mehari 0.29.6

Variant effect prediction all in Rust
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[![DOI](https://zenodo.org/badge/609124150.svg)](https://zenodo.org/badge/latestdoi/609124150)

# Mehari

<img align="right" width="200" height="200" src="misc/camel.jpeg">

Mehari is a software package for annotating VCF files with variant effect/consequence.
The program uses [hgvs-rs](https://crates.io/crates/hgvs) for projecting genomic variants to transcripts and proteins and thus has high prediction quality.

Other popular tools offering variant effect/consequence prediction include:

- [SnpEff](http://pcingola.github.io/SnpEff/)
- [VEP (Variant Effect Predictor)](https://www.ensembl.org/info/docs/tools/vep/index.html)

Mehari offers predictions that aim to mirror VariantValidator, the gold standard for HGVS variant descriptions.
Further, it is written in the Rust programming language and can be used as a library for users' Rust software.

## Supported Sequence Variant Frequency Databases

Mehari can import public sequence variant frequency databases.
The supported set slightly differs between import for GRCh37 and GRCh38.

**GRCh37**

- gnomAD r2.1.1 Exomes [`gnomad.exomes.r2.1.1.sites.vcf.bgz`](https://gnomad.broadinstitute.org/downloads#v2)
- gnomAD r2.1.1 Genomes [`gnomad.genomes.r2.1.1.sites.vcf.bgz`](https://gnomad.broadinstitute.org/downloads#v2)
- gnomAD v3.1 mtDNA [`gnomad.genomes.v3.1.sites.chrM.vcf.bgz`](https://gnomad.broadinstitute.org/downloads#v3-mitochondrial-dna)
- HelixMTdb `HelixMTdb_20200327.tsv`

**GRCh38**

- gnomAD r2.1.1 lift-over Exomes [`gnomad.exomes.r2.1.1.sites.liftover_grch38.vcf.bgz`](https://gnomad.broadinstitute.org/downloads#v2)
- gnomAD v3.1 Genomes [`gnomad.genomes.v3.1.2.sites.$CHROM.vcf.bgz`](https://gnomad.broadinstitute.org/downloads#v3)
- gnomAD v3.1 mtDNA [`gnomad.genomes.v3.1.sites.chrM.vcf.bgz`](https://gnomad.broadinstitute.org/downloads#v3-mitochondrial-dna)
- HelixMTdb `HelixMTdb_20200327.tsv`

## Building from scratch
To reduce compile times, we recommend using a pre-built version of `rocksdb`, either from the system package manager or e.g. via `conda`:

```bash
# Ubuntu
sudo apt-get install librocksdb-dev

# Conda
conda install -c conda-forge rocksdb
```

In either case, either add
```toml
[env]
ROCKSDB_LIB_DIR = "/usr/lib/" # in case of the system package manager, adjust the path accordingly for conda
SNAPPY_LIB_DIR = "/usr/lib/"  # same as above
```
to `.cargo/config.toml` or set the environment variables `ROCKSDB_LIB_DIR` and `SNAPPY_LIB_DIR` to the appropriate paths:

```bash
export ROCKSDB_LIB_DIR=/usr/lib/
export SNAPPY_LIB_DIR=/usr/lib/
```

By default, the environment variables are defined in the `.cargo/config.toml` as described above, i.e. may need adjustments if not using the system package manager.

