SPO11

Summary

SPO11 (SPO11 initiator of meiotic double strand breaks, HGNC:11250) is a protein-coding gene on chromosome 20q13.31, encoding Meiotic recombination protein SPO11 (Q9Y5K1). Component of a topoisomerase 6 complex specifically required for meiotic recombination.

Meiotic recombination and chromosome segregation require the formation of double-strand breaks (DSBs) in paired chromosome homologs. During meiosis in yeast, a meiotic recombination protein is covalently-linked to the 5’ end of DSBs and is essential for the formation of DSBs. The protein encoded by this gene is similar in sequence and conserved features to the yeast meiotic recombination protein. The encoded protein belongs to the TOP6A protein family. Several transcript variants encoding different isoforms have been found for this gene, but the full-length nature of only two of them have been described.

Source: NCBI Gene 23626 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 43 total — 1 likely-pathogenic
• MANE Select transcript: NM_012444

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11250
Approved symbol	SPO11
Name	SPO11 initiator of meiotic double strand breaks
Location	20q13.31
Locus type	gene with protein product
Status	Approved
Aliases	CT35, SPATA43, TOPVIA, TOPOVIA
Ensembl gene	ENSG00000054796
Ensembl biotype	protein_coding
OMIM	605114
Entrez	23626

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 4 protein_coding, 1 nonsense_mediated_decay

ENST00000345868, ENST00000371260, ENST00000371263, ENST00000418127, ENST00000494972

RefSeq mRNA: 2 — MANE Select: NM_012444 NM_012444, NM_198265

CCDS: CCDS13456, CCDS13457

Canonical transcript exons

ENST00000371263 — 13 exons

Exon	Start	End
ENSE00000511006	57333188	57333276
ENSE00000662928	57331833	57331946
ENSE00000662934	57335798	57335907
ENSE00000845732	57333687	57333753
ENSE00000845733	57333987	57334095
ENSE00000845734	57334750	57334836
ENSE00000845735	57335419	57335455
ENSE00000845737	57338276	57338375
ENSE00000845739	57340102	57340178
ENSE00001431668	57329803	57329998
ENSE00003503100	57342729	57342840
ENSE00003784511	57338989	57339026
ENSE00003889039	57343341	57343993

Expression profiles

Bgee: expression breadth broad, 20 present calls, max score 92.48.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0075 / max 7.6684, expressed in 3 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
185465	0.0075	3

Top tissues by expression

272 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	92.48	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	87.99	gold quality
right testis	UBERON:0004534	74.54	gold quality
left testis	UBERON:0004533	72.93	gold quality
testis	UBERON:0000473	72.36	gold quality
secondary oocyte	CL:0000655	58.49	silver quality
adult organism	UBERON:0007023	53.00	gold quality
lower lobe of lung	UBERON:0008949	49.56	silver quality
Brodmann (1909) area 46	UBERON:0006483	49.30	gold quality
blood vessel layer	UBERON:0004797	49.29	gold quality
cervix squamous epithelium	UBERON:0006922	49.20	gold quality
hair follicle	UBERON:0002073	49.18	gold quality
olfactory bulb	UBERON:0002264	48.92	gold quality
quadriceps femoris	UBERON:0001377	48.90	gold quality
choroid plexus epithelium	UBERON:0003911	48.89	gold quality
myocardium	UBERON:0002349	48.87	gold quality
type B pancreatic cell	CL:0000169	48.83	gold quality
oviduct epithelium	UBERON:0004804	48.73	gold quality
epithelial cell of pancreas	CL:0000083	48.56	gold quality
tibialis anterior	UBERON:0001385	48.55	silver quality
cardiac muscle of right atrium	UBERON:0003379	48.55	gold quality
CA1 field of hippocampus	UBERON:0003881	48.50	gold quality
vastus lateralis	UBERON:0001379	48.44	gold quality
left ventricle myocardium	UBERON:0006566	48.24	gold quality
orbitofrontal cortex	UBERON:0004167	48.20	gold quality
upper arm skin	UBERON:0004263	48.06	gold quality
cervix epithelium	UBERON:0004801	48.04	gold quality
tongue squamous epithelium	UBERON:0006919	47.92	gold quality
mucosa of urinary bladder	UBERON:0001259	47.80	gold quality
nasal cavity epithelium	UBERON:0005384	47.70	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.76

