Genetics and Genomics Flashcards
What is a haplotype?
=an individuals set of alleles at a locus or cluster or loci on a chromosome
What are single gene disorders?
- these disorders are determined primarily by the alleles at a SINGLE locus
- recurrence risk describes the likelihood of passing on the gene
Mendelian Genetics… what is it concerned with?
-monogenetic traits aka single gene traits
Independent assortment
is one gene locus is independently transmitted from a gene on a different locus
Autosomal dominant disease
seen in every generation
M=F
-structural genes are often seen in this inheritance pattern
-no skipping generations unless new mutation!
-probability to inherit=50%
ex. achondroplasia
Achondroplastics are…
rizomyere???
their limbs (humerus and femur) are short but their tib/fib and radius/ulna are normal length
What is the danger with 2 people who have an AD disease mating?
-they have more problems in those who will become homozygotes much more severe issues
Autosomal Recessive
-rare
-often seen in metabolic disorders
-this is sometimes seen in those who are relatives who mate CONSANGUINITY
-those that are heterozygotes may have reduced enzyme activity and then combine to make no activity
M=F
-probability to inherit from heterozygote parents 25%
Ex.
-Hurler/Hunter
What is hurler syndrome?
- AR disease
- skeletal abnormalities
- similar to hunter
Cystic fibrosis
- mutation to CTFR gene
- Cl transporter mutation
- pleiotropic: effects more than one organ
Remember that dominant and recessive refer to ___ not ___
traits not genes!
Sex linked inheritance
types:
X linked dominant
X linked recessive
Y linked
x chromosome: larger so more mutations
-common in men
y linked: much smaller contains less genes
X linked recessive
M > F–bc males usually only ones affected
-SONS of heterozygote mothers have 50% chance of being affected
X linked dominant
M and F can be affected
-all female offspring of affected father will be affected
Y linked
only father to son transmission
Mitochondrial Inheritance
- only given from mother
- all offspring of affected females show signs of disease
- not all mitochondria congregate in specific organs… so they effect organs different =heteroplasmy
New mutations
- this can complicate the “normal” pattern of inheritance
- the gene transmitted undergoes a mutation from the normal allele
Achondroplasia and risks and what they have!
- most cases are due to new mutations
- only 1/8 are transmitted from dwarf parents
- distinguish this by taking a family hx
remember they are: Rhizomelic—> refers to either a disproportion of the length of the proximal limb, such as the shortened limbs of achondroplasia, or some other disorder of the hip or shoulder.
What is gremlin mosaicism?
- when 2 or more offspring present with an AD disease with no familial hx
- this is when all parts of the germline cells are affected by the same mutation
- mutation occurs during the parents embryonic development of the germ cells
Age Dependent Penetrance
aka delayed age onset
- ex. of this is BRCA gene
- this is when the disease does not present until AFTER patients reach reproductive age or adulthood
- this can cause a difficulty in detecting the mode of inheritance
other ex.
huntingtons
polycystic kidney disease
alzheimers
Reduced penetrance
-this is when those that have the genotype fail to express the appropriate phenotype although they pass it to the next generation
penetrance is the general idea that a phenotype expression is dependent upon the predisposing genotype
ex. retinoblastoma
Variable expression
a trait in which the same genotype can produce phenotypes of varying severity or expression
- penetrance=complete
- severity is what varies
- a parent with midl expression may pass on the disease
ex. neurofibroblastoma
What are some causes for variable expression?
- environmental factors
- modifier genes
- allelic heterogeneity
What is pleiotropy?
-genes that affect multiple aspects of physio or anatomy
ex. sickle cell
OI
CF
Marfan syndrome
- mutation to fibrillar
ex. of pleiotropy
Locus heterogeneity
=single disease phenotype caused by mutations at different loci in different families
a risk of this is testing for the wrong mutation
-ex. OI
Genomic Imprinting… ex. of this
=process by which genetic material is expressed differently when inherited from the mother than when inherited from the father
- methylation
ex. prader will an anglemans
Prader willi is inherited from the PATERNAL side
Anglemans is MATERNAL (heavy retardation)
Anticipation
=progressivle earlier onset and increased severity of certain diseases in successive generations of a family
ex. myotonic dystrophy
Population genetics: what factors determines it?
the branch of genetics dealing with genetic variation and genetic evolution of population
-it looks at how these frequencies change or are maintained in different populations
a. genetic factors
b. environmental and societal factors
What is the multiplication rule?
probability that BOTH event 1 and 2 will occur together
multiply probabilities together
What is the addition rule?
probability that EITHER event 1 or 2 will occur together
add the probabilities together
hardy weinberg
states that population frequencies will stay at a constant from generation to generation
p=normal
q=mutant
p+q=1
*calculates genotype frequencies
p^2 +2pq + q^2=1
p^2=homozygous normal
what are the assumptions for hardy weinberg to be true? 4
- large population
- no mutation
- no selection
- no migration
when is hardy weinberg used in the clinical setting?
often used for autosomal recessive conditions
what is the 2/3 rule?
