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302 Cards in this Set

  • Front
  • Back
what are the 2 sorts of human characters?
dichotomous or discontinues characters and continuous or quantitative characters
what are dichotomous characters also known as dicontinuous ?
like diseases and malformations, that you have or do not have
what are continuous or quantitiative characters?
characters that everybody has, but to different degrees such as height, weight or blood pressure
what are teh 3 subdivisions of human genetic diseases?
mendelian diseases
chromosomal diseases
multifactorial disease
Difference b/n Mendelian and Multifactorial diseases
Mendelian: mostly rare, single gene mutations (monogenic), autosomal or X, Dominant or Recessive
Multifactorial: combo of genetic and environmental causes (polygenic), most common diseases
what is the lifetime risk of a multifactorial disorder in western populations?
what does polygenic mean?
caused by the presence of disease allele at MULTIPLE genetic loci
*characteristic of multifactorial
which type of disorders are influenced by environment?
describe the inheritance of multifactorial disorders.
aggregation in families, but no Mendelian segregation
Ex of multifactorial disorders.
CVS, asthma, RA, cancer, psychiatric diseaese, diabetes, Alzheimers
Ex of Mendelian diseases.
what does it mean to be fully penetrant?
other genes and environmental factors have no effect
in terms of penetrance where do mendelian and multifactorial diseases fall?
fully penetrant: Mendelian
low penetrance: Multifactorial because genetic factors play a major part in determining susceptibility but each individual factor has a low penetrance (ex MS)
which inheritance is also known as polygenic inheritance?
quantitative inheritance: determined by many genes, each having a small ADDITIVE effect (additive implies that the effects of the genes are cumulative no one gene is dominant or recessive)
will you see a phenotype with normal distribution w/ polygenic inheritance?
yes, may generate a phenotype with a normal distribution in the population such as blood pressure, height involving the action of many genes at different loci, each of which exerts an equal additive effect
what is the relationship b/n number of loci and normal distribution?
as the number of loci incraeses, the distribution increasingly comes to resemble a normal curve thereby lending support to the concept that characteristics such as height are determinied by the additive effects of many genes at different loci
what is liability?
according to the liability/threshold model, all of the factors which influence the development of a multifactorial disorder, whether genetic or environmental, can be considered as a single entity known as liability
do liabilities show a normal distribution?
yes, in both the general population and in relatives of affected individuals
what does the threshold theory postulate?
that susceptibility to the disease is a continuous character (every has a blood sugar) but disease is dichotomous (not everyone has diabetes) *look at blood sugar for diabetes sugar level and see wide distribution. threshold determines if someone has diabetes
congenital malformations (cleft lip, spina bifida) and aquired diseases of childhood and adult life (diabetes, asthma)show what type of inheritance?
what does the liability/threshold model solve?
To account for a discontinous phenotype (affected or not) with an underlying continous distribution it is proposed that a threhold exists above which the abnormal phenotype is expressed called population incidence or familial incidence
How do the liability curves shift and why?
in relatives of affected inidividuals, the curves will be shifted to the righ, with the extent to which they are shifted being directly related to the closeness of their relationship to the affected index case (the risk increases with close relatives) *the more affected family members the more your risk incrases
what is Heritability?
proportion of the total phenotypic variance of a condition which is caused by additive genetic variance
when a condition is only genetically determined what is the Heritability?
H^2 = 1 (fully genetic)
When a condition is only determined by environmental factors what is the heritability?
H^2 = 0 (fully environmental)
what is the general range of H2 in multifactorial disorders?
the greater the value of heritability, the greater the role of what?
genetic factors
what 3 types of studies can be done to aid in determining that genes have a signif influence on a disease
familial aggregation
twin studies
adoption studies
in familial aggregation studies, what do you use to obtain info on the occurence of disease in relatives?
use probands (1st afffected member of family) and compare to the population freq frm the same population
who shares 50% of genes?
parents, siblings, and children
who shares 25% of genes?
uncles, aunts, nephews and neices, grandparents, grandchildren and half siblings
who do you share 12.5% of your genes with?
first cousin, great-grandparents, great-grandchildren
waht is the sib-sib coorelation for height?
what tests can you do to test for familial aggregation?
chi square test of association (test if observed differences are significant)
Familial relative risk (RR of lambda)
in familial relative risk, waht is a measure of familial clustering?
lambda value
in familial relative risk, what is RR?
empiric risks, derived from surveys of families, not from theoretical calculations and can vary b/n pop over time
what does familial relative risk tell us?
quantifies the degree of risk to relatives and provides some indication of the magnitude of genetic effects (should be greater than 1)
what is RR based on?
population frequencies
how do you calculate RR?
take the population freq and divide by the chance of being affected this will tell you how many times more likely a relative is of being affected than a random individual
is the relative risk higher or lower in multifactoria disorders vs mendelian?
much lower b/c you are dividing the number of affected relatives that have an affected relative over the number of affected controls who dont have an affected relative
MZ twins share how many of their genes?