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

47 targeting SPO11, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-374A-5P	99.90	71.34	2923
HSA-MIR-374B-5P	99.90	69.98	2734
HSA-MIR-579-3P	99.86	71.66	3628
HSA-MIR-664B-3P	99.84	71.65	3590
HSA-MIR-1323	99.83	69.89	2471
HSA-MIR-2052	99.79	69.37	2031
HSA-MIR-6885-3P	99.75	70.36	3187
HSA-MIR-548O-3P	99.74	69.30	2228
HSA-MIR-518A-5P	99.70	69.01	2209
HSA-MIR-527	99.70	69.01	2209
HSA-MIR-379-3P	99.69	69.60	1524
HSA-MIR-411-3P	99.69	69.63	1524
HSA-MIR-548BA	99.69	69.14	1514
HSA-MIR-12123	99.52	71.79	2990
HSA-MIR-3128	99.50	67.85	1258
HSA-MIR-183-3P	99.41	69.41	1598

Literature-anchored findings (GeneRIF, showing 7)

• Mutations in the human SPO11 gene are not common causes of infertility in man (PMID:16169419)
• Data show that there is no association between SPO11 gene mutation and premature ovarian failure. (PMID:18166824)
• SPO11 might has an effect on premorbid functioning, which increase susceptibility for idiopathic male reproduction (PMID:21556891)
• Polymorphisms within the SPO11 gene are linked to the susceptibility of azoospermia and oligozoospermia male infertility. (PMID:25005169)
• Data suggest that the combined genotypes of glutathionine S-transferase GSTM1 (-/-), GSTT1 (+/+), GSTP1 (AA) and meiotic recombination protein SPO11 (CT) may be associated with idiopathic male infertility in ethnic Han Chinese. (PMID:26663067)
• SPO11 gene C631T polymorphism may contribute as a genetic factor susceptible to cause male infertility in Chinese. (PMID:28050928)
• Centromeres are dismantled by foundational meiotic proteins Spo11 and Rec8. (PMID:33658710)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	spo11	ENSDARG00000013837
mus_musculus	Spo11	ENSMUSG00000005883
rattus_norvegicus	Spo11	ENSRNOG00000006732
drosophila_melanogaster	mei-W68	FBGN0002716
caenorhabditis_elegans		WBGENE00004985

Protein

Protein identifiers

Meiotic recombination protein SPO11 — Q9Y5K1 (reviewed: Q9Y5K1)

Alternative names: Cancer/testis antigen 35

All UniProt accessions (4): Q9Y5K1, H0YCK9, Q5TCH6, Q5TCH7

UniProt curated annotations — full annotation on UniProt →

Function. Component of a topoisomerase 6 complex specifically required for meiotic recombination. Together with TOP6BL, mediates DNA cleavage that forms the double-strand breaks (DSB) that initiate meiotic recombination. The complex promotes relaxation of negative and positive supercoiled DNA and DNA decatenation through cleavage and ligation cycles. Essential for the phosphorylation of SMC3, HORMAD1 and HORMAD2.

Subunit / interactions. Heterotetramer of SPO11 and 2 TOP6BL chains. Interacts with TOP6BL.

Subcellular location. Nucleus.

Tissue specificity. Highly expressed in testis.

