annonars 0.42.1

//! Implementation of the actix server.

pub mod annos_db_info;
pub mod annos_range;
pub mod annos_variant;
pub mod clinvar_data;
pub mod clinvar_sv;
pub mod error;
pub mod fetch;
pub mod genes_clinvar;
pub mod genes_info;
pub mod genes_lookup;
pub mod genes_search;
pub mod versions;

use std::{
    collections::HashMap,
    path::{Path, PathBuf},
    str::FromStr as _,
    time::Instant,
};

use clap::Parser;
use indicatif::ParallelProgressIterator;
use prost::Message;
use rayon::prelude::*;
use utoipa::OpenApi as _;

use crate::{
    clinvar_sv::cli::query::{self as clinvarsv_query, IntervalTrees as ClinvarsvIntervalTrees},
    common::{self, cli::GenomeRelease},
    pbs::genes,
};

use actix_web::{middleware::Logger, web::Data, App, HttpServer};

/// Module with OpenAPI documentation.
pub mod openapi {
    use crate::{
        common::cli::GenomeRelease,
        server::run::annos_variant::{self, response::*, SeqvarsAnnosQuery},
        server::run::clinvar_data::*,
        server::run::clinvar_sv::{self, response::*, StrucvarsClinvarQuery},
        server::run::genes_clinvar::{self, response::*, GenesClinvarQuery},
        server::run::genes_info::{self, response::*},
        server::run::genes_lookup::{self, GenesLookupResponse, GenesLookupResultEntry},
        server::run::genes_search::{
            self, GenesFields, GenesScoredGeneNames, GenesSearchQuery, GenesSearchResponse,
        },
        server::run::versions::{
            self, VersionsAnnotationInfo, VersionsCreatedFrom, VersionsInfoQuery,
            VersionsInfoResponse, VersionsPerRelease, VersionsVersionSpec,
        },
        server::run::{error::CustomError, AnnoDb, GeneNames},
    };

