Like all animals, humans are under constant selective pressure from their
food supply. The evolutionarily recent switch from a predominantly
meat-based hunter-gatherer diet to a predominantly plant-based agricultural
diet represents a profound change that is most assuredly reshaping our
genetics. How much adaptation has taken place? Not much, the argument goes,
given the limited time available. Still, there are assumptions involved in
making this judgment and the general tendency is to err on the side of
underestimation rather than overestimation when considering the rapidity of
possible genetic change. Nature almost always works more efficiently than
we think.
One candidate for such genetic adaptation that has not been fully
appreciated is the mutation responsible for hereditary hemochromatosis (HH)
(1). This is a particularly interesting situation insofar as its prevalence
within the population can be viewed as the result of strong (positive)
selective pressure for dietary change, while the altered gene itself, once
established, can also be viewed as the agent of weaker (negative) selective
pressure for the same dietary change.
HH is the predominant member of a class of disorders referred to
collectively as iron overload disease. In these diseases, massive amounts
of iron (up to 5-10x normal) gradually accumulate in the body leading to
any of a panoply of health problems such as cirrhosis, arthritis, diabetes,
impotence, heart failure and even death. The iron is deposited in the form
of a storage compound (hemosiderin) in major organs such as liver,
pancreas, heart, joints, and endocrine glands. Tissue damage, once
evident, is at best only partially reversible if at all. Iron overload in
HH is progressive over an individual's lifetime. Most people (usually
males, as females are protected to a large extent due to menstruation)
present clinically between the ages of 40 and 60. The primary treatment is
early detection and frequent phlebotomy (blood-drawing), usually
accompanied by a diet low in meat and other iron-rich foods. Phlebotomy
works to prevent and/or partially reverse HH because a certain amount of
iron can be mobilized to form new red blood cells. Significant early
mortality is associated with lack of treatment.
It is not generally appreciated that HH is the most common inherited
metabolic disorder among whites worldwide (2). It is also the most
underdiagnosed. Recently the HH gene has been identified and cloned (3). It
is now known that more than 80% of HH cases are due to the identical
mutation which probably arose somewhere in Northern Erurope (3-5). Large
scale studies have shown that HH is present in European populations (or
derivatives) at frequencies of 10-16% (6). This number represents
heterozygotes having one good copy of the HH gene and one mutated. It is
obviously an extremely high value. Heterozygotes do not show disease
symptoms. The corresponding frequency for homozygous individuals having two
copies of the mutated gene is 0.3-0.8% (6). On a normal diet and in the
absence of intervention, homozygotes will progress to disease.
How did the frequency of this mutation get to be so high? Conceivably it
could be a chance event resulting from a population bottleneck (genetic
drift). A more powerful argument, however, is that there has been strong
selective pressure for enrichment. This can easily be envisioned
considering the mechanism by which iron overload occurs: through increased
absorption of dietary iron. Iron absorption is normally regulated in humans
such that rates rise only in response to anemia. In HH, however,
absorption remains high regardless of iron status. Given that iron
deficiency problems most likely increased for humans following the
transition from hunter-gatherer modes to agricultural life (it is currently
one of the most prevalent nutritional deficiencies in the world), the
presence of this mutation would prove extremely useful to individuals faced
with reduced meat intake (meat is a particularly good source of
bioavailable iron) and/or increased reliance on cereals or other plants
containing inhibitors of iron absorption such as phytates or polyphenols
(7) and/or increased milk intake, which is an inhibitor of iron absorption
due to casein, calcium, whey protein and phosphates (see 8). Iron overload
is in fact rare in populations existing primarily on cereal diets, even for
individuals homozygous for HH.
The fact that heterozygous asymptomatic individuals also absorb
increased,though lesser, quantities of iron (9) is particularly significant
and could be the primary basis for penetrance of HH into the population.
The situation here would be somewhat analogous to that for sickle cell
anemia, where strong selection is maintained for heterozygosity as
protection against malaria.
Lastly, one can imagine that, once present, HH itself implements weak
negative selective pressure in the direction of a reduced iron diet.
Selection is weak owing to the generally post-reproductive nature of the
pathology. Factors that can be considered in this regard include:
early-presenting situations of severity (which do occur), speculative
neonatal effects (10), increased bacterial infections (e.g Yersinia
enterocolitica, which is normally iron-dependent for infection), or group
selection mechanisms.
1) Bothwell and MacPhail (1998) Seminars in Hepatology 35(1) 55-71.
2) Bonkovsky et al (1996) Hepatology 24(3): 718-29.
3) Feder et al (1996) Nature Genet 12: 399-408.
4) Risch (1997) Nature Genetics 17: 375-376.
5) Merryweather-Clarke et al (1997) J Med Genet 34: 275-278.
6) Niederau et al (1994) Adv Exp Biol Med 356: 303-308.
7) Hurrell (1997) Euro J Clinical Nutr (1997) 51: Suppl, S4-S8.
8) Olivares et al (1997) J of Nutr 127(7):1407-11.
9) Bulaj et al N Eng J Med (1996) 335: 1799-1805.
10) Parkilla et al (1997) Proc Nat Acad Sci 94(24): 13198-202.
Gary Ditta
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