Similarity. Belongs to the TOP6A family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9Y5K1-1	1	yes
Q9Y5K1-2	2

RefSeq proteins (2): NP_036576, NP_937998 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002815	Spo11/TopoVI_A	Family
IPR004084	Meiosis_Spo11	Domain
IPR013048	Meiotic_Spo11	Family
IPR013049	Spo11/TopoVI_A_N	Domain
IPR034136	TOPRIM_Topo6A/Spo11	Domain
IPR036078	Spo11/TopoVI_A_sf	Homologous_superfamily
IPR036388	WH-like_DNA-bd_sf	Homologous_superfamily

Pfam: PF03533, PF04406, PF21180

UniProt features (10 total): sequence variant 4, binding site 2, chain 1, domain 1, active site 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y5K1-F1	91.12	0.80

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 138 (o-(5’-phospho-dna)-tyrosine intermediate)

Ligand- & substrate-binding residues (2): 224; 277

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-912446	Meiotic recombination
R-HSA-1474165	Reproduction
R-HSA-1500620	Meiosis
R-HSA-1640170	Cell Cycle

MSigDB gene sets: 187 (showing top): GOBP_MEIOTIC_CHROMOSOME_SEGREGATION, REACTOME_MEIOTIC_RECOMBINATION, GOBP_CHROMOSOME_ORGANIZATION, GOBP_CHROMOSOME_LOCALIZATION, GOBP_OOGENESIS, GOBP_MALE_GAMETE_GENERATION, KAUFFMANN_DNA_REPAIR_GENES, GOBP_SYNAPTONEMAL_COMPLEX_ORGANIZATION, TCF4_Q5, GOBP_OVARIAN_FOLLICLE_DEVELOPMENT, GOBP_ORGANELLE_FISSION, GOBP_REPRODUCTIVE_SYSTEM_DEVELOPMENT, GOBP_PROTEIN_LOCALIZATION_TO_CHROMOSOME, GOBP_DNA_DAMAGE_RESPONSE, GOBP_MALE_MEIOSIS_I

GO Biological Process (16): meiotic DNA double-strand break processing (GO:0000706), ovarian follicle development (GO:0001541), synaptonemal complex assembly (GO:0007130), reciprocal meiotic recombination (GO:0007131), male meiosis I (GO:0007141), spermatogenesis (GO:0007283), spermatid development (GO:0007286), female gamete generation (GO:0007292), protein localization to chromosome (GO:0034502), meiotic DNA double-strand break formation (GO:0042138), meiotic telomere clustering (GO:0045141), oogenesis (GO:0048477), double-strand break repair involved in meiotic recombination (GO:1990918), DNA metabolic process (GO:0006259), homologous chromosome pairing at meiosis (GO:0007129), meiotic cell cycle (GO:0051321)

GO Molecular Function (8): DNA binding (GO:0003677), DNA topoisomerase type II (double strand cut, ATP-hydrolyzing) activity (GO:0003918), ATP binding (GO:0005524), metal ion binding (GO:0046872), catalytic activity (GO:0003824), DNA topoisomerase activity (GO:0003916), protein binding (GO:0005515), isomerase activity (GO:0016853)

GO Cellular Component (4): nuclear chromosome (GO:0000228), chromosome, telomeric region (GO:0000781), nucleus (GO:0005634), chromosome (GO:0005694)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Meiosis	1
Reproduction	1
Cell Cycle	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
meiotic cell cycle process	3
chromosome organization involved in meiotic cell cycle	3
meiotic cell cycle	2
meiosis I	2
male gamete generation	2
germ cell development	2
DNA double-strand break processing	1
female gonad development	1
anatomical structure development	1
homologous chromosome pairing at meiosis	1
cellular component assembly	1
synaptonemal complex organization	1
reciprocal homologous recombination	1
male meiotic nuclear division	1
developmental process involved in reproduction	1
spermatid differentiation	1
gamete generation	1
protein localization to organelle	1
DNA metabolic process	1
meiosis I cell cycle process	1
telomere localization	1
chromosome localization to nuclear envelope involved in homologous chromosome segregation	1
female gamete generation	1
double-strand break repair	1
reciprocal meiotic recombination	1
nucleic acid metabolic process	1
homologous chromosome segregation	1
cell cycle	1
sexual reproduction	1
reproductive process	1
meiotic nuclear division	1
nucleic acid binding	1
DNA topoisomerase activity	1
ATP-dependent activity, acting on DNA	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
cation binding	1
molecular_function	1
DNA binding	1
nucleic acid conformation isomerase activity	1