DZ twins share how many of their genes?
what will be shown b/n MZ and DZ twins if genetic factors play a significan role in etiology?
MZ twins will have a higher concordance rate than DZ twins
what is the concordance of MZ twins in monogenic disorder?
100% concorance H^2 =1
*only genes involved
What is the concordance of DZ twins in monogenic disorder?
50% concordance H^2 = 0.5
*only genes involved
what is the concordance of MZ twins in mutifactorial disorders like Type 2 diabetes?
80% concordance
*genes play a significant role, but not solely!
What is the concordance of DZ twins in multifactorial disorders?
40% concordance
*genes play a significant role, but not solely!
what is the bias in twin studies?
MZ twins are more likely to be very similar, to be dressed and treated the same way. they share more of their environment than DZ twins
what is the ideal twin experiment?
MZ twins separated at birth and brought up in entirely seperate environments to see what effect this has
Adoption studies are important for waht?
most powerful to disentangle genetic and environmental factors
Test: to see if adopted indiv are more concordant w/ their adoptive parents or with their biologic parents for a disease
what does it mean if an adopted individual is more concordant with their adoptive parents?
common environment is responsible
what does it mean if adopted indiv are more concordant w/ biologic parents?
genes are implicated in disease etiology
what does concordance mean?
the presence of the same trait in both members of a pair of twins, or in sets of individuals
what is recombination fraction?
measure of the distance separating 2 loci, or more precisely an indication of the likelihood that a cross-over will occur b/n them
If 2 loci are NOT linked, then what does theta equal?
0.5 as on avg genes at unlinked loci will segregate together during 50% of all meiosis
what does it mean if theta equals 0.05?
on avg the syntenic alleles (located on same chrom) will segregate 19 times out of 20.. a cross over will occur b/n them during 1 in 20 meiosis
what is a centimorgan?
unit of measurement for genetic linkage b/n two loci
What happens as you increase distance b/n loci?
an increasing number of crossovers is expected to occur (recombination)
linked loci: recombination fraction =
less than or equal to 50%
unlinked loci: recombination fracition =
what is used as a marker for linkage analysis?
STR: simple tandom repeats
how many primers do you need for linkage analysis markers?
2 primers: forward and bachward primer specific for 1 site; complementary to repeat
on avg how long are the simple tandom repeats? what is teh most well known repeat?
1-5 bp
CA repeat
in creating markers for linkage analysis, what is the allele discriminated by?
allelic discrimination by size
use PCR to determine length of fragment
what do you tag one of the primers with in analyzing STR markers?
fluorescent marker
what is the purpose of linkage analysis?
study the segregation of the disease in large families w/ polymorphic markers from each chromosome. Eventually a marker will be identified which cosegregates w/ the disease more often than would be expected by chance: the marker and disease are linked
what are the likelihood ratios?
the likelihood ratio at a given value of theta equals the likelihood of the observed data if the loci are linked at recomb value of theta divided by teh likelihood of the observed data if the loci are not linked. The log to the base 10 of this ratio is the LOD score
a LOD score greater than 3 means what?
evidence for linkage
What are LOD scores based on?
prior probabilty of localizing teh gene to one of the 46 chromosome arms (apprx 1:50)
wht is the likelihood ratio for an LOD score +3 or higher?
what is teh likelihood ration for an LOD score of -2 or lower?
An LOD score b/n -2 and +3 means?
what is the first step in positional cloning to a disease gene?
linkage analysis
linkage analysis is mostly used for?
