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Genetics 3


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If two monozygotic twins demonstrate 100% concordance what type of genetic inheritance is this?
completely genetic
If two dizygotic twins demonstrate 50% concordance, what type of genetic inheritance is this
completely genetic
If concordance is greater among monozygotic twins than dizygotic twins, what does this say about whether or not this is a genetic trait?
there is a component of genetics with the trait
If the concordance for MZ=DZ what type of genetic inheritance is this?
totally environmental
If pyloric stenosis shows concordance for MZ=22% and DZ=2%, is there a significant genetic component?
Which of the following has a genetic component? Cleft lip & palate, pyloric stenosis, schizophrenia, insulin dependent diabetes melitus
What do multiple miscarriages and retardation suggest?
chromosomal abnormalitites
What do earlier age of onset and increasing severity with generation suggest? (anticipation⬦ males)
trinucleotide repeat disease
What is a compound heterozygote?
2 different mutant alleles at the same loci, from mom and dad
If affected individuals are seen in every generation, what does this suggest?
Dominant inheritance
What is the probability of the child of affected and unaffected heterozygous parents having an affected child?
What term does the following define? The range of phenotypic expression seen among family members carrying the same mutation.
Variable expressivity
What term does the following define? Individuals carry the disease gene but don not show clinical symptoms (all or none)
Reduced penetrance
What type of inheritance is demonstrated with Marfans?
autosomal dominant with reduced penetrance
What type of inheritance does Huntington's disease demonstrate?
Autosomal dominance with age dependent penetrance⬦trinucleotide repeat (CAG)
If no male to male transmission occurs, what type of inheritance is suggested and the disease is rarely expressed in females? Why is there no male to male inheritance?
X-linked recessive⬦ because males get their X from their mothers⬦ and females get two Xs
What is the chance that the daughter of an affected male of an X-recessive inheritance will be a carrier?
What are the odds that carrier females of an X-linked recessive disease will transmit an allele to their⬦ a) son⬦ b) daughter
both are 50%
If there is an affected in each generation, both males and females are affected, but there are no male to male transmissions and all of the daughters of an affected male are affected, what type of inheritance is suspected?
X-linked dominance
In X-linked dominant, who are more likely to be affected, males or females, why?
Females are 2X as likely to be affected, because they receive an X from mom and an X from dad
What is the probability that an affected male will have an affected⬦ a) son⬦ b) daughter
a) son - zero⬦ b) daughter 100%
In X-linked dominance inheritance, which gender is more likely to be mildly affected, why?
females, because they have X-inactivation (mosaic), while males can't switch to another X because they have only one X
What is anticiaption and which gender is likely to produce this phenomenon?
a)progressively earlier onset and increasing severity with sucessive generations⬦ b) males
For Huntington's what are the respective penetrance following CAG repeats? <27 CAG⬦ 27-35 CAG⬦ 36-39 CAG⬦ > 39 CAG
<27 CAG: Normal⬦ 27-35 CAG: premutation⬦ 36-39 CAG: reduced penetrance⬦ > 39 CAG: complete penetrance
What is a polymorphism as compared to a mutant allele?
Polymorphism is an allele that exhibits many forms (at least two different types in the population), while a mutant differs from both wild-type and polymorphic alleles (can be used to indicate diseased gene)
What does hemizygous mean?
males having an X and a Y
What is incomplete dominance?
when an intermediate for a trait exists between homozygous and heterozygous phenotypes
What is codomince?
When the phenotype for both alleles is expressed
In sickle cell anemia for a heterozyous individual, what type of inheritance is seen with respect to each allele?
the normal allele is incompletely dominant⬦ the abnormal allele is incompletely recessive⬦ it manifests as a recessive trait
With resect to inheritance, what is it called when less than what is required for normal function of a normal protein causes disese due to mutation?
haploinsufficient: when a mutation lowers the amount of gene product below a critical level needed for normal activity
What is it called when the abnormal allele interferes with the function of the normal allele?
