Linkage and Recombination Flashcards
1
Q
indirect testing with markers
A
- not possible to test for disease causing mutations because too many mutations or because gene isn’t known- use linkage to perform carrier testing or prenatal diagnosis
- when disease is on large gene its impractical to try and find disease causing mutation
- indirect test using linkage analysis
2
Q
disadvantages of indirect testing with linkage
A
- need correct disease diagnosis and no locus heterogeneity
- DNA from critical family members will be needed and their cooperation is required- paternity needs to be as stated!
- need to find marker that is informative- need to flag bad gene
- if using extragenic marker, error rate associated with recombination-intragenic better
3
Q
polymorphisms
A
- need to flag the chromosomes to follow them through meiosis
- SNPs or microsatellites (Tandem repeats)
- microsatellites likely more variable and thus more useful than SNPs, but higher mutation rate so need more than one marker
4
Q
mutation
A
- permanent heritable change in genomic DNA sequence
- often used incorrectly to indicate a bad change
5
Q
polumorphism
A
- sequence variant found at a frequency of at least 1% (at least 2% of people are heterozygotes)
- often incorrectly used to mean benign
6
Q
-rare genetic variant
A
-mutation with a frequency of less than 1%
7
Q
informative markers
A
- ex- parents are heterozygote carriers and affected child is homozygous- can id gene that travels with disease causing gene
- if parents were homozygote and child hetero- can’t tell because all progeny will be hetero
- if parents hetero but child is too- can’t tell (parents don’t have it) two 1/2 combos- one diseased one not (risk-50%)
**disease is linked to different alleles in different families
8
Q
recombination
A
- formation of new combinations of linked genes by crossing over between loci
- on average three crossovers per chromosome per generation
9
Q
linkage/haplotype
A
- genes close enough together on the same chromosome have a tendency to be transmitted together through meiosis more often than expected by chance
- linked genes form haplotypes
10
Q
haplotype
A
- a group of alleles from closely linked loci, usually inherited as a unit
- a set of restriction fragment lenth polymorphisms closely linked to one another and to a gene of interest
11
Q
crossing over
A
- reciprocal exchange of segments between chromatids of homologous chromosomes
- mechanism of recombination
- happens at prophase I
- misalignment can lead to deletions or duplications
12
Q
double corssovers
A
-the reason why map distance and recombination fraction don’t follow same path
13
Q
centimorgan (cM)
A
-1 cM is a 1% chance of recombination between loci as the chromosome is passed from parent to child
14
Q
recombination distance
A
- 3,300 cM in human genome
- 1 cM per 10^6 bp, average chromosome is 150 cM, but that can vary
15
Q
linkage disequilibrium
A
- tendency of specific combinations of alleles at two or more linked loci to occur together (in coupling) on the same chromosome more frequently than one would expect by chance
- deviation from Mendel’s second law of Independent Assortment
- is the difference between genotypic frequencies and the product of the allele frequencies
- decays with recombination distance and time
- can indicate loci are close and can be used to indicate that gene mapping is closing in on target gene
16
Q
linkage disequilibrium and CF
A
- deltaF508 arose on chromosome 7 with markers 60 kb from CFTR
- few crossover events, CFTR still found with the same alleles
- mutation arose once in human history 52,000 years ago
- same conserved region of mutation
17
Q
three classes of mutations
A
- linked extragenic markers-label attached to suitcase by string (the longer the string the more likely crossing over will happen)
- intragenic-label on suitcase
- disease causing mutations-see inside suitcase
**DMD intragenic still have high rates of recombination because gene is so big
**flanking markers more useful- double cross over to cause error
18
Q
coupling
A
- alleles at different loci are in coupling when on the same chromosome
- cis
- likely to travel together onto next generation-depends on recombination distance
- same parent inheritence
19
Q
repulsion
A
- alleles at different loci are in repulsion when on opposite chromosome
- trans
- different parent inheritence
20
Q
phase
A
- mutations are known to be on the same or different homologous chromosomes (2- one from mom, one from dad), in coupling or repulsion, phase is known
- unknown when it is not known which mutation is on which homologous crhomosome
- can tell down pedigree but not up
21
Q
theta
A
- recombination distance
- see pedigrees
22
Q
Lod Score
A
- statistical method that tests genetic marker data in families to determine whether two loci are linked
- lod score is the log base 10 of the odds in favor of linkage
- lod of 3 in autosome or 2 in x-linked is taken as proof of linkage and -2 is unlinked
- threshold for a genome wide level allowing for multiple markers is 3.3, for non-mendelian characters any score below 5 is provisional
- series of likelihood ratios at various possible recombination distances and plotted in a table or graph
- theta varies from 0 (linked) -0.5 (unlinked)
- value of theta that gives highest value of Z is best estimate of distance between marker and disease causing gene (7 in family)
23
Q
likelihood of odds
A
= [likelihood (data/given theta)]/ [likelihood (data/given theta=0.5)]
24
Q
Meiotic Recombination Hot Spots
A
- 30,000 + spaced om average every 50-100 kb
- avoid coding regions
- 1-2kb long
- 13 bp motif is over represented in ~40% of hotspots
- variation within motif associated with variation in hotspot activity
- PRDM9, several tandem zinc fingers of 28 aa, recognizes this motif and trimethylates H3K4 on nucleosomes
- PRDM9 and hotspots are rapidly evolving
