Copy Number Variations and Association Mapping Advanced Topics in Computa8onal Genomics

Transcription

1 Copy Number Variations and Association Mapping Advanced Topics in Computa8onal Genomics

2 SNP and CNV Genotyping SNP genotyping assumes two copy numbers at each locus (i.e., no CNVs) CNV genotyping assumes no SNPs in the region However, SNP and CNV coexist throughout the genome Ignoring either SNP or CNV will result in genotyping error E.g., genotypes like AAB, A

3 BirdSuite A joint es8ma8on of SNP calls and CNV calls by combining SNP and CNV probe informa8on Discover CNV genotypes for known CNVs (previously catalogued CNVs) Discovery of novel and rare CNVs Associa8on analysis that incorporate both SNP and CNV informa8on

4 BirdSuite Canary: assigns copy number for known common CNPs BirdSeed: assigns genotypes for SNPs BirdEye: detects novel and rare CNVs Fawk: integrates SNPs, CNPs and CNVs

5 Birdsuite

6 Detecting CNPs Probe intensi8es for CNPs across mul8ple individuals

7 Detecting CNPs Correlated CNP probe intensi8es across neighboring genome regions

8 Detecting CNPs One- dimensional mixture model Mean: intensity loca8on of the CNP Variance around each copy number EM algorithm to es8mate the parameters

9 Detecting CNPs Mixture models in different popula8ons Anomalous CNPs for YRI

10 Birdseed: Genotyping SNPs SNP probe intensi8es across samples at a locus

11 Birdseed: Genotyping SNPs Combining SNP and CNP probe data Two- dimensional mixture model for two- copy genotypes

12 Birdseed: Genotyping SNPs Mixture component for minor allele homozygous sites may be hard to detect if minor allele frequency is low

13 Birdseed: Genotyping SNPs Impu8ng mixture components for SNP genotypes of other CNPs

14 Birdseye: Detecting De Novo CNVs Combine informa8on from Canary and Birdseed CNV probes SNP probes

15 Birdseye: Detecting De Novo CNVs Combine informa8on from Canary and Birdseed

16 Birdseye: Detecting De Novo CNVs Parents Child

17 Evaluation There is no ground- truth available. However, consistency in Mendelian inheritance (Mendelian inconsistency, or MI) in HapMap trio samples can be used for evalua8on.

18 Evaluation Birdsuite vs. Birdseed: the rate of mendelian inconsistency (MI) in SNPs that overlap a known CNP for 91 children

19 Association Analysis with SNPs and CNVs At each locus, we have both SNP and CNV informa8on and want to incorporate both SNP and CNV in associa8on test How can we disentangle the effects of SNPs and CNVs? If the SNP for copy B lowers ac8vity than A, A and BB may have similar phenotypes

20 Association Analysis with SNPs and CNVs Assuming A, B represent two SNP alleles, we fit a regression model A+B: total copy numbers A- B: SNP genotypes b1: CNV effect b2: SNP effect

21 Association Analysis with SNPs and CNVs Assuming A, B represent two SNP alleles, we fit a regression model When there is no copy number varia8ons at the locus, the model reduces the regression model with only SNP effects When there is no SNP genotype varia8on at the locus, the model reduces the regression on only CNVs

22 Simulation Study Scenarios to be considered Dele8on: genotypes {A, B, - } at candidate locus Duplica8on: genotypes {A, B, BB} at candidate locus Fix the frequency of B alleles and duplica8on/dele8on events Different associa8on tests

23 Association Analysis with SNPs and CNVs Simula8on study results

24 SNP and CNV Associations CNVs have been found implicated in rare genomic disorders CNVs have been implicated in only a few percent of the 2000 or more mendelian diseases Complex diseases might be more suscep8ble to sod forms of varia8on (varia8on in noncoding sequences and copy number varia8ons) In an eqtl study, SNPs and CNVs were associated with 83% and 18% of the gene expression traits Poten8ally greater roles of SNPs Possible underes8ma8on of CNV effects - need a more extensive catalogue of CNVs

25 Association Studies with CNVs Gender ar8fact for dispersed duplica8ons: males/females are not equally represented in case and control groups

26 Summary Birdsuite determines the genotypes based on both CNVs and SNPs The combined genotypes for CNVs and SNPs can be used to disentangle the effects of SNPs and CNVs on phenotypes