Dominant negative effect
What is it called when the mutant allele is enhanced in one or more of its normal properties? Give two examples.
simple gain of function⬦ Huntington's and dwarfing condition achondroplasia
Contrast the following 1) Allelic heterogeneity, 2) locus heterogeneity and, 3) genetic heterogeneity
1) Allelic Heterogeneity is a different mutation at the same loci, 2) locus heterogeneity are mutations at different loci, 3) Genetic Allelic encompasses both heterogeneity and locus heterogeneity
Give two examples of locus heterogeneity.
1) Retinitis pigmentosa (x-linked, autosomal recessive and autosomal dominant forms⬦ and sometimes with retardation) 2) Ehlers-Danlos syndrome [connective tissue collagen being fragile or too elastic] ( x-linked, autosomal recessive and autosomal dominant forms)
T/F Allelic heterogeneity is defined by a mutation at a given locus that results in a clinically indistinguishable or similar disorders.
True, but not completely true⬦ these disorders can also be very different
Give an example of allelic heterogeneity.
Some mutations in the RET gene can cause Hirschsprung disease (colonic motility/severe constipation) or multiple endocrine neoplasia (dominantly inherited cancer) or both
What are the 4 types of mutation?
missense, nonsense, splicing, and frameshift
Of the 4 types of mutation, which 2 commonly account for Loss of Function mutations?
Nonsense and frameshift, which makes sense if you consider these changes will stop and/or shorten the RNA length⬦ thus loss of function would be probable
How are loss of function disorders usually inherited?
autosomal recessive, however some dominant diseases manifest in loss of function.
What is a dominant negative mutation?
Seen in protein multimeric complexes, a mutant gene can interact with the wild-type gene rendering the normal gene non-functional
What is it called when an altered protein product (due to mutation) produces a new property? How is this type of mutation usually inherited.
Gain of Function⬦ Autosomal dominant
In a novel protein, what type of mutation serves to point to functionally important residues on a protein?
What is in vitro and in vivo?
in vitro: in cell culture⬦ in vivo: in animals
What types of experiments are done first when working with novel genes?
Descriptive: to determine where in the cell the normal protein is express and how this pattern may change in mutant proteins⬦ Also microarrays can be used comparatively between subjects
For a loss of function mutation, what will a knock-out mouse produce?
For a gain of function mutation, what will a knock-in mouse provide?
clues to the normal function of the gene in question by not producing the phenotype and giving evidence about the mechanism involved
What is a knock-in mouse and how is it used?
it is a mouse where the human mutation is added which will result in an expression of the human gene of interest⬦ it can be used to check the efficacy of a novel treatment
How does one determine function of a novel gene? (3 things)
clues from: sequence analysis, mutations, and experimental models
what 3 things are used for sequence analysis?
1) homology searches (function or mutant phenotype), 2) domain and motif searches (specific characteristics, i.e., phosphorylation glycosylation), 3) Gene families (family members become candidates for similar diseases)
what 3 things are comparative genomics used for?
1) determine evolutionary relationship, 2) identification of regulatory elements using sequence conservation in non-coding regions, 3) Gene identification
What 3 clues do you use to determine the function of a novel gene?
Clues from: 1) sequence analysis, 2) Mutations, 3) Experimental models
identify the following mutations as either a substitution, Deletion, Insertion, or duplication: 1) nonsense, 2) frameshift, 3) missense, 4) loss of codon, 5) TOM GET TOM GET
1) nonsense = substitution, 2) Frameshift = deletion, 3) missense = substitution, 4) loss of codon=deletion, 5) frameshift=deletion
What is a missense mutation
Substitution: Where a mutation causes a change in residue, but its still a residue.
What is a nonsense mutation?
Substitution: where the codon does not represent an actual amino acid (stop codon)
What is a frameshift mutation?
Deletion or Insertion: where an insertion or deletion causes a mis-reading in the codon for an amino acid, usually causes termination of the transcription/translation
Name the 3 types of Loss of Function mutation.
