allele-specific-accessibility

Name: allele-specific-accessibility
Author: GPTomics

1.1kstars185forks

How to install allele-specific-accessibility?

gptomics/bioskills/allele-specific-accessibility

$npx -y skills add GPTomics/bioSkills --skill allele-specific-accessibility

Installs into the current project.

Summary

Detect allele-specific chromatin accessibility from ATAC-seq using WASP, GATK ASEReadCounter, or RASQUAL. Use when mapping cis-regulatory genetic variants from heterozygous SNPs, separating cis from trans regulation, building chromatin QTL (caQTL) maps, validating GWAS variant fu

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SKILL.md

1	## Version Compatibility
2
3	Reference examples tested with: WASP 0.3.4+, GATK 4.4+, RASQUAL 1.1+, samtools 1.19+, bcftools 1.19+, vcftools 0.1.16+, plink 2.00+, MatrixEQTL 2.3+, QuASAR 0.1+, bowtie2 2.5+, bwa-mem2 2.2.1+, scipy 1.11+ (false_discovery_control), pandas 2+, pybedtools 0.10+.
4
5	Verify before use:
6	- CLI: `<tool> --version` then `<tool> --help` to confirm flags
7	- Python: `pip show <package>` then `help(module.function)` to check signatures
8	- R: `packageVersion('<pkg>')` then `?function_name` to verify parameters
9
10	If code throws unexpected errors, introspect the installed package and adapt rather than retrying.
11
12	# Allele-Specific Accessibility
13
14	"Does this heterozygous SNP affect chromatin accessibility on its allele?" -> Count ATAC reads supporting reference vs alternative allele at heterozygous sites in the same individual; significant deviation from 50:50 indicates cis-regulatory effect. Requires careful handling of reference-allele mapping bias (WASP filtering) and within-individual binomial testing.
15
16	- CLI: `WASP` (Geijn 2015) for de-biased reference mapping
17	- CLI: `gatk ASEReadCounter` for allele-specific count tables
18	- CLI: `RASQUAL` (Kumasaka 2016) for joint cis-mapping with allelic counts
19	- R: `QuASAR` (Harvey 2015) for genotype + ASE inference simultaneously
20
21	ASE/ASB analysis is fundamentally different from cohort-level differential. Statistical framework is binomial within-individual; sample size is the count of heterozygous SNPs in accessible regions, not the number of individuals.
22
23	## Algorithmic Taxonomy
24
25	\| Tool \| Method \| Input \| Strength \| Fails when \|
26	\|------\|--------\|-------\|----------\|------------\|
27	\| WASP (Geijn 2015) \| Realign reads where alt allele swap could change mapping; filter mapping-bias affected sites \| BAM + VCF + reference \| Mandatory for any ASE/ASB analysis; controls reference-allele bias \| Slow on deep coverage; requires re-alignment step \|
28	\| GATK ASEReadCounter \| Count REF and ALT reads at known heterozygous sites \| BAM + VCF \| Mature; integrates with GATK ecosystem; standard counter \| Doesn't fix mapping bias (needs WASP first); single-sample \|
29	\| RASQUAL (Kumasaka 2016) \| Joint cis-eQTL/caQTL model: total counts + allelic imbalance \| BAM + VCF + peak counts \| Best statistical power for caQTL when sample size is moderate (N=20-100); models genotype uncertainty \| Complex setup; per-feature regression (slow); requires LD computation \|
30	\| QuASAR (Harvey 2015) \| Genotype + ASE inference from RNA-seq or ATAC alone \| BAM (no VCF needed) \| Useful when genotypes are limited; integrates phasing \| Less accurate than WASP+GATK when genotypes are known \|
31	\| MatrixEQTL on per-feature counts \| Linear model fit on accessibility per peak \| Genotypes + peak counts \| Standard cohort-level caQTL; well-supported \| No allelic imbalance information; needs sample size N >= 50 \|
32	\| Allelic Imbalance from Bayesian models (MAJIQ-style) \| Bayesian beta-binomial \| BAM + VCF \| Models overdispersion appropriately \| Niche; less mature than WASP+GATK \|
33
34	Methodology evolves; verify against current Geijn 2015, Kumasaka 2016, Buchkovich 2015 before locking pipelines. Modern caQTL studies typically combine WASP + RASQUAL at modest N or WASP + GATK + linear caQTL at large N.
35
36	## Reference Allele Mapping Bias (The Single Most Important Issue)
37
38	When aligning reads to the reference genome, reads carrying the reference allele align with 0 mismatches; reads carrying the alternative allele have 1 mismatch and may fail to align (especially with `bwa-mem` -k or `bowtie2 --very-sensitive` thresholds). This inflates the apparent reference-allele frequency at every SNP and confounds ASE.
39
40	Trigger: Always (mapping bias is universal at heterozygous SNPs).
41
42	Mechanism: Aligners are mismatch-penalized. Without correction, ALT reads systematically under-align. Effect size: 1-5% bias toward reference at typical mismatch penalties.
43
44	Symptom: Per-SNP REF allele fraction skews above 50% even at sites without true allelic imbalance.
45
46	Fix: WASP. Pseudo-alleles every read at heterozygous sites; re-aligns swapped reads; keeps only reads that map identically to both haplotypes. Mandatory for any ASE/ASB analysis.
47
48	Goal: Remove reference-allele mapping bias before counting allele-specific ATAC reads.
49
50	Approach: Identify reads overlapping heterozygous SNPs, re-align allele-swapped versions, keep only reads consistent across both haplotypes, then count REF/ALT with GATK ASEReadCounter.
51
52	```bash
53	# WASP read-correction pipeli

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allele-specific-accessibility

1.1kstars185forks

View on GitHub

How to install allele-specific-accessibility?

gptomics/bioskills/allele-specific-accessibility

$npx -y skills add GPTomics/bioSkills --skill allele-specific-accessibility

Installs into the current project.

