Complex Traits Most neurobehavioral traits are complex –Multifactorial –Polygenic –Multigenic...
-
Upload
marvin-ellis -
Category
Documents
-
view
221 -
download
0
Transcript of Complex Traits Most neurobehavioral traits are complex –Multifactorial –Polygenic –Multigenic...
Complex Traits
• Most neurobehavioral traits are complex– Multifactorial– Polygenic– Multigenic
• QTL: quantitative trait locus– Region of a chromosome that contains a gene(s) with different
alleles that contributes quantitatively to the variance in a trait
Quantitative Trait Loci (QTL):the specific loci whose allelic differences are
responsible for the genetic variation in a quantitative trait (e.g. total sleep time)
Note: QTL does not refer to the sum total of all loci that influence a particular trait, only those
loci that are functionally polymorphic (with respect to the trait of interest) between the
parental strains. Mutagenesis and engineered KOs can artificially alter any gene, however, polymorphisms can represent more subtle
“natural” variations.
QTL Mapping• QTL mapping: identification of chromosomal regions containing
gene(s) that correlate with measured phenotypes
• Different methods– Single-marker analysis: compares phenotypic means of different
marker genotypes – Interval mapping: estimates position of QTL between two markers
using maximum likelihood– Composite Interval mapping: IM and multiple regression– Multiple QTL models
• QTL present when LOD score exceeds critical threshold– LOD = Log of the Odds = log10 (H1/H0) – often for single locus analysis, 3.0 is significant and 2.0 is
suggestive depending on sample size, number of markers, and other variables.
Generating the Backcross
Cast/EiJ x C57BL/6J
F1 x Cast/EiJ
BC1s
Backcross progeny have on average:
75% CE, 25% B6 alleles50% C/C, 50% C/B genotypes for all loci
C57BL/6J (B6)
Cast/EiJ (CE)
Some types of detectable variation
• RFLPs (Restriction fragment length polymorphisms)
• VNTRs (Variable nucleotide tandem repeats) = minisatellites
• Microsatellites
• SNPs (Single nucleotide polymorphisms)
Microsatellite Analysis by PCR
Genotyping
• Extract DNA from brain, liver or tail• Genotype mice using markers distributed throughout
genome (10 cM resolution)• Use microsatellite repeats
CACACACACACACACAC CEGTGTGTGTGTGTGTGTG
CACACACACACACACACACACACACACACA B6GTGTGTGTGTGTGTGTGTGTGTGTGTGTGT
• Using primers flanking the repeat region gives PCR products of different size
GenotypingD1Mit119Chr 1, 10 cM
D12Mit141Chr 12, 55 cM
D14Mit169Chr 14, 54 cM
D18Mit122Chr 18, 31 cM
Genetic Map of Markers used in Analysis
Genome-Wide Scan for QTL
Black = Max likelihood (EM algorithm) Blue = Haley-Knott regression
QTL-analysis in Recombinant Inbred (RI) Strains of Mice
Generation of C57BL/6J X DBA/2J (BXD-RI) Strains