1) Truncation, 2) Haploinsufficiency, 3) Dominant Negative
What is a truncation loss of function mutation? Give an example.
Gross inactivation due to nonsense or frameshift⬦ Parkinson's
Is a truncation loss of function usually dominant or recessive?
What is a haploinsufficiency loss of function mutation? Give an example
1) protein below a critical level⬦ 2) Waardenburg's syndrom is a loss of function in the Pax3 gene that leads to (deafness),
Is haploinsufficiency usually dominant or recessive?
What is a Dominant negative loss of function mutation? Give an example
1) mutant protein poisoning the normal protein⬦ 2) early onset dystonia.. (a movement disorder)
What is a Gain of Function mutation? Give an example.
Altered protein w/ a new property⬦ Huntington's disease
What does a loss of function in the Pax3 gene lead to? What types of mutation cause this?
Haploinsufficiency -> Waardenburg's syndrom (deafness)⬦ b) nonsense and frameshift (+/-)
What types of mutation would be nontruncating
Huntington's disease is a ____ of Function disease. What is its mechanism?
Gain⬦ CAGn repeat expansion that codes for a polyglutamin tract that promotes aggregations that may kill the cell
What are the 3 tests you can use to identify the gene product?
1) Expression Pattern, 2) Cellular localization, 3) intracellular localization
Which 2 tools do you use to characterize the gene product EXPRESSION PATTERN?
Northern Blot (mRNA) and Western blot (protein)
Which 2 tools do you use to characterize the gene product by CELLULAR LOCALIZATION (Spatial patterns in tissues or cells)?
1) in situ hypridization (mRNA), 2) immunohistochemistry (protein)
What is immunohistochemistry used for?
cellular localization of proteins
What is in situ hybridization used for?
cellular localization of mRNA activity
What is Northern blot used for?
mRNA degree of expression and which tissues
What is Western Blot used for?
protein degree of express and which tissues are expressing
Which 2 tools do you use to characterize the gene product via INTRACELLULAR LOCALIZATION (Localization within a cell) ?
1) cell fragmentation (protein), 2) immunofluorescence microscopy (protein)
What is cell fragmentation used for?
to characterize gene expression of a protein inside the cell
What is immunofluorescence microscopy used for?
to characterize gene expression of a protein inside the cell (e.g., expression of wt and mt torsinA in CAD cells)
What is "in situ" hybridization" used for?
cellular localization of mRNA (spatial patterns of expressed mRNA within tisues or cells)
What is a immunohistochemistry assay used for?
cellular localization (to determine the spatial patterns of expressed proteins in tissues or cells)
What type of mouse does the following scenario represent? Destroy normal function in mouse, if disease is due to loss of function this should produce an animal model of the disease
Knock-out mouse
What type of mouse does the following scenario represent? Destroy normal function in mouse, if disease is due to gain of function then we should be able to insert the human disease mutation in the mouse and produce the human disease.
When and how is a Transgenic Mouse Model used?
When? it is used to test Gain of Function mutations where a single copy of a gene is sufficient to cause the disease⬦ How? Insertion fo of the human gene at random
What 2 things can explain why a mouse model does not express phenotype or partial phenotype?
1) Differences in pathways (mouse may have alternative pathways), 2) Genetic modifiers
A) How was Huntingtin's disease confirmed NOT to be a loss of function? B) How was the disease confirmed as a gain of function?
A) a knock-out mice die in utero⬦ thus, when they lack the gene they are not viable.. B) knock-in mice with the human gene developed inclusions consisten with the human diease HD.
Which model oranism is used for developmental and neurologic studies?
C. elegans
Which model is used to study developmental pathways?
which models are used to screen for suppressors and enhancer of mutant phenotypes?
worms and flies
What 3 things can the human genome sequence be used for?
Functional genomics, pharmacogenomics, and whole genome association studies.
What is functional genomics?
large scale investigation of gene function
What is pharmacogenomics used for?