    /// Utoipa-based `OpenAPI` generation helper.
    #[derive(utoipa::OpenApi)]
    #[openapi(
        paths(
            versions::handle,
            clinvar_sv::handle_with_openapi,
            annos_variant::handle_with_openapi,
            genes_clinvar::handle_with_openapi,
            genes_info::handle_with_openapi,
            genes_lookup::handle_with_openapi,
            genes_search::handle_with_openapi
        ),
        components(schemas(
            VersionsInfoQuery,
            VersionsInfoResponse,
            VersionsVersionSpec,
            VersionsPerRelease,
            VersionsAnnotationInfo,
            VersionsCreatedFrom,
            GenomeRelease,
            AnnoDb,
            CustomError,
            GenesAcmgSecondaryFindingRecord,
            GenesClingenDosageScore,
            GenesClingenDosageRecord,
            GenesDecipherHiRecord,
            GenesDominoRecord,
            GenesDbnsfpRecord,
            GenesGnomadConstraintsRecord,
            GenesHgncLsdb,
            GenesHgncRecord,
            GenesRifEntry,
            GenesNcbiRecord,
            GenesOmimTerm,
            GenesOmimRecord,
            GenesOrphaTerm,
            GenesOrphaRecord,
            GenesRcnvRecord,
            GenesShetRecord,
            GenesGtexTissueRecord,
            GenesGtexRecord,
            GenesPanelAppRecord,
            GenesGeneData,
            GenesPanelStats,
            GenesPanelType,
            GenesPanel,
            GenesEntityType,
            GenesDiseaseAssociationEntryConfidenceLevel,
            GenesPenetrance,
            GenesConditionsRecord,
            GenesGeneDiseaseAssociationEntry,
            GenesDiseaseAssociationSource,
            GenesDiseaseAssociationConfidenceLevel,
            GenesLabeledDisorder,
            GenesDiseaseAssociation,
            GenesPanelappPanel,
            GenesPanelappAssociation,
            GenesPanelappRecordConfidenceLevel,
            GenesPanelappAssociationConfidenceLevel,
            GenesPanelappEntityType,
            GenesGeneRecord,
            GenesHgncStatus,
            GenesGtexTissue,
            GenesGtexTissueDetailed,
            GenesGeneInfoRecord,
            GenesInfoResponse,
            GenesSearchQuery,
            GenesFields,
            GenesSearchResponse,
            GenesScoredGeneNames,
            GeneNames,
            GenesLookupResponse,
            GenesLookupResultEntry,
            GenesClinvarQuery,
            GenesExtractedVariantsPerRelease,
            GenesCoarseClinsigFrequencyCounts,
            GenesGeneImpact,
            GenesImpactCounts,
            GenesGeneImpactCounts,
            GenesClinvarPerGeneRecord,
            GenesClinvarResponseEntry,
            GenesClinvarResponse,
            StrucvarsClinvarQuery,
            StrucvarsClinvarPageInfo,
            StrucvarsClinvarResponseRecord,
            StrucvarsClinvarResponse,
            ClinvarAccession,
            ClinvarAffectedStatus,
            ClinvarAge,
            ClinvarAgeType,
            ClinvarAgeUnit,
            ClinvarAggregateClassificationSet,
            ClinvarAggregatedGermlineClassification,
            ClinvarAggregatedOncogenicityClassification,
            ClinvarAggregatedSomaticClinicalImpact,
            ClinvarAggregateGermlineReviewStatus,
            ClinvarAggregateOncogenicityReviewStatus,
            ClinvarAggregateSomaticClinicalImpactReviewStatus,
            ClinvarAllele,
            ClinvarAlleleDescription,
            ClinvarAlleleFrequency,
            ClinvarAlleleGene,
            ClinvarAlleleName,
            ClinvarAlleleScv,
            ClinvarAlleleScvGene,
            ClinvarAssemblyStatus,
            ClinvarAssertion,
            ClinvarAttribute,
            ClinvarAttributeSetElement,
            ClinvarAttributeSetElementType,
            ClinvarBaseAttribute,
            ClinvarChromosome,
            ClinvarCitation,
            ClinvarClassificationScore,
            ClinvarClassificationScv,
            ClinvarClassificationScvSomaticClinicalImpact,
            ClinvarClassifiedCondition,
            ClinvarClassifiedRecord,
            ClinvarClassifiedVariation,
            ClinvarClinicalAssertion,
            ClinvarClinicalAssertionAttributeSetElement,
            ClinvarClinicalAssertionRecordHistory,
            ClinvarClinicalAssertionRecordStatus,
            ClinvarClinicalFeaturesAffectedStatusType,
            ClinvarClinicalSignificance,
            ClinvarComment,
            ClinvarCommentType,
            ClinvarCooccurrence,
            ClinvarDeletedScv,
            ClinvarDescriptionHistory,
            ClinvarDosageSensitivity,
            ClinvarEvidenceType,
            ClinvarExtractedRcvRecord,
            ClinvarExtractedVariationType,
            ClinvarExtractedVcvRecord,
            ClinvarFamilyData,
            ClinvarFunctionalConsequence,
            ClinvarGender,
            ClinvarGeneralCitations,
            ClinvarGenericSetElement,
            ClinvarGeneVariantRelationship,
            ClinvarGenotype,
            ClinvarGenotypeScv,
            ClinvarGlobalMinorAlleleFrequency,
            ClinvarHaplotype,
            ClinvarHaplotypeScv,
            ClinvarHaploVariationType,
            ClinvarHgvsExpression,
            ClinvarHgvsNucleotideExpression,
            ClinvarHgvsProteinExpression,
            ClinvarHgvsType,
            ClinvarIdType,
            ClinvarIncludedRecord,
            ClinvarIndication,
            ClinvarIndicationType,
            ClinvarLocation,
            ClinvarMethod,
            ClinvarMethodAttribute,
            ClinvarMethodAttributeType,
            ClinvarMethodListType,
            ClinvarMethodSourceType,
            ClinvarMethodType,
            ClinvarMolecularConsequence,
            ClinvarNucleotideSequence,
            ClinvarObservedData,
            ClinvarObservedDataAttribute,
            ClinvarObservedDataAttributeType,
            ClinvarObservedIn,
            ClinvarObsMethodAttribute,
            ClinvarObsMethodAttributeType,
            ClinvarOrigin,
            ClinvarOtherName,
            ClinvarPhenotypeSetType,
            ClinvarProteinSequence,
            ClinvarRcvAccession,
            ClinvarRcvAccessionSomaticClinicalImpact,
            ClinvarRcvClassifications,
            ClinvarRcvClassifiedConditionList,
            ClinvarRcvGermlineClassification,
            ClinvarRcvGermlineClassificationDescription,
            ClinvarRcvList,
            ClinvarRcvOncogenicityClassification,
            ClinvarRcvOncogenicityDescription,
            ClinvarRcvSomaticClinicalImpactDescription,
            ClinvarRcvTraitMapping,
            ClinvarRcvTraitMappingMedgen,
            ClinvarRcvTraitMappingType,
            ClinvarRecordHistory,
            ClinvarRelativeOrientation,
            ClinvarResultType,
            ClinvarSample,
            ClinvarSampleDescription,
            ClinvarSampleSourceType,
            ClinvarScv,
            ClinvarSequenceLocation,
            ClinvarSeverity,
            ClinvarSoftware,
            ClinvarSomaticVariantInNormalTissue,
            ClinvarSpecies,
            ClinvarStatus,
            ClinvarSubmissionId,
            ClinvarSubmitter,
            ClinvarSubmitterIdentifiers,
            ClinvarSubmitterReviewStatus,
            ClinvarSubmitterType,
            ClinvarTrait,
            ClinvarTraitRelationship,
            ClinvarTraitRelationshipType,
            ClinvarTraitSet,
            ClinvarTraitSetType,
            ClinvarVariationArchive,
            ClinvarVariationArchiveRecordStatus,
            ClinvarVariationArchiveRecordType,
            ClinvarVariationRelease,
            ClinvarVariationType,
            ClinvarVersionedAccession,
            ClinvarXref,
            ClinvarZygosity,
            SeqvarsAnnosQuery,
            SeqvarsAnnosResponse,
            // TODO: more here!
        ))
    )]
    pub struct ApiDoc;
}

