dnaerys/onekgpd-mcp

Natural language access to _**1000 Genomes Project dataset**_, hosted online in _Dnaerys variant store_
Sequenced & aligned by _New York Genome Center_ (_GRCh38_). _3202 samples_: 2504 unrelated samples from phase
three panel + 698 samples from 602 family trios - dataset details
Key Features
- _real-time_ access to _138 044 723_ unique variants and _~442 billion_ individual genotypes
- variant, sample and genotype selection based on coordinates, annotations, zygosity, population
- filtering by VEP (impact, biotype, feature type, variant class, consequences), ClinVar Clinical Significance (202502),
gnomADe + gnomADg 4.1, AlphaMissense Score & AlphaMissense Class annotations
- annotated with VEP 115 / GENCODE 49
- GENCODE Primary set transcripts
- full annotation composition
- returned variants annotated with _HGVSp_, _gnomADe + gnomADg_, _AlphaMissense score_ + cohort-wide statistics
- _**HGVSp**_ annotations are for **_Canonical transcripts_** to reduce LLMs cognitive load
- samples annotated with: _familyId, gender, paternalId, maternalId, relationship, children, population, superpopulation, phase3 indicator_
Online Service
Remote MCP service via _Streamable HTTP:_
- http://db.dnaerys.org/mcp
- https://db.dnaerys.org/mcp
Examples
Macromolecular structural complexes
> _Treat the 26S Proteasome as a mechanically redundant 3D machine and map every missense variant from the KGP individuals
across all 33 subunits. Perform a spatial analysis to determine if pathogenic variation is statistically partitioned toward
the distal 'Lid' (Zone C) rather than the more evolutionary constrained 'Core' (Zone A) or 'Gating' (Zone B) interfaces.
Identify individuals with a high cumulative burden (2+ 'Likely Pathogenic' variants) to investigate inter-subunit compensation,
searching for paired 'weakening' and 'stabilizing' mutations at protein-protein hinges. Finally, define the 'mechanical
tolerance' of the proteasome by establishing the maximum cumulative structural disruption observed in a single healthy
individual based on AlphaMissense scores and calculated ΔΔG values._
Macromolecular structural complexes
> _The MCM2-7 Complex (The "DNA Helicase Motor") is a molecular masterpiece. It’s a heterohexameric ring where each subunit is
a distinct "gear" in the DNA-unzipping motor. Unlike homomeric rings (where every subunit is the same), this complex is asymmetric.
Each interface between subunits is unique, and they don't all burn ATP at the same rate. The MCM2/5 interface is the "gate" that
must physically open to allow DNA to enter the ring and then snap shut. This is a high-stress mechanical point._
>
> _Identify individuals in the KGP cohort carrying missense variants at the MCM2/5 interface. Specifically, look for
'charge-reversal' variants (e.g., Aspartate to Lysine). In these specific samples, analyze the 'compensatory coupling':
do they carry a secondary, reciprocal charge-reversal variant on the opposing subunit interface that restores the
electrostatic 'latch' ?_
>
> _Identify individuals in the KGP cohort who carry high-pathogenicity variants in the Walker A or Walker B motifs
(the ATP-burning heart) of any MCM subunit in MCM2-7 Complex. For these individuals, perform a 'Systemic Flux' analysis:
look at their variants in the leading-strand polymerase (POLE) and the sliding clamp (PCNA). Do you detect a signature of
'Coordinated Deceleration' where the motor, the clamp, and the polymerase all carry variants that suggest a slower but
highly-accurate replication fork ?_
Macromolecular structural complexes
> _The human RNA Exosome (Exo-9 core) is a "dead machine" that acts as a scaffold. In lower organisms the ring itself can degrade RNA.