To determine how an individual's genetic inheritance affects the body's response to a drug
What are whole genome association studies used for?
Using SNPs, they identify genes involved in complex traits
What is used to predict survival probabilities?
functional genomics
How can pharmacogenetics be used?
using SNPs, we can correlate the efficacy of the drug in trials with the SNPs to predict.
Lecture 11
What 4 things caues and maintain genetic variation?
Mutation, gene flow, selection, and drift over evolutionary time
When did the mutations that are responsible for many common human genetic disease arise (or underwent expansion in frequency)?
relatively recently in human evolution
What is the Hardy-Weinberg law used for?
to quantify geneotype frequency and allele frequency in a population⬦ it can also be used to assess the risk of genetic disease
What proves that genetic frequencies do not change from one generation to the next?
Hardy-Weinberg law
The Hardy-Weinberg law is based on which 6 assumptions?
large population, random mating, no novel mutation, lack of selection, lack of genetic drift and land of gene flow
Which word characterizes the point at which a particular allele becomes the only allele at its locus in a population - the frequency of the allele.
What is purifying selection?
selection that results in favoring the predominant allele
What is diversitying selection?
Natural selection that favors extreme over intermediate phenotypes
What is balanced selection
A selection regime that results in the maintenance of two or more alleles at a locus in a population (e.g. overdominance)
What is genetic drift?
Random fluctuations in gene frequencies, most evident in small populations
What is gene flow
the movement of genes from one population to another
What is assortive mating?
Where sexually reproducing organisms tend to mate with others that are like themselves
what causes a SNP?
nucleotide substitution
Give 4 examples of mutation that can bring about genetic variability.
Nucleotide substitution (SNP), 2) Insertion/deletion, insertion of a transposable element, or chromosomal rearrangement (tranlocations, inverstion or duplications)
According to Kimura's neutral mutation theory, what are the 3 possible effects of mutations?
advantageous, neutral or deleterious
Rank Kimura's mutation in order of least common to most.
neutral > deleterious > advantageous
What does it mean when the frequency of an allele in a population = 1?
This is Fixation⬦ it is the only allele in the population
What is the fixation (for new alleles) equation for a nearly neutral mutations, where s=~0 (s= selective advantage)?
P = 1/(2N)=q⬦ where P= probability of fixation⬦ and q= for a new allele⬦ thus, the probability of fixation is equal to the frequence of the new allele when there is no selectivce advantage for the new allele
If there is selective advantage in a new allele (advantageous mutation), is it likely to undergo fixation? Does the same apply to deleterious mutation?
a) no⬦ for example if a mutation increases fitness by 1%, the probability would increase by 2%⬦ b) yes, it has a low but finite probablity of fixation
A) What is the time to fixation for advantageous mutation of about 1%? B) And time to fixation for neutral mutations?
A) ~40,000 years⬦ B) 800,000 years
What does a larger ancestrial population suggest about the diversity of a given population⬦ and why?
A large ancestrial population would result in greater current diversity within a population, because the larger the population the more time is needed for fixation
Name the mechanisms of Drift
1. Random fluctionations in allelic segregation⬦ 2. Also founder effect and bottle neck will cause this.
what 2 things can account for allele frequencies being substantially different from one population to another?
Selection and drift
What effects do new mutation have on genetic variability in a population?
Increase variability
What effects do new loss of alleles by selection or drift have on genetic variability in a population?
decrease variability
give the hardy-weinberg equation
p + q = 1⬦ p^2 + 2pq + q^2⬦ where p=dominant and q=recessive⬦ (note: p + q = 1⬦ and p=AA, 2pq=AB and q=BB)
Given a the total number of people in a population (N) and the total number of a homozygous individuals (Ho) in a population, and the number of heterozygotes (He) in a population ( determine the frequency of both alleles
p= (2Ho + He)/ N⬦ q=1-p
Given p, what is the frequency of heterozygotes in a population?
q=1-p⬦ thus, 2pq
How do you calculate carrier frequency for an autosomal recessive mutation from Disease incidence?
q^2=disease incidence⬦ thus, q= square root of q^2⬦ thus, p=1-q⬦ Therefore: carriers = 2pq= 2 X q X (1-q)
How do you determine the probability that the mating of two individuals will produce a child with a recessive autosomal disorder? Where one person has a 1 degree relative that is affected and the other has an estimated ethnic risk (carrier freq).