/// Main entry point for the actix server.
///
/// # Errors
///
/// If the server cannot be started.
#[actix_web::main]
pub async fn main(args: &Args, dbs: Data<WebServerData>) -> std::io::Result<()> {
    let openapi = openapi::ApiDoc::openapi();

    HttpServer::new(move || {
        let app = App::new()
            .app_data(dbs.clone())
            .service(annos_variant::handle)
            .service(annos_variant::handle_with_openapi)
            .service(annos_range::handle)
            .service(annos_db_info::handle)
            .service(clinvar_sv::handle)
            .service(clinvar_sv::handle_with_openapi)
            .service(genes_clinvar::handle)
            .service(genes_info::handle)
            .service(genes_info::handle_with_openapi)
            .service(genes_search::handle)
            .service(genes_search::handle_with_openapi)
            .service(genes_lookup::handle)
            .service(genes_lookup::handle_with_openapi)
            .service(versions::handle)
            .service(
                utoipa_swagger_ui::SwaggerUi::new("/swagger-ui/{_:.*}")
                    .url("/api-docs/openapi.json", openapi.clone()),
            );
        app.wrap(Logger::default())
    })
    .bind((args.listen_host.as_str(), args.listen_port))?
    .run()
    .await
}

/// Encode annotation database.
#[derive(
    Debug,
    Default,
    Clone,
    Copy,
    PartialEq,
    Eq,
    PartialOrd,
    Ord,
    Hash,
    strum::Display,
    strum::EnumString,
    strum::EnumIter,
    serde::Serialize,
    serde::Deserialize,
    enum_map::Enum,
    utoipa::ToSchema,
)]
#[strum(serialize_all = "snake_case")]
#[serde(rename_all = "snake_case")]
pub enum AnnoDb {
    /// Other database.
    #[default]
    Other,
    /// CADD annotations.
    Cadd,
    /// dbSNP annotations.
    Dbsnp,
    /// dbNSFP annotations.
    Dbnsfp,
    /// dbscSNV annotations.
    Dbscsnv,
    /// gnomAD mtDNA annotations.
    GnomadMtdna,
    /// gnomAD exomes annotations.
    GnomadExomes,
    /// gnomAD genomes annotations.
    GnomadGenomes,
    /// HelixMtDb annotations.
    Helixmtdb,
    /// UCSC conservation annotations.
    UcscConservation,
    /// ClinVar with minimal data extracted.
    Clinvar,
}

