(technically lactase-phlorizin hydrolase), is a protein produced
in the cells of the epithelium of the small intestine. It is most
concentrated in the mucosal cells of the brush border of the jejunum
(Buller and Grand 1990). Production of lactase begins to decline
in most children between the ages of 2 to 5, around the time of
weaning. Most adults retain only about 10 percent of infant-level
lactase activity. But Finnish children who become lactase deficient
often do so as teenagers; the reasons for this late onset are
unknown (Arola and Tamm 1994).
lactose-intolerant people consume significant quantities of milk
or other dairy products, unmetabolized lactose passes through
the small intestine to the large intestine, where it is acted
upon by the resident facultative bacterial flora. These bacteria
split lactose into acetic, butyric, propionic, and other short-chain
fatty acids, which can be absorbed by intestinal cells and used
as metabolites. Among the by-products are carbon dioxide, hydrogen,
and methane, which can cause a gassy, bloated, and/or nauseous
is generally thought that the abundance of short-chain molecules
increases osmotic pressure within the intestinal lumen, causing
water to pass into the lumen, sometimes in amounts that produce
diarrhea (Castiglia 1994), but this has recently been questioned
by H. Arola and A. Tamm (1994). They suggest that bacteria that
produce larger amounts of iso-fatty acids those with branched
carbon chains in contrast to the normal straight chain forms
may provide protection against diarrhea. Although the intestinal
flora of an individual tend to remain relatively stable over time,
commensal bacterial populations vary considerably among people.
Those persons with large colonies of the types of bacteria that
efficiently metabolize lactose and produce significant quantities
of iso-fatty acids (for example, members of the genus Bacteriodes)
would be less likely to display symptoms (Arola and Tamm 1994).
They would be lactose malabsorbers but not necessarily lactose
mechanisms controlling lactase production were disputed for many
years. Some researchers, drawing on studies of gene regulation
in bacteria, argued in the 1960s that lactase was a substrate-inducible
enzyme; that is, that lactase production was believed to be stimulated
by the presence of its substrate, lactose. In this view, populations
that did not use milk as adults lost the ability to produce lactase,
whereas groups that did consume milk and milk products retained
studies cast doubt on this theory, and family studies have demonstrated
that lactase production is controlled by an autosomal gene, recently
located on chromosome 2. Persistence of lactase production is
a dominant trait (Buller and Grand 1990; Arola and Tamm 1994).
Following the terminology suggested by Gebhard Flatz (1987), the
two alleles are designated LAC*P for lactase persistence and LAC*R
for normal adult lactase restriction. The LAC locus appears to
be a regulatory gene that reduces lactase synthesis by reducing
the transcription of messenger RNA (Arola and Tamm 1994). Persons
inheriting LAC*P from both parents would have lactase persistence
into adulthood; those getting LAC*R alleles from both parents
would display lactase restriction as adults. Heterozygotes would
get different alleles and be LAC*P/LAC*R, but since LAC*P is dominant,
lactase activity and ability to digest milk would persist beyond
milk and milk products are such rich sources of protein, calcium,
carbohydrates, and other nutrients, the nutritional consequences
of lactose intolerance in infants and children can be devastating,
even lethal, unless other dietary sources are used. Formulas based
on soybeans help many youngsters. Adults can get protein from
other animal and vegetable sources or from fermented milk products.
Yoghurt with live bacterial cultures may be tolerated well. Calcium
can be obtained from dark green vegetables or from the bones of
small sardines or anchovies consumed whole (Kretchmer 1993). It
has been suggested that low milk consumption in elderly lactose
intolerance adults might contribute to osteoporosis (Wheadon et
al. 1991), but this has not been demonstrated. Lactose-free dairy
products and oral lactase preparations are commercially available
and help many people enjoy and gain the nutritional benefits of
ice cream and other milk-based foods (Ramirez, Lee, and Graham
persistence is uncommon in Africans, Asians, southern Europeans,
and the indigenous populations of the Americas and the Pacific.
Questions have arisen concerning the use of milk as food for children.
The American Academy of Pediatrics (AAP), noting the high nutritional
value of milk for growing children, has determined that almost
all U. S. children under 10, regardless of family background,
can digest reasonable quantities of milk. The AAP recommends that
the school-lunch half pint (about 240 milliliters [ml]) of milk
be supplied to children up to this age, and notes that intolerance
to 240 ml is rare even among older teens (American Academy of
Pediatrics 1978). Similar results have been reported for African
children in South African orphanages (Wittenberg and Moosa 1991).
Malnourished African children, such as famine victims, also tolerate
up to 350 ml of milk well, which allows the use of this valuable
source of nutrients in emergency situations (OKeefe, Young,
and Rund 1990).
for Lactase Persistence
diagnosis and population surveys for lactose digestion capabilities
present several challenges. Clinical symptoms are discovered by
self-reporting; thus, double-blind studies, in which neither the
experimenter nor the subject knows if a challenge dose contains
lactose or a placebo, are most useful. Direct lactase assay using
biopsy specimens of intestinal mucosa is obviously an expensive
and invasive method, practical only in particular clinical cases.
