Genetics Flashcards
what is genetic disease
an illness caused in whole or in part by an abnormality in the individual’s DNA, may be inherited or acquired
are genetic diseases familial
sometimes but not always
environmental disease can also be familial (ie transmittable diseases)
define congenital
present at birth
NOT genetic
are genetic diseases congenital
some but not always
an inherited disease is not always present at birth
environmental disease can be congenital
when can a familial disease be considered to be genetic
if large mendelian pedigree or if not, familial clustering, twin studies, adoption studies
what is familial clustering
familial clustering aims to show the closer the genetic relationship the higher the risk of disease bc the more shared genes= greater chance of that disease
h/e also share environment
what are twin studies
show differences in disease incidence (concordance rate) between MZ and DZ twins as share 100% vs 50% genes
genetically determined diseases show higher concordance MZ than DZ
h/e environment
adoption studies
whether shared genes or shared environment- ie does the adopted child have the disease?
what are diseases that affect onevs multiple genes called
single gene disease
polygenic disease
what are diseases of chromosomes called
what are diseases that involve many genes and the environment called
chromosomal disease
multifactorial disease
a disease of a germline cell leads to (and what is it)
(sperm/ova) an inherited condition
a disease of a somatic cell leads to
(body cells) non-inherited condition
single gene conditions vs complex diseases
single gene conditions are pathological mutations, present only in affected and carriers, significantly alter gene and its protein
complex diseases combination of normal variants present in everyone, subtly alter gene and protein,
how does risk of developing vary between single gene and complex diseases
more positive risk of developing if single gene disease
in complex diseases, genetic susceptibility factors in- ie how good or bad the versions of the gene are but lifestyle influences
PKT
phenyketonuria
autosomal recessive condition, both parents carriers
all tested at birth with Guthrie test
1 in 10000
disease arises due to lack of phenylaline hydroxylase
if know and do not eat phenylaline, no effects. if unaware and eat causes mental retardation, microcephaly, growth failure
karyotyping and normal karyotype
chromosomes are fixed in metaphase when chromosomes have condensed so visible
stain applied, banding used to identify chromosomal abnormalities as there is a unique regular pattern of banding for each chromosome
normal karyotype= 46XX or 46XY
what percentage of all conception have chromosomal abnormality
what percentage of first trimester miscarriages have chromosonal abnormality
7.5% all conceived have chromsomal abnormality
60% of 1st trimester miscarriages have chromsomal abnormality
how many chromsomes are in somatic vs germ cells, what are they otherwise called
somatic cells are diploid, have 46 chromosomes, so 2N.
germ cells (sperm and eggs) are haploid so 23 chromosomes
what is polyploidy
cells with chomsoms in multiples of N greater than 2N
what is aneuploidy
chromsomes NOT in multiples of N, ie missing or extra chromsome
What causes triploidy
Egg fertilised by 2 spermatozoa (dispermy) or by fertilisation of a diploid gamete that arises from failure of maturation
Aneuploidy and polyploidy are what type of chromosomal abnormality?
Numerical
What are the two outcomes of aneuploidy?
Trisomy of that chromosome or monosomy of that chromosome
What is a trisomy
An extra copy of that chromosome, ie downs is a trisomy of 21,,, trisomy 21
What is a monosomy
A loss of a copy of that chromosome is a monosomy of that chromosome
What type of aneuploidy is lethal
All complete monosomies of autosomal chromosomes 1-22 are lethal.
Partial monosomies may survive.
What is the only type of monsomy that is not lethal?
Monosomy X, Turner’s syndrome
What 2 things may aneuploidy result from
Non disjunction
Anaphase lag
What is non disjunction
Failure of chromosomes/sister chromatids to separate at anaphase in cell division
What is anaphase lag
Delayed movement of chromosomes after separation at anaphase
What does non disjunction in meiosis or mitosis result in?
