PROJECT STRANDSHIFT | GENE-LOCI FAULT MATRIX: Phase 3 — HTT and Gene-Loci Profiling

Program: PROJECT STRANDSHIFT

Classification: Multi-Class Gene-Loci Fault Mapping Deliverable

Primary Purpose:

To map HTT, DNA repair, autoimmune, neurodevelopmental, apoptosis, neuroimmune, viral-mimicry, mitochondrial, and angiogenesis-associated loci into a structured SCF fault architecture for disease-origin, progression, and therapeutic vulnerability analysis.

1. EXECUTIVE SUMMARY

The Gene-Loci Fault Matrix defines the genomic architecture of PROJECT STRANDSHIFT by organizing disease-relevant genes into functional loci classes.

The matrix prioritizes loci that may contribute to:

HTT CAG repeat instability
Somatic expansion
DNA injury and repair deficiency
Neuroimmune activation
Autoimmune convergence
Neurodevelopmental vulnerability
Apoptosis and cell fate dysregulation
Viral mimicry and endogenous retroelement activation
Mitochondrial dysfunction
Angiogenic remodeling

This deliverable is designed to support sequencing panel design, multi-omic integration, biomarker discovery, and therapeutic target prioritization.

2. MATRIX DESIGN LOGIC

Core Loci Classes

Loci Class	Function in STRANDSHIFT
HTT Primary Disease Locus	Disease initiation and mutant huntingtin biology
DNA Repair Loci	Somatic expansion, genome stability, DNA injury repair
Autoimmune Loci	Immune tolerance, interferon signaling, inflammatory amplification
Neurodevelopmental Loci	Synaptic architecture, cognitive reserve, developmental vulnerability
Apoptosis Loci	Cell fate, neuronal loss, injury execution
Neuroimmune Loci	Microglial activation, cytokine signaling, complement injury
Viral-Mimicry Loci	cGAS-STING, dsRNA sensing, retroelement response
Mitochondrial Loci	Energy failure, oxidative stress, mtDNA instability
Angiogenesis Loci	Hypoxia, vascular remodeling, oncologic convergence

3. HTT PRIMARY DISEASE LOCUS

Gene / Locus	Primary Fault	Disease Role	Assay Priority
HTT	CAG repeat expansion	Primary disease-initiating locus	Tier 1
HTT Exon 1	Expanded polyQ coding region	Toxic mutant huntingtin fragment biology	Tier 1
HTT promoter	Expression regulation	Disease expression modulation	Tier 2
HTT haplotype region	Linked inheritance architecture	Family-risk stratification	Tier 2

Required Assays

HTT CAG repeat sizing
Long-read sequencing
Allele-specific expression analysis
HTT transcript profiling
Mutant huntingtin protein quantification

4. DNA REPAIR LOCI MATRIX

Gene	Pathway	Fault Type	STRANDSHIFT Interpretation
MSH3	Mismatch repair	Expansion acceleration	Major somatic expansion driver
MSH2	Mismatch repair	Expansion-prone repair	Repeat instability facilitator
MLH1	Mismatch repair	Repair signaling dysregulation	Expansion modifier
PMS1	Mismatch repair	Repair complex modulation	Expansion modifier
PMS2	Mismatch repair	Repair complex modulation	Expansion modifier
FAN1	Fanconi-associated repair	Loss of expansion suppression	Protective modifier if functional
EXO1	Excision repair	Repeat processing instability	Expansion modifier
LIG1	DNA ligation	Repair completion failure	Genome stability modifier
PCNA	Replication/repair coordination	Replication stress	Expansion susceptibility locus
ATM	DNA damage response	Double-strand break signaling	DNA injury response locus
ATR	Replication stress response	Fork-stress signaling	Repeat instability risk locus
PARP1	Single-strand break repair	Repair overload	DNA injury amplification locus
BRCA1	Homologous recombination	DSB repair deficiency	Genome stability locus
BRCA2	Homologous recombination	DSB repair deficiency	Genome stability locus
RAD51	Homologous recombination	Repair execution defect	DSB repair competence locus
XRCC1	Base excision repair	Oxidative damage repair failure	ROS injury locus
OGG1	Base excision repair	Oxidized base repair	8-OHdG-associated injury locus
APEX1	Base excision repair	Abasic site repair	Oxidative repair locus

Required Assays

WGS or targeted DNA repair panel
DNA repair variant annotation
γH2AX and 53BP1 DNA damage assays
Comet assay
Repair-capacity functional assays
Somatic expansion correlation analysis

