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How does the concept of new mutation apply to Autosomal dominant diseases? what diseases does it occur commonly in?

= de novo mutations;
causes the AD to appear like an AR pedigree

AD de novo mutations = common in achondroplasia, HD, NF becausue all 3 mutations are located on "large" genes and therefore more likely for a new mutation to occur


How does the concept of variable expression relate to AD?

affected individuals present differently and go unrecognized as "affected" and mislabeled on pedigree (ie: NF-1 presents with all sorts of different tumors)


How does non-penetrance affect an AD pedigree?

makes the pedigree look like it skips a generation


How does anticipation affect an AD pedigree?

age of onset occurs younger and younger with successive generations;
seen in HD because increase in expansions with each generation and increased expansions = decreased age of onset


What are the genetic mutations that often present LIKE autosomal dominant (but they are not inherited likewise)

1. Haploinsufficiency = when a diploid organizm only has a single copy (that is functional) of chromosome and thus the organism doesn't producse enough gene product to bring out wild-type gene activity (dominant LOSS OF FUNCTION.. an allele is unable to produce its gene product so it is no longer considered "functional")

2. Dominant Negative Alleles = when a mutant allele doesn't function normally and either directly inhibits the activity of wild-type proteins or inhibits the activity of another protein that is required for the normal function of the wild-type protein (ie: an activator downstream); *mutated protein acts with normal protein to block the normal proteins' function.

3. Dominant GAIN OF FUNCTION (GOF): mutations that result in elevated levels of gene activity or genes gain new activity:
for EX: cancer proto-oncogenes become mutated and become oncogene, stimulating massive growth (LOSS OF GROWTH CONTROL!)


What are the characteristic patterns of AR inheritance?

-HORIZONTAL distribution of affected individuals (only sibships in one generation are affected, not typically seen in parents, offspring, or other relatives)
-risk of each sibling of an affected individual = INDEPENDENT; 25% chance affected, but 2/3 chance unaffected and CARRIER
-consanguinity and ethnicity increase risk
-males and females equally likely to be affected


Explain the effect of consanguinity and ethnicity on the etiology and incidence of AR conditions

Ethnicity: groups of people who identify with each other through a common heritage; generally they are separated from larger populations by geographical, religious, or linguistic factors and are considered genetic isolates

-most mutant alleles are in heterozygotes who do not realize they have a mutant gene so the gene gets passed for several generations, perpetuating itself in these isolates.

-mating in ethnicity groups is not typically consanguineous

Consanguinity: mating between individuals related by blood, second cousins, or closer.
-increases the risk for mating between heterozygotes because consanguinity increases the chance that each offspring has inherited the same mutatnt allele from common ancesors (leading to birth of a baby with AR disease)

EX: ataxia with vitamin E deficiency (mutation in vit E absorbs protein, found in middle east where first cousin marriages are common)


What is the basis for carrier detection screen across ethnic distributions?

carrier screening to identify couples at risk for having offspring with AR conditions that are more prevalent in their ethnic group

Ex: ashkenazi jews: Tay sachs, Gaucher
Africans = sickle cell disease
N. Europeans = cystic fibrosis


How do gene modifiers impact the phenotype of a disease? (ie in an AR disease?)

SMN 2 = gene modifier so when SMN is mutated, SMA occurs because SMN2 cannot fully compensate for the lack of functional SMN protein, however, when the SMN2 copy number increase, small amounts of full length transcripts are generated by SMN2 and able to function thus resulting in a milder SMA II or III phenotype. If an individual has SMA, they will have a milder phenotype if there are greater than 3 copies of SMN2


What is an example where carrier testing is complicate in an AR disease?

Testing for SMA:
98% of parents are heterozygotes and carry SMN1 mutation
2% de novo causing mutation (paternal origin);
Gets complicated when:
a parent has 2 copies of SMN1 on one chromosome and no copies on the other chromosome; testing involves dosage analysis (just looking for the number of copies.. so you think you have 2 copies, but really you have a chromo that doesn't have a copy, so you can pass on a chromo without the gene!)
False negative: because 2 copies of SMN1 are on one chromosome


What is x-inactivation and what is the lyon hypothesis?

x-inactivation= dosage compensation.. phenomenon of equalization of gene activity in spite of females having 2x the gene number of x-chromosomes

Lyon hypothesis: in early embryonic somatic (non-germ cells) female cells, one of 2 X chromosomes is randomly inactivated, such that only one is transcriptionally active and makes proteins and other is permanently inactivated in that cell and all progeny of that cell

Such that a female is a mosaic with 50% of the cells expressed maternally derived X and other 50% = paternally derived

Barr body = visibly inactive X-chromosome in non-mitotic cells as a dense clump of chromatin at the periphery of a cell's nucleus


What is XIST (X-Inactive-Specific Transcript)?

= has an important role in regulating inactivation process;
-encodes non-coding mRNA transcripts that coat the chromosome and initiate transcriptional silencing through binding of repressor proteins
-maintained through subsequent cell divisions via DNA methylation


How is X-inactivation involved in the etiology of X-linked diseases?