Protein interactions and networks

STRING

2118 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SPO11	TOP6BL	Q8N6T0	986
SPO11	REC8	O95072	907
SPO11	HORMAD1	Q86X24	897
SPO11	RAD51	Q06609	893
SPO11	MEI1	Q5TIA1	881
SPO11	MSH4	O15457	875
SPO11	PRDM9	Q9NQV7	871
SPO11	SKIC8	Q9GZS3	868
SPO11	REC114	Q7Z4M0	866
SPO11	MSH5	O43196	845
SPO11	SYCP3	Q8IZU3	844
SPO11	EXO1	Q9UQ84	843
SPO11	SLC39A1	Q9NY26	838
SPO11	HORMAD2	Q8N7B1	815
SPO11	RNF212	Q495C1	813

IntAct

4 interactions, top by confidence:

A	B	Type	Score
SPO11	TUBB8	psi-mi:“MI:0915”(physical association)	0.400
ATF1	ESYT2	psi-mi:“MI:0914”(association)	0.350
CEBPA	SAP18	psi-mi:“MI:0914”(association)	0.350
STAT3	NACA	psi-mi:“MI:0914”(association)	0.350

BioGRID (3): SPO11 (Affinity Capture-MS), TCF4 (Two-hybrid), TUBB8 (Affinity Capture-MS)

ESM2 similar proteins: A0A0U1RQE8, A3BLS0, B2RXZ1, B6DMK2, O22190, O24357, O81829, O82243, O82333, O82504, P0C0M2, P0C0M3, Q0D4Z6, Q16P87, Q28CZ9, Q3EBC8, Q43839, Q4V8A1, Q4V8Q1, Q502J0, Q5R6R6, Q654M1, Q655R6, Q6J756, Q6QR59, Q6ZLA3, Q6ZLA7, Q7L7V1, Q7TS68, Q8GZ29, Q8LGM7, Q8LQM5, Q8NA58, Q969I3, Q9C5X8, Q9D5U0, Q9FZ87, Q9LND7, Q9LQ68, Q9LSQ4

Diamond homologs: A2BLE8, A2XFC1, B0R4D2, O05208, O27089, O29322, O59209, P40384, Q0DSV9, Q2QM00, Q3IPW7, Q57815, Q5JH82, Q5V4R4, Q5ZPI9, Q5ZPV8, Q6ZD95, Q7KPA5, Q7Y021, Q8TQF8, Q8U0K9, Q971T1, Q9HR32, Q9LZ03, Q9M4A1, Q9M4A2, Q9WTK8, Q9Y5K1, Q9YE67, C4VB43, P23179, Q22236, Q468I6, Q8PUB7, Q9V134, Q8SVS9

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

43 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	39
Likely benign	1
Benign	1

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
1244233	NM_012444.3(SPO11):c.744G>A (p.Thr248=)	Likely pathogenic

SpliceAI

1935 predictions. Top by Δscore:

