine Others Glutamine-valine Histidine - leucine Valine-glutamic acid
Name trinucleotide expansion genetic disease
Huntington
Freidrichs ataxia
Fragile X
myotonic dystrophy
Genomic lmprinting is selective inactivation of genes of either maternal or paternal origin
15q same region deletion gives two syndrome they are
Prader willi—when chr with deletion comes from papa
Angelman— mommy gene has deletion
What is pleio tropy
One gene mutation leads to multiple unrelated abnormalities
Linkage disequillibrium occurs due to
Physical proximity of genes on the same chromosome
If two genetic loci are on different strands then their gametes will have each halplotype with equal 1:4 frequency
This is called
Linkage equillibrium
What does hla DQA1 and HLA DQ B1 code for
A1 alpha chains on mhc 2
B1 beta chains in mhc 2
Severity of mitochondrial disease is related to proportion of abnormal to normal mitochondria
What is heteroplasmy
Presence of different mitochondrial genomes mutated as well as wild in single cell
Law of segregation is seen in
Gametogenesis
Ie separation of paired chromosomes
So that offspring inherit only half of each parents composition
Congential hypothyroidsm babies are normal at birth
Symptoms come at around 2 months becausd
Maternal T4 in circulation helps
It wanes by 2 months
Symptms of congenital hypothyroidism
Lethargy Enlarged fontanelle Protruding tongue Poor feeding Constipation Dry skin Jaundice
Increased TSH
LOW FREE T4
Affected males will always produce unaffected sons and carrier daughters
Carrier females have 50percent chance of producing affected son or carrier daughter
This inheritance is
XL recessive
Male offspring of unaffected parents is affected
Affected person has at least one parent who is also affected regardless of sex
He will always produce affected daughters but none of the sons will be affected
X linked dominant
In FISH test
Gold standard for genetic
genes of interest are hybridised with fluroscently labelled DNA probe
Lack of fluroscent signal suggests
Microdeletion
Autosomal recessive microtubular defects dynein arm is
Kartagener syndrome
Primary site of ribosomal RNA rRNA TRANSCRIPTIOM
Nucleolus
Contains RNA polymerase 1
Function of RNA POLYMERASE 1
Strictly seen only in nucleolus
Only one function to transcribe 45s Pre-rRNA gene to single template
It gets further processed to 18s, 5.8s and 28s rRNA
Two places where endonuclease enz plays a role
DNA REPAIR
RNA SPLICING
Role of RNA POLYMERASE 2
Transcription ie mRna synthesis
Also forms small nuclear RNA and microRNA
Function of RNA POLYMERASE 3
Synthesis of tRNA and 5S rna
Of all rRNA
5s rna genes are located
Outside nucleolus
Post transcriptional RNA SPLICING
Is done by SN RNA
HOW
It removes introns from hnRNA
Which contains GU at 5’ splice site and AG at 3’ splice site
In eukaryotes things required for translation initiation are
Both ribosomal units- 60s and 40s Associated rRNA and mRNA INITIATION FACtors Initiator tRNA charged WITH METHIONINE And GTP
Two promoters situated upstream the transcription initiation site in dna are
Tata box—25 bp upstream
And
Caat box - 70 to 80 bp upstream
Which human enz is a reverse transciptase
Telomerase
Component of telomerase are
TERC—telomerase rna component
TERT- rev transcriptase enz
Funxtion of terc—built in RNA TEMPLATE WHICH IS CONSTANTLY READ BY REVERSE TRANSCRIPTASE ENZ TO PRODUCE ssDNA
What is the function of telomerase
To keep the telomeres long
Since after critical shortening programmed cell death occurs
Cancer cell and adult stem cells have long telomeres dont die
What is added to 3’ end of chromosome by telomerase
Telomeres are lengthened by enz telomerase
It adds TTAGGG at 3’end of chromosomes
Stem cells on skin are located in
Epidermal basal layer
What is kozak sequence
It is a sequence for initiation of translation on mRNA in eukaryotes
it is gcc-Rcc-AUG
Here R has to be adenine or guanine 3bases upwards from AUG to have translation started
Who recognises AUG start codon in protein translation
40s smaller ribosomal subunit
Binds to 5’ cap of mRNA and scans for AUG CODON
If it finds AUG. with kozak consensus sequenxe upstream it translation is started
What is prokaryotic equivalent of kozak consensus sequence
Shine dolgarno sequence upstream for AUG codon
What is co translation protein targeting
Process wherein SIGNAL RECOGNITION PARTICLe
recognise the n terminal amino acid sequence
Of the enlarging polypeptide and tagg it
It helps to transport it to rough ER
What is the component and function of larger ribosomal subunit
Large ribosomal subunit has enz peptidyl transferase
Which catalyses the peptide bond formation
What is translocation in protein synthesis
During elongation the ribosome moves 3 nucleotides towards 3’ end of mRNA
