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Identification and evaluation of causative genetic variants corresponding to a certain phenotype
Xidan Li
Outline
• SIT - identify and evaluate the causative genetic variants within a QTL/GWAS defined region.
• PASE - evaluate the effect of amino acid substitution to the hosting protein function
• DIPT - to identify causative genes underlying an expression phenotype
• Parallelizing computing
Working process of SITVCF file
SNPs analysis in non-coding regions SNPs analysis in coding regions
Splicing sites
CpG island
UTR region
Non-synonymous SNPs
PASE
Candidate genes with candidate SNPs
List of ranking Non-synonymous SNPs
Ensembl
Selected seven physico-chemical properties of Amino acids
Seven Physiochemical properties of Amino acid
Transfer free energy from octanol to water
Normalized van der Waals volume
Isoelectric point
Polarity
Normalized frequency of alpha-helix
Free energy of solution in water
Normalized frequency of turn
Formula for conservation calculation
1-.95N
Probability of 20 different AAs in a position for N random equal frequent sequences.
nobserved /Ntotal
(1-.95N)*(nobserved /Ntotal)Blast search clustalw
Protein kinase AMP-activated gamma 3 (PRKAG3) gene
• (R200Q) in AMPK3 in purebred Hampshire pigs – RN• (V199I) in AMPK3 Co-participate in the effective
process with R200Q • RN that causes excess glycogen content in pig skeletal
muscle
• Milan D, et. al. (2000). A mutation in PRKAG3 associated with excess glycogen content in pig skeletal muscle. Science 288 (5469): 1248–51.
• Ciobanu,D, et. al. (2001). Evidence for New Alleles in the Protein Kinase Adenosine Monophosphate-Activated 3-Subunit Gene Associated With Low Glycogen Content in Pig Skeletal Muscle and Improved Meat Quality . Genetics, 159, 1151-1162.
Genes ID Coordinate REF ALT Conservations score (MSAC)
PASE score
PASEC (combined)
score
PRKAG_3 200 R Q 0.93 0.54 0.50
PRKAG_3 199 V I 0.85 0.14 0.12
(R200Q) Cause major increase in the muscle glycogen content(V199I) Contribute with smaller effect
Ciobanu,D, et. al. (2001). Evidence for New Alleles in the Protein Kinase Adenosine Monophosphate-Activated 3-Subunit Gene Associated With Low Glycogen Content in Pig Skeletal Muscle and Improved Meat Quality. Genetics, 159, 1151-1162.
Testing with SIFT and POLYPHEN
Conservation scores
(MSAC)
PASE scores(Physico-chemical
properties changings)
PASEC score(combined)
SIFTTolerated (1987) 0.47 0.39 0.18
Deleterious (1351) 0.60 0.51 0.30
PolyPhen
Benign (1637) 0.44 0.37 0.16
Possibly damaging (539)
0.56 0.43 0.24
Probably damaging (1162)
0.63 0.53 0.33
Features• Other tool
SIFT, PolyPhen
MAINLY rely on calculating sequence conservation scores (finding homologous sequences).
• PASE
not only uses the physico-chemical property changing score, but also combine with sequence conservation score
Potentially being able to analyze the evolutionary-distant protein sequence
Cuda Vs. C#include <cuda.h>#include <stdio.h>
// Prototypes__global__ void helloWorld(char*);
// Host functionint main(int argc, char** argv){ int i;
// desired output char str[] = "Hello World!";
// mangle contents of output ; the null character is left intact for simplicity for(i = 0; i < 12; i++) str[i] -= i;
// allocate memory on the device char *d_str; size_t size = sizeof(str); cudaMalloc((void**)&d_str, size);
// copy the string to the device cudaMemcpy(d_str, str, size, cudaMemcpyHostToDevice);
// set the grid and block sizes dim3 dimGrid(2); // one block per word dim3 dimBlock(6); // one thread per character // invoke the kernel helloWorld<<< dimGrid, dimBlock >>>(d_str);
// retrieve the results from the device cudaMemcpy(str, d_str, size, cudaMemcpyDeviceToHost);
// free up the allocated memory on the device cudaFree(d_str); // everyone's favorite part printf("%s\n", str); return 0;}
// Device kernel__global__ void helloWorld(char* str){ // determine where in the thread grid we are int idx = blockIdx.x * blockDim.x + threadIdx.x;
// unmangle output str[idx] += idx;}
#include <stdio.h>
int main(void){ printf("Hello World\n"); return 0;}