One daughter cell with an extra copy (trisomy) and one daughter cell with a missing copy (monosomy)
What is the result of non disjunction in meiosis 1 and what happens at fertilisation
Meiosis 1 will have one cell with 4 copies of chromosome and one cell will have no copies of chromosome. (Instead of 2 each)
After meiosis 2, there will be 2 cells with 2 copies of the chromosomes and 2 cells with no copies of the chromosome
After fertilisation, 2 cells will be trisomy as sperm adds a chromosome and 2 cells will be monosomic
What happens when there is non disjunction of a chromosome in meiosis 2
1 cell will have 2 copies of chromosome, it’s partner cell will have no copies of chromosome. Next 2 cells will have one copy of chromosome each.
At fertilisation, the cell with 2 copies of chromosome will become trisomic, it’s partner cell will be monosomic, the next 2 cells will be disomic (normal)
What happens if there is non disjunction in meiosis 1 of chromosome 21 of oogenesis
After meiosis 1, one cell will have 4 X chromosomes, one cell will have no X chromosomes
After meiosis 2, first 2 cells will have 2 X chromosomes, next 2 cells will have no X chromosomes
At fertilisation, if an X is added, either of first 2 will become trisomic as 47XXX. Either of the second pair will be monosomic as 45X, Turners.
If a y is added, either of first pair will be trisomic as 47XXY, klinefelters, either of second pair will be monosomic as 45Y, this is lethal
45X is?
Turners syndrome
47XXY is
Klinefelter’s syndrome
Non disjunction of chromosome 21 in meiosis 1 of spermatogenesis results in
At meiosis 1, one cell will have 2X and 2Y, other cell will have none
After meiosis 2, one pair will have XY and one pair will have none
At fertilisation, both XY cells become 47XXY as klinefelters, both cells without will become 45X, turners
Non disjunction of chromosome 21 is more likely lethal in oogenesis or spermatogenesis?
Oogenesis
What happens if there is non disjunction of chromosome 21 in meiosis 2 of spermatogenesis
After meiosis 2 there will either:
be one XX chromosome and one without and next 2 cells will be Y and Y (normal)
At fertilisation, the XX cell will become 47XXX, next 45 X, next 2 normal XY
Or: after meiosis 2 there will be one cell YY, one cell without and 2 normal with an X each
After fertilisation there will be one XYY, one X and 2 normal xx
What is the only way 47XYY can arise
Non disjunction of meiosis 2 in spermatogenesis
What happens if non disjunction of chromosome 21 in mitosis happens early in post fertilisation?
A substantial proportion of cells will have trisomy 21 phenotype
How early this occurs influences how severe (early is severe)
Why do structural chromosomal abnormalities happen
Result from chromosomal breakage and usually involves 1 or 2 chromosomes
May be spontaneous, but rate is increased by exposure to mutagenic agents or inherited conditions with defects in DNA replication
What structural abnormalities may be seen in a single chromsome
Deletion
Inversion
Duplication
Isochromosome
Deletion is what? what type of chromosomal abnormality? occurs in how many chromosomes?
Deletion is a structural abnormality seen in a single chromosome
Deletion is the loss of part of a chromosome
Inversions are what? what type of chromosomal abnormality? occurs in how many chromosomes?
Inversions are structural abnormalities seen in a single chromosome
Inversions are the inversion of a segment of chromosome which may/may not involve the centromere
Duplications are what? what type of chromosomal abnormality? occurs in how many chromosomes?
Duplications are structural abnormalities seen in a single chromosome
Duplication of a chromosomal segment, in tandem or inverse configuration of original sequence
An isochromosome is what? what type of chromosomal abnormality? occurs in how many chromosomes?
An isochromosome is a structural abnormality seen in a single chromosome
An isochromosome is the duplication of 1 arm of that chromosome, coupled with the loss of the other arm, so there are 2 identical arms
What type of structural abnormalities would we see in 2 chromosomes
Insertions
Translocations- reciprocal or robertsonian
Insertions are what? what type of chromosomal abnormality? occurs in how many chromosomes?