impl AnnoDb {
    /// Return the expected column family name of the database.
    pub fn cf_name(self) -> &'static str {
        match self {
            AnnoDb::Cadd => "tsv_data",
            AnnoDb::Dbsnp => "dbsnp_data",
            AnnoDb::Dbnsfp => "tsv_data",
            AnnoDb::Dbscsnv => "tsv_data",
            AnnoDb::GnomadMtdna => "gnomad_mtdna_data",
            AnnoDb::GnomadExomes => "gnomad_nuclear_data",
            AnnoDb::GnomadGenomes => "gnomad_nuclear_data",
            AnnoDb::Helixmtdb => "helixmtdb_data",
            AnnoDb::UcscConservation => "ucsc_conservation",
            AnnoDb::Clinvar => "clinvar",
            AnnoDb::Other => panic!("cannot get CF name for 'Other'"),
        }
    }

    /// Return the key for the database version.
    fn db_version_meta(&self) -> Option<&'static str> {
        match self {
            AnnoDb::Cadd => Some("db-version"),
            AnnoDb::Dbsnp => Some("db-version"),
            AnnoDb::Dbnsfp => Some("db-version"),
            AnnoDb::Dbscsnv => Some("db-version"),
            AnnoDb::GnomadMtdna => Some("gnomad-version"),
            AnnoDb::GnomadExomes => Some("gnomad-version"),
            AnnoDb::GnomadGenomes => Some("gnomad-version"),
            AnnoDb::Helixmtdb => None,
            AnnoDb::UcscConservation => None,
            AnnoDb::Clinvar => None,
            AnnoDb::Other => panic!("cannot get meta version name name for 'Other'"),
        }
    }
}

/// Identifier / name information for one gene.
#[derive(Debug, Clone, serde::Serialize, serde::Deserialize, utoipa::ToSchema)]
pub struct GeneNames {
    /// HGNC gene ID.
    pub hgnc_id: String,
    /// HGNC gene symbol.
    pub symbol: String,
    /// Gene name from HGNC.
    pub name: String,
    /// HGNC alias symbols.
    pub alias_symbol: Vec<String>,
    /// HGNC alias names.
    pub alias_name: Vec<String>,
    /// ENSEMBL gene ID.
    pub ensembl_gene_id: Option<String>,
    /// NCBI gene ID.
    pub ncbi_gene_id: Option<String>,
}

/// Gene information database.
#[derive(Debug)]
pub struct GeneInfoDb {
    /// The database with overall genes information.
    pub db: rocksdb::DBWithThreadMode<rocksdb::MultiThreaded>,
    /// ClinVar gene information.
    pub db_clinvar: Option<rocksdb::DBWithThreadMode<rocksdb::MultiThreaded>>,
    /// Gene information to keep in memory (for `/genes/search`).
    pub gene_names: Vec<GeneNames>,
    /// Mapping from allowed gene name string to index in `gene_names`.
    pub name_to_hgnc_idx: HashMap<String, usize>,
}

/// Genome-release specific annotation for each database.
pub type ReleaseAnnos = enum_map::EnumMap<
    AnnoDb,
    Option<WithVersionSpec<rocksdb::DBWithThreadMode<rocksdb::MultiThreaded>>>,
>;

/// Database information
#[derive(serde::Serialize, Debug, Clone, Default)]
pub struct DbInfo {
    /// Identifier of the database.
    pub name: AnnoDb,
    /// Version of the database.
    pub db_version: Option<String>,
    /// Version of the builder code.
    pub builder_version: String,
}

