Lecture 6 Flashcards
Lecture 6
what are single gene disorders caused by?
mutations in one gene
what does the mutation in single gene disorder do?
makes the protein it encodes not function properly or not at all
how can single gene disorder diseases be inherited as?
dominant, recessive, or X linked
most single gene disorders manifest when?
at birth
why are single gene disorders called mendelian
they are inherited essentially in the same way as smooth/wrinkled seed trait in peas
what are the two mendel laws single gene disorders conform to?
law of segregation and law of independent assortment
what is an autosomal gene
gene located on chromosomes 1-22 (not on y or x)
what is an X linked gene
gene located on chromosome X
what is a locus
place on the chromosome where gene is located (also called site)
what are alleles
alternative forms (copies ) of the same gene. gene is always present in 2 copies in normal human genome
gene is always present in how many copies?
2 copies in normal human genome
for a homozygous individual, could have 2 identical copies of a mutated gene and have what?
a genetic disorder
for heterozygous individuals, how does dominant inheritance happen
may have one normal and one mutated copy of the gene and have genetic disorder
for heterozyguos individuals, how does recessive inheritance happen
may have one normal and one mutated copy of the gene and remain healthy
what are hemizygous individuals
refers to genetic state when individual is having 2 mutated copies of the gene and these mutations are non-identical
what is a phenotype
observed effect of the action of a gene
what is locus heterogeneity
implies that same genetic condition can be caused by mutations at different loci
what is allelic heterogeneity
implies that same disease is caused by several different mutations in the same locus
what is an example of locus heterogeneity
waardenburg syndrome, caused by PAX3, MITF, and SOX10
what is an example of allelic heterogeneity
cystic fibrosis, CFTR
who is affected by autosomal dominant inheritance
both males and females, both can transmit disease to sons and daughters as opposed to x linked traits
for autosomal dominant inheritance, if an affected individual and a healthy parent have children, what are the chances the child will be affected
one chance in two that child will be affected
in families for autosomal dominant inheritance, in how many generations does the disease show up
each generation, sometimes referred to as vertical transmission
what is achondroplasia
dwarfism characterised by short limbs and a normal-sized trunk
what is adult polycystic kidney disease
multiple cysts in the kidneys and liver
what is brachydactyly
short fingers or toes
what is familial adenomatous polyposis (FAP)
numerous polyps in the large intestine becoming cancerous in most cases
what is huntingtons disease
a late-onset neurological disorder with abnormal, involuntary writhing movements (chorea) and behaviour and personality disorders
what is marfan syndrome
a disorder of connective tissue. Tall stature, wide arm span, spidery fingers + Cardidiovascular abnormalities (e.g. aortic aneurysm or heart valve incompetence).
what is neurofibromatosis
numerous cafe-au-lait pigmented patches and multiple benign tumours of the nerve sheaths (neurofibromas)
what is retinoblastoma
hereditary eye tumor in infants and toddlers
what are some situations that might modify the pattern of autosomal dominant inheritance
- variable expression/expressivity
- reduced penetrance
- homozygousity
- late manifestation
- novel mutations
- pseudo-dominant inheritance
what does variable expression mean?
Variable expressivity means that degree of severity for the disease vary from person to person within the same family. example is baldness
what is reduced penetrance
genuine skip of generation by autosomal dominant disease, all or nothing phenomenon, examples are retinoblastoma, split hand and foot
what is homozygousity
In autosomal dominant disease when two diseased individuals mate,
there is 25% chance of birth with much more severe phenotype
what are some statistics for homozygousity?
in most cases, 25% die in utero, ones who survive have achondroplasia, hypercholesterolemia. Exclusion from the rule is huntington disease
what is an example of conditions that manifest themselves late in life
huntington disease, Degeneration of neurons, especially in the frontal lobes
The age at onset of the disease
is ranging from 20 to 70 years.
Some individuals may die of unrelated causes before onset, so they will be never diagnosed
(it will look like disease skipped a generation in a family, but in fact, it’s not)
what are some traits of novel mutations?
