Lactase nonpersistence is directed by DNA-variation-dependent epigenetic aging
VOLUME 23 NUMBER 6 JUNE 2016 nature structural & molecular biology
The inability to digest lactose, due to lactase nonpersistence, is a common trait in adult mammals, except in certain human populations that exhibit lactase persistence. It is not known how the lactase gene is dramatically downregulated with age in most individuals but remains active in some individuals. We performed a comprehensive epigenetic study of human and mouse small intestines, by using chromosome-wide DNA-modification profiling and targeted bisulfite sequencing. Epigenetically controlled regulatory elements accounted for the differences in lactase mRNA levels among individuals, intestinal cell types
and species. We confirmed the importance of these regulatory elements in modulating lactase mRNA levels by using CRISPR–
Cas9-induced deletions. Genetic factors contribute to epigenetic changes occurring with age at the regulatory elements,
because lactase-persistence and lactase-nonpersistence DNA haplotypes demonstrated markedly different epigenetic aging.
Thus, genetic factors enable a gradual accumulation of epigenetic changes with age, thereby influencing phenotypic outcome.
DISCUSSION
This study reveals that epigenetic factors are involved in the regulation of the human and mouse lactase genes and, by corollary, the regulation of lactase nonpersistence and related lactose intolerance. DNA-modification studies, in combination with chromatin maps and our functional studies of mutant mice and cell lines, revealed a complex regulation of the lactase gene. Indeed, we found that epigenetic modifications targeting several different regulatory elements account for species- and tissue-specific effects as well as the interindividual variation of LCT expression. A key finding is that different LCT–MCM6 haplotypes exhibit differential epigenetic ‘aging’. This result suggests that the epigenetic ‘clock’19 may be individualized by the genetic landscape. Our findings demonstrate that the lactase-nonpersistence haplotypes containing the C(−13910) allele accumulate modified cytosines that silence the regulatory elements in MCM6 and LCT, whereas the lactase-persistence haplotype containing the T(−13910) allele displays age-related modification changes that maintain LCT activity. Because infant LCT mRNA levels are high irrespective of DNA haplotype, DNA variation may not be directly involved in LCT transcription. Instead, genetic variation may mediate the accumulation or loss of epigenetic
modifications at specific enhancers and promoters, which, in turn, directly orchestrate gene activity.
Thanks for your links, but I was looking for PROOF that this is a mutation.
Also consider this article:
Adult Lactose Tolerance Is Not an Advantageous Evolutionary Trait
DOI: 10.1542/peds.2004-1088 Pediatrics 2004;114;1372
To the Editor.—
I read with great interest the recent article from Fomon1 in
which he refers to the well-known hypothesis that views the
variable frequencies of lactase persistence in different human populations
and, consequently, the possibility for some adults to feed
on milk (lactose tolerance) as an advantageous evolutionary trait
that has been genetically determined and brought about through
centuries of natural selection. This notion stands as a common
statement in current medical literature, and most authors have
accepted its validity since the 1970s.2,3
Because adult mammals are lactose-intolerant, this hypothesis
is, moreover, based on the low percentage of lactose malabsorption
and high enterocyte lactase activity (0–30%) among populations
originating in northwestern Europe and in some ethnic
groups around the Mediterranean and Near East, in Africa, and on
the Indian subcontinent. These people share the longest known
tradition of dairying, since humans first domesticated livestock
and practiced milk-based pastoralism (6000–9000 years ago), making
milk abundant for adults. Accordingly, lactose tolerance is
supposed to be due to a genetic mutation for lactase persistence,
allowing carriers to have milk as a nutritional resource, especially
useful in times of food shortage. For the majority of the world’s
populations, however, the absence of genetic challenge has meant
that no evolution has occurred.
Mutation, in combination with natural selection, is most frequently
the mechanism utilized to explain these changes in genetic
frequency, assuming that the ancestral state was that of nonpersistence
(the normal mammalian state) and that the relevant mutation
probably originated before the geographical expansion of
modern humans. Mathematical models trying to explain this genetic
polymorphism require high selection coefficients and a reasonable
starting gene frequency.4 Such outstanding genetic
change during so short an evolutionary span, as claimed, implies
an increase in the survival and fertility rates of the lactase-persistence
gene carriers to displace the noncarriers in so few (200 –300)
generations.
Evidence does not support such a hypothesis; the rate of recurrent
mutation needed to explain these changes in the genetic
frequencies would be very high, 100 to 1000 the usual ( 10 5 or
10 6 per generation for most loci in most organisms). At these
usual rates, mutation without selection would bring about only
slow changes in the gene frequency in 250 generations. In addition,
individual fitness (the contribution of offspring to the next
generation) does not exhibit any difference between lactose-tolerant
and lactose-intolerant people; no differences in viability or
fertility rates in the prereproductive or reproductive periods have
been noticed up to now. Moreover, fitness is greater by far in
lactose-intolerant populations, and figures show, curiously, that
an increase in lactose-tolerance rates is, in general, paralleled by a
decrease in demographic values, and vice versa. There are additional
unexplained facts concerning the lactase-persistence polymorphism
that the evolutionary hypothesis has been unable to
explain, but expounding on them would make this letter too
protracted.
However, what is more important is that the rationale of evolutionary
analysis tells us that restricting milk to the nursing
period of mammals is more efficient (greater fitness) than to share
it with older individuals. As Fomon points out, the evolutionary
forces are focused on the survival of the mother-offspring unit;
postreproductive individuals (“the genetic dustbin”5) do not directly
contribute to evolutionary changes.
In short, evidence does not support the evolutionary hypothesis
of lactase persistence in human adults as a consequence of
selection. A founder effect could be a more suitable explanation to
justify this trait, and this mechanism does not need the cooperation
of natural selection.
Juan Brines, MD
Department of Pediatrics, Obstetrics, and Gynecology
Universidad de Valencia
46022 Valencia, Spain