To build the project, run:
```bash
cargo build --release
```

To install the project locally, run:
```bash
cargo install --path .
```
## Internal Notes

```
rm -rf /tmp/out ; cargo run -- db create seqvar-freqs --path-output-db /tmp/out --genome-release grch38 --path-helix-mtdb ~/Downloads/HelixMTdb_20200327.vcf.gz --path-gnomad-mtdna ~/Downloads/gnomad.genomes.v3.1.sites.chrM.vcf.bgz --path-gnomad-exomes-xy tests/data/db/create/seqvar_freqs/xy-38/gnomad.exomes.r2.1.1.sites.chrX.vcf --path-gnomad-exomes-xy tests/data/db/create/seqvar_freqs/xy-38/gnomad.exomes.r2.1.1.sites.chrY.vcf --path-gnomad-genomes-xy tests/data/db/create/seqvar_freqs/xy-38/gnomad.genomes.r3.1.1.sites.chrX.vcf --path-gnomad-genomes-xy tests/data/db/create/seqvar_freqs/xy-38/gnomad.genomes.r3.1.1.sites.chrY.vcf --path-gnomad-exomes-auto tests/data/db/create/seqvar_freqs/12-38/gnomad.exomes.r2.1.1.sites.chr1.vcf  --path-gnomad-exomes-auto tests/data/db/create/seqvar_freqs/12-38/gnomad.exomes.r2.1.1.sites.chr2.vcf --path-gnomad-genomes-auto tests/data/db/create/seqvar_freqs/12-38/gnomad.genomes.r3.1.1.sites.chr1.vcf --path-gnomad-genomes-auto tests/data/db/create/seqvar_freqs/12-38/gnomad.genomes.r3.1.1.sites.chr2.vcf

rm -rf /tmp/out ; cargo run -- db create seqvar-freqs --path-output-db /tmp/out --genome-release grch37 --path-gnomad-mtdna ~/Downloads/gnomad.genomes.v3.1.sites.chrM.vcf.bgz --path-gnomad-exomes-xy tests/data/db/create/seqvar_freqs/xy-37/gnomad.exomes.r2.1.1.sites.chrX.vcf --path-gnomad-exomes-xy tests/data/db/create/seqvar_freqs/xy-37/gnomad.exomes.r2.1.1.sites.chrY.vcf --path-gnomad-genomes-xy tests/data/db/create/seqvar_freqs/xy-37/gnomad.genomes.r2.1.1.sites.chrX.vcf --path-gnomad-exomes-auto tests/data/db/create/seqvar_freqs/12-37/gnomad.exomes.r2.1.1.sites.chr1.vcf  --path-gnomad-exomes-auto tests/data/db/create/seqvar_freqs/12-37/gnomad.exomes.r2.1.1.sites.chr2.vcf --path-gnomad-genomes-auto tests/data/db/create/seqvar_freqs/12-37/gnomad.genomes.r2.1.1.sites.chr1.vcf --path-gnomad-genomes-auto tests/data/db/create/seqvar_freqs/12-37/gnomad.genomes.r2.1.1.sites.chr2
```

```
prepare()
{
    in=$1
    out=$2

    zcat $in \
    | head -n 5000 \
    | grep ^# \
    > $out

    zcat $in \
    | grep -v ^# \
    | head -n 3 \
    >> $out
}

base=/data/sshfs/data/gpfs-1/groups/cubi/work/projects/2021-07-20_varfish-db-downloader-holtgrewe/varfish-db-downloader/

mkdir -p tests/data/db/create/seqvar_freqs/{12,xy}-{37,38}

## 37 exomes

prepare \
    $base/GRCh37/gnomAD_exomes/r2.1.1/download/gnomad.exomes.r2.1.1.sites.chr1.vcf.bgz \
    tests/data/db/create/seqvar_freqs/12-37/gnomad.exomes.r2.1.1.sites.chr1.vcf
prepare \
    $base/GRCh37/gnomAD_exomes/r2.1.1/download/gnomad.exomes.r2.1.1.sites.chr2.vcf.bgz \
    tests/data/db/create/seqvar_freqs/12-37/gnomad.exomes.r2.1.1.sites.chr2.vcf
prepare \
    $base/GRCh37/gnomAD_exomes/r2.1.1/download/gnomad.exomes.r2.1.1.sites.chrX.vcf.bgz \
    tests/data/db/create/seqvar_freqs/xy-37/gnomad.exomes.r2.1.1.sites.chrX.vcf
prepare \
    $base/GRCh37/gnomAD_exomes/r2.1.1/download/gnomad.exomes.r2.1.1.sites.chrY.vcf.bgz \
    tests/data/db/create/seqvar_freqs/xy-37/gnomad.exomes.r2.1.1.sites.chrY.vcf

## 37 genomes

prepare \
    $base/GRCh37/gnomAD_genomes/r2.1.1/download/gnomad.genomes.r2.1.1.sites.chr1.vcf.bgz \
    tests/data/db/create/seqvar_freqs/12-37/gnomad.genomes.r2.1.1.sites.chr1.vcf
prepare \
    $base/GRCh37/gnomAD_genomes/r2.1.1/download/gnomad.genomes.r2.1.1.sites.chr2.vcf.bgz \
    tests/data/db/create/seqvar_freqs/12-37/gnomad.genomes.r2.1.1.sites.chr2.vcf
prepare \
    $base/GRCh37/gnomAD_genomes/r2.1.1/download/gnomad.genomes.r2.1.1.sites.chrX.vcf.bgz \
    tests/data/db/create/seqvar_freqs/xy-37/gnomad.genomes.r2.1.1.sites.chrX.vcf

## 38 exomes

prepare \
    $base/GRCh38/gnomAD_exomes/r2.1.1/download/gnomad.exomes.r2.1.1.sites.chr1.vcf.bgz \
    tests/data/db/create/seqvar_freqs/12-38/gnomad.exomes.r2.1.1.sites.chr1.vcf
prepare \
    $base/GRCh38/gnomAD_exomes/r2.1.1/download/gnomad.exomes.r2.1.1.sites.chr2.vcf.bgz \
    tests/data/db/create/seqvar_freqs/12-38/gnomad.exomes.r2.1.1.sites.chr2.vcf
prepare \
    $base/GRCh38/gnomAD_exomes/r2.1.1/download/gnomad.exomes.r2.1.1.sites.chrX.vcf.bgz \
    tests/data/db/create/seqvar_freqs/xy-38/gnomad.exomes.r2.1.1.sites.chrX.vcf
prepare \
    $base/GRCh38/gnomAD_exomes/r2.1.1/download/gnomad.exomes.r2.1.1.sites.chrY.vcf.bgz \
    tests/data/db/create/seqvar_freqs/xy-38/gnomad.exomes.r2.1.1.sites.chrY.vcf

## 38 genomes

prepare \
    $base/GRCh38/gnomAD_genomes/r3.1.1/download/gnomad.genomes.r3.1.1.sites.chr1.vcf.bgz \
    tests/data/db/create/seqvar_freqs/12-38/gnomad.genomes.r3.1.1.sites.chr1.vcf
prepare \
    $base/GRCh38/gnomAD_genomes/r3.1.1/download/gnomad.genomes.r3.1.1.sites.chr2.vcf.bgz \
    tests/data/db/create/seqvar_freqs/12-38/gnomad.genomes.r3.1.1.sites.chr2.vcf
prepare \
    $base/GRCh38/gnomAD_genomes/r3.1.1/download/gnomad.genomes.r3.1.1.sites.chrX.vcf.bgz \
    tests/data/db/create/seqvar_freqs/xy-38/gnomad.genomes.r3.1.1.sites.chrX.vcf
prepare \
    $base/GRCh38/gnomAD_genomes/r3.1.1/download/gnomad.genomes.r3.1.1.sites.chrY.vcf.bgz \
    tests/data/db/create/seqvar_freqs/xy-38/gnomad.genomes.r3.1.1.sites.chrY.vcf
```