1. if a woman has a deletion on one X-chromosome then the abnormal X-chromosome is INACTIVE
2. If an X chromosome is translocated to an autosome: then the non-translocated X is inactivated, otherwise inactivation will spread to the autosome, creating functional monosomy

-pseudoautosomal region = share homology between X and Y chromosome
-gene escape X inactivation = mutations cause disease


What are the characteristics of X-linked disorders (recessive vs. dominant)

-usually only males affected
-females = asymptomatic usually; may express condition with variable severity due to x-inactivation
-transmission = through unaffected female carriers to sons (such that the disease appears to SKIP generations)
-affected males at risk of transmitting disorder to their grandsons through obligate carrier daughters

-affected males have NO affected sons but ALL affected daughters:
-no male to male transmission
-both male/female children of a female affected
-have a 50% risk of inheriting phenotype (similar to autosomal dominant)


What is the rationale for choosing a karyotype?

-need live tissue (blood sample/bone marrow)
-detect: chromosomal imbalances (numerical such as anaploidy or structural such as translocations/inversions/deletions/duplications)


What is the rationale for choosing FISH?

DNA/RNA probe binds to specific gene of interest on chromosome;
Used for specific localization of genes + direct visualization of anomalies (ie: microdeletions) at molecular level (when deletion is too small to be visualized by karyotypes)
-known deletions/duplications, reciprocal/robertsonian translocations


What is the rationale for choosing a microarray?

thousands of nucleic acids arranged in grids on glass. DNA/RNA probes are hybridized to the chip and a scanner detect the relative amount of complementary binding
Use: to profile gene expression levels of thousands of genes simultaneously to study certain disease treatments

Its able to detect SNPs for genotyping, predisposition of disease etc.
this allows for detection of ALL chromosomal imbalances that karyotyping can and few others;
uses DNA therefore done need a viable tissue/blood


When should an array based recommendation for detection of abnormality be the first line test?

for individuals with multiple anomalies (Not specific to defines syndrome)
non-syndromic developmental delay or intellectual disability
autism spectrum disorder


What is the rationale for doing a single gene test?

for sequencing of genes associated with disease and interpretation of results based on degree that a particular sequence variation is/might be related to actual /future illness

"known disease causing variants"


What is the rationale for whole exome sequencing?

-selectively sequence the coding region of genome
-come DNA to reference--compare variants and filter:
missense = mutation results in changed amino acid
nonsense = mutations base change results in a premature stop codon causing protein product to be truncated/incomplete

*only need 1% of genome
detects: base substitutions and small deletions and duplications-- most but not all mutations

since only exons are sequenced, dont cover non-coding elements, untranslated regions, enhancers etc. does not cover copy number variations (ie: repeat expansions)

vs. whole genome sequencing --> sequences all nucleotides


What are mutifactorial traits? polygenic inheritance? continuous traits? discontinuous traits?

1. Multifactorial traits: multiple genes at different loci all have a small additive effect with multiple environmental factors and other trigger usually contributing to etiology (predisposition = inherited from both parents)
2. Polygenic inheritance = additive effect of multiple genes and no environmental influences
3. Continuous/quantitative traits = can be measured along an uninterrupted scale and tend to follow a normal or "bell-shaped" distribution in a population (ie: height, weight, BP, intelligence); when continuos traits have normal distribution, measurements with more than 2 standard deviations above or below average = "abnormal"
4. Discontinuous traits = either present or absent; not measure on a scale/range, but severity of trait can range


Explain the multifactorial threshold model/liability model; what concepts can the MFT model be used to explain?

all of the factors which influence the development of a multifactorial disorder (genetic or environmental) can be considered a single entity known as liability;
liabilities of all indviduals in a population form a continuous variable (has a normal distribution) but the curves are shifted right and the extend to which they are shifted relates their threshold for a disease/discontinuous phenotype (affect/not)
ABOVE THE THRESHOLD: abnormal phenotype expressed
In a general population: proportion beyond threshold = 'population incidence'
in a relative population: proportion beyond threshold = 'familial incidence'

MFT model assumes a susceptibility to a particular trait/disorder: susceptibility is normally distributed but not measurable: at one end of normal distribution = threshold of liability: individual who exceeds this threshold of liability/susceptibility will have the trait (ex: single congenital malformation)

MFT model can be used to explain:
1. Gender Bias: how different populations may have different thresholds; one gender may have a higher occurrence than the other; the susceptibility distribution is the same in both Male and female but the threshold beyond which an individual will have a trait is different (depending on gender)
2. Population Bias: how different distributions among populations is possible but the threshold is the same
(one population may have a higher occurrence for a disease than other populations.. explains the risks present in first degree relatives of an affected individual; frequency within a population is changed but the the threshold is the same)


Apply the threshold liability model to underlying etiology of common congenital malformations and adult onset diseases