Advancing peptidyl tRNA moves from A TO P site
Needs GTP hydrolysis
Needs elongation factor 2
Genetics of sickle cell disease
A to T Mutation in beta globin gene
Resulting in glutamic acid to be replaced by valine at 6th position
Small gap in the tip of long arm of chromosome X
Leads to which disease
Fragile X syndrome
Most common inherited cause of intellectual disability
Due to CGG trinucleotide expansion
Why is fragile X CALLED SO
When pts cells are cultured in folate deficient medium
The area of increased repeats do not stain and appears broken
Hence a gap near tip of long arm of chromosome X
What is the genetic abnormality in fragile X
CGG trinucleotide expansion repeats in
FxMR1 gene aka fragile x mental retardation gene 1
It is located on long arm of chromosome X
Features of fragile X syndrome
Intellectual problems with delayed motor and language milestones
Everything is big— macrocepahly big forehead jaw, chin and ears
Big testes -macroorchidism
Long narrow face
Features are subtle in infancy but they become prominent in puberty
What do these features point to Lens dislocation Aortic root dilation Arachynodactyly Scoliosis Mitral valve prolapse Breast bone changes Tall pts thin slender Flat feet Increased arm to height ratio
Marfans
Most common genetic cause of intellectual disability
Most common inheritable cause of intellectual disability
Genetic— downs
Inheritable— fragile X
What does these features point to Long legs Intellectual disability Sparse facial and body hair Infertility Gynaecomastia Cryptorchidism
Kleinfelters syndrome
Testes is fibrotic and cryptorchid
No testosterone
Causes oligospermia and hence infertility
In general most enz deficiency have what type of genetic inheritance
Autosomal recessive
In exam confusion can arise between primary ciliary dyskinesia and cystic fibrosis
What is the pathogenic difference
Kartagener is abnormal ciliary motion due to DYNEIN arm defect
Cystic fibrosis is due to CFTR gene mutation and impaired chloride ion transport
In exam confusion can arise between primary ciliary dyskinesia and cystic fibrosis
What is the diagnostic ways to differentiate
Kartageners needs LOW NO levels in nasal specimens
Bronchoscopy and microscopy shows impaired cilia motility
Cystic fibrosis— has elevated sweat chloride levels and abnormal nasal transepithelial potential difference
Then obviously genetic testing helps
In exam confusion can arise between primary ciliary dyskinesia and cystic fibrosis
Extapulmonary manifestation differ which are
Kartagener has— normal growth situs inversus, and infertility due to immotile sperms
Cystic fibrosis pts — failure to thrive, pancreatic insufficiency and infertility due to bilateral absence of vas deferens( azospermia)
Inherited disorder and associated cvs developmental defects
Downs syndrome
Endocardial cushion defects
That is osteum primum asd and regurgitants AV valves
Inherited disorder and associated cvs developmental defect
Digeorge synd
Tof
Interrupted aortic arch
Remember 3rd ph pouch problem
Inherited disorder and associated cvs developmental defect
Freidrichs ataxia
Hypertrophic cardiomyopathy
Inherited disorder and associated cvs developmental defect
Marfans
Aortic root dilatation dissection and aneurysm due to cystic medial necrosis
Mitral valve prolapse
Inherited disorder and associated cvs developmental defect
Tuberous sclerosis
Cardiac rhabdomyomas
Causing valvular obstruction
Inherited disorder and associated cvs developmental defect
Turners syndrome
Coarctation of aorta
Biscuspid aortic valve
What do these features point to
Skin normal in infancy
By 1 year sun exposed areas shows signs of sunburns
Atrophic scaly skin
Light snd dark pigmented skin with telangiectasia
Skin malignancies like malignant melanoma, SCC, BCC as early as 5 to 6 years to age
Xeroderma pigmentosa
Autosomal recessive
Defective nucleotide excision repair of DNA damaged by UV LIGHT
Steps in nucleotide excision repair are
Uv exposure causes thymine dimers
Deformed dna strand identified by ENDONUCLEASE COMPLEX
ss breaks in DNA made up and downstream the dimers
Removed
Dna polymerase replaces the lost segment of dna
Dna ligase seals it
Most common inherited cause of aplastic anemia
Fanconis anemia
Genetics of fanconis anemia
AR
MUTATION IN GENE RESPONSIBLE FOR REPAIR OF INTERSTRAND DNA CROSS LINKS
What does this features point to
Short stature
Absent thumbs
Increased malignancy
Aplastic anemia reduced rbc and other lines
Fanconis anemia
Name imp mitochondrial inheritable dis
Lebers hereditory optic neuropathy
myoclonic epilepsy with ragged red fibres
Melas/ mitochondrial encephalopathy with lactic acidosis and stroke like episodes
What helps transcription in eukaryotic genes
Promotor where rna polymerase and transcription factors binds