Mendelian disorders
what is 2 point linkage analysis used for?
map a disease locus to a specific chromosome region
what is mulitpoint linkage analysis for?
after using 2 point linkage and mapping a disease locus to a specific chromosome region, you use a series of polymorphic markers that are known to map to the disease region to "fine" tune the probable position w/n the narrow interval defined by the smaller marker loci
multipoint linkage analysis maps disease gene with respect to ?
genetic linkage map
is multipoint linkage analysis more or less sensitive?
less sensitive to limit informativeness of markers
what is fine mapping of disease locus?
use a founder chromosome w/ disesae associated mutation. then compare with patients from different families the represent a multigenerationsl family. Contruct haplotypes for markers that travel together durin segretation (dont recombinate). Look at where they all have the same allele..this is the shared haplotype
what are haplotypes?
certain # alleles at a location on a chromosome
"copy" of the ancestral chromosomal region in which the mutation occured. identification of surrounding region INDIRECTLY detects the mutation
when comparing haplotypes, where there is no common allele b/n families this means what?
that recombination occured
advantages of LOD scores?
scores from individual families can be added up
can also be used to exclude parts of the genome
pitfalls in LOD score calculations?
gentic heterogeniety
reduced penetrance
genotyping errors
what does non-parametric mean?
dont know what type of inheritance is involved
difference b/n monogenic and multifactorial disorders in terms of family size?
monogenic: large families
multifactorial: small families
difference b/n monogenic and multifactorial disorders in terms of genes/family?
monogenic: one disease gene/family
multifactorial: multiple disease genes/patient
difference b/n monogenic and multifactorial disorders in terms of penetrance genes?
monogenic: highly penetrant genes
multifactorial: low penetrance genes
difference b/n monogenic and multifactorial disorders in terms of unaffected individuals?
monogenic: unaffected individuals also of use
multifactorial: unaffected individuals can also carry susceptibility alleles
difference b/n monogenic and multifactorial disorders in terms of mapping methods?
monogenic: parametric genetic mapping methods (LOD score analysis)
multifactorial: nonparametric genetic mapping methods (affected sibpair analysis)
Homozygosity mapping is used for what type of disorders?
monogenic disorders: when indiv are homo at a particular loci through identity by descent: all affectd relatives will be homo at teh region surrounding the disease locus
parametric linkage analysis requires knowledge of what parameters?
-mode of inheritence of disease gene
-disease gene freq
-affected status of every family member
-relationship b/n family members
Non-parametric linkage analysis does not require knowledge on what/does not have the info available?
the parameters used in LOD score analysis therefore it uses a model-free method of linkage analysis that seeks to identify alleles or chromosome regions shared by affected individuals
what approaches for linkage analysis are used for multifactorial disorders?
allele-sharing approaches: family based: affected sibpair analysis
population based: association studies
what is the most common non-parametric method of linkage analysis?
affeced sibpair method
wht is the underlying concept of affected sibpair method?
at a single genetic locus, an offspring can receive any 2 of 4 parental alleles. Pairs of siblings can share 2, 1 or 0 alleles transmitted from their parents
what is the probability that any two children will have both alleles of their parents in common?
1 in 4 Z= 0.25
What is the probability that any two children will have one allele in common?
1 in 2 or Z = 0.5
what is the probabiity that any two children will have no alleles in commone?
1 in 4 Z=0.25
If siblings who are affected with a particular disease show deviation from the 1:2:1 ratio for a particular variant, what does this imply?
there is a causal relatinships b/n the locus and the disease
*linkage will cause a shirt in this distribution
an excess of alleles sharing (greater than 50%) in sibpair analysis indicates what?
marker probably linked to disease gene
nonparametric linkage analysis ignores wht?
ignore unaffected people, and look for alleles or chromosomal segments that are shared by affected individuals
what is identical by state?
IBS alleles look the same, and may have the same DNA sequence, but they are not derived from a known common ancestor (the same allele, but not necessarily identical)
What does identical by descent mean?
Alleles IBD are demonstrably copies of the same ancestral (usually parental) allele..inherited from the same parent.If two sibs each have allele A1, the shared allele is IBS, but it may or may not be IBD
when does identical by state become a problem?
when parents are unavailable for genotyping
occurs when one of the parents is homo for a marker allele
can occur when parents are hetero for the same marker alleles
when can we not determine identical by descent?
if parents are both hetero for the same marker alleles or if one of the parents is homo for a marker allele
if the parents are hetero for same alleles, what are the chances of IBS? IBD?
2 or 0 IBD
what is needed for conducting a sibpair study?
-collect families w/ at least 2 affected siblings
-perform a genome-wide scan w/ reguarly spaced polymorphic markers
what is seen in sibs affected by dominant disease? receessive disease?