Explains the gender/population bias in relation to:
spina bfida = more common in F>M (gender bias)
population bias:
cystic fibrosis = more common in n.europeans + ashkenazi jews
sickle cell = more common in africans
thalassemia = more common in mediterranean, african, indian, and asians


What is the difference between absolute risk and relative risk?

family aggregation = occurrence of more cases of a give disorder in close relatives of a person with disorder than in control families; due to shared genetic or shared environmental factors (familial aggregation cant distinguish between the two)

Absolute risk = an individuals risk for developing a given disease over a period of time

relative risk = used to compare risk between two groups of people: one group has a certain risk factor (ie: family history) and the other does not; ie: someones risk compared to general population risk (if relative risk = 1 then no difference)

relative risk = incidence in relatives of proband / incidence in general population

since relatives share a portion of their genes, the multifactorial trait is seen in proportion to the degree of relationship (ie: more first degree relatives affected than second degree)
Monozygotic twins = share 100% of genes
Parents/siblings/dizygotic twins = share 50% of genes


How do twin studies help to determine the genetic contribution of multifactorial conditions and traits?

1. monozygotic twins = identical genetics, therefore any differences = due to environment (1 egg, 2 sperm)
2. Dizygotic twins = differ by environment AND genes (2 eggs, 2 sperm)
by comparing MZ and DZ, can figure out genetic component

concordant = if both twins share a discontinuous trait
disconcordant = if both twins do NOT share discontinuous traits

if a disease is genetic: 100% of MZ will be concordant and 50% of DZ will be concordant

If a trait does NOT have a genetic contribution, there is no difference in concordance

Correlation coefficient = measure of association of a CONTINUOUS train between two relatives (if correlation coefficient = 1 (in MZ) = trait is entirely genetic


what is heritability

the measure of total phenotype variance contribute by genetic variance

h^2 = heritance = Variance genetic/ (variance genetic + variance environment)


What do adoption studies reveal about genetic contribution?

= children born to parents who have a particular condition but adopted by parents who do not have the condition are studied to determine effect of genetics on condition


Describe the basis for emperic risk estimates, their limitations, and influencing factors

incidence of a multifactorial trait among 1st degree relatives of an affected person ~ approx = to the squareroot of the incidence in general population;
*used to estimate recurrence risk

emperic risk = statistic that represents the average risk that is specific to the population that was tested; NOT NECESSARILY specific for a particular family because heterogeneity of many disorder requires consideration of other, non-functional etiologies;

-skewed populations test (ie: town near radiation plant)
-small population
-heterogeneity (locus): other nonfunctional etiologies

-recurrence risk depends on the number of people who exceed the threshold
-risk decreases with further away from proband (therefore relative other an the primary relatives can be ignored)

so: things that increase the recurrence risk:
-increased number of people affected (relatives)
-increased severity of affected proband
-if one sex is more often affected, then, if the affected is of the OPPOSITE SEX (if proband is in the less affected gender)


Describe the function of mitochondria and their role in energy production

= make ATP by using electrons from intermediary metabolism (from H+ brough in primary by NADH from glucose breakdown) and also by FADH2 from FA breakdown and removing energy in a controlled manner as electrons move down the ETC

energy released is used by complex I, III, cyt C, IV, to pump protons through the mitchondrial innermembrane
this creates a charge and pH gradient such that mito = charged and acts as a capacitor (storing potential energy); the potential energy drives ATP synthase (complex V), which couples the reaction of ADP + Pi to ATP with inflow of protons


Describe mitochondrial DNA characteristics, including maternal inheritance, threshold, heteroplasmy, and segregation during cell division

1. Maternal Inheritance:
"uniparental inheritance": non-mendelian; ALL offspring carry trait if its present on mom's DNA; none carry it if its present on fathers mtDNA (because all mitochondira are inherited in oocyte and sperm only carries DNA, no mtDNA)

2. Heteroplasmy = presence of a mixture of more than one type of mtDNA with in a cell/individual; since eukaryotes contain hundreds of mitochondria with hundreds of copies of mtDNA, it is possible that both wild-type and mutant molecules in the same cell will exist (heteroplasmy) because the mtDNA ploidy is so high, heteroplasmy can encompass virtually continuous variation in proportion of mutant molecules

3. Threshold: genotypic blending of wild type and mutant mtDNA (Heteroplasmy) does not lead to equivalent phenotypic blending. A significant decrease in energy production appears not to occur until the proportion of mutant molecules rises enough that some mitochondria contain few or no-wild type molecules; a threshold exists in the expression of deleterious mtDNA mutations (~70% or more mutant molecules need) in vitro; in vivo, depends on: energy needs of a particualr tissue and on specific mutation

4. Segregation (during cell division):
different tissues can harbor different proportions of mutant and wild type molecules: depends in part on the developmental time and place of the original mutation as this will affect to which daughter cells the mutation partitions during cell division;
phenotype severity depends on the wild type to normal fraction and how aerobic a given tissue is and whether or not the mutation occurred early (potential and sever affect) or at terminal differentiation (little affect)