Insertions are a structural abnormality seen in 2 chromosomes
Insertion is the breakage of material from 1 chromosome and insertion into another
Translocation is what? what type of chromosomal abnormality? occurs in how many chromosomes?
Translocation is a structural abnormality, seen in 2 chromosomes
Translocation is the exchange of material between 2 chromosomes
What is a reciprocal translocation
Reciprocal translocation is a structural abnormality seen in 2 chromosomes
Reciprocal translocation is the reciprocal exchange of material between chromosomes
What is robertsonian translocation
Structural abnormality of 2 chromosomes
Only involve Acrocentric chromosomes (small arms are very short). The small arms are lost and the long arms of the 2 chromosomes join together
Leads to reduction by one chromosome
Why do robertsonian translocations not have significant phenotypic effects
All important genes are in long arm of chromosomes
Though there will be issues when forming gametes
Outcomes of a balanced reciprocal translocation in meiosis
Normal
Carrier of balanced translocation
Partial trisomy of 1 and partial monosomy of 1
Outcome of meiosis in robertsonian translocation
Normal
Carrier if balanced translocation
Complete monosomy of 1 and complete trisomy of 1
Phenotypic consequence of chromosomal abnormality in a single gene
Disrupt a single gene lead to loss of its product
Translocate the gene to a region of active chromatin domain so it is inappropriately expressed
Create a chimaeric gene that expresses an altered protein
Phenotypic consequences of chromosomal abnormality in deletion of a small group of genes
If deletion of small group, phenotype due to lack of product of several genes (contiguous gene syndrome)
Phenotypic consequence of abnormality of large regions or whole chromosomes results in
Phenotypic change
Severe birth defects including mental and growth retardation
Specific abnormalities largely due to dosage imbalance of only a few genes on that chromosome.
Most common chromosomal causes of miscarriage?
Aneuploidy.
Aneuploidy so significantly disrupts cell eq not compatible with life mostly.
Trisomies represent 35% of miscarriages before 20 weeks
Complete autosomal monosomies lethal
Monosomy 14, trisomy 14, monosomy 21 are
Lethal
What is a balanced translocation
Even exchange of material with no genetic material being extra or missing
Correct amount genetic material present but not in normal pattern
What is an unbalanced translocation
Exchange of material is unbalanced resulting in extra or missing material
When does an unbalanced translocation occur
Fetid inherits a a chromosome with extra or missing genetic material from parent with balanced translocation (extra or missing bc parent has 2 of it where the other fills in the gaps)
When are balanced chromosomal translocations identified
Subfertility leading to investigations
Raised risk result from combined test
Parental testing after child born with unbalanced
How do balanced translocations affect risk of miscarriage
Increase risk.
What happens when a balanced translocation carrier has children?
Balanced translocation carrier’s sperm or eggs have incomplete or partially duplicated sets of chromosomes
Tiny unbalanced structural abnormalities can affect many genes leaving severe effects on individual
May cause:
Fatal monosomy or trisomy
Normal chromosomes
Balanced translocation
what are the types of chromosomal abnormality?
numerical-
aneuploidy
polyploidy
structural- Deletion Inversion Duplication Isochromosome Insertions Translocations- reciprocal or robertsonian
aside from chromosomal abnormality, what other type of dna abnormality is there?