Pairs of sibs who are both affected by a dominant condition share one or two parental haplotypes for the relevant chromosomal segment. (C) Pairs of sibs who are both affected by a recessive condition share both parental haplotypes for the relevant chromosomal segment.
the basis of phylogenetics is?
how is the speed of the molecular clock determined?
by species and type of DNA
genetic diversity is the highest in ?
Africans, making it the major source for the current world population
variation w/n popultions is greater than what?
variation b/n populations
what is at the bottome of the trunk of the tree of life?
ancestral species
the basis of phylogenetics is?
how is the speed of the molecular clock determined?
by species and type of DNA
genetic diversity is the highest in ?
Africans, making it the major source for the current world population
variation w/n popultions is greater than what?
variation b/n populations
what is at the bottome of the trunk of the tree of life?
ancestral species
genomes evolve by ?
gradual ammuluation of mutations
what indicates how recently two genomes shared a common ancestor?
amt of difference in NT sequences
what is the objective of molecular phylogenetics?
comparing 3 or more genomes to work out the eveolutionary relationships b/n them
what is the absolute necessity that provides phylogenetic information?
what are the 3 sources of variability?
D-loop of mtDNA
what is the mutation rate for microsatellites?
10^-3 per generation
*high mutation rate
what is the mutation rate for D-loop of mtDNA?
2-3 x 10^-7 per generation
*highly variable b/n individuals b/c of heteroplasmy
what is the mutation rate for SNPs?
*lowest mutation rate of the 3 sources of variability
how is the data that is used to reconstruct a DNA-based phylogenetic tree obtained?
comparing NT sequencing of homologous sequences and calculating distance matrix
what is a rooted tree?
A rooted phylogenetic tree is a directed tree with a unique node corresponding to the most recent common ancestor of all the entities at the leaves of the tree *tells you the evolutionary path
what is an unrooted tree?
Unrooted trees illustrate the relatedness of the leaf nodes without making assumptions about ancestry
how are trees created?
A multiple sequence alignment (MSA) is a sequence alignment of three or more biological sequences, In general, the input set of query sequences are assumed to have an evolutionary relationship by which they share a lineage and are descended from a common ancestor. From the resulting MSA, sequence homology can be inferred and phylogenetic analysis can be conducted to assess the sequences' shared evolutionary origins. Want to look for the sequences w/ the least amt of aa substitutions (mutations)
how was it established that chimps are our closest releatives?
analysis of mutliple DNA sequences
multiple sequence alignment can be done by looking at sequnes of what?
protine, DNA and RNA
*can group based on mtDNA b/c they don't change rapidly
what is the molecular clock hypothesis?
technique in genetics, which researchers use to date when two species diverged. It deduces elapsed time from the number of minor differences between their DNA sequences.
Africans have what?
highest genetic diversity
what does evolutionary theory predict about the genetic diversity of africans?
the older "source" population will typically have greater diversity than a population derived recently form it (everyone that descended from the Africans will have additional variants)
what 3 sources of variability show greater diversity in African than that in Asia and Europe?
mtDNA polymorphisms
Y chromosome polymorphism
polymorphic satellites
What is coalescence analysis?
Coalescence analyses seek to trace back lineages until they coalesce in a single individual
how can you track uniparental inheritance?
uniparental inheritance which can be tracked using mt DNA markers (inheritance through the maternal line) or by using markers from the nonrecombining portion of the Y chromosome (paternal inheritance).
what does the clock hypothesis assume?
NT substitution occurs at a constant rate
how is the molecular clock calibrated?
reference to the fossil record
rate of the molcular clock is dependent on what?
species and type of DNA (mtDNA has a faster clock than nuclear DNA)
how do you calculate the molecular clock?
The number of substitutions is determined for a pair of homologous genes from human and orangutan: call this number 'x'. The number of substitutions per lineage is therefore x/2, and the number per million years is
x/(2 × 13).
what is the opposite of divergence?
what is the purpose of coalescence analysis?
trace back gene or DNA seq lineages until they coalesce in a single individual
what type of variants are suitable for coalescece anaylses?
mtDNA variants and Y-chromosome variants b/c no confounding recombination
compared to other animal species, how are humans genetically different?
we are a genetically homogeneaous population: chimp D-loop is 3x as variable
what percent genetic variation is there w/n human populations among individuals?
93-95% variation w/n populations
what percent variation b/n populations?
only 3-5%
molecular phylogenetics is based on what?