Indirect assays require subjects to fast for several hours before
being given doses of lactose in solution.
various tests are used to measure the splitting and subsequent
metabolism of the disaccharide. Many of the older methods are
cumbersome and imprecise. Blood samples may be tested for glucose
before lactose challenge and at intervals afterward. High blood
glucose levels after lactose ingestion indicate that lactose is
being split in the intestine. A variant of this method is to measure
blood galactose. Since the liver metabolizes galactose, a dose
of ethanol is given shortly before the experimental lactose to
inhibit liver action. Another approach is to measure hydrogen
gas excreted through the lungs. Subjects who cannot digest lactose
will have hydrogen produced by colonic bacteria. Respiratory hydrogen
can be conveniently and efficiently measured by gas chromatography.
The ethanol-galactose and hydrogen methods are considered the
most reliable; the hydrogen technique is cheaper, easier, and
noninvasive (Flatz 1987).
only must the population studies of lactase activity be methodologically
correct, the subjects must also be truly representative of their
populations. Studies done on very small numbers of subjects or
on hospital patients or other special groups may be unrepresentative.
Indeed, some older studies may be unreliable due to poor techniques
or sampling problems. Intermarriage and genetic interchange also
complicate analysis of the distribution of lactase persistence.
Nonetheless, there has been great interest in the geographical
and ethnic distribution of adult lactase persistence and the evolution
of this unusual phenotype.
of Lactase Persistence
authors have compiled the results of regional studies (Flatz 1987;
Kretchmer 1993; Sahi 1994). Some of the major findings are summarized
here in Table IV.E.6.1.
should be noted that data for northern India and Pakistan are
suspect and that figures for Finno-Ugrian groups in northern Russia
and western Siberia (Khanty, Mansi, Mari, Mordva, Nentsy) are
based on small, possibly unrepresentative, samples and older methods
(Valenkevich and Yakhontova 1991; Kozlov, Sheremeteva, and Kondik
1992). There is little hard information for the Balkan or Iberian
peninsulas, Slavic territories east of Poland, Siberia, central
Asia, or the Indian subcontinent. It would also be interesting
to have more data on East African pastoralists, such as the Maasai,
and on Baggara Arab and other cattle-keeping groups of the West
high proportion of lactase persisters was noted in northwestern
Europe in the early 1970s, and there were similar reports from
northern India, from Bedouin and other pastoral populations in
the Middle East and northern Africa, and from the Tutsi pastoralists
of the Uganda-Rwanda region of East Africa. Very low rates were
found among eastern, and most southern, Asians, most Africans,
and native populations of the Americas and the Pacific, and only
modest rates were found in southern and eastern Europe. In North
and South America, Australia, and New Zealand, adult lactase ability
is closely linked to place of origin; for example, white Australians
resemble their European counterparts in lactase persistence, whereas
Aborigines are almost entirely lactose intolerant. Varying degrees
of Spanish and Indian ancestry may explain regional differences
in Mexico (Rosado et al. 1994). Similarly, a higher than expected
prevalence of lactase persistence among Buryat Mongols of Russias
Lake Baikal region may be due to gene flow from European Russians
(Kozlov et al. 1992).
lactase capability appears to have evolved in two, and possibly
three, geographic areas. The case is clearest and best documented
for northern Europe, where there are very high percentages around
the Baltic and North Seas. High levels of lactase persistence
seem closely linked to Germanic and Finnic groups. Scandinavia,
northern Germany, and Britain have high levels, as do the Finns
and Estonians, the Finnic Izhorians west of St. Petersburg, the
Mari of the middle Volga basin, and, to a lesser extent, their
more distant relations, the Hungarians.
is a general northsouth gradient in Europe, which is evident
within Germany, France, Italy, and perhaps Greece. As noted, more
information is needed for Spain, Portugal, and eastern Europe,
but there may be something of a westeast gradient in the
Slavic lands. Varying frequencies of the LAC*P allele among Lapp
groups may be related to differing lengths of historical use of
reindeer and cows milk and to admixture with other Scandinavians
second center of adult lactase persistence lies in the arid lands
of Arabia, the Sahara, and eastern Sudan. There, lactase persistence
characterizes only nomadic populations heavily dependent on camels
and cattle, such as the Bedouin Arabs, the Tuareg of the Sahara,
the Fulani of the West African Sahel, and the Beja and Kabbabish
of Sudan. Lower rates among Nigerian Fulani may indicate a higher
degree of genetic mixing with other peoples than among the Fulani
of Senegal. In contrast, surrounding urban and agricultural populations,
whether Arab, Turkish, Iranian, or African, have very low rates.
It is interesting to note that the Somali sample also had a low
frequency of the LAC*P allele. Possibly, pastoral Somali have
higher prevalences than their urban compatriots.
third center of adult lactase persistence has been suggested among
the Tutsi population of the Uganda-Rwanda area of the East African
interior. The Tutsi are an aristocratic cattle-herding caste of
Nilotic descent who have traditionally ruled over agricultural
Bantu-speakers. Table IV.E.6.1 shows that only 7 percent of a
sample of 65 Tutsi adults were lactase deficient, but the data
are old, there certainly has been some mixture with Bantu-speakers,
and the study should be replicated. The Nilotic peoples of the
southern Sudan, whence the Tutsi originated a few centuries ago,
do not display this trait. Unless the Tutsi result can be confirmed,
and the Maasai and other East African Nilotic groups can be tested,
this third center of the LAC*P allele must be considered doubtful.
