An evolutionary approach to function (and roles!)

Phillip LordNewcastle University

Bio-Ontologies 2009http://hdl.handle.net/10101/npre.2009.3228.1

Overview

• Existing definitions of function, role and biological function are limited

• I provide alternative definitions to overcome these limitations

• The definitions seek not to change current usage but formalize it.

Introduction

• Lots of biology consists of analysing function– The heart pumps blood in circles– The brain is the bit we think with

• (sometimes)– Subcellular homeostasis of phytohormone

auxin is mediated by the ER-localized PIN5 transporter doi:10.1038/nature08066

Introduction

• We've ontologized it.

• But what actually is it!

Methodology

• Why do we need function in an ontology

• What are the current definitions

• Evolve new definitions from examples

• Test these against a substantial independent usage.– Aim to give definitions which are simple, clear

and, critically, applicable.

Why do we need function

• Phil participates_in Talking– A thing (that's me) is involved in a process

(that's this).

• Why is this not enough? – Phil is able to participate in Talking– Phil is paid to participate in Talking– Phil is meant to participate in Talking

• These relationships are prime candidates for an upper ontology

Phil

Talking

participates_in

Modelling Function

Phil

Talking

Disposition

bearer_of

realized_in

RoleFunction

BFO's treatment

• BFO – Basic Formal Ontology– Small upper ontology meant to provide key

concepts for use in biomedicine. – Used within some OBOFoundary ontologies– Includes concepts for function

BFO:Function

Function is a realizable entity the manifestation of which is an essentially end-directed activity of a continuant entity being a specific kind of entity in the kind or kinds of context that it is made for.

In English: A hammer was made to hammer nails in a hammering process

But what about biology?

• The previous definition works as a definition of ArtifactualFunction

• An organism isn't made for anything. So, no functions.

• So, we need a definition for biological function

BFO:Biological Function

A biological function is a function which inheres in an independent continuant that is i) part of an organism and ii) exists and has the physical structure as a result of the coordinated expression of that organism's structural genes.http://hdl.handle.net/10101/npre.2008.1941.1

In English: A foot is part of an organism, exists and develops in a coordinated way and we walk on it.

Biological Function

• But:– A differentiated tumour

• Is part of organism• Grows

– So can have a function

– A male ant • Is not part of an organism

– So cannot have a function

• it appears to have genetic eusocial function

– A protein• Has a structure which does not depend on structural genes

– So cannot have a function

My new definition

A biological function is a realizable entity where the homologous structure(s) of individuals of closely related (or the same) species bear this same biological function.

•In English: My feet function in walking because I walk on them, so do you, and so does my pet chimp

– A tumour has no homologs• So has no function

– A male ant has homologs and they behave in the same way• So can have a function

– Likewise, proteins

How do the functions relate?

Sole of Foot

Shock Resistance

is_bearerBio. Function

realized_in

• What distinguishes a biological function from an artifactual function?

• The process? Shock Resistance?– But the sole of my shoe does the same– But the sole of my shoe is not an organism or part of one

• It is the bearer which makes the difference, not the process

How do the functions relate

• Can a function be both a biological and artifactual function?– A bacteria produced using synthetic biology

techniques which changes colour in the presence of a toxin.

– So, probably we can be both at the same time.

So, a definition of function

• A function is a realizable entity which is either a biological function or an artifactual function.

Roles

• A front foot has function to resist shock in a process of shock resistance

• But humans do not walk on their hands, although they can, mostly for fun, or for show– So, the ability to resist shock "can be served or

participated in by that kind of continuant in some kinds of natural, social or institutional context"

– This is a BFO:Role

• A hand has a role to resist shock in a process of shock resistance

Roles

• So, it is the manner of the bearing relationship which makes the distinction– A concept like "to resist shock", can have

instances which are roles, biological or artifactual functions.

• My model is descriptive of my examples, but is it predictive: does it work against usage from other people?

In practice with OBI

• Ontology for Biomedical Investigations– Describes the equipment, people and

technology behind an experiment

• OBI was built post-BFO and with knowledge of it

• Has many concepts under function and role.

OBI Functions

• Perturb– I can perturb a tube with my fingers

• Measure– I can measure a distance with my arm

• Most OBI Functions are not necessarily functions– Full details in paper

OBI Roles

• Label Role (reagent role realized in detection of label assay)– But S35 CTP was produced specifically for

this purpose

• Reference Role (support observation of relative magnitude)– The international kilogram prototype was

manufactured for this purpose

http://en.wikipedia.org/wiki/File:CGKilogram.jpghttp://en.wikipedia.org/wiki/File:Silicon_sphere_for_Avogadro_project.jpg

Summary so far

• I define biological function by homology– Artifactual and Biological Function are

probably not disjoint

• I define Function as one or the other

• Many entities can be either roles or functions (or subcategories)

Axiomatisation

– A relationship between RealizableEntity and Process

– Function and Role are defined subclasses– Most children asserted under

RealizableEntity, • Individuals inferred under Function (bio or

artifactual) or Role

How to apply these definitions

• How do I know if I have a function (bio or arti…) or role?– What is my assay?