molecular- gene level abnormality
what types of molecular changes may we see in DNA
Point mutations, includes:
- Truncating mutations
- Non Truncating mutations
Promoter Methylation
define point mutation
mutation affecting only one or very few nucleotides (bases) in a gene sequence
Define truncating mutation
truncating mutation is a type of point mutation, whereby the wrong size protein or no protein product is made
Define non-truncating mutation
non- truncating mutation is a type of point mutation, whereby there is a spelling mistake but an otherwise normal gene product
in short, what is the difference between truncating and non truncating point mutations
truncating mutations= protein product wrong/ not made
non truncating mutation= protein functions
what are the types of truncating mutations
nonsense mutation
frameshifting mutation
splice mutation
what is a nonsense mutation
codon for an amino acid is replaced by a STOP codon
= ribosome stops mid protein synthesis
what is a frameshifting mutation
deletions or insertions that alter the triplet reading frame
ie remove 1 codon and all others bump down one so meaning changes (or add one and all move up one)
beyond point of frameshifting mutation, doesn’t make sense as all shift by +/- 1
if 3 deleted may still make sense but not fully
often leads to early stop codon
Outline splicing
exons= the coding bits introns= junk sequences
exons are seperated by introns
when mRNA synthesised, introns are removed so only exons remain
there is a specific sequence at start and end of exons, recognised by splicing machinery
what is a splice site mutation
mutation at splice sit leads to error in where spliced, may result in aboloshing a splice site or creation of a novel site
ie may keep an intron, may skip an exon, may splice early etc
what are the types of non-truncating mutations
missense
silent
expansion of trinucleotide repeats
what is a missense mutation
one AA is replaced with another
result depends on how different the new AA is and how important the original AA is for function of protein
what is a silent mutation
mutation that does not result in replacement of one AA with another due to degeneracy in the code
what is expansion of trinucleotide repeats
trinucleotide repeat sequences eg (CAG)n occur relatively frequently in genome
therefore may be okay, but if too many repeat sequences= unstable may cause disease
2 classes of trinucleotide repeats
what is the first class of trinucleotide repeats?
genes with modest expansion of a particular trinucleotide repeat WITHIN CODING REGION
results in either
- stable alleles= 10-30 repeats, no phenotypic change
- unstable alleles= 40-200 repeats, eg huntingtons
what is the other type of trinucleotide repeat mutations
genes with very large expansions of repeat sequences in NON CODING sequences
stable alleles= 5-50 repeats
unstable alleles= over 100, result in inhibition of gene expression or aberrant splicing
what is the normal method for regulating expression of genes?
promoter methylation
gene transcription can be switched off by methylation of nucleotide bases, particularly cytosine in their promoter regions
this is how normally regulate expression of genes
what is hyper/hypomethylation
a molecular abnormality, may occur pathologically (ie cancer)
hypermethylation= inappropriate switching off of affected gene
hypomethylation= inappropriate switching on of affected gene
pathological mutation of nuclear DNA vs mitochondrial DNA
mutation of DNA=
mendelian inheritance,
wide range phenotypes,
wide range affected tissues
mutation of mitochondrial DNA=
maternal inheritance,
restricted phenotype as affects most energy consuming tissues
highly variable severity, depends how many mitochondria affected
mutation in germ cell vs somatic cell
germ cell mutation= INHERITED mutation in DNA of egg or sperm, every cell of organism will be affected, can be passed onto offspring
somatic cell mutation= cannot be inherited. mutation in a single body cell, only tissues/cells that arise from this cell will be affected. No phenotype unless develops very early in development
are there differences in the types of mutations seen in somatic vs germ cell mutations?
exact same mutations, but observed spectrum different
many mutations seen in somatic cells would be lethal if constitutional
most inherited germ cell mutations would have no observable consequences if only present in a few somatic cells
when may somatic cell mutations be clinically significant in terms of phenotype
if occurs early in embryogenesis, significant proportion of clones of mutant cells, gives the cell a growth advantage so forms a tumour
what does the outcome of mutation in DNA depend on?