Variant	Effect	Δscore
20:57329927:G:GT	donor_gain	1.0000
20:57331947:G:GG	donor_gain	1.0000
20:57333168:T:TA	acceptor_gain	1.0000
20:57333174:A:AG	acceptor_gain	1.0000
20:57333175:A:G	acceptor_gain	1.0000
20:57333178:A:AG	acceptor_gain	1.0000
20:57333178:AAAAT:A	acceptor_gain	1.0000
20:57333179:A:G	acceptor_gain	1.0000
20:57333180:A:AG	acceptor_gain	1.0000
20:57333272:ATTTT:A	donor_gain	1.0000
20:57333273:TTTT:T	donor_gain	1.0000
20:57333274:TTT:T	donor_gain	1.0000
20:57333275:TT:T	donor_gain	1.0000
20:57333277:G:GG	donor_gain	1.0000
20:57333983:ATAG:A	acceptor_gain	1.0000
20:57333983:ATAGG:A	acceptor_gain	1.0000
20:57334092:TATA:T	donor_gain	1.0000
20:57334093:ATA:A	donor_gain	1.0000
20:57334094:TA:T	donor_gain	1.0000
20:57334095:AGTAA:A	donor_loss	1.0000
20:57334096:G:GG	donor_gain	1.0000
20:57334096:GT:G	donor_loss	1.0000
20:57334097:TAAGT:T	donor_loss	1.0000
20:57334098:AAGTA:A	donor_loss	1.0000
20:57334747:CA:C	acceptor_loss	1.0000
20:57334748:A:AG	acceptor_gain	1.0000
20:57334748:AGTT:A	acceptor_loss	1.0000
20:57334749:G:GG	acceptor_gain	1.0000
20:57334749:GT:G	acceptor_gain	1.0000
20:57334749:GTT:G	acceptor_gain	1.0000

AlphaMissense

2613 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:57335837:A:T	K225I	0.999
20:57334765:G:C	G176R	0.997
20:57335834:A:T	E224V	0.997
20:57338277:G:A	G249E	0.996
20:57338305:A:C	R258S	0.996
20:57338305:A:T	R258S	0.996
20:57338362:T:A	D277E	0.996
20:57338362:T:G	D277E	0.996
20:57340147:T:A	W310R	0.996
20:57340147:T:C	W310R	0.996
20:57335858:T:C	L232P	0.995
20:57343452:T:A	W395R	0.995
20:57343452:T:C	W395R	0.995
20:57333987:G:C	R134S	0.994
20:57333987:G:T	R134S	0.994
20:57334766:G:A	G176D	0.994
20:57338276:G:A	G249R	0.994
20:57338276:G:C	G249R	0.994
20:57338289:C:A	P253H	0.994
20:57338361:A:T	D277V	0.994
20:57335842:G:C	A227P	0.993
20:57338277:G:T	G249V	0.993
20:57338360:G:C	D277H	0.993
20:57339019:G:A	G292E	0.993
20:57343371:G:C	A368P	0.993
20:57343436:A:C	K389N	0.993
20:57343436:A:T	K389N	0.993
20:57335835:A:C	E224D	0.992
20:57335835:A:T	E224D	0.992
20:57338304:G:C	R258T	0.992

dbSNP variants (sampled 300 via entrez): RS1000010226 (20:57337785 A>G), RS1000148419 (20:57343889 T>C), RS1000177783 (20:57331285 C>T), RS1000232361 (20:57330008 C>G), RS1000372374 (20:57336673 T>C), RS1000565163 (20:57328986 G>A,T), RS1000842706 (20:57331613 G>A,C), RS1000853131 (20:57342198 T>A), RS1001278523 (20:57331037 T>A), RS1001374166 (20:57337949 G>A), RS1001647840 (20:57331330 G>C), RS1001737200 (20:57339758 A>G), RS1001853579 (20:57343991 G>A), RS1002340704 (20:57328748 C>A,T), RS1002443418 (20:57334583 A>T)

Disease associations

OMIM: gene MIM:605114 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST90002383_303	Hematocrit	1.000000e-12
GCST90002384_475	Hemoglobin	3.000000e-10

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004348	hematocrit
EFO:0004509	hemoglobin measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

6 total (human), top 6 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases expression, increases methylation	2
bisphenol A	increases expression	1
Valproic Acid	decreases methylation	1
Aflatoxin B1	decreases methylation	1
Sodium Selenite	decreases expression	1
Copper Sulfate	decreases expression	1

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.