/// Fetch database information from the given RocksDB.
fn fetch_db_info(
    db: &rocksdb::DBWithThreadMode<rocksdb::MultiThreaded>,
    name: AnnoDb,
) -> Result<(GenomeRelease, DbInfo), anyhow::Error> {
    let genome_release: GenomeRelease = rocksdb_utils_lookup::fetch_meta(db, "genome-release")?
        .ok_or(anyhow::anyhow!("meta:genome-release not found in data"))?
        .as_str()
        .parse()?;
    let db_version = name
        .db_version_meta()
        .map(|db_version_meta| {
            rocksdb_utils_lookup::fetch_meta(db, db_version_meta)?.ok_or(anyhow::anyhow!(
                "meta:{} not found in database",
                db_version_meta
            ))
        })
        .transpose()?;
    let builder_version =
        rocksdb_utils_lookup::fetch_meta(db, "annonars-version")?.ok_or(anyhow::anyhow!(
            "meta:annonars-version not found in database {}",
            db.path().display()
        ))?;
    let db_info = DbInfo {
        name,
        db_version,
        builder_version,
    };
    Ok((genome_release, db_info))
}

/// Generic type to store a database together with version specification.
#[derive(Debug)]
pub struct WithVersionSpec<T: std::fmt::Debug> {
    /// The actual data.
    pub data: T,
    /// Version specification.
    pub version_spec: Option<versions::schema::VersionSpec>,
}

impl<T> WithVersionSpec<T>
where
    T: std::fmt::Debug,
{
    /// Construct with the given data and path to specification YAML file.
    pub fn from_data_and_path<P>(data: T, path: &Option<P>) -> Result<Self, anyhow::Error>
    where
        P: AsRef<Path>,
    {
        let version_spec: Option<versions::schema::VersionSpec> = path
            .as_ref()
            .map(versions::schema::VersionSpec::from_path)
            .transpose()?;
        Ok(Self { data, version_spec })
    }
}

/// Data for the web server.
#[derive(Debug, Default)]
pub struct WebServerData {
    /// Gene information database.
    pub genes: Option<WithVersionSpec<GeneInfoDb>>,
    /// Release-specific annotations for each `GenomeRelease`.
    pub annos: enum_map::EnumMap<GenomeRelease, ReleaseAnnos>,
    /// Release-specific ClinVar SV interval tree indexed databased.
    pub clinvar_svs: enum_map::EnumMap<GenomeRelease, Option<ClinvarsvIntervalTrees>>,
    /// Version information for each database.
    pub db_infos: enum_map::EnumMap<GenomeRelease, enum_map::EnumMap<AnnoDb, Option<DbInfo>>>,
}

/// Command line arguments for `server rest` sub command.
///
/// Each path can be given more than one time to support multiple releases.  When the server
/// is started, it needs to be given a file for each database with each release.
#[derive(Parser, Debug, Clone)]
#[command(author, version, about = "Run annonars REST API", long_about = None)]
pub struct Args {
    /// Path to genes database.
    #[arg(long)]
    pub path_genes: Option<String>,
    /// ClinVar per-gene database(s), one for each release.
    #[arg(long)]
    pub path_clinvar_genes: Option<String>,
    /// ClinVar database(s), one for each release.
    #[arg(long)]
    pub path_clinvar: Vec<String>,
    /// ClinVar SV database(s), one for each release.
    #[arg(long)]
    pub path_clinvar_sv: Vec<String>,
    /// CADD database(s), one for each release.
    #[arg(long)]
    pub path_cadd: Vec<String>,
    /// dbSNP database(s), one for each release.
    #[arg(long)]
    pub path_dbsnp: Vec<String>,
    /// dbNSFP database(s), one for each release.
    #[arg(long)]
    pub path_dbnsfp: Vec<String>,
    /// PdbscSNV database(s), one for each release.
    #[arg(long)]
    pub path_dbscsnv: Vec<String>,
    /// gnomAD mtDNA database(s), one for each release.
    #[arg(long)]
    pub path_gnomad_mtdna: Vec<String>,
    /// gnomAD-exomes database(s), one for each release.
    #[arg(long)]
    pub path_gnomad_exomes: Vec<String>,
    /// gnomAD-genomes database(s), one for each release.
    #[arg(long)]
    pub path_gnomad_genomes: Vec<String>,
    /// HelixMtDB database(s), one for each release.
    #[arg(long)]
    pub path_helixmtdb: Vec<String>,
    /// UCSC conservation database(s), one for each release.
    #[arg(long)]
    pub path_ucsc_conservation: Vec<String>,