Building tx database


```
cd hgvs-rs-data

seqrepo --root-directory seqrepo-data/master init

mkdir -p mirror/ftp.ncbi.nih.gov/refseq/H_sapiens/mRNA_Prot
cd !$
wget https://ftp.ncbi.nih.gov/refseq/H_sapiens/mRNA_Prot/human.files.installed
parallel -j 16 'wget https://ftp.ncbi.nih.gov/refseq/H_sapiens/mRNA_Prot/{}' ::: $(cut -f 2 human.files.installed | grep fna)
cd -

mkdir -p mirror/ftp.ensembl.org/pub/release-108/fasta/homo_sapiens/cdna
cd !$
wget https://ftp.ensembl.org/pub/release-108/fasta/homo_sapiens/cdna/Homo_sapiens.GRCh38.cdna.all.fa.gz
cd -
mkdir -p mirror/ftp.ensembl.org/pub/release-108/fasta/homo_sapiens/ncrna
cd !$
wget https://ftp.ensembl.org/pub/release-109/fasta/homo_sapiens/ncrna/Homo_sapiens.GRCh38.ncrna.fa.gz
cd -
mkdir -p mirror/ftp.ensembl.org/pub/grch37/release-108/fasta/homo_sapiens/cdna/
cd !$
wget https://ftp.ensembl.org/pub/grch37/release-108/fasta/homo_sapiens/cdna/Homo_sapiens.GRCh37.cdna.all.fa.gz
cd -
mkdir -p mirror/ftp.ensembl.org/pub/grch37/release-108/fasta/homo_sapiens/ncrna/
cd !$
wget https://ftp.ensembl.org/pub/grch37/release-108/fasta/homo_sapiens/ncrna/Homo_sapiens.GRCh37.ncrna.fa.gz
cd -

seqrepo --root-directory seqrepo-data/master load -n NCBI $(find mirror/ftp.ncbi.nih.gov -name '*.fna.gz' | sort)
seqrepo --root-directory seqrepo-data/master load -n ENSEMBL $(find mirror/ftp.ensembl.org -name '*.fa.gz' | sort)

cd ../mehari

cargo run --release -- \
    -v \
    db create txs \
        --path-out /tmp/txs-out.bin.zst \
        --path-lable-tsv PATH_TO_MANE_LABEL.tsv \
        --path-cdot-json ../cdot-0.2.21.ensembl.grch37_grch38.json.gz \
        --path-cdot-json ../cdot-0.2.21.refseq.grch37_grch38.json.gz \
        --path-seqrepo-instance ../hgvs-rs-data/seqrepo-data/master/master
```

## Development Setup

You will need a recent version of protoc, e.g.:

```
# bash utils/install-protoc.sh
# export PATH=$PATH:$HOME/.local/share/protoc/bin
```