If it does exist, it probably arose as a fairly recent mutation,
as there are no obvious historical mechanisms to account for gene
flow between the Tutsi and desert dwellers farther north.
of Lactase Persistence
J. Simoons (1969, 1970) has advanced the thesis that lactase persistence
is closely linked to dairying. His culture-evolution hypothesis
is that groups that kept cattle and other milk animals would gain
a selective advantage if adults retained the ability to use milk
and milk products as food.
A mutation like LAC*P would be nutritionally beneficial, and the
growing number of milk-using adults would then be encouraged to
devote more effort toward livestock raising. In general, the distribution
of adult lactase persistence and dairy ing shows a positive relationship.
In areas with
no dairying tradition, such as China, Oceania, Pre-Columbian America,
or tropical Africa, few adults can digest lactose.
Europe presents the opposite case. More data around the periphery
of the two postulated centers would be highly desirable, and we
know little about most of the stock-raising societies of central
Asia. Still, although the correspondence is not perfect, and gene
flow through population mixing complicates the picture, the association
seems strong. Given the origins of cattle keeping about 4000 to
3500 B.C. in northern Europe, and even earlier in the Middle East,
there probably has been enough time for modest selective pressures
to have produced observed LAC*P rates (Sahi 1994).
selective forces may also have been at work. Flatz (1987) has
suggested that calcium absorption was such a factor in northern
Europe. Lactose is known to facilitate calcium absorption in the
intestine. The cold, cloudy climate frequently discouraged skin
exposure to sunlight, thereby reducing the bodys production
of vitamin D. Relatively little dietary vitamin D was available,
and so in its absence, calcium was poorly absorbed. Northern populations
were thus vulnerable to rickets and osteomalacia. Pelvic deformities
made births more difficult. The gradual extinction of the Greenland
Viking colony is an example; skeletal evidence shows that such
bone diseases were common among this moribund population. A mutant
LAC*P allele would not only allow adults to use an excellent source
of calcium, but the lactose would also facilitate its absorption.
While not proven, this hypothesis has attracted much attention.
It would complement the theory that the pale skin of northern
Europeans is a genetic trait maximizing the utility of sunlight
in vitamin D production and, hence, calcium absorption.
other selective pressures facilitating the survival of mutant
LAC*P alleles have been postulated for the SaharaArabian
Peninsula desert region. There is a high degree of dependency
on milk among many groups of desert pastoralists, and so a positive
link between lactase persistence and milking seems very plausible.
In addition, it has been argued (Cook 1978) that the simple fact
that milk is a liquid would give adults who could consume it in
large quantities a powerful selective advantage. The theory, while
unproven, certainly seems plausible. G. C. Cooks suggestion
that lactase persistence conveyed some resistance to gastrointestinal
diseases has attracted much less support. At least for cholera,
his claim must be rejected, based on what we know of the historical
geography of the disease. Cholera seems to have been restricted
to the Indian subcontinent until very recent times.
it seems most likely that the European and Arabia-Sahara centers
of LAC*P prevalence, and the Uganda-Rwanda center (if it in fact
exists), arose independently. Population movement and gene flow
can be very extensive and, no doubt, have played a substantial
role around the centers. Despite the efforts of some authors to
find a common origin in the ancient Middle East, it is simpler
to suggest independent origins than to postulate gene flow from
the Middle East to Scandinavia and to the interior of East Africa.
The problem might be resolved in the future if gene sequencing
could show that the LAC*P alleles in Sweden and Saudi Arabia are,
in fact, the same or are distinct forms of the gene with a similar
malabsorption is the normal condition of most adults. Many suffer
the clinical symptoms of lactose intolerance if they consume milk,
especially in large amounts. In two, or possibly three, places,
genetic mutations have arisen that allow adults to gain the nutritional
and culinary benefits of milk and many other dairy products. This
ability has evolved along with cultural developments with profound
implications for livelihood, including, in the northern European
case, the development of mixed farming. East Asian, African, Oceanic,
and Amerindian peoples, of course, thrived without this genetic
trait and its cultural consequences. Their infants and young children
enjoyed the nutritional advantages of milk; adults ate other things,
including fermented milk products. Milk can be consumed by most
lactose-intolerant older children in moderate amounts, and so
milk can be a valuable nutrient for the undernourished or famine
stricken. Modern commercial lactase products allow most lactose-intolerant
adults to consume dairy products; thus, pizza and ice cream need
not be forbidden foods.
the LAC*P and LAC*R genes are interesting far beyond their biomedical
significance. Along with linguistics, archaeology, and physical
anthropology, further research on lactase genes and other genetic
markers will provide clues to the prehistory of peoples, their
migrations and interminglings, and the origins and development
of major language families.
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