---
res:
  bibo_abstract:
  - 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.@eng
  bibo_authorlist:
  - foaf_Person:
      foaf_givenName: Lada H.
      foaf_name: Isakova, Lada H.
      foaf_surname: Isakova
  - foaf_Person:
      foaf_givenName: Elizaveta
      foaf_name: Streltsova, Elizaveta
      foaf_surname: Streltsova
      foaf_workInfoHomepage: http://www.librecat.org/personId=57a170da-dc96-11ea-b7c8-ab3565071bf7
  - foaf_Person:
      foaf_givenName: Olga
      foaf_name: Bochkareva, Olga
      foaf_surname: Bochkareva
      foaf_workInfoHomepage: http://www.librecat.org/personId=C4558D3C-6102-11E9-A62E-F418E6697425
    orcid: 0000-0003-1006-6639
  - foaf_Person:
      foaf_givenName: Peter K.
      foaf_name: Vlasov, Peter K.
      foaf_surname: Vlasov
  - foaf_Person:
      foaf_givenName: Fyodor
      foaf_name: Kondrashov, Fyodor
      foaf_surname: Kondrashov
      foaf_workInfoHomepage: http://www.librecat.org/personId=44FDEF62-F248-11E8-B48F-1D18A9856A87
    orcid: 0000-0001-8243-4694
  bibo_doi: 10.1073/pnas.2532018123
  bibo_issue: '14'
  bibo_volume: 123
  dct_date: 2026^xs_gYear
  dct_isPartOf:
  - http://id.crossref.org/issn/1091-6490
  dct_language: eng
  dct_publisher: National Academy of Sciences@
  dct_title: Descent from a common ancestor restricts exploration of protein sequence
    space@
  fabio_hasPubmedId: '41915737'
...