Fast fuzzy search over biological sequences (amino-acid or nucleotide), as a C++ core with a minimal Python binding. Build an immutable index once, then search single queries or massive batches in parallel.

Two search engines over one trie:

• seqtm — branch-and-bound enumeration. Exact per-type edit caps (max_subs / max_ins / max_dels) and a fast Hamming-only path. Best for small edit distances (UMI collapse, error correction, CDR3/epitope matching).
• seqtrie — full-width edit-distance DP carried down the trie. Honours the max_penalty score budget only; it ignores the per-type edit caps. Use it when the budget is the whole specification.

engine="auto" always picks seqtm, because it is the only engine that enforces the caps you asked for. Results are payload-agnostic: (ref_id, score, n_subs, n_ins, n_dels). Downstream libraries map ref_id back to their own payloads (V gene, MHC, counts) and filter.

Beyond search, seqtree ships:

• Substitution matrices — built-in identity, BLOSUM45, BLOSUM62, BLOSUM80, PAM250, PAM100, and structural — a Miyazawa–Jernigan interaction-strength matrix: each residue's strength q(a)=mean_b e(a,b) is read off the MJ contact potential, so substitutions between residues of like interaction strength are cheap. It separates strong (hydrophobic F W C L Y M I V) from weak (polar/charged S Q D E K) interactors — the strong/weak-interactor axis of TCR-recognition models (Košmrlj et al., PNAS 2008; MJ contact energies from Miyazawa & Jernigan, J Mol Biol 1996) — letting dissimilar-but-chemically-equivalent loops align. Plus custom matrices via SubstitutionMatrix.from_similarity (Gram penalty s(a,a)+s(b,b)−2·s(a,b)).
• E-values / significance — calibrate hit counts against a background control repertoire (load_control + evalues), the TCRNET approach on a finite-sample footing. See the E-value guide.
• Calibrated cutoffs — threshold_for_evalue inverts the E-value into the score cutoff that achieves it, per query. A fixed cutoff is not a calibrated one: a control repertoire is dense near germline and sparse among rare junctions, so the same threshold buys a common query far more chance neighbours than a rare one.
• Gap-block alignment — gapblock restricts alignment to one contiguous indel, which is the right model for a V(D)J junction and, measured against unrestricted affine alignment, is exactly optimal on 98.8% of genuinely related pairs at a calibrated gap_open. A gap prior (central_prior, profile_prior, frame_prior) chooses where the block goes — a sequence score alone cannot. score_matrix scores a whole query set against a whole reference set in one GIL-released C++ call (532 M pairs/s on 16 cores; numpy.asarray wraps the result with no copy), the shape a prototype-distance embedding needs.
• Pairwise alignment without BioPython — seqtree.pairwise is Needleman–Wunsch (mode="global") and Smith–Waterman (mode="local") with affine or linear gaps, on the raw log-odds scale. It is a drop-in for Bio.Align.PairwiseAligner — verified against it as an oracle across three matrices, ten gap/mode settings and sixty sequence shapes with zero disagreements — and 65–87× faster, since there is no Python in the per-pair loop. dist_matrix gives d = s(a,a) + s(b,b) − 2·s(a,b) directly. BioPython is a test-only dependency; seqtree still needs nothing at runtime.
• Plain edit distances — seqtree.distance is unweighted hamming and levenshtein (unit costs, no matrix, no alphabet) for when you just need a number, not a scored alignment. hamming_matrix / levenshtein_matrix score a whole set against a whole set in one GIL-released C++ call (numpy.asarray wraps the result with no copy) — no python-Levenshtein or rapidfuzz dependency needed. Hamming requires equal lengths (it raises otherwise); comparison is case-sensitive.
• Island profiles — IslandProfile.fit builds a position weight matrix over a set of frame-aligned junctions (an island) and scores a query column by column against the island consensus, as a non-negative penalty that flows through threshold_for_evalue unchanged. At a repertoire-scale cutoff it recovers 48.5% of held-out members against 37.6% for min-over-members; at a loose cutoff the two are indistinguishable, so it earns its keep only where the cutoff is strict.

pip install seqtree       # prebuilt wheels for CPython 3.10–3.13

Prebuilt wheels cover Linux x86-64, macOS arm64 (Apple Silicon), and Windows x86-64. There are no Intel/x86-64 macOS wheels — Intel Macs build from source (see below), which just needs a C++17 compiler and CMake (pulled in automatically by the build).

