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The Gene Concept
Sonja Prohaska
Computational EvoDevo
Universitaet Leipzig
January 3, 2015
The Gene Concept

What is a gene?
“I can’t tell but I recognize a gene when I see one.”
a biologist
“Something is a gene when a biologist says it is one.”
a bioinformatician
“A gene is a database entry with an Ensembl gene ID.”
a computer scientist
“A gene is what Wikipedia says it is.”
a student
“A gene is a locatable region of genomic sequence, corresponding
to a unit of inheritance, which is associated with regulatory
regions, transcribed regions and/or other functional sequence
regions.” Wikipedia
The Gene Concept

Historical view – really short
In the beginning...
◮ a phenotype has characteristics
◮ some characteristics are independent
◮ some characteristics are heritable
◮ all heritable characteristics need to go through a single cell (gamete)
How to put (all) characteristics of a phenotype into a gamete?
◮ miniature organism within gamete?
◮ gemmule, shed by the organs accumulated in gametes? (Darwin
1868)
◮ distinct, discrete entities that specify characteristics (Mendel 1866)
“special conditions, foundations and determiners which are present [in the
gametes] in unique, separate and thereby independent ways [by which]
many characteristics of the organism are specified” by Johannsen (1909)
... the gene is a (unknown) substance representing a characteristic.
The Gene Concept

linkage of genes
◮ Morgan (1915)
◮ segregation experiments and crossbreeding
◮ the observed linkage of genes best fitted a model of a linear
arrangement
◮ size of genes and distance between genes could be inferred
◮ the model had predictive power in breeding
How did this change the understanding of a gene?
◮ genes are continuous
◮ genes are nonoverlapping
◮ distinct genes have distinct dimensions
◮ genes are linked to verying degrees
A gene is an abstract entity whose existance is reflected in the way
a phenotypeis transmitted between generations.
The Gene Concept

◮ 1941 Beadle and Tatum: “one gene, one enzyme”
The gene is the information behind the individual molecule.
◮ 1955 Hershey and Chase: the substance for genes is DNA
◮ 1955 Benzer: a cistron (gene) is a region of DNA defined by
mutations that in trans could not genetically complement each
other.
◮ 1953 Watson and Crick: how DNA could function as a molecule of
heredity
◮ 1958 Crick: flow of information from DNA → RNA → protein
◮ 1970 – 1980 Fiers: RNA and DNA sequencing
◮ understanding of how genes are expressed, discovery of splicing
◮ development of computational tools
◮ the “nominal gene” is defined by its predicted sequence rather
than a genetic locus
◮ 1986 the gene effectively became identified as an annotated ORF
The Gene Concept

pre-ENCODE: the birth of the structural gene
a gene is...
“... a DNA segment that contributes to phenotype/function. In
the absence of demonstrated function a gene may be characterized
by sequence, transcription or homology.” Human Genome
Nomenclature Organization
“... a locatable region of genomic sequence, corresponding to a
unit of inheritance, which is associated with regulatory regions,
transcribed regions and/or other functional sequence regions”
Sequence Ontology Consortium
“ ... the entire nucleic acid sequence that is necessary for the
synthesis of a functional polypeptide (or RNA)” by Lodish (2000)
The Gene Concept

Problematic issues with the gene concept
◮ regulatory sequence: part of a gene or associated with a
gene?
◮ overlapping genes: same strand different reading frame or
readingframes on opposite strands
◮ splicing: open reading frame is segmented
◮ alternative splicing: multiple different transcripts with
different function
◮ trans-splicing: distinct transcripts can be joint
the gene as a single locus no longer applies
◮ run-through transcripts and fusion proteins
◮ parasitic and mobile elements
A gene is a set of connected transcripts where “connected” means
sharing of exons.
The Gene Concept

How ENCODE ruined/challenged the gene concept
◮ functional non-coding RNAs
◮ unannotated transcription: only 50% of spliced transcripts are
annotated
◮ transcription from (distal) alternative transcription start sites
(TSS)
◮ alternative 3’UTRs
◮ transcription at regulatory elements
◮ dispersed regulation and elements (upstream, downstream,
within the first exon, within the first intron, anywhere else)
◮ blurring of the destinction between genic and intergenic,
exonic and intronic
◮ act of transcription of functional importance, transcript
irrelevant
◮ pseudogenes
◮ highly conserved elements, only 20% in annotated regions
The Gene Concept