DNA sequence analignment
which disease is autoimmune disorder of the small bowel that occurs in genetically predisposed individuals in all age groups after early infancy.
celiac disease
what is the most common food intolerance in western populations (0.5-1%)?
celiac disease
what is the problem in celiace disease?
abnormal immune response to gluten proteins in wheat, barley, and rye that leads to inflammation and damage to small intestine of genetically susceptible individuals**
what does celiac disease lead to?
malnutrition and associated complications
what type of individuals develop inflammation and damage to the small intesting in celiac disease?
genetically susceptible individuals
when looking at twin studies for celiac disaese, what is the concordance of MZ twins? DZ twins?
MZ 86%
DZ 20%
therefore important role for environmental factors (gluten)
when looking at family studies for celiac disase what is the recurrenc risk for sibling of CD patient?
RR= 20X for siblings
therefore important role for genetic factors
95% of all celiac disease patients carry waht gene?
HLA-DQ2 (6p25) other important HLA-DQ8
what is a major risk factor for CD?
HLA-DQ2/8 (95% of CD patients express HLA-DQ2 or 8 heterodimer)
what is the celiace disease paradox?
95% of CD patients have HLA-DQ2/8 gene but
25% of general pop also expresses HLA-DQ2/8 and only 0.5-1% of general pop develops CD suggesting additional genetic roles
concordance for MZ twins of CD is higher than what? what does this tell us?
higher than HLA-DQ2/8 matched controls this tells us that Celiac Disease is a complex, multifactorial disorder involving many genes including environmental factors such as high gluten diet
what is the evidence of CD being multifactorial?
sibpair study revealed genetic loci on 6q21 and 19p13.1. Chrom 19 is a non-HLA loci
what was done to determine if CD is really multifactorial?
recruit family materials by looking at pts diagnosed in more than 50 diff hospitals, re-evaluating intestinal biopsies
genome wide sreen with many markers
linkage for CD showed LOD scores +3 for what 2 chromsomes?
19 and 6!
how many genes where found on Chrom 19 when looking for CD markers?
92 genes therefore needed to narrow the chrom region
what are the 2 strategies used to identify the region on chrom 19 that contained the CD genes?
gene-based: have assumpotion of where you think it is
haplotype-based: look at smaller region based on association
the chromsome 19 locus found assoiciated with Celiace disease is what type of gene?
myosin-like gene, important for epithelial barrier fxn
association for CD was found on chrom 19 w/n what single gene? what are the risks for hetero and homo?
hetero: 1.66 fold increased risk of developing CD
homo: 2.27 fold increase
both very modest risks
what does Myosin IXB encode?
unconventional myosin molecule that has role in actin remodeling of epithelial enterocytes
why can immunogenic gluten peptides enter the deep mucosal layer easily in epethelial enterocytes of CD pt?
b/c MYOIX B variant impairs tight jxn assembly resulting in enhanced epithelial paracellular perm
hirschsprungs affects how many newborns?
problem with hirschsprungs?
congenital intestinal agangloinosis (absence of nerve cells in the large bowel, no bowel movment causng abdominal distention)
hirschsprungs has a defect in migration of what?
neural crest derived intestinal ganglion cells to the intestinal tract during devleopment
what is the sex ration for hirschsprungs?
4:1 males 80%males
what is the protein with which RET has to interact?
The protein with which RET has to interact in order for Hirschsprung’s disease to develop is termed EDNRB, and is encoded by the gene EDNRB located on chromosome 13. Six other genes were discovered to be associated with Hirschsprung’s.
when is the proportion of affected sibs with Hirschsprungs higher?
when the affected patient is female (ie the sister) *genetic influence more powerful in females than males
what is the recurrence risk of hirschsprungs?
what is the RR of hirschsprungs?
What are the System 1 genes involved in Hirsh?
RET: receptor tyrosine kinase
loss of fxn
ligands for RET?
GDNF (glial cell line-derived neurotrophin factor) and NRTN (neuroturin)
role of GDNF?
ligand for RET
role in migration of neural crest cells
role of NRTN
ligand for RET
promotes neural crest cell survival as they migrate
GNDF and NRTN genes where found by what type of analysis?
candidate gene analysis
insufficient to cause hirsh by themselves
role of RET?
neural crest stem cell migration to the intestine
how was RET gene found?
linkage analysis w/ large families
is RET effect in Hirsh dominant or recessive?
