Evolutionary genetic mechanisms of metabolic adaptation
When consumers experience selection for n-3 LC-PUFA synthesis, they can
increase enzymatic activity with three different types of genetic
processes: 1) gene copy number increases, 2) enzymatic activity changes
by amino acid substitutions, and 3) regulatory mutations that increase
transcription rates (Fig. 6). These three mechanisms differ in their
effect sizes and pleiotropy (i.e., the number of phenotypic traits
influenced by the gene). Copy number increases may have the strongest
effects on metabolic processes like fatty acid synthesis
(Loehlin and Carroll
2016; Loehlin et al. 2019), but are also likely to have pleiotropic
effects on other metabolic processes. This is because an increase in
copy number may affect expression in multiple tissues throughout
different ontogenetic stages (developmental pleiotropy) and/or they may
change the amounts of other organic compounds produced as by-products
when enzymes are multifunctional (biochemical pleiotropy) (Fig. 6B).
Pleiotropic changes may be neutral, favorable, or unfavorable with
respect to fitness. For instance, because n-3 and n-6 fatty acids are
elongated and desaturated via the same metabolic pathway (Fig. 4),
increased fatty acid desaturase and/or elongase activity may result in
increased production of both n-3 or n-6 LC-PUFA, depending on the
relative availability of n-3 and n-6 precursors. Amino acid
substitutions generally have even more pleiotropic effects than copy
number increases (Carroll
2005), but their effect sizes are reported to be smaller in some cases
(Loehlin et al. 2019).
Regulatory mutations may have relatively strong effects
(Loehlin et al. 2019) and
enable tissue- or ontogenetic stage-specific expression, but may still
be biochemically pleiotropic. Importantly, these three types of
mutations often occur together. After gene duplication, these mutations
can diverge in both functional amino acid sequences and expression
patterns (Ohno 1970; Lynch 2007), becoming more specific
(neo-functionalization) and thus reducing pleiotropic effects while
still having strong effect sizes (Fig. 6C).
Examples of all three types of genetic mechanisms can be found within
the evolution of fatty acid metabolism. Copy number variation in fatty
acid desaturase (Fads ) genes is widely observed in vertebrates
(Castro et al. 2012). For
instance, Ishikawa et al. (2019) recently found that freshwater
threespine stickleback have increased Fads2 copy number and thus
greater capability to synthesize DHA, thereby overcoming the nutritional
constraints of freshwater ecosystems. However, increased expression ofFads2 also results in increased production of n-6 LC-PUFA, such
as ARA, in sticklebacks, thus demonstrating a biochemical pleiotropic
effect (Ishikawa et al.
2019). In humans, regulatory mutations are known to underlie adaptation
to low n-3 LC-PUFA diets
(Fumagalli et
al. 2015; Ye et al. 2017; Tucci et al. 2018). Derived alleles with
higher Fads1 expression appear to have enabled humans to survive
better on cultivated, land plant-derived, and n-3 LC-PUFA-deficient
diets, allowing them to expand their distribution
(Ameur et al. 2012;
Fumagalli et al. 2015; Tucci et al. 2018). In contrast, human
populations that consume n-3 LC-PUFA-rich diets with high amounts of
fish and meat have the ancestral haplotypes (Amorin et al. 2017). Amino
acid changes that alter enzymatic functions can also help consumers
adapt to diets that vary in n-3 LC-PUFA content. For example, although
zebrafish (Danio rerio ) have just one copy of Fads2 , they
have high ∆5 and ∆6 desaturase activities as a result of amino acid
changes (Hastings et al.
2001). Neo-functionalization following duplication appears to be a
common genetic process
(Ohno 1970; Zhang
2003). In fishes, for instance, the acquisition of ∆4 activity occurred
in one copy of Fads2 after gene duplication (Li et al. 2010;
Morais et al. 2012; Oboh et al. 2017). Further genetic analysis of
variation in fatty acid metabolism across a greater diversity of taxa
will help us to understand which mechanisms are the most prevalent and
how mechanisms differ in their effect sizes and pleiotropy on fatty acid
adaptive landscapes.