    /// IP to listen on.
    #[arg(long, default_value = "127.0.0.1")]
    pub listen_host: String,
    /// Port to listen on.
    #[arg(long, default_value_t = 8081)]
    pub listen_port: u16,
}

/// Open a RocksDB database.
///
/// # Arguments
///
/// * `path` - Path to the database.
/// * `cf_name` - Name of the column family to open (besides the mandatory `meta` column family).
fn open_db(
    path: &str,
    cf_name: &str,
) -> Result<rocksdb::DBWithThreadMode<rocksdb::MultiThreaded>, anyhow::Error> {
    tracing::info!("Opening database {}...", path);
    let before_open = Instant::now();
    let res = rocksdb::DB::open_cf_for_read_only(
        &rocksdb::Options::default(),
        common::readlink_f(path)?,
        ["meta", cf_name],
        true,
    )
    .map_err(|e| anyhow::anyhow!("problem opening database: {}", e));
    tracing::info!("...done opening database in {:?}", before_open.elapsed());
    res
}

/// Obtain gene names from the genes RocksDB.
fn extract_gene_names(
    genes_db: &rocksdb::DBWithThreadMode<rocksdb::MultiThreaded>,
) -> Result<Vec<GeneNames>, anyhow::Error> {
    let mut result = Vec::new();

    let cf_read = genes_db.cf_handle("genes").unwrap();
    let mut iter = genes_db.raw_iterator_cf(&cf_read);
    iter.seek(b"");
    while iter.valid() {
        if let Some(iter_value) = iter.value() {
            let record = genes::base::Record::decode(std::io::Cursor::new(iter_value))?;
            // Useful snippet to ensure that all gene records can be converted into serializeable ones.
            // if !genes_info::response::GenesGeneInfoRecord::try_from(record.clone()).is_ok() {
            //     tracing::warn!("Skipping record: {:?}", record.clone().hgnc.unwrap().hgnc_id);
            // }
            let genes::base::Record { hgnc, .. } = record;
            if let Some(hgnc) = hgnc {
                let genes::base::HgncRecord {
                    hgnc_id,
                    symbol,
                    name,
                    alias_symbol,
                    alias_name,
                    ensembl_gene_id,
                    entrez_id,
                    ..
                } = hgnc;
                result.push(GeneNames {
                    hgnc_id,
                    symbol,
                    name,
                    alias_symbol,
                    alias_name,
                    ensembl_gene_id,
                    ncbi_gene_id: entrez_id,
                })
            }
        }
        iter.next();
    }

    Ok(result)
}

/// Main entry point for `server rest` sub command.
pub fn run(args_common: &common::cli::Args, args: &Args) -> Result<(), anyhow::Error> {
    tracing::info!("args_common = {:?}", &args_common);
    tracing::info!("args = {:?}", &args);

    if let Some(log::Level::Trace | log::Level::Debug) = args_common.verbose.log_level() {
        std::env::set_var("RUST_LOG", "debug");
        env_logger::init_from_env(env_logger::Env::new().default_filter_or("info"));
    }

    tracing::info!("Opening databases...");
    let mut data = WebServerData::default();
    let before_opening = Instant::now();

    if let Some(path_genes) = args.path_genes.as_ref() {
        tracing::info!("Opening genes database {}...", path_genes);
        let before_open = Instant::now();
        let db = open_db(path_genes, "genes")?;
        tracing::info!(
            "...done opening genes database in {:?}",
            before_open.elapsed()
        );