Hirschsprung’s disease exhibits autosomal dominant transmission, with the gene RET being dominant.
penetrance of RET loss of fxn?
What are the system 2 genes involved in Hirsch?
EDNRB:endothelin receptor kinase type B
how was EDNRB found?
linkage analysis in large Mennoite family w/ syndromic hirsch associated w/ sensineuronal deafness, white fore lock (hirsh variant)
what is the founder effect involved in EDNRB mutation in hirsch?
mennonite family associated with sensineuronal deafness, white fore lock
ligand for EDNRB?
gene effects of EDNRB are dom or recessive?
what is the role of EDNRB?
involved in spread of neural precursors from the small bowel to the large bowel but also of melanocytes therfore causing by themselves Waardenburg syndrome;white forelock
how do you develop hirsch?
Variations in RET and EDNRB have to coexist in order for a child to get Hirschsprung’s. However, although six other genes were shown to have an effect on Hirschsprung’s
besides EDNRB, other system 2 Hirsch genes?
SOX10,GDNF (7 total)
What is SOX 10?
TF required for differentiation of enteric glial cells that acts on an enhancer element of EDNRB locus that is activated at the time the enteric NS precursors are populating the distal gut
what gene mutations are found in dominant hirsch syndromes?
Sox 10 gene mutations
what percent of hirsch is familial? sporatic?
60-70% familial
10-30% sporadic
there are 7 genes involved in hirsch that are all related to what?
neuronal crest cell diff, migration and survival
what does lambda stand for?
The degree of family clustering of a disease can be expressed by the quantity LamdaR, the risk to relative R of an affected proband compared with the population risk. Separate values can be calculated for each type of relative, for example LamdaS for sibs
familial but non mendelian describes what disease?
multipoint statistical analysis tests what instead of single loci?
haplotypes: # alleles on particular chromsome simlar to early affected ancestor
what does multipoint analysis give you more confidence in dtermining?
IBD *more accurate b/c looking at haplotypes instead of single loci
If looking at single loci you will only be able to dtermine that either 1 or 2 IBD but by looking at both loci simultaneoiusly, can say with confidence 2 IBD
what is the size of disease locus in multipoint?
wide regions: 20-30cM
interval will NOT get smaller w/ markers spaced less than 5cM
pitfalls to sibpair analysis?
missing parents: genotypes must be estimated from allele freq
wrong marker allele freq may give spurious results (false postive linkages)
What is the trio analysis of transmission disequilibrium test (TDT)?
affected individual plus parents
what does the TDT equation tell us?
deviation from chance (whether or not alleles of mom and dad are passed down in 50:50 proportion or not)w/ chi square distribution, 1 degree of freedom
diff b/n linkage and linkage disequlibrium?
Linkage disequilibrium (LD) is a term used in the study of population genetics for the non-random association of alleles at two or more loci, not necessarily on the same chromosome. It is not the same as linkage, which describes the phenomenon whereby two or more loci on a chromosome have reduced recombination between them because of their physical proximity to each other. LD describes a situation in which some combinations of alleles or genetic markers occur more or less frequently in a population than would be expected from a random formation of haplotypes from alleles based on their frequencies
what are case-control studies?
gentic association studies
Case-control studies use subjects who already have a disease, trait or other condition and determine if there are characteristics of these patients that differ from those who don’t have the disease or trait. In genetic case-control studies, the frequency of alleles or genotypes is compared between the cases and controls.
in case control studies, excess of certain marker alleles indicates what?
association b/n DNA marker and disease
what is the TDT test?
measures association (and linkage) in families with observed transmissions of genetic markers from parents to offspring, in a nuclear family termied the trio. Under no association with the disease, the alleles of the genetic marker under test will have an equal chance of being transmitted from a heterozygous parent to the offspring. If, however, one allele increases risk of disease or trait, this allele will be transmitted to the affected offspring more often than expected by chance alone.
(distortion from 50:50)
what 3 situtaions can you apply association studes in multifactorial disorders?
1. have existing knowledge about biology and disease
2. have existing knowledge about candidate region that was id through linkage
3. no existing knowldege (hyptothesis free analysis)
when you have exisitng knowldege about biology and disease, how many markers do you need for association study?
few DNA markers tested
when you have existing knowledge about candidate gene region, how many markers do you need for association studies?
10-100 DNA markers tested
when you have no existing knowledge, how many markers do you need for association studies?