If the relative is a sib, and neither parent is affected: that person has a 1/3 chance of being a carrier. The other person has an assigned risk (carrier freq). These combined are the risk of both being⬦ 1/3 X carrier freq X 1/4⬦ the 1/4 is the probability of a recessive from two heterozygotes.
How do you determine the risk of two people having a child with an autosomal recessive disorder if neither has a family history of the disease, but both belong to a ethnic group that expresses this mutation?
[(carrier frequency)^2] X 1/4
what are the chances that 2 caucasian will marry each other?
What are the the problems with genetic testing?
reliability and cost⬦ so probability is sometimes used
How would you find the total frequency of affected individuals for a dominantly inherited disease, given the frequency of unaffecteds (p^2)
p = square root of P^2⬦ q=1-p⬦ 2pq = heterozygous affected⬦ thus: number of affected would be = (1-p)^2 + 2p(1-p)
How do you find the allele frequency of X-linked recessive disorders for: females and males?
1) females: treat as a normal autosomal question⬦ 2) p + q = 1⬦ where p = unaffected and q = affected.
How do you find the allele frequency of X-Linked dominant disorders for females and males?
For females: Exactly like dominant disorder, where allele frequency = P^2 +2pq⬦ For Males: p + q = 1
Which population is at increased risk for Tay-Sachs disease and what are the mutations?
Ashkenazi Jews: exon 11 insertion and intron 12 splice signal⬦ French-Canadian: 7.6 kb 5' deletion
Which populations are at riskfor Familial Hypecholesterolemia?
French-Canadian: promoter + exon 1 deletion⬦ and Lebonese: premature stop at aa 660
What are the exceptions to H-W equilibrium?
Exception to random mating, purifying & diversity selection, new mutations, founder effects/ bottleneck, genetic drift (short time in large populations is negligible, but long time in small populations drift is inevitible, and balance selection
What are 3 exceptions to random mating?
Stratification, assortive mating, and consanguinuity
Define: Balancing Selection (aka heterozygous advantage)
might explain the prescence of recessive disease gene in a population
Name two mutational diseases that gives strong support for balancing selection and and the protection it provides
sickle cell anamia, ß-thalassemia: both Malaria
Name a disease that gives some evidence in support of balancing selection hypothesis
cystic fibrosis: supports against typhoid and cholera
What 2 disease and the supposed disease they support agains have little evidence that support the balancing selection
Hypercholesterolemia and hypertension: both protect against starvation⬦ little support
How do disease alleles persist in humans?
If Dominant allele is lethal at birth⬦ then All mutations are new⬦
Lecture 12
What causes Prader-Willis Syndrome?
Inappropriate expression of the mathernal gene: 15q11-q13⬦ caused by the Paternal deletions of 15q11-q13⬦ or caused by Maternal uniparental disomy
What causes Angelman Syndrome?
Inappropriate expression of the mathernal gene: 15q11-q13⬦ caused by the Maternal deletion of 15q11-q13⬦ or caused by paternal uniparental disomy
How do you treat Prader-Willi Syndrome?
Growth hormone
What is Beckwith-Wiedeman syndrome and what causes it?
it is a uniparental disomy for portions of the 11p15 chromosome inherited from the father
See page 42 of Genetics Syllabus for genomic imprinting pedigree
Is having the appropriate numbers of genes (chromosomes) enough to ensure normal development? E.g. two XX from the mother or the father and not one from each
not enough because the functions of the respective maternal and paternal genomes is complementary
T/F: once gene are in herited, they become the indivduals genes and have no "memor" of recent germline passage
False, this is genomic imprinting⬦ where the complementary functional memory of maternal and parental germlines is retained
When is the insulin-like growth factor 2 receptor expressed? What does this mean?
when there is a deletion on the Thp gene from the father⬦ thus, the active copy is on the maternal chromosome
T/F once imprinting occurs, (e.g., male imprinted after conception to signify its male inheritance) it will always remain a male imprinted gene.
false, if a female inherits this gene, then passes it on to her son or daughter, the gene will be imprinted by her offspring as a female gene.