The Gerstein-Snyder gene definition
The Gene Concept

The Gerstein-Snyder gene definition – in words
◮ a gene is a genomic sequence on DNA (or RNA)
◮ it encodes (one or many) functional product molecules (RNA or
ppotein)
◮ functional products sharing overlapping genomic regions are united
◮ the union must be coherent
◮ i.e. union built separately for RNA and protein products, plus and
minus
◮ does not require that all products necessarily share a common
subsequence
Example: Three functional protein products built from genomic elements A,B,C: A+B, A+C, C only
belong to the same gene even though A+B and C only do not share a common subsequence.
Notice: sharing of UTRs or regulatory regions is not sufficient (see D,E).
“The gene is a union of genomic sequences encoding a coherent
set of potentially overlapping functional products.”
The Gene Concept

The Gerstein-Snyder gene definition – problemes
◮ a container term
◮ “a genomic region” versus “an ordered set of genomic
sequences”
◮ region = intervall [x1, x2] where x1 <= x2
◮ what the authors mean: a gene is “an set of genomic
sequences”
◮ “gene” = concatenation of the “oriented and ordered set of
genomic sequences”
◮ results in a sequence that does not exist in the genome as
such (hint: introns)
◮ conceptual translation of the “gene” does not necessarely
result in an existing functional product (example: A+B+C
does not exist)
◮ “overlapping” versus “sequence in common”
◮ one genomic region but two unrelated protein sequences due to
frame-shifted ORFs
The Gene Concept

Is everything that makes a functional gene product
encoded in the gene?
For proteins this would mean:
◮ each aa can be mapped onto a nucleotide triplet/codon on the DNA
◮ key: genetic code
◮ these triplets might be parted in two (introns)
◮ and put together by gene expression
◮ no addition or modification of amino acids
◮ counter examples: selenoproteins (stop codon UGA is mapped onto
selenocystein in the presence of SECIS), cleavage, deamination,
deimination, racemization,...
For RNAs this means:
◮ each RNA nucleotide can be mapped to a single continuous locus
◮ key: transcription
◮ may counter examples: splicing, polyadenylation, cleavage, ligation,
poly-adenylation, CCA-addition, pseudouridinylation,...
The Gene Concept

The Stadler-Prohaska gene definition
in red ... function Fct(a) of miRNA a is inhibition of translation of a particular set of mRNA → miRNA a →
derived from its precursor hairpin → ... → genomic footprint Γ(a) of miRNA a); b – classic eukaryotic protein
Γ(b)isidenticaltotheCDSsof b;c,d− − proteolyticallycleavedproteinsfromatrans − splicedmRNA;e− −
functionalprimarytranscript;
The Gene Concept

The Stadler-Prohaska gene definition
◮ a function Fct(a) is carried out by a biomolecule a
◮ project the sequence of the molecule a down onto the original
genomic sequence from which it was derived
◮ projection rules are specified by conceptual revers gene
expression
◮ from protein to RNA: genetic code
◮ from RNA to DNA: error-free transcription
◮ result: genomic footprint Γ(a) of the functional biomolecule
A gene represents the duality of a functional product and its
genomic footprint.
The Gene Concept

Literature
Gerstein MB, Bruce C, Rozowsky JS, Zheng D, Du J, Korbel JO,
Emanuelsson O, Zhang ZD, Weissman S and Snyder M (2007).
What is a gene, post-ENCODE? History and updated definition.
Genome Res. 17:669-681
Griffiths PE (2002). Lost: One Gene Concept. Reward to Finder.
Biology and Philosophy 17:271-283
Prohaska SJ and Stadler PF (2008) “Genes” Theory Biosci. 127:
215-221
Stadler PF, Prohaska SJ, Forst CV and Krakauer DC (2009).
Defining genes: a computational framework. Theory in Biosciences
128:165-170
Engelhardt, Kirsten T, Stadler PF and Prohaska S (2010).
Genome Annotation without Genes. Technical report.
The Gene Concept

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