Summary

Files · 1

View on GitHub

SKILL.md

1	## Version Compatibility
2
3	Reference examples tested with: WASP 0.3.4+, GATK 4.4+, RASQUAL 1.1+, samtools 1.19+, bcftools 1.19+, vcftools 0.1.16+, plink 2.00+, MatrixEQTL 2.3+, QuASAR 0.1+, bowtie2 2.5+, bwa-mem2 2.2.1+, scipy 1.11+ (false_discovery_control), pandas 2+, pybedtools 0.10+.
4
5	Verify before use:
6	- CLI: `<tool> --version` then `<tool> --help` to confirm flags
7	- Python: `pip show <package>` then `help(module.function)` to check signatures
8	- R: `packageVersion('<pkg>')` then `?function_name` to verify parameters
9
10	If code throws unexpected errors, introspect the installed package and adapt rather than retrying.
11
12	# Allele-Specific Accessibility
13
14	"Does this heterozygous SNP affect chromatin accessibility on its allele?" -> Count ATAC reads supporting reference vs alternative allele at heterozygous sites in the same individual; significant deviation from 50:50 indicates cis-regulatory effect. Requires careful handling of reference-allele mapping bias (WASP filtering) and within-individual binomial testing.
15
16	- CLI: `WASP` (Geijn 2015) for de-biased reference mapping
17	- CLI: `gatk ASEReadCounter` for allele-specific count tables
18	- CLI: `RASQUAL` (Kumasaka 2016) for joint cis-mapping with allelic counts
19	- R: `QuASAR` (Harvey 2015) for genotype + ASE inference simultaneously
20
21	ASE/ASB analysis is fundamentally different from cohort-level differential. Statistical framework is binomial within-individual; sample size is the count of heterozygous SNPs in accessible regions, not the number of individuals.
22
23	## Algorithmic Taxonomy
24
25	\| Tool \| Method \| Input \| Strength \| Fails when \|
26	\|------\|--------\|-------\|----------\|------------\|
27	\| WASP (Geijn 2015) \| Realign reads where alt allele swap could change mapping; filter mapping-bias affected sites \| BAM + VCF + reference \| Mandatory for any ASE/ASB analysis; controls reference-allele bias \| Slow on deep coverage; requires re-alignment step \|
28	\| GATK ASEReadCounter \| Count REF and ALT reads at known heterozygous sites \| BAM + VCF \| Mature; integrates with GATK ecosystem; standard counter \| Doesn't fix mapping bias (needs WASP first); single-sample \|
29	\| RASQUAL (Kumasaka 2016) \| Joint cis-eQTL/caQTL model: total counts + allelic imbalance \| BAM + VCF + peak counts \| Best statistical power for caQTL when sample size is moderate (N=20-100); models genotype uncertainty \| Complex setup; per-feature regression (slow); requires LD computation \|
30	\| QuASAR (Harvey 2015) \| Genotype + ASE inference from RNA-seq or ATAC alone \| BAM (no VCF needed) \| Useful when genotypes are limited; integrates phasing \| Less accurate than WASP+GATK when genotypes are known \|
31	\| MatrixEQTL on per-feature counts \| Linear model fit on accessibility per peak \| Genotypes + peak counts \| Standard cohort-level caQTL; well-supported \| No allelic imbalance information; needs sample size N >= 50 \|
32	\| Allelic Imbalance from Bayesian models (MAJIQ-style) \| Bayesian beta-binomial \| BAM + VCF \| Models overdispersion appropriately \| Niche; less mature than WASP+GATK \|
33
34	Methodology evolves; verify against current Geijn 2015, Kumasaka 2016, Buchkovich 2015 before locking pipelines. Modern caQTL studies typically combine WASP + RASQUAL at modest N or WASP + GATK + linear caQTL at large N.
35
36	## Reference Allele Mapping Bias (The Single Most Important Issue)
37
38	When aligning reads to the reference genome, reads carrying the reference allele align with 0 mismatches; reads carrying the alternative allele have 1 mismatch and may fail to align (especially with `bwa-mem` -k or `bowtie2 --very-sensitive` thresholds). This inflates the apparent reference-allele frequency at every SNP and confounds ASE.
39
40	Trigger: Always (mapping bias is universal at heterozygous SNPs).
41
42	Mechanism: Aligners are mismatch-penalized. Without correction, ALT reads systematically under-align. Effect size: 1-5% bias toward reference at typical mismatch penalties.
43
44	Symptom: Per-SNP REF allele fraction skews above 50% even at sites without true allelic imbalance.
45
46	Fix: WASP. Pseudo-alleles every read at heterozygous sites; re-aligns swapped reads; keeps only reads that map identically to both haplotypes. Mandatory for any ASE/ASB analysis.
47
48	Goal: Remove reference-allele mapping bias before counting allele-specific ATAC reads.
49
50	Approach: Identify reads overlapping heterozygous SNPs, re-align allele-swapped versions, keep only reads consistent across both haplotypes, then count REF/ALT with GATK ASEReadCounter.
51
52	```bash
53	# WASP read-correction pipeli

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