The thrifty epigenotype: An acquired and heritable predisposition for obesity and diabetes?

Abstract

Obesity and type 2 diabetes arise from a set of complex gene-environment interactions. Explanations for the heritability of these syndromes and the environmental contribution to disease susceptibility are addressed by the "thrifty genotype" and the "thrifty phenotype" hypotheses. Here, the merits of both models are discussed and elements of them are used to synthesize a "thrifty epigenotype" hypothesis. I propose that: (1) metabolic thrift, the capacity for efficient acquisition, storage and use of energy, is an ancient, complex trait, (2) the environmentally responsive gene network encoding this trait is subject to genetic canalization and thereby has become robust against mutational perturbations, (3) DNA sequence polymorphisms play a minor role in the aetiology of obesity and type 2 diabetes-instead, disease susceptibility is predominantly determined by epigenetic variations, (4) corresponding epigenotypes have the potential to be inherited across generations, and (5) Leptin is a candidate gene for the acquisition of a thrifty epigenotype.

Full text

A as in actor: A 6mAshing performance
(Comment on DOI 10.1002/bies.201500076)
Reinhard St
€
oger
‘A’ is the new star. Until now, ‘C’ was the
sole celebrity; a diva stealing the lime-
light in the four-letter DNA alphabet,
which isdefinedbythebasesAdenine‘A’,
guanine ‘G’, thymine ‘T’ and cytosine ‘C’.
Like an actor, ‘C’ can change
character and has, thereby, caught the
imagination and attention of more than
just a small scientific community.
Escaping the typecast of playing the
same character over and over again, the
potential implications of ‘C’s’ trans-
forming properties have been a trending
topic on social media and are often
featured with gusto on magazine covers,
radio and TV.
This fascination stems from the fact
that ‘C’ can acquire information through
addition of small chemical ‘tags’. The
extra ‘epigenetic’ information can be
inherited and allows ‘C’ to appear not
only under different shapes and names,
but to play vitally different roles during
the spectacle of cell differentiation, the
comedy of animal development and the
drama of human disease. Because the
different guises of ‘C’ are so important, a
large body of work during recent years
has helped to uncover the mechanisms
that influence and interpret ‘C’s’ per-
formance in DNA.
But now a light is shining on ‘A’ as it
enters the big stage in the role of a
hitherto overlooked character. In the
November Issue of BioEssays, Dahua
Chen and colleagues discuss N6-meth-
yladenine (6mA), a methylated – or
variant – form of ‘A’ [1]. Why should this
be news? After all, the ability of ‘A’ to
morph into ‘6mA’ has long been known.
However, this character change was
thought to occur primarily in the DNA of
lowly bacteria, and therefore ‘A’s’
performances were applauded for the
most part only by an audience that is
interested in ‘Underground Produc-
tions’ of biology – Bacteriology.
Lately ‘A’ has come to prominence
through reports describing its appear-
ance as ‘6mA’ in eukaryotic DNA;
namely in the green alga Chlamydomo-
nas [2], as well as in the worm
Caenorhabditis elegans and the fruit
fly Drosophila melanogaster [3, 4].
Having been studied intensively for
decades, the later two critters are
considered to be proper, multicellular
model organisms that earned their
rightful place in molecular biology’s
hall of fame. This of course appeals to a
broad audience – and it raises a lot of
questions.
Whatis the roleof ‘6mA’in eukaryotic
DNA? How does ‘A’ change into ‘6mA’? Is
‘6mA’ removed from DNA or does it
morph back into ‘A’? Is ‘6mA’ heritable?
Indeed, has a new epigenetic mechanism
been discovered in eukaryotes, with a
modus operandi comparable to the
processes that made ‘C’ famous?
These questions and more are consid-
ered in the insightful hypothesis paper
on pages 1155–1162. The discourse is
timely and in good hands, as the
authors also reflect on a big puzzle
emerging from their own recent data:
the ever so low levels of ‘6mA’ in fruit fly
DNA [4]. How can ‘6mA’ be of biological
relevance and have any potency in
eukaryotic DNA when present in appa-
rently ‘homeopathic’ quantities? The
answer could be that ‘A’ plays ‘6mA’
only during rare stage appearances –
among them in a select few cells that
ensure the transmission of information
to the next generation. Surely such a
smashing performance as ‘6mA’ should
win ‘A’ some prizes.
References
1. Sun Q, Huang S, Wang X, Zhu Y,etal. N6-
methyladenine function s as a potential epige-
netic mark in eukaryotes. BioEssays 37:
1155–62.
2. Fu Y, Luo GZ, Chen K, Deng X,etal. 2015.
N6-methyldeoxyadenosine marks active tran-
scription start sites in chlamydomonas. Cell
161: 879–92.
3. Greer EL, Blanco MA, Gu L, Sendinc E,etal.
2015. DNA methylation on N6-adenine in C.
elegans. Cell 161: 868–78.
4. Zhang G, Huang H, Liu D, heng CY,etal.
2015. N6-methyladenine DNA modification in
Drosophila. Cell 161: 893–906.
DOI 10.1002/bies.201500125
University of Nottingham, School of Biosciences,
Sutton Bonington Campus, Nottingham, UK
Corresponding author:
Reinhard St
€
oger
E-mail: reinhard.stoger@nottingham.ac.uk
1152 www.bioessays-journal.com Bioessays 37: 1152, ß 2015 WILEY Periodicals, Inc.
Idea to watch
R. St
€
oger Thoughts & Opinion .