Where does imprinting occur?
a DNA element called the Imprinting Center of the imprinting region
State the mechanism by which imprinting inherited disorders occur.
Typically, we are suppose to express alternative alleles on the basis of its maternal or paternal origin, However, if the appropriate gene is deleted the allele selection will default to the other available allele. It is in the expression of the allele that is inappropriate with respect to its origin (maternal/paternal) that causes the disease and not the actual deletion (although the deletion is the indirect cause)... for example if a gene is expressed that came from the mother that should be expressed for the father... the disease state will arise
What is trisomy rescue?
it is the post-zygotic loss of an extra chromosome to avoid Uniparental Disomy (UPD)⬦ 2/3 cells will be "normal" in chromosome distribution, one cell will have two pairs of chromosomes from the same parent and a missing chromosome the other parent.
What percentage of genes are thought to be imprinted?
How is IGF2 inherited?
it is imprinted (inactive) on maternal and active only on the paternal chromosome
What does X-chromosome inactivation resemble on a pedigree chart?
X-linked recessive⬦ because the mother does not express the disease due to mosaic
If a pedigree shows a suspected imprinting disase where 2 offspring are affected (a male and a female), but only the male passes the disease on to his offspring, what is the disases?
If there are only males affected by a disease, (although some women may express some disease state), and x-linked is not an option, what is suspected?
What is an example of a disease associated with X-inactivation?
Onithine transcarbamoylase (OTC) deficiency
With respect to gender, who is affected more by OTC deficiency? Why?
males affected more severely than females⬦ X-inactivation
What is the main concern with OTC deficiency? How is this treated?
brain damage, retardation⬦ b) restrict protein, sodium phenylacetate (which diverts ammonia to clearance in urine), hemodialysis, and liver transplant
Which X-allele expresses the Xist transcript? Where is the Xist gene?
The inactivated X allele⬦ Xist is located in the X inactivation center, but it's transcript remains in the nucleus as a complex XIST-RNA/Barr Body complex
What is epigenetic?
a factor that changes the phenotype without changing the geneotype
What is the mechanism for genomic imprinting and X-inactivation, are they the same?
Yes, they are the same⬦ involves the methylation of cytosine on histones⬦ this is an example of epigenetics
Do epigenetic processes occur in all cells? Why do they exist at all? What kind of disease can arise from these epigenetic regulatory programs not being executed appropriately?
1) yes, all cells⬦ 2) adapt to environmental conditions⬦ 3) Cancer: inappropriate silencing of tumor suppressor genes OR inappropriate activation of oncogenes
What are the following genes an example of? RB1 (retinoblastoma), p16 (melanoma), VHL (renal cell carcinoma), APC (Colorectal carcinoma)
Tumor suppressor genes (proteins) which when inappropriately silenced via cytosine methylation can result in cancer
What are the following genes an example of? R-Ras (gastric cancer), MAGE1 melanoma, MASPIN (gastric cancer), PAX2 (Endometrial cancer)
Oncogenes, which normally would function in growth state, but should be silenced via cytosine methylation, when this fails it can produce cancer.
What is mutational homogeneity?
a disease is caused by on mutation
What is a haplotype?
Different combinations of polymorphisms are known as haplotypes inherited as a single (haplo=one) together
What is oligogenic?
when two or more genes work together to produce a phenotype
What is linkage disequilibrium?
when combinations of alleles occur more often than would be expected for given allele frequencies
Is biological function required to perform positional cloning?
What is the first step in performing positional cloning to find a gene that causes a disease?