100,000 dna markers tested
advantage of case control study?
easy to collect cases and controls
dont need all the family members
detection of risk alleles w/ small relative risk sib value
what are the disadvantages of case control study?
matched control group needed: genotype and haplotype frequencies vary between ethnic or geographic populations. If the case and control populations are not well matched for ethnicity or geographic origin then false positive association can occur because of the confounding effects of population stratification
sample size is important (genes with small relative risks requre large numbers)
wht are the best DNA markers and why?
SNPs b/c easy to type in large numbers and abundant
what are SNPs?
major source of fxnl polymorphisms by influencing gene splicing, promotor fxn, protein structure, RNA stability
what is a major source of disease susceptibility in common genetic diseases?
what is a SNP?
a DNA sequence variation occurring when a single nucleotide - A, T, C, or G - in the genome (or other shared sequence) differs between members of a species (or between paired chromosomes in an individual). For example, two sequenced DNA fragments from different individuals, AAGCCTA to AAGCTTA, contain a difference in a single nucleotide. In this case we say that there are two alleles : C and T. Almost all common Single Nucleotide Polymorphisms have only two alleles.
characteristics of SNPs?
mutationally stable
frequent (1/1000 bp)
equally spaced, both w/n and out side genes
how many SNPs in human genome?
10 x 10^6
majority of human SNPs are present in what?
different ethnic populations : that there are variations between human populations, so a Single Nucleotide Polymorphism that is common enough for inclusion in one geographical or ethnic group may be much rarer in another
what percent of SNPs are common ? low freq? very rare?
5% common variation
0.05-5% low freq variation
0.05% very rare mutations
linkage studies examine families while association studies look at ?
populations (ex founder)
which study type do you need to know pedigree/relatinship b/n patients?
in association stidies they are unknown
in which study is the number of recomb events b/n patients low?
in which study is the nuber of recomb events b/n unrelated pts high?
difference in regions sharing IBD in linkage and association
linkage: large regions (Mbs) of DNA sharing IBD b/n pts w/n one family
association: small regions (kbs) of DNA sharing IBD b/n unrelated pts
number of markes for linkage? associateion?
linkage: limited number of markers
association: large number markers
what does the strength of association depend on?
age and number of mutations
diff b/n rare diseases and common diseases
rare diseases= rare alleles
common diseses = common allesles
rare disease see selection and loss of disesae alleles
common diseases see no selection and disesae alleles accumulate
what is the problem in DM type I?
autoimmune disorder: destruction of pancreatic islet beta cells: no insulin production
what accounts for 40% familal aggregation in diabetes mellitus type 1?
MHC at 6p21
what HLA is present in 30% of type 1 diabetes patients?
what HLA is absent in type 1 diabetes patients?
HLA-DQ6: conferring dominant protection
what is the population risk for type 1 diabetes?
0.2% up to 2.5% with HLADQ2/8
what is the sibling risk for type I diabets?
7% up to 20-25% with HLADQ2/8 shared
what is the risk of type I diabetes in offspring from affected female?
what is the risk of type 1 diabetes in offspring from affected male?
5% (higher risk from affected male than female)
what percent of adults in the US are at risk for type 2 diabets?
what percent of first degree relatives of type 2 diabetes are at risk?
what do we see b/n populations in terms of type 2 diabetes?
large variation b/n populations and clear migration effects
is type 2 diabets heterogenous disorer of hom?
heterogenous disorder, glucose intolerance
type 2 diabetes can be influenced by?
beta cell mass
insulin secretion
insulin action
fat distribution
what has a big effect on type 2 diabets?
lifestyle: moderate diet and exercise beneficial
is Type 1 diabetes homogenous or hetero?
homogenous b/c autoimmune
what does MODY stand for?
maturity-onset diabetes of the young
inheritance of MODY?
AD and no association w/ obesity or lifestyle
MODY 1-3 are due to what?
single gene type 2 diabetes mellitus
MODY 2 is due to what?
Glucokinase deficiency (first step in glycolysis takes glucose to glucose 6 p)
what do 50% of type 2 MODY heterozygous women develop?
gestational diabetes
MODY are monogenic variants of what?
type 2 diabetes
in MODY type 1 and 3 involve what?
hepatocyte nuclear factor 1A and 4A. HNF1A is activator of HNF4A activation of liver specific genes in glucose, choleasterol and fatty acid metabolism
what is PPARgamma (peroxisome proliferator activated receptor gamma)?
ligand - dependent transcription factor regulating genes involved in lipid and glucose metabolism and adipocyte differenntiation
deficiency of PPARgamma causes what?
diabetes and severe obesity
how many SNPs were used to test whole genome for type 2 diabetes?
what TF was used in whole genome association study for type 2 diabets?