Needs uv (brew install uv); setup.sh uses it for the venv and the editable install.

bash setup.sh            # uv-managed .venv + editable install
bash setup.sh --tests    # + pytest
bash setup.sh --bench     # + benchmark deps (huggingface_hub, psutil)

import seqtree

idx = seqtree.Index.build(["CASSLAPGATNEKLFF", "CASSLELGATNEKLFF"], alphabet="aa")

p = seqtree.SearchParams(max_subs=2, engine="seqtm")
for hit in idx.search("CASSLAPGATNEKLFF", p):
    print(hit.ref_id, hit.score, hit.n_subs)

# parallel batch (releases the GIL)
results = idx.search_batch(queries, p, threads=0)   # 0 = all cores

# matrix-weighted budget
pm = seqtree.SearchParams(matrix="BLOSUM62", max_penalty=12, engine="seqtrie")
top = idx.search_top("CASSLAPGATNEKLFF", pm, k=5)

# alignment on demand
aln = idx.align(0, "CASSLELGATNEKLFF", p)
print(aln.aligned_query, aln.aligned_ref, aln.ops)

# batch-vs-batch (auto-indexes the larger set)
pairs = seqtree.pairwise_batch(query_set, db_set, p, alphabet="aa")

# E-values against a background control repertoire (TCRNET-style significance)
control = seqtree.load_control("human_trb_aa", size=1_000_000)
target = seqtree.Index.build(vdjdb_cdr3s, alphabet="aa")
for q, r in zip(queries, seqtree.evalues(target, control, queries, p)):
    if r["p_enrichment"] < 1e-3:
        print(q, r["E"], r["n_target"], r["n_control"])

# ...and the cutoff that achieves a target E, per query (-1 = unreachable at this control size)
ceiling = seqtree.SearchParams(max_subs=14, max_penalty=50, matrix="BLOSUM62", engine="seqtm")
thetas = seqtree.threshold_for_evalue(target, control, queries, ceiling, e_target=0.05)

# one contiguous gap block, placed by a prior rather than by the score alone
from seqtree.gapblock import GapBlockIndex, central_prior, embed_in_frame

gbi = GapBlockIndex(cdr3s, "aa", d_max=2)
mat = seqtree.SubstitutionMatrix.blosum62()
for ref_id, score, block_len, block_pos in gbi.search(
        "CASSLGQAYEQYF", 40, mat, gap_open=2 * mat.scale(),
        gap_prior=central_prior(int(1.5 * mat.scale()))):
    ...

# a fixed frame column makes gap placement transitive -- and a column index, hence a PWM, possible
embed_in_frame("CASSGQAYEQYF", width=14, c=4)      # 'CASS--GQAYEQYF'

# a whole query set vs a whole reference set, in one GIL-released C++ call
from seqtree.gapblock import score_matrix, IslandProfile
sm = score_matrix(clonotypes, prototypes, mat, gap_open=2 * mat.scale(), threads=0)
import numpy as np
distances = np.asarray(sm)                          # (len(clonotypes), len(prototypes)) int32, zero-copy

# a position weight matrix over an island, still a non-negative penalty (feeds threshold_for_evalue)
profile = IslandProfile.fit(island_members)
profile.score("CASSLGQAYEQYF")                      # 0 on the consensus, > 0 for deviations

# ordinary pairwise alignment -- Needleman-Wunsch / Smith-Waterman, no BioPython
from seqtree.pairwise import align, score, dist_matrix
score("CASSLGQAYEQYF", "CASSPGQAYEQF", mat)                    # global, BLAST defaults (11/1)
score("WWWAAAWWW", "KKKAAAKKK", mat, mode="local")             # Smith-Waterman
score("AAA", "AAAAA", mat, gap_open=5, gap_extend=5)           # linear gaps: open == extend
aln = align("CASSLGQAYEQYF", "CASSPGQAYEQF", mat)              # + aligned strings and ops

d = np.asarray(dist_matrix(v_genes, v_genes, mat, threads=0))  # s(a,a)+s(b,b)-2s(a,b), zero diagonal

# plain edit distances -- unweighted Hamming / Levenshtein, no matrix, no dependency
from seqtree.distance import hamming, levenshtein, hamming_matrix, levenshtein_matrix
hamming("CASSLGQYF", "CASSPGQYF")                             # 1  (equal length only)
levenshtein("kitten", "sitting")                             # 3
h = np.asarray(hamming_matrix(umis, umis, threads=0))        # (len, len) int32, zero-copy

cmake -S . -B build -G Ninja -DSEQTREE_TESTS=ON
cmake --build build
ctest --test-dir build           # C++ unit tests
pytest tests/python              # Python tests

python bench/bench_gnuplot.py        # throughput / scaling / matrix / collisions → SVG (needs gnuplot)
python bench/bench.py                # recall vs ground truth (real VDJdb data)
python bench/bench_evalue.py         # true E-value benchmark (target vs background control)
python bench/bench_evalue_matrix.py  # significance across reference/control/query/scope grid
python bench/bench_epitope.py        # epitope detection-complexity (GIL vs NLV)
python bench/bench_gapblock.py       # the gap-freedom ladder: fixed centre → prior → flat → affine
python bench/bench_score_matrix.py   # dense batch gap-block throughput (µs/pair, M pairs/s, RSS)

Figures (throughput, scaling, matrix-scoring overhead, collisions, E-value matrix, epitope detection) and the full methodology are in the benchmarks docs. Set RUN_BENCHMARK=1 for the large tiers.

This repo follows git-flow:

• master — stable, release-ready; CI + docs deploy run here.
• dev — integration branch for day-to-day work.
• feature branches branch off dev and merge back via PR; releases merge dev → master.

Roadmap (affine gaps, position-specific matrices, succinct memory packing) lives in docs/roadmap.rst. Control-set E-values already ship — see the E-value guide.