• Artifactual Function– Was the artifact intended for a purpose?

• We can guess this for ancient artifacts.

– Does the structure support this purpose?

Applying biological function

• Biological Function– Measures exist for "closely related" and for

"homolog".

• Other definitions are less applicable– Definitions based on "caused by evolution" are

imprecise – which bit of evolution?– Definitions based on selection are:

• Hard or impossible to measure• Natural, sexual or artificial?• Ignore drift, founder effects or other forms of neutral

evolution.

Summary

• Existing definitions of function, role and biological function are limited

• These limitations have been demonstrated using OBI

• I provide alternative definitions to overcome this.

• The definitions seek not to change current usage but formalize it.

Acknowledgements

• From NCL– Frank Gibson (now abcam)– Matt Pocock– Dan Swan– Simon Cockell

• James Malone, Helen Parkinson, Bjoern Peters and all at OBI

• Robert Stevens• The reviewers!

Questions

1. Does BFO2.0 not fix this?2. What about organisms with no homologs?3. What about "gain-of-function" mutations?

– What about hyper variable genes?

4. What about chemical function?5. Does this work with GO?6. You used OWL, what about OBO?7. Why homology, rather than orthology?8. But the Kilogram prototype will lose it's role soon?9. How will this help? Is it the cure for old age?

Does BFO 2.0 not fix this

• No. BFO 2.0 uses an "evolved this way" clause which I think is problematic.

• It also uses the notion of a typical life plan which is hard to measure.

What about organisms with no homologs?

• Surely, if there are no homologs there are no functions?– First, all organisms have homologs – the

definition does not require that they be extant.• Not all structures do. See "what about gain-of-

function" mutations.

– If we can't find the homologs, then it means we don't know whether we have a function, not that there isn't one.

What about "gain-of-function" mutations?

• What about hyper variable genes?– A gain-of-function mutation, as a new mutation has no homolog.

We would therefore use a role or a realizable entity. – Also, for hyper-variable genes.

• At heart, I side with Dumontier(2008)– Genes and proteins only do what their structure allows.– And they are capable of doing anything that their structure

allows. – The distinctions we make between roles and functions are just

not that useful at this level of granularity. – My definition is at least applicable. Whether the distinction is

useful is a different question.

What about chemical function?

• We may need a definition for chemical function, but I am not sure; I don't have the examples yet. – As with genes and proteins, I am not that

convinced that the distinction between role and function is that useful at this level.

• See "gain-of-function".

Does this work with GO?

• Yes, as far as I can tell, although I have not done a complete survey. – Homology is already used to determine function.– In most cases, the evidence codes tell us whether we

have enough information to be sure we have a function as opposed to realizable entity.

– Molecular function would actually become a child of realisable entity – the naming is unwieldy, but would have little other consequences. This is also the case with BFO now as it stands.

– I'm not convinced the distinction between role and function is that useful for genes. See "gain-of-function"

You used OWL, what about OBO?

• I believe that my axiomatisation is mostly translatable into OBO– I think OBO lacks an universal quantification

relationship which I used.

• The English definitions are useful irrespective of the axiomatisation.

Why homology rather than orthology?

• In some ways orthology is a more natural fit, to exclude paralogy.

• But the distinction between orthology and paralogy is normally made only at a genetic level; so the more general term makes sense

• Especially given that the role/function distinction is least useful at a genetic level.– See "gain-of-function"

But the Kilogram prototype will lose it's role soon?

• The international kilo will no longer be a reference soon. The prototype never changed. So it's a role?– Perhaps. But it's highly manufactured state

suggests otherwise. – My imperial spanner set has no function now,

because I can't buy nuts and bolts in inches. But the spanners have not changed. Is this a role too?

How will this help? Is it the cure for old age?

• It helps insofar as an upper ontology helps• My experience suggests upper ontologies can help in

building new ontologies– But only if its obvious how to apply the definitions outside of their

original use

• It may help interoperability between ontologies– Although, it's not clear how often we care about these top level

distinctions when querying

• My definitions do avoid problems of scale in biology.– While the definitions work, it's not clear that the distinctions are

useful at all levels of granularity.

• Yes, it will cure old age.– This is a joke