        let db_clinvar = if let Some(path_clinvar_genes) = args.path_clinvar_genes.as_ref() {
            tracing::info!("Opening ClinVar genes database {}...", path_clinvar_genes);
            let before_open = Instant::now();
            let clinvar_db = open_db(path_clinvar_genes, "clinvar-genes")?;
            tracing::info!(
                "...done opening ClinVar genes database in {:?}",
                before_open.elapsed()
            );
            Some(clinvar_db)
        } else {
            None
        };

        tracing::info!("Building gene names...");
        let before_open = Instant::now();
        let gene_names = extract_gene_names(&db)?;
        let name_to_hgnc_idx = {
            let mut result = HashMap::new();
            for (idx, gene_name) in gene_names.iter().enumerate() {
                result.insert(gene_name.hgnc_id.clone(), idx);
                if let Some(ensembl_gene_id) = gene_name.ensembl_gene_id.as_ref() {
                    result.insert(ensembl_gene_id.clone(), idx);
                }
                if let Some(ncbi_gene_id) = gene_name.ncbi_gene_id.as_ref() {
                    result.insert(ncbi_gene_id.clone(), idx);
                }
                result.insert(gene_name.symbol.clone(), idx);
            }
            result
        };
        tracing::info!("...done building genes names {:?}", before_open.elapsed());
        let gene_info_db = GeneInfoDb {
            db,
            db_clinvar,
            gene_names,
            name_to_hgnc_idx,
        };
        let path_buf = PathBuf::from_str(path_genes)?
            .parent()
            .ok_or_else(|| anyhow::anyhow!("cannot get parent directory of path {}", path_genes))?
            .join("spec.yaml");
        let path_buf = path_buf.exists().then_some(path_buf);
        data.genes = Some(
            WithVersionSpec::from_data_and_path(gene_info_db, &path_buf).map_err(|e| {
                anyhow::anyhow!(
                    "problem loading gene info spec from {}: {}",
                    if let Some(path_buf) = path_buf.as_ref() {
                        format!("{}", path_buf.display())
                    } else {
                        "None".to_string()
                    },
                    e
                )
            })?,
        );
    }

    tracing::info!("Opening ClinVar SV databases...");
    let before_clinvar_sv = Instant::now();
    for path_clinvar_sv in &args.path_clinvar_sv {
        tracing::info!("  - {}", path_clinvar_sv);
        let (clinvar_sv_db, clinvar_sv_meta) = clinvarsv_query::open_rocksdb(
            path_clinvar_sv,
            "clinvar_sv",
            "meta",
            "clinvar_sv_by_rcv",
        )
        .map_err(|e| anyhow::anyhow!("problem opening RocksDB database: {}", e))?;
        let genome_release: GenomeRelease = clinvar_sv_meta.genome_release.parse()?;
        tracing::info!("    => {}", genome_release);
        let clinvar_sv_interval_trees =
            ClinvarsvIntervalTrees::with_db(clinvar_sv_db, "clinvar_sv", clinvar_sv_meta)
                .map_err(|e| anyhow::anyhow!("problem building interval trees: {}", e))?;
        data.clinvar_svs[genome_release] = Some(clinvar_sv_interval_trees);
    }
    tracing::info!(
        "...done opening ClinVar SV databases in {:?}",
        before_clinvar_sv.elapsed()
    );