TF 7- like 2 was consistently replicated in multiple populations
what transporter is exclusively exprssed in insulin producing beta cells?
Zinc transporter SLC30A8
how many loci were narrowed down to involving beta cell development of function?
2 loci
what does it mean to have a common varient?
more than 20% of population has variant
common variant = common disease
wht is the incresaed risk of type 2 diabetes pts for coronary heart disease, stroke and MI?
3 fold increase
what is the most common cause of demetia?
alzheimers: accounts for over 50% of all forms of demetia
what is the lifetime risk for alzheimers?
35% to age of 80
what is the strongest risk factor for alzheimers?
age. 10% of all individuals age 65 and over have alzheimers
when are monogenic diseases usually present?
early in life like diabets type I
when are monogenic forms of alzheimers usually seen?
as early as 3rd decade
what is the brain pathology seen in alzheimers?
abundant extracellular senile plaques and intracellular neurofibrillary tangles
waht are the 2 forms of alzheimers disesae?
early onset: before 60
late onset: after 60
what is the most common form of alzheimers?
late onset
early onset is rare <10%
inheritance of alzheimer early onset?
highly penetrant dominant disorder
inheritance of alzheimer late onset?
some forms are familial, complex inheritance
what are the 3 genes associated with early onset alzheimers?
amyloid precursor protein
presenilin 1
presenilin 2
what percent of early onset alzheimers have amyloid precursor protein?
what chromosome is amyloid precursor protein located?
chrom 21 (50% of downs patients develop alzheimers)
what percent of early onset alzheimers are associated with presenilin 1?
what percent of early onset alzheimers is associated with presenilin 2?
what is amyloid precursor protein?
cell surface protein and is highly conserved in evolution
what are presenilin 1 and 2 involved in?
proteolytic cleavage of amyloid precursor protein
abnomal cleavage of amyloid precursor protein results in what?
beta-amyloid (Abeta42) which aggregates with other proteins in senile plaques
what aggregates in senile plaques of alzheimers patients?
abnormal cleavage of amyloid precursor protein by presenilin leaves beta-amyloid in INCREASED amounts which aggregates
what was discovered in linkage analysis of late onset alzheimers families?
increased association of ApoE4 allele compared with controls by discovery of ApoE4 in amyloid plaques
what does ApoE4 bind to?
Abeta42 peptide fragment
what are the 3 ApoE protein common allelic forms?
Apo E2, E3, E4
what aa are in the Apo E2 alleles
what aa are in the Apo E3 alleles?
what aa are in the ApoE4 alleles?
what is the percent of Apo E2 in alzheimers compared to normals?
alzheimers: 2%
normal: 10%
thefore protective
what is the percent of ApoE3 in alzheimers compared to normals?
alzheimers: 60%
normals: 75%
*15% less in AD
what is teh percent of Apo E4 in alzheimers compared to normals?
alzheimers: 40%
normals: 15%
*20% incresae in AD
*30-50% genetic risk
what is higher in E4 homo than E3 homo?
total plasma cholesterol and LDL cholesterol
what is an ancestral allele found in primates?
ApoE4 is higher in waht populations?
higher in foraging populations and lower in settled agricultured populations
although ApoE4 is associated with late onset alzheimers, it has what affect on age?
earlier age of onset: instead of 70 see it at 60yrs
presence of 1 apoE4 allele increases lifetime risk to what?
from 9% to 29%
what does it mean that there is a gene-dose effect of ApoE4 on age of onset?
E4/E4 : 15 fold increase
E4/E1: 2.3-3fold increase
can you do ApoE4 genotyping for prediction of alzheimers?
no! only useful for investigating dyslipidemias
what does it mean that apoE4 is neither necessary nor sufficient for alzheimers?
the association b/n alzheimer and ApoE4 is ONLY statistical and is not predictive for an individual
is type I diabetes monogenic or poygenic?
polygenic autoimmunde disorder with a prominent HlA effect
whole genome association analysis are beginning to identify waht in diabetes ?
common variants in type 2
how many monogenic variants are in alzheimers?
waht is an important risk factor for sporatic alzheimers?