The more severe the disease, the greater is the proportion of cases arising as new mutations because the chances of affected individuals reproducing would be very small. many autosomal dominant diseases negatively affect individuals chances for reproduction. example is dwarfism
what is pseudo-dominant inheritance
when autosomal recessive disease shows autosomal dominant inheritance. happens in small inbred communities and assortative mating communities
what are some traits of autosomal recessive iheritance
manifests only in homozygous state, when two parents are carriers, 1/4 are sick, 1/4 are normal, and 1/2 are heterozygous carriers. both males and females are affected
what is cystic fibrosis
unusual sweat and a thick mucus which prevents the body from properly cleansing the lungs, part of over 1000 autosomal disease that are identified in man
what is sickle cell anemia
part of over 1000 autosomal disease that are identified in man, involves the rbc’s or hemoglobin, and their ability to carry oxygen
what is tay sach’s disease
part of over 1000 autosomal disease that are identified in man, a fatal disorder in children that causes a progressive degeneration of the central nervous system. It is caused by the absence of an enzyme called hexosaminidase A
what are some traits in the autosomal recessive pedigree
Generally, only sibship
is affected (horizontal inheritance). Very often,
Consanguinity is a part of the picture
what limits genetic admixture in human populations?
- Marriages usually occur within narrow geographical boundaries
- Positive assortative mating, i.e. proactive choice of a marriage partner with similar physical characteristics, religious beliefs, educational backgrounds, and even political opinions
- Marriages within specific clans or tribes
- Marital endogamy in many migrant communities resident in western countries
most rare autosomal recessive diseases are found only in what kinds of marriages
consanguineous, As rarer the disease, as greater the chance that the child is from consanguineous marriage.
what is significant about Henri de Toulouse-Lautrec
He had picnodisostosis, fragile bones, facial features were considered bizarre, fontanelle never closed, fingers were very short, parents were first cousins
what is compound heterozygosity?
the autosome recessive disease resulting from two different mutations in two copies of the same gene (individual is sick)
what is double heterozygosity?
carrier carry two different mutated genes for two different disorders (individual remains healthy)
if heterozygote is serisously ill or slightly unwell what kind of disorder is it?
if seriously ill then dominant disorder (familial hypercholesterolerolemia)
if slightly unwell, then recessive disorder (sickle cell anemia)
what are some traits of x linked recessive inheritance?
- caused by mutation in a gene on x chromosome
- usually manifests in males
- carrier male and carrier female transfer disease differently
for x linked inheritance, what are the stats for female carriers transmitting disease?
-50% of daughters will be carriers and 50% of sons will be sick
for x linked inheritance, what are the stats for sick fathers transmitting disease?
100% of daughters will be carriers and 0% of sons will have it
what are some x linked recessive disorders?
- androgen insensitivity
- duchenne and becker muscular dystrophy
- haemophilia (a and b)
- red and green blindness
- menkes disease
- lesch nyhan syndrome
t or f: gene expression levels of x chromosome genes are higher in females
false! they are approximately the same in females and males
what is the purpose of one x chromosome being inactivated in every cell of female body at 1-2 week after conception?
dosage compensation
what are the steps to inactivating an X chromosomes in female embryo?
- Xist RNA expresses from one of the x chromosomes
- Xist RNA coats one of the x chromosomes
- histone hypoacetylation
- methylation of promoters
- inactivate paternal or maternal x chromosome in the particular cell
in males what is the dosage compensation on par region for x chromosome?
genes on par-x and par-y are identical, so genes are expressed from both x and y
what is the x chromosome dosage compensation on par region for females?
no dosage compensation is needed for par region, female par regions have evolved mechanisms to escape x inactivation
what is a barr body
inactivated x chromosome visible in female cells
due to what were cases of xy male zygote developed as a phenotypically female adult?
failure of androgen receptors
what are the reasons for x linked recessive disorders may in some cases be diagnosed in females?
