---
OA_place: publisher
OA_type: hybrid
_id: '21704'
abstract:
- lang: eng
text: How functional protein sequences are distributed in sequence space is fundamentally
important for evolutionary theory and protein design, particularly if a large
diversity of protein functions are hidden in evolutionarily unexplored areas of
the sequence space. However, this question is understudied in part because experimental
and computational studies use extant sequences as a starting point to study sequence
space. Here, we study whether extant sequences are representative of the entire
functional sequence space. Across thousands of protein families from vertebrates
and bacteria we calculate the dimensionality and the volume of sequence space
occupied by extant homologs. We find that the observed dimensionality and volume
of extant sequence space are minuscule, many orders of magnitude smaller than
what we estimated using a model of protein evolution. Simulating sequence evolution
we then quantify the impact of phylogeny, selection, and epistasis on restricting
the evolutionary exploration of sequence space. We find that sequence evolution
from a single common ancestor, or a single point of origin in sequence space,
is by far the largest limiting factor that reduces the dimensionality and volume
of extant sequence space. These results indicate that there are vast areas of
functional sequence space that have not been explored in evolution because of
the excessive restrictions on natural exploration of the protein sequence space
imposed by the point of origin effect. We suggest that protein design methods
that rely on extant sequences may be limited in their ability to discover truly
novel functions.
acknowledgement: We thank Olga Kalinina for feedback on our manuscript, Vsevolod Kuksin
for fruitful discussions and Lev Tsarin for participation in the design of our models.
This work was supported by Japan Science and Technology Agency as part of Adopting
Sustainable Partnerships for Innovative Research Ecosystem, Grant No. JPMJAP24B2
(F.A.K. and L.H.I.), and Fonds Zur Förderung der Wissenschaftlichen Forschung Grant
ESP253-B (O.O.B.)
article_processing_charge: Yes (in subscription journal)
article_type: original
author:
- first_name: Lada H.
full_name: Isakova, Lada H.
last_name: Isakova
- first_name: Elizaveta
full_name: Streltsova, Elizaveta
id: 57a170da-dc96-11ea-b7c8-ab3565071bf7
last_name: Streltsova
- first_name: Olga
full_name: Bochkareva, Olga
id: C4558D3C-6102-11E9-A62E-F418E6697425
last_name: Bochkareva
orcid: 0000-0003-1006-6639
- first_name: Peter K.
full_name: Vlasov, Peter K.
last_name: Vlasov
- first_name: Fyodor
full_name: Kondrashov, Fyodor
id: 44FDEF62-F248-11E8-B48F-1D18A9856A87
last_name: Kondrashov
orcid: 0000-0001-8243-4694
citation:
ama: Isakova LH, Streltsova E, Bochkareva O, Vlasov PK, Kondrashov F. Descent from
a common ancestor restricts exploration of protein sequence space. Proceedings
of the National Academy of Sciences. 2026;123(14):e2532018123. doi:10.1073/pnas.2532018123
apa: Isakova, L. H., Streltsova, E., Bochkareva, O., Vlasov, P. K., & Kondrashov,
F. (2026). Descent from a common ancestor restricts exploration of protein sequence
space. Proceedings of the National Academy of Sciences. National Academy
of Sciences. https://doi.org/10.1073/pnas.2532018123
chicago: Isakova, Lada H., Elizaveta Streltsova, Olga Bochkareva, Peter K. Vlasov,
and Fyodor Kondrashov. “Descent from a Common Ancestor Restricts Exploration of
Protein Sequence Space.” Proceedings of the National Academy of Sciences.
National Academy of Sciences, 2026. https://doi.org/10.1073/pnas.2532018123.
ieee: L. H. Isakova, E. Streltsova, O. Bochkareva, P. K. Vlasov, and F. Kondrashov,
“Descent from a common ancestor restricts exploration of protein sequence space,”
Proceedings of the National Academy of Sciences, vol. 123, no. 14. National
Academy of Sciences, p. e2532018123, 2026.
ista: Isakova LH, Streltsova E, Bochkareva O, Vlasov PK, Kondrashov F. 2026. Descent
from a common ancestor restricts exploration of protein sequence space. Proceedings
of the National Academy of Sciences. 123(14), e2532018123.
mla: Isakova, Lada H., et al. “Descent from a Common Ancestor Restricts Exploration
of Protein Sequence Space.” Proceedings of the National Academy of Sciences,
vol. 123, no. 14, National Academy of Sciences, 2026, p. e2532018123, doi:10.1073/pnas.2532018123.
short: L.H. Isakova, E. Streltsova, O. Bochkareva, P.K. Vlasov, F. Kondrashov, Proceedings
of the National Academy of Sciences 123 (2026) e2532018123.
date_created: 2026-04-12T22:01:47Z
date_published: 2026-04-07T00:00:00Z
date_updated: 2026-05-04T06:57:31Z
day: '07'
ddc:
- '570'
department:
- _id: UlWa
doi: 10.1073/pnas.2532018123
external_id:
pmid:
- '41915737'
file:
- access_level: open_access
checksum: 11b7a13a359e302498b2367906093a6b
content_type: application/pdf
creator: dernst
date_created: 2026-05-04T06:46:31Z
date_updated: 2026-05-04T06:46:31Z
file_id: '21783'
file_name: 2026_PNAS_Isakova.pdf
file_size: 3355016
relation: main_file
success: 1
file_date_updated: 2026-05-04T06:46:31Z
has_accepted_license: '1'
intvolume: ' 123'
issue: '14'
language:
- iso: eng
month: '04'
oa: 1
oa_version: Published Version
page: e2532018123
pmid: 1
publication: Proceedings of the National Academy of Sciences
publication_identifier:
eissn:
- 1091-6490
publication_status: published
publisher: National Academy of Sciences
quality_controlled: '1'
scopus_import: '1'
status: public
title: Descent from a common ancestor restricts exploration of protein sequence space
tmp:
image: /images/cc_by_nc_nd.png
legal_code_url: https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode
name: Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
(CC BY-NC-ND 4.0)
short: CC BY-NC-ND (4.0)
type: journal_article
user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87
volume: 123
year: '2026'
...