Enhancer— which enhances / acclerates the rate of transcription
Promoters are caat box and tata box upsteam to start codon ATG
What do enhancer sequences bind to
Activator protein
This complex act to help bending of DNA
Which allows activator proteins to interact with transcription factors and RNA polymerase 2 to increase the rate of transciption
Location of promotor and enhancer
Promotor is upstream towards 5’ end of start codon
Enhancers can be anywhere— up down in introns etc
Role of silencers
Bind to repressor proteins
Reduce the rate of transcription
Name the phases of arrests in gametogenesis
Oogonia—G0
Primary oocyte— prophase M1
Secondary oocyte-metaphase M2
Mature ovum—telophase M2
Arrested primary oocyte resumes meiosis 1 under the effect of
FSH AND LH
Prior to fertilization
Secondary oocyte released from ovum is arrested in
Metaphase of M2
What do these features point to Clenched fist with overlapping fingers Low set ears Micrognathia—small jaw mandible Prominent occiput Heart and renal defects Limited hip abduction Rockerbottom feet
Edwards syndrome
Trisomy 18
Majority die by 2
If not severe intellectual disability
What do these features point to
Low set ears hypertelorism Broad nasal bridge Microcephaly Developmental delay Failure to thrive Hypotonia Weak cat like cry
Cri du chat syndrome
5p deletion
What are the components of telomeres
Function
Telomere are complex of protein( shelterin) and DNA REPEATS TTAGGG which is added by enz telomerase
This telomeres prevent chromosomal degradation
Prevent fusion with neighbouring chromosomes
Most common sex chromosomal abnormality in females
47 XXX
Incidentally detected
Patients are normal
What happens when one ovum is fertilised by 2sperms
Karyotype becomes 69 XXX or 69 XXY
they are partial molar pregnancy
Ovum has maternal chromosomes so fetal parts do develop unlike in complete mole
What happens when ovum without maternal chromosomes fertilise
Complete molar pregnancy The sperm ( with 23X haplotype) contributes chromosomes solely Which duplicate into 46 XX of only paternal DNA
46YY ( with 23 Y) IS NOT compatible and not seen in zygotes
46XY molar is also possible but rare wherein two sperms with x and y haplotypes fertilize empty ovum
Why do turner girls have short height
Loss of entire or part of X chromosome leads to loss of SHOX gene
It normally promotes long bone growth
Name the mutation in which difference in number of niucleotides is not divisible by 3
Frame shift mutation
Due to insertion or deletion of nucleotides
What tests determines type and quantity of RNA based in size
RNA— norther blot tests
Hla genes are located on
Single chromosome 6
HLA A B C are on short arm ch6
DQ DR DP are on long arm chr 6
Since all hla genes are on the same chromosome
Their cross over is negligent
This helps what
Hla inheritance follows rules of haplotype
Ie two siblings have 25 percent chance of being identical and being non identical
And 50 percent chance of being half identical
TTN. Gene mutation
Usually a non sense mutation leads to
Truncated titin protein
Dilated cardiomyopathy
Which genetic disease leads to right ventricular myocardium scarring
Ventricular arrhythmias
Sudden cardiac death
Arrythmogenic right ventricular cadiomyopathy
Caused by impaired desmosomes
Because of mutations in genes for proteins of desmosomes like desmoplakin and plakoglobin
Mutations in NOTCH 1 gene
It codes for transcription regulatory proteins
Mutations in NOTCH1 gene
Leads to familial bicuspid aortic valve
Examples of point mutation are
Mis sense mutation- can be convervative( properties remain same) non conservative( properties change)
Non sense- early stop codon
Silent — no change in amino acid coded
If a karyotype shows shortened chromosome 22 and elongated chromosome 9
What disease is seen
Chronic myeloid leukemia
It is philadelphia chromosome
Trans 9-22 bcl-abr fusion
Genetic causes / phenomenons in downs syndrome
In order of occurence
- Meiotic non disjunction
- Unbalanced robertsonian translocation
- Mosaicism in less than 2% affected pts due to non disjunction during mitosis
Assay to detect proteins in a mixed sample
Western blot
Steps of western blot
Separation of proteins on gel electrophoresis
Primary antibody added
Secondary labelled antibody added to detect the complex of protein and primary antibody
Malignancies increased in downs
ALL
ACUTE MEGAKARYOCYTIC LEUKEMIA
Function of cyclin D
Helps in G1 —-> S transition
Cyclin D is produced in which phase of cell cycle
G1
Hence helps in G1S TRANSITION
Overexpression of cyclin D results in
Unchecked g1/S transition
Hence uncontrolled proliferation
Malignancy
Git diseases in downs
Tracheo esophageal fistula Duodenal atresia Celiac disease Hirschsprung disease Imperforate anus