- homozygosity
- turner syndrome
- androgen insensitivity
- skewed x chromosome inactivation
know some of the rarer types of inheritance
X-linked autosomal dominant Y-linked inheritance Pseudoautosomal inheritance Anticipation Phenocopy Germline mosaicism and novel mutations Genomic imprinting Mitochondrial inheritance
what are some traits in x linked dominant inheritance?
- mutation on x chromosome that manifests in heterozygous female
- both males and females are affected
- males affected more severely
- 50% chance that son or daughter of female will be affected
- male to male transmission can not occur
- father to daughter transmission is 100%
what is incontinentia pigmenti?
- x linked dominant disease
- mutation in x chromosomal gene NEMO
- cells too susceptible to apoptosis
- males dont survive
- females do
- blistering stage, verrucous stage
what are blaschkos lines
unusual pigmented patterns caused by mosaicism
what x linked dominant diseases more severely affects males than females?
- fragile x syndrome
- ornithine transcarbamylase OTC deficiency
- vitamin D resistant rickets
what x linked dominant diseases are lethal in males?
- rett syndrome (females are severely retarded)
- incontinentia pigmenti
what is y linked inheritance
aka holandric inheritance, father to son only
what is one way to to treat y linked male sterility
can be treated in vitro fertilizations, but all sons will be sterile
skeletal disorders with partial sex linkage perform as what?
as autosomal dominant disease
what happens in heterozygous and homozygous SHOX mutation
hetero: leri-weill dyschondrosteosis
homo: langer mesomelic dysplasia
what does SHOX protein do?
- developmental of the skeleton
- important role in growth and maturation of bones in arms and legs
what is anticipation?
phenomenon whereby the symptoms of a genetic disorder worsen or become apparent at an earlier age as it is passed on to the next generation
t or f: anticipation is not always associated with repeat expansion
true
what is phenocopy?
environmental condition
that imitates (copies) one
produced by a gene. example is a baldness
what is genomic imprinting
phenomenon of parent of origin gene expression.
fill in the blank: classical mendelian genes are expressed (1)______ as paternal and maternal gene copies. For some genes only (2) ______ or only (3) _______ copy are expressed. These genes are (4) ______ as they pass from sperm or egg cells. Disease can occur if the normally expressed (5) ________is mutant.
(1)-equally
(2)-maternal
(3)-paternal
(4)-tagged (imprinted)
(5)-allele
classical mendelian genes are expressed (1) equally as paternal and maternal gene copies. For some genes only (2) maternally or only (3) paternally copy are expressed. These genes are (4) tagged (imprinted) as they pass from sperm or egg cells. Disease can occur if the normally expressed (5) allele is mutant.
what is the physical basis of imprinting?
dna methylation pattern
what is uniparental disomy (upd)
an individual may receive 2 copies of a specific chromosome from one parents instead of 1 from mom and 1 from dad. if 2 copies of the chromosome with the nonexpressed allele are inherited, that gene wont work
what are some traits with upd
chromosomes are looking normal, not possible to detect cytogenetically, examples are angelman syndrome and prader-willi syndrome
what are traits of prader-willi syndrome
- both maternal
- poor muscle tone
- low levels of sex hormones
- constant feeling of hunger
- floppy at birth
- developmental delays
what are traits of angelman syndrome
- both paternal
- developmental delay (severe)
- speech impediment
- sleep disturbance
- unstable jerky gait
- hand flapping movements
- frequent laughter/smiling (happy puppet syndrome)
what is heteroplasmy?
presence of a mixture of more than one type of an mtDNA within a cell
maternal ancestry can be followed back using what?
mtDNA
what are the traits of lebers hereditary optic neuropathy?
- mitochondrially inherited disorder
- visual loss beginning in young adulthood
- affects the cells within the optic nerve
- when cells stop working right, results in severe loss of vision
- if cells dont recover, then loss of vision becomes permanent