depends where change is and how critical
if non critical then little to no effect
if critical then:
lack/reduced synthesis of protein
reduced or no protein function
altered protein function
loss of protein function is usually associated with what type of inherited condition
recessive
gain of protein function usually associated with what type of inherited condtion
dominant
what does a square, circle and diamond mean on a pedigree chart
square= male circle= female diamond= unknown sex
what does full shading, hashed shading, half shading mean on pedigree chart
full shading= affected
hash shading= don’t know
half shading= carrier
eldest sibling is where on pedigree chart
to the left
a single straight line connecting people vs a double straight line connecting people
single line= marriage
double line= consanguinous mating
how does genetic disease result in phenotypic consequences
change in DNA= change in AA sequence= change in protein function= dysfunction
why is it important to make diagnoses in genetic disorders
common cause child morbidity and hospitalisation (25% paeds patients have genetic disorder)
appropriate clinical management, treatment to improve prognosis if poss
info for family, risk estimation future offspring
how do we identify genetic disorders
clinical presentation (some very clear, don’t need genetic testing)
family history and mendelian pedigree
genetic testing
some have blood markers etc
tell me the most basic info about genes and inheritance of traits
2 genes (alleles are different versions of genes) for each trait inherit one gene from each parent
may be homozygous- have two identical alleles, AA or aa
may be heterozygous, 2 different allels, Aa
in which case one will be:
Dominant: allele that is expressed, overrides the recessive
or
Recessive: hidden allele, not expressed
or have
Co-Dominance: both alleles are expressed
what is segregation and independent assortment
segregation: for every gene, each parent contributes one of their alleles to offspring, so one allele from each
independent assortment: genes passed on in independent manner to other genes (except where linked traits, then genes will segregate as a unit)
what are the characteristics of an autosomal dominant disorder
the mutant allele is dominant so only one mutant allele needed to cause disease
every affected child has an affected parent
vertical transmission
males and females affected equally
50% recurrence amongst children
normal children of affected parents will only have normal children
Aa= disease aa= unaffected
what are the characteristics of autosomal recessive disorders
2 mutant recessive alleles= disease
aa= affected Aa= unaffected carrier
males and females affected equally
parents must both be carriers or one carrier one diseased
frequent in consanguity
horizontal inheritance- where one child affected likely see others in that family, but not seen in every generation
if both parents are carriers, what is the probability of their children bein affected/not/ a carrier
25% normal
50% carrier
25% affected
what are the characteristics of X linked recessive inheritance
MALES more affected
no male to male transmission
affected mother 100% has affected son
affected father 100% has carrier daughter
in males one copy of allele sufficient to cause disease as only have one X chromsome, in daughters would need 2 copies so males more affected
knights move transmission/ diagonal as usually carrier mother to afected son to carrier daughter and so on
what are the characteristics X linked dominant
FEMALES more affected
no male to male transmission
affected father has 100% affected daughter
affected mum 50% affected son or daughter
characteristics of Y linked inheritance
only father to son, never any females
dominant or recessive don’t apply as only one Y
seen in all male descendants
characteristics of mitochondrial inheritance
only egg cells contribute mitochondria to embryo so only females can pass on
no male to male
female to son or daughter, maternal iniheritance
mother to all children
what type of inheritance is this? no male to male affected mother 100% affected son carrier mother 50% to son affected father 100% carrier daughter more males affected
x linked recessive
what type of inheritance is this?
horizontal inheritance
males and females equally
affected child has carrier parent
autosomal recessive
what type of inheritance is this
no male to male
maternal inheritance
mother to all children
mitochondrial
what type of inheritance is this no male to male affected father 100% affected daughter affected mum 50% chance to son or daughter more females affected
X linked dominant`
what type of inheritance is this?
only male to male
seen in all descendant males
never in females
Y linked
what type of inheritance is this?
affected child has affected parent
males and females equally
vertical transmission
autosomal dominant
if there is no male to male transmission, does every affected father have 100% affected daughters? yes vs no what is it
yes, X linked dominant
no, X linked recessive
no and every child of affected mum has it, mitochondrial
does every affected child have an affected parent? yes vs no
yes, autosomal dominant sign
no, autosomal recessive sign
if no male to male, does every affected mother have 100% affected son? yes vs no
yes, x linked recessive
no, x linked dominant
what type of inheritance is it a sign of if
females affected more
males affected more
females more= X dominant
males more= X recessive
the Smith family have one child with cystic fibrosis but the other 3 children are healthy, what is the chance that one of the other siblings is a carrier
know he isnt affected so
NO affected 25%
maybe carrier 50%
maybe normal 25%
therefore 2/3 chance carrier