5. AUTOIMMUNE AND IMMUNE-TOLERANCE LOCI MATRIX

Gene / Locus	Immune System Role	Fault Type	STRANDSHIFT Interpretation
HLA-A	Antigen presentation	Altered immune recognition	Autoimmune susceptibility locus
HLA-B	Antigen presentation	Immune-risk modulation	Tissue inflammation locus
HLA-C	Antigen presentation	NK/T-cell signaling modulation	Immune surveillance locus
HLA-DRB1	MHC II antigen presentation	Autoimmune-risk allele effects	Major autoimmune convergence locus
HLA-DQA1	MHC II antigen presentation	Antigen presentation drift	Adaptive immune locus
HLA-DQB1	MHC II antigen presentation	Immune tolerance variation	Autoimmune susceptibility locus
PTPN22	T-cell receptor signaling	Immune tolerance loss	Autoimmune risk modifier
CTLA4	Immune checkpoint	T-cell inhibition failure	Tolerance failure locus
IL2RA	T-cell regulation	Regulatory T-cell imbalance	Autoimmune amplification locus
TNFAIP3	NF-κB suppression	Inflammatory overactivation	Immune braking failure locus
STAT1	Interferon signaling	IFN amplification	Viral-mimicry/autoimmune bridge
STAT3	Cytokine signaling	Inflammatory skewing	Neuroimmune convergence locus
IRF5	Interferon regulation	IFN pathway escalation	Autoimmune interferon locus
IRF7	Antiviral transcription	Antiviral-state activation	Viral-response mimicry locus
JAK1	Cytokine signaling	JAK-STAT activation	Immune amplification locus
TYK2	Type I IFN signaling	Autoimmune/IFN sensitivity	Viral-response immune locus

Required Assays

HLA typing
Autoimmune SNP panel
Cytokine profiling
Interferon-stimulated gene expression panel
T-cell and monocyte immune phenotyping

6. NEURODEVELOPMENTAL LOCI MATRIX

Gene	Primary Function	Fault Type	STRANDSHIFT Interpretation
BDNF	Neurotrophic support	Reduced trophic resilience	Cognitive reserve and striatal vulnerability
NTRK2	BDNF receptor signaling	Neurotrophic signaling failure	Neuroplasticity locus
SHANK3	Synaptic scaffold	Synaptic architecture disruption	Neurodevelopmental vulnerability locus
CNTNAP2	Neural connectivity	Circuit maturation disruption	Connectomic vulnerability locus
GRIN2A	NMDA receptor subunit	Excitatory signaling imbalance	Synaptic plasticity locus
GRIN2B	NMDA receptor subunit	Excitotoxicity susceptibility	Neurodevelopmental and degeneration bridge
RELN	Neuronal migration	Cortical organization vulnerability	Developmental architecture locus
MECP2	Epigenetic regulation	Neurodevelopmental transcriptional instability	Epigenomic vulnerability locus
TSC1	mTOR regulation	Growth-signaling dysregulation	Neurodevelopmental-metabolic bridge
TSC2	mTOR regulation	Cellular growth imbalance	Synaptic and metabolic vulnerability
FMR1	RNA-binding regulation	Synaptic translation instability	Repeat/RNA biology bridge
DLG4	Postsynaptic density	Synaptic transmission disruption	Cognitive network locus
CAMK2A	Synaptic plasticity	Learning/memory impairment	Cognitive resilience locus
COMT	Dopamine metabolism	Executive-function modulation	Behavioral vulnerability locus
DRD2	Dopamine receptor	Motor/cognitive modulation	Striatal signaling locus

Required Assays

Neurodevelopmental gene panel
RNA-seq expression profiling
methylation profiling
synaptic protein quantification
connectomic imaging correlation

7. APOPTOSIS AND CELL-FATE LOCI MATRIX

Gene	Pathway	Fault Type	STRANDSHIFT Interpretation
TP53	DNA damage checkpoint	Cell-fate activation	Genome injury-to-apoptosis bridge
BAX	Intrinsic apoptosis	Pro-apoptotic activation	Neuronal loss driver
BCL2	Anti-apoptotic control	Survival failure	Resilience locus
CASP3	Executioner caspase	Apoptotic execution	Neuronal death marker
CASP7	Executioner caspase	Apoptotic execution	Injury execution marker
CASP8	Extrinsic apoptosis	Death-receptor signaling	Immune-mediated apoptosis locus
CASP9	Intrinsic apoptosis	Mitochondrial apoptosis	Mitochondrial injury bridge
APAF1	Apoptosome formation	Apoptotic amplification	Cell-fate transition locus
FAS	Death receptor	Immune-triggered death	Neuroimmune apoptosis bridge
FASLG	Death ligand	Cytotoxic signaling	Immune-cell death signaling locus
BAD	Mitochondrial apoptosis	Survival-signal imbalance	Stress apoptosis locus
XIAP	Caspase inhibition	Apoptosis restraint	Survival-protection locus