Linkage analysis
What is the basis of linkage analysis?
When two genes are inherited together they are generally close to each other.
What type of inheritance is linkage analysis used for?
single gene inheritance (Mendelian)
Do you need to know the functional biology of a disease state to use linkage analysis?
Can you perform linkage analysis with poorly defined phenotypes?
no, because you may miss a person that is not fully expressing the disease and it will confound the analysis
T/F you don't need a good chromosome map that is constructed with numerous genetic markers to use linkage analysis?
False you need these⬦ such that you need to have knowledge of the location of these markers as points of reference.
What type of family histories are useful in performing linkage analysis?
a DNA sequence of known location that can be used as probes in family or population studies and for the construction of genetic maps
A genetic marker found in more than1% of the population
What are Simple Sequence Repeats (SSR, microsatellites)
Genetic markers
Why are microsatellites so useful as markers?
1) there are thousands of them in genome, 2) they are di, tri, or tetra nucleotides repeats, 3) they give a lot of good informatin, 4) they are easy to analyze
How often are SNPs found? 1/?
500-1000 bp
What does a LOD score of < -2.0 represent?
evidence against linkage: 1:100
Can LOD scores for different families be combined?
What is the second step in clonal positioning?
Find disease causing gene in linked region (Pre-genome era)
What 4 things are done to find the disease causing gene in the linked region?
1) subclone the region of interest⬦ 2) identify coding elements⬦ 3) sequence genes in patients and controls⬦ 4) indentiry diease-causing alleles
What is the genetic cause of cystic fibrosis?
homozygosity in loss of function mutation in CFTR, which loses control of chloride and water transport in secretory cells
What is exon trapping?
A rapid and efficient means of finding expressed DNA sequences in a genome sequence and is based on selection for functional splice sites in genomic DN
What diseases was linkage analysis used to identify the responsible gene?
HD, Alzheimer, retinitis pigmentosis, MD, Hemochromatosis, marfans, hereditary forms of deafness⬦ every medelian disorder
How is Identification of Disease-causing gene in positional cloning done with the advent of PCR?
1) SNP arrays⬦ and Bioinfomatics has eliminated the need for subcloning and Exon hunting⬦ 2) almost every annotated gene has been mapped.
What 3 things are now possible if a disease causing gene is found?
1) molecular diagnosis/genetic counseling, 2) Functional studies (understand the pathogenesis), 3) new treatments (gene therapy)
What are the two major modes of inheritance?
Mendelian and Complex
Name the 3 types of complex inheritance.
Oligogenetic (more than one gene), 2) Locus heterogeneity (Different genes can cause the same trait), 3) environmental factors contribute to the phenotype expression
What is Locus heterogeneity?
when more than one gene causes the same trait
What are 3 patterns associated with Complex inheritance
1) Fewer family members affected compared with mendelian⬦ 2) Monozygotic Concordance is less than 100%⬦ 3) the ratio of MZ concordance to DZ is greater than would be predicted
Which are more common, mendelian inherited diseases or complex trait disease?
Which type of inherited disease is easier to identify?
Can you use a single family classic linkage analysis to identify genes involved in a complex disease trait?
No⬦ you can't use classic linkage analysis at all
What 3 things would you consider to identify genes involved in complex disease traits?
1) Oligogenicity, 2) locus heterogeneity, 3) Assortive mating?
What are the 3 steps in identifying the genes involved in complex traits?
1) define your phenotype⬦ 2) Non-parametric linkage analysis⬦ 3) Use fine mapping (haplotypes and linkage disequlibrium
In complex inheritance, what 2 things do you do to define the phenotype?
1) Identify distinct diagnostic subgroups⬦2) Identify endophenotypes that may be transmitted in families by mendelian genetics.
Why would you say that two alleles in linkage disequilibrium are non-randomly associated?
Because, because they are closely situated they are inherited more often than would be expected based on allele frequency in a population
What is the difference between an examination by linkage analysis performed on a families and linkage disequilibrim.