2/3 for heterozygotes who are carriers and do not have disease. 1/4 chance for child who does not have the disease and multiple these by the population frequency
What are some causes in population change frequencies?
- natural selection
- genetic drift
- founder effect
- gene flow
natural selection… ex. of some diseases
-sickle cell: protects from malaria
-CF: protects against diarrhea
leiden V: entourage coagulation
What are some examples of the founder effect?
- the founder effect is a large shift in frequencies in a small population containing little genetic variation
- often subsets of populations
a. islands
b. small towns
c. ashkenazi jews
Why is knowing the ethnic population of your patient important for genetic testing?
- if you know the ethnic population you can order more specific genetic testing
- this can ultimately save cost
What is cytogenetics?
=the study of chromosomes and their abnormalities
-uses cytology and genetics
What is a karyotype? What criteria are they numbered by?
- chromosomes are extracted from nucleus, stained, and matched according to
a. size
b. banding patterns
c. location of centromere
nomenclature for chromosomes
p=petitie small arm
q=long arm
metacentric: equal on each side of centromere
submetacentric: longer on once side
acrocentric: very small p arm
What is the problem with acrocentric chromosomes?
they often can have robertsonian translocations
What is euploid?
a multiple of a haploid number (N=23)
What is aneuploid?
trisomy or monosomy
=extra or missing chromosomes
-it is the state of not having euploidy
most common cause is nondisjunction
When does nondisjunction occur?
it can occur during meiosis 1 or 2.
- Often occurs during meiosis 1 in female gametes
- it can occur in men but much later in life at about ~60 years old
What is polyploidy?
=more than 2 sets of homologous chromosomes
ex.
2 sperm–1 egg
1 sperm–diploid egg
Down syndrome… what is its MAIN cause?
47 chromosomes (21)
- retardation
- heart problems
- early onset alzheimers
main cause: maternal meiosis I
Kleinfelter syndrome
XXY
47
XYY syndrome
XYY 47
-very tall
-severe acne
lots in prison population?
Turner Syndrome
45 XO
-monosomy X
“webbed neck”
infertile
-could also have mosaic turners which are fertile therefore it is important to know where its full turners or not
-this is the SINGLE MOST COMMON ABNORMALITY IN ABORTIONS
Edward Syndrome
47 trisomy 18 -mental retardation -overlap of middle and index fingers -only 5% survive to 1 year
Patau Syndrome
47
trisomy 13
-microcephaly
polydactyl
Prader Willi
- paternal chromosome
- 15 mutation
- fat
- short stature
Angelmans Syndrome
- From maternal side
- severe
- absence of speech
Whats the difference between genetics and genomics?
genetics: study of traits
genomics: is the study of genes
Inactivating changes in genes
- these are more common that activating changes
- mutations which reduce expression
- reduce activity of protein
- can alter splicing balance
What are reasons for gaps in the genome?
- chromosomes are not continuous
- some sequences are hard to read high GC
- some sequence is hard to align–repeats
human genome is the ARTIFICIAL reconstruction of chromatin
What is some evidence for a genetic contribution to a disease?
- congenital disorders
- family hx
- cross cultural
- multigenerational
- GWAS
- identical twins separated at birth ideal
- expression analysis
what is missing heritability?
-we know its heritable but we do not know the gene for it
Lamina A mutations
C–> T conversion
- mutation is absent in both parents
- usually acquired from a gremlin mutation
- it is what causes progeria
What is the difference between family Hx and Genetic status?
They are often used interchangeably but they are 2 different things
Family hx: stress, diet, exercise, infections, drugs/alcohol, exposure level to various things
genetic statusL shuffling, mutation to germ line, donor egg, adoption
where do they overlap? SNPs, most disease risks
What are PROBLEMS with family hx?
- time consuming
- not recorded in a usable format
- mistakes in recalling cause of death
- many know little about health hx due to secrecy, and low privacy rates
- adoption or donor eggs
- false paternity
- health records die with people
What are some advantages to multi-generational pedigree analysis?
-families have low genetic noise (they are very similar)
-example ashkenazi jews
mormons
gene–disease replationships
- gene is perfectly associated with disease
* high penetrance- typical of monogenic - gene is poorly associated with disease
* low penetrance- typical of multi genic diseases - gene is strongly associated with disease but at variable levels
* high penetrant but variable EXPRESSIVITY
What are the steps to test pre-implantation embryos for IVF?
- induct the F to produce multiple oocytes
- harvest the embryos by transvaginal aspiration with US
- IVF with fathers sperm
- Harvest one of the 8 cells
- test cells for known mutations that you are looking for
- only implant the unaffected embryos