Required Assays

caspase activity panel
TUNEL assay
BAX/BCL2 ratio
p53 activation
apoptosis proteomics
single-cell cell-fate mapping

8. NEUROIMMUNE LOCI MATRIX

Gene	Function	Fault Type	STRANDSHIFT Interpretation
TREM2	Microglial activation	Microglial response imbalance	Neuroimmune progression locus
CX3CR1	Microglia-neuron signaling	Communication failure	Synaptic pruning/inflammation locus
C1QA	Complement activation	Synaptic tagging	Complement-mediated synaptic injury
C3	Complement cascade	Inflammatory synapse loss	Neurodegenerative amplification locus
IL1B	Pro-inflammatory cytokine	Neuroinflammation	Microglial injury locus
IL6	Cytokine signaling	Inflammatory amplification	Systemic-neural bridge
TNF	Inflammatory cytokine	Synaptic toxicity	Neuroimmune toxicity locus
NLRP3	Inflammasome	Innate immune activation	Inflammatory cell-death bridge
CXCL10	Chemokine	IFN-associated recruitment	Viral-mimicry immune marker
CCL2	Monocyte recruitment	Immune-cell trafficking	Peripheral-neural immune bridge

Required Assays

cytokine multiplex panel
microglial activation markers
complement protein profiling
inflammasome activation assays
CSF and plasma immune biomarker analysis

9. VIRAL-MIMICRY AND RETROELEMENT RESPONSE LOCI MATRIX

Gene / Element	Function	Fault Type	STRANDSHIFT Interpretation
CGAS / MB21D1	Cytosolic DNA sensing	DNA injury immune sensing	Genome-stress-to-IFN bridge
STING1	DNA sensing adaptor	Innate immune activation	Cytosolic DNA response locus
TBK1	IFN pathway kinase	Antiviral signaling	Viral-mimicry signaling locus
IRF3	IFN transcription factor	Antiviral-state activation	Viral mimicry output
IFIH1 / MDA5	dsRNA sensing	RNA viral mimicry	dsRNA injury detector
DDX58 / RIG-I	RNA sensing	Antiviral sensing	RNA instability immune bridge
OAS1	Antiviral effector	IFN response	Viral-response marker
RNASEL	Antiviral RNA degradation	RNA stress response	dsRNA processing locus
HERV-K	Endogenous retroviral element	Retroelement activation	Genome derepression marker
HERV-W	Endogenous retroviral element	Immune activation potential	Autoimmune/viral-mimicry bridge
LINE-1	Retrotransposon	Genome instability signal	Retroelement mobility risk marker
TREX1	Cytosolic DNA clearance	Self-DNA accumulation	Autoimmune DNA-sensing bridge
ADAR1	RNA editing	dsRNA misclassification	Viral mimicry restraint locus

Required Assays

HERV-K/HERV-W transcript profiling
LINE-1 RNA/protein detection
cGAS-STING activation panel
interferon-stimulated gene expression
dsRNA staining
metagenomic viral exclusion panel

10. MITOCHONDRIAL AND OXIDATIVE STRESS LOCI MATRIX

Gene	Function	Fault Type	STRANDSHIFT Interpretation
PPARGC1A	Mitochondrial biogenesis	Energy resilience failure	HD metabolic vulnerability locus
TFAM	mtDNA maintenance	mtDNA instability	Mitochondrial genome locus
SOD1	ROS detoxification	Oxidative stress	DNA injury amplifier
SOD2	Mitochondrial ROS detoxification	Mitochondrial oxidative injury	Neuronal stress locus
GPX1	Peroxide detoxification	Redox imbalance	Oxidative injury locus
NDUFS1	Complex I	OXPHOS dysfunction	Energy failure locus
COX4I1	Complex IV	Respiratory chain dysfunction	ATP failure locus
POLG	mtDNA polymerase	mtDNA repair failure	Mitochondrial genome instability
PINK1	Mitophagy	Mitochondrial quality-control failure	Neurodegeneration bridge
PRKN	Mitophagy	Damaged mitochondria persistence	Proteostasis-energy bridge

11. ANGIOGENESIS AND ONCOLOGIC REMODELING LOCI MATRIX

Gene	Function	Fault Type	STRANDSHIFT Interpretation
VEGFA	Angiogenesis	Vascular remodeling	Hypoxia-response locus
HIF1A	Hypoxia response	Oxygen-stress signaling	Metabolic-angiogenic bridge
MMP9	ECM remodeling	Tissue remodeling	Neurovascular remodeling locus
TGFB1	Fibrosis/inflammation	Repair-remodeling drift	Chronic injury remodeling locus
ANGPT2	Vascular remodeling	Endothelial instability	Neurovascular risk locus
NOS3	Endothelial nitric oxide	Vascular tone dysregulation	Cerebral perfusion locus
KDR / VEGFR2	VEGF receptor	Angiogenic signaling	Vascular response locus