LD looks at allele pattern in a population among unrelated individuals
What is the expected allele frequency of seeing two alleles (A=0.2 and B=0.6) in a population if the these genes are not linked? What would a frequency of 0.2 for A&B occuring together in a population?
a) 0.2 X 0.3 =0.06⬦ b) they are in disequilibrium⬦ and likely to be linked
What are 4 aspects of the non-parametric linkage analysis?
1) it's model free, so there are no assumptions made about mode of inheritance⬦ 2) Many small family units (hopefully affected sib pairs) are needed⬦ 3) False positive rate is high so duplication is needed)⬦ 4) You cannot use genetic recombinatino to fine-map locus
In non-parametric linkage analysis, can you assume anything about the mode of inheritance?
no⬦ you just can't be sure
In non-parametric linkage analysis, are the results conclusive?
no, high false positive
In non-parametric linkage analysis, can you use genetic recombination to fine-map the locus?
On average, how many bp do linkage disequilibia extend to?
60,000 bp
What type of distribution is found in LD?
With out LD, would mapping for disease gene of complex inheritance be possible?
Is LD more or less extensive in older populations, e.g., Africans as opposed to newer/isolated populations?
Older: LD are less extensive.
How many SNPs are needed for fine mapping complex traits by LD? (Hint:SNPS 1/?)
1 SNP/(5-10 kb)
What improved the efficiency of Haplotype/LD mapping?
the Hapmap project, which reduced the number of SNPs needed to define the greatest LD
What is done after fine mapping in the search for a the genes in complex inheritance?
locate potential disease-associated alleles using bioinformatics
What is the mutation that causes Sickle Cell Anemia?
an autosomal recessive condition caused by a missense mutation at the 6th codon of the ß-globulin gene
What does a substitution of valine to glutamic acid at the 6th codon of the ß-globulin protein cause?
What happens to hemoglobin in de-oxygenated RBC with SCA patients?
they polymerize --> causing reduced RBC survival (causing anemia) and increasing adhessiveness to small blood vessels --> clinical manifestation brought on by occlussions, e.g., bone pain, damage to spleen, destruction of ball-and-socket joints, life-threatening infections (pneumococcal spesis and Salmonella), pulmonary damage, stroke and shortened lifespan
What is the essential problem with Thalassemias?
decrase in the expression of globin genes.
What are the types of mutations that cause Thalassemias?
nonsense, frame shift, splicing, promoter, deletion of the enhancer
What is hemoglobin electrophoresis?
A laboratory technique to determine the type of hemoglobin an individual has. This technique differentiates between normal hemoglobin (A) , sickle hemoglobin (S) and other different kinds of hemoglobin (such as C, D. E . etc.).
What is sickle cell crisis?
1. a broad term used to describe several different acute conditions occurring with sickle cell disease, including aplastic crisis, hemolytic crisis, and vaso-occlusive crisis⬦ 2. the cells to become stuck in capillaries which deprives the downstream tissues of oxygen and causes ischemia and infarction
What is hemoglobinopathy?
blood disease characterized by the presence of abnormal hemoglobins in the blood
What is Balanced polymorphism?
A multiplicity of forms in which the frequencies of the different variations do not differ significantly over time because of selection against the extremes, ie., sickle cell anemia
What is ß-Thalassemia Minor?
heterozygous for Thalassemia mutation with reduced synthesis of ß-globin and hemoblobin A sequelae
What 4 consideration (symptoms, etc.) are found in ß-Thalassemia Minor afflected (heterozygotes)?
1) no symptoms, 2) often confused with anemia, 3) diagnosed with hemoglobin electrophoresis, 4) Two heterozygous parents have a 25% chance of having an affected child.
Which population is at risk for ß-Thalassemia Minor?
Mediterranian, Blacks and Far East
What do sickle cell heterozygotes experience?
asymptomatic anemia⬦ clinically benign
T/F: there is clincial pretation of symptoms due to vaso-occlusion in SCA patients.

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