    // Argument lists from the command line with the corresponding database enum value.
    let paths_db_pairs = [
        (&args.path_clinvar, AnnoDb::Clinvar),
        (&args.path_cadd, AnnoDb::Cadd),
        (&args.path_dbnsfp, AnnoDb::Dbnsfp),
        (&args.path_dbsnp, AnnoDb::Dbsnp),
        (&args.path_dbscsnv, AnnoDb::Dbscsnv),
        (&args.path_gnomad_mtdna, AnnoDb::GnomadMtdna),
        (&args.path_gnomad_exomes, AnnoDb::GnomadExomes),
        (&args.path_gnomad_genomes, AnnoDb::GnomadGenomes),
        (&args.path_helixmtdb, AnnoDb::Helixmtdb),
        (&args.path_ucsc_conservation, AnnoDb::UcscConservation),
    ];
    // "Unpack" the list of paths to single paths.
    let path_db_pairs = paths_db_pairs
        .iter()
        .map(|(paths, anno_db)| {
            paths
                .iter()
                .map(|path| (path.clone(), *anno_db))
                .collect::<Vec<_>>()
        })
        .collect::<Vec<_>>()
        .into_iter()
        .flatten()
        .collect::<Vec<_>>();
    // Open the corresponding databases in parallel and extract database infos.  Store the
    // resulting database infos in `data`.
    path_db_pairs
        .par_iter()
        .progress_with(crate::common::cli::progress_bar(path_db_pairs.len()))
        .map(|(path, anno_db)| -> Result<_, anyhow::Error> {
            let db = open_db(path, anno_db.cf_name())?;
            let (genome_release, db_info) = fetch_db_info(&db, *anno_db)?;

            Ok((path, db_info, genome_release, db))
        })
        .collect::<Result<Vec<_>, _>>()?
        .into_iter()
        .try_for_each(
            |(path_rocksdb, db_info, genome_release, db)| -> Result<(), anyhow::Error> {
                let spec_path = PathBuf::from_str(path_rocksdb)?
                    .parent()
                    .ok_or_else(|| {
                        anyhow::anyhow!("cannot get parent directory of path {}", path_rocksdb)
                    })?
                    .join("spec.yaml");
                let spec_path = spec_path.exists().then_some(spec_path);
                let name = db_info.name;
                data.db_infos[genome_release][name] = Some(db_info);
                data.annos[genome_release][name] = Some(
                    WithVersionSpec::from_data_and_path(db, &spec_path).map_err(|e| {
                        anyhow::anyhow!(
                            "problem loading gene info spec from {}: {}",
                            if let Some(spec_path) = spec_path.as_ref() {
                                format!("{}", spec_path.display())
                            } else {
                                "None".to_string()
                            },
                            e
                        )
                    })?,
                );

                Ok(())
            },
        )?;
    tracing::info!(
        "...done opening databases in {:?}",
        before_opening.elapsed()
    );

    tracing::info!(
        "Launching server main on http://{}:{} ...",
        args.listen_host.as_str(),
        args.listen_port
    );
    tracing::info!(
        "  try: http://{}:{}/genes/search?q=BRCA",
        args.listen_host.as_str(),
        args.listen_port
    );
    tracing::info!(
        "  try: http://{}:{}/genes/search?q=BRCA&fields=hgnc_id,ensembl_gene_id,ncbi_gene_id,symbol",
        args.listen_host.as_str(),
        args.listen_port
    );
    tracing::info!(
        "  try: http://{}:{}/genes/lookup?q=BRCA,BRCA1,HGNC:1100",
        args.listen_host.as_str(),
        args.listen_port
    );
    tracing::info!(
        "  try: http://{}:{}/genes/info?hgnc_id=HGNC:12403",
        args.listen_host.as_str(),
        args.listen_port
    );
    tracing::info!(
        "  try: http://{}:{}/genes/clinvar?hgnc_id=HGNC:12403",
        args.listen_host.as_str(),
        args.listen_port
    );
    tracing::info!(
        "  try: http://{}:{}/annos/db-info?genome_release=grch37",
        args.listen_host.as_str(),
        args.listen_port
    );
    tracing::info!(
        "  try: http://{}:{}/annos/variant?genome_release=grch37&chromosome=1&pos=55505599&reference=C&alternative=G",
        args.listen_host.as_str(),
        args.listen_port
    );
    tracing::info!(
        "  try: http://{}:{}/annos/variant?genome_release=grch37&chromosome=1&pos=10001&reference=T&alternative=A",
        args.listen_host.as_str(),
        args.listen_port
    );
    tracing::info!(
        "  try: http://{}:{}/annos/range?genome_release=grch37&chromosome=1&start=1&stop=55516888",
        args.listen_host.as_str(),
        args.listen_port
    );
    main(args, actix_web::web::Data::new(data))?;

    tracing::info!("All done. Have a nice day!");
    Ok(())
}