12. INTEGRATED SCF FAULT CLASSIFICATION

Fault Tier	Dominant Gene Classes	Disease Meaning
Tier 1	HTT	inherited disease initiation
Tier 2	MSH3, FAN1, MSH2, MLH1, PMS1, PMS2	somatic expansion and repair modulation
Tier 3	ATM, ATR, PARP1, BRCA1/2, RAD51	DNA injury response failure
Tier 4	BDNF, GRIN2B, SHANK3, CNTNAP2	neurodevelopmental vulnerability
Tier 5	HLA, PTPN22, CTLA4, STAT1, IRF5	autoimmune convergence
Tier 6	TREM2, C3, IL1B, TNF, NLRP3	neuroimmune amplification
Tier 7	cGAS, STING1, IFIH1, DDX58, HERV-K/W, LINE-1	viral mimicry and retroelement activation
Tier 8	TP53, BAX, BCL2, CASP3/7/9	apoptosis and neuronal death
Tier 9	PPARGC1A, TFAM, SOD2, POLG	mitochondrial collapse
Tier 10	VEGFA, HIF1A, MMP9, TGFB1	remodeling and angiogenic drift

13. PRIMARY GENE-LOCI DATA PACKAGES

Data Package	Required Contents
GLFM-DP1	HTT CAG repeat and haplotype data
GLFM-DP2	DNA repair variant and function data
GLFM-DP3	autoimmune and HLA typing data
GLFM-DP4	neurodevelopmental and synaptic loci data
GLFM-DP5	apoptosis and cell-fate loci data
GLFM-DP6	neuroimmune and cytokine loci data
GLFM-DP7	viral-mimicry and retroelement data
GLFM-DP8	mitochondrial loci data
GLFM-DP9	angiogenesis and remodeling loci data
GLFM-DP10	integrated multi-loci risk model

14. COMPOSITE LOCI INDICES

14.1 HTT Initiation Index

Inputs:

CAG repeat length
HTT haplotype
HTT transcript burden
mutant huntingtin protein burden

14.2 DNA Repair Instability Index

Inputs:

MSH3 burden
FAN1 protective capacity
mismatch repair pathway activity
DNA damage response activity

14.3 Autoimmune Convergence Index

Inputs:

HLA risk profile
interferon signaling
immune checkpoint variation
cytokine-risk loci

14.4 Neurodevelopmental Resilience Index

Inputs:

BDNF/NTRK2 axis
synaptic scaffold loci
excitatory signaling loci
cognitive-reserve markers

14.5 Apoptotic Execution Index

Inputs:

TP53 activation
BAX/BCL2 ratio
caspase activation
TUNEL burden

14.6 Viral Mimicry Gene Activation Score

Inputs:

cGAS-STING activation
dsRNA sensing loci
HERV/LINE-1 activity
IFN pathway output

15. STRANDSHIFT GENE-LOCI INTERPRETATION MODEL

Inherited HTT CAG Expansion

↓

DNA Repair Modifier Burden

↓

Somatic Expansion and DNA Injury

↓

RNA Instability and Viral-Mimicry Signaling

↓

Neuroimmune Activation

↓

Mitochondrial Stress

↓

Apoptotic Execution

↓

Neurodegenerative Clinical Phenotype

16. REQUIRED VALIDATION STRATEGY

Validation Layer	Method
Genetic validation	WGS, targeted panels, long-read sequencing
Transcript validation	RNA-seq, qPCR, long-read transcriptomics
Protein validation	proteomics, western blot, ELISA
Functional validation	DNA repair assays, apoptosis assays
Tissue validation	single-cell multiome, spatial transcriptomics
Clinical validation	biomarker correlation with UHDRS and functional scales

17. CONCLUSION

The Gene-Loci Fault Matrix establishes the core genomic and pathway architecture for PROJECT STRANDSHIFT. It identifies the HTT disease-initiating locus, DNA repair modifiers of somatic expansion, autoimmune and neuroimmune convergence loci, neurodevelopmental resilience loci, apoptosis execution loci, viral-mimicry response loci, mitochondrial stress genes, and angiogenic remodeling markers.

This matrix provides the required foundation for sequencing panel development, multi-omic fault mapping, biomarker discovery, patient stratification, and therapeutic target prioritization.