Critical Review How Long Have Adult Humans Been Consuming Milk?

Pascale Gerbault1* lanie Roffet-Salque2 Me Richard P. Evershed2 Mark G. Thomas1

1

Research Department of Genetics, Evolution and Environment, University College London, London WC1E 6BT, UK 2 Organic Geochemistry Unit, School of Chemistry, University of Bristol, Cantock’s Close, Bristol BS8 1TS, UK

Abstract Lactase is the enzyme that breaks down the milk sugar lactose, and in most mammals, including most humans, lactase activity is down-regulated after the weaning period is completed. However, in about 35% of adults worldwide, lactase continues to be expressed throughout adulthood, a feature termed lactase persistence (LP). Genetic evidence indicates that LP is a recent human adaptation, and its current geographic distribution correlates with the relative historical importance of dairying in different human populations. Investi-

gating archaeological evidence for fresh milk consumption has proved crucial in building an account of the joint evolution of LP and dairying. A powerful technique for investigating food processing, including milk processing, in ancient populations is lipid residue analysis on archaeological pottery. We review here the archaeological and genetic evidence available that have contributed to a better understanding of the gene-culture C co-evolution of LP and dairying. V 2013 IUBMB Life, 65(12):983–990, 2013.

Keywords: evolution; fatty acids; gas chromatography; genetics; protein expression; enzyme mechanisms; lactase

Introduction Lactose is the main carbohydrate in milk and constitutes a major energy source for most infant mammals. The enzyme responsible for the hydrolysis of lactose into its two monosaccharide components, glucose and galactose, is lactasephlorizin hydrolase (LPH), usually abbreviated to lactase. The enzyme takes its name from its two activities (1,2): bgalactosidase and b-glucosidase. The former is responsible for the hydrolysis of lactose, and the latter for hydrolysing phlorizin (1); a 20 -glucoside of phloretin (a type of flavonoid, i.e. a plant polyphenol) found in roots and bark of plants from the

C 2013 International Union of Biochemistry and Molecular Biology V

Volume 65, Number 12, December, Pages 983–990 *Address correspondence to: Pascale Gerbault, Research Department of Genetics, Evolution and Environment, University College London, Darwin building, Gower Street, London WC1E 6BT, U.K. E-mail: [email protected] Received 30 September 2013; Revised 1 November 2013; Accepted 4 November 2013 DOI 10.1002/iub.1227 Published online 13 December 2013 in Wiley Online Library (wileyonlinelibrary.com)

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Rosacaeae family (e.g., pear and apple trees) and some seaweeds and other plant glucosides (3–5). In most mammals, including most humans, lactase activity decreases after weaning (6), a phenotype termed lactase non-persistence. In humans, about 68% of adults worldwide are lactase nonpersistent (7). However, some humans continue to express lactase as adults, a trait called lactase persistence (LP) (Fig. 1a). LP is not evenly distributed worldwide (7) but appears to be more frequent in populations with a history of dairying (8,9).

Evidence of Milk Consumption in the Past Archaeological evidence for the intensification of dairying dates back to the Neolithic, a period characterized by plant cultivation, animal keeping, and social and techno-economic changes from the preceding Mesolithic period (10–13). The evidence for dairying comes from various approaches. One involves using the age and sex distribution of animals (at death) in archaeological skeletal assemblages. These distributions, referred to as kill-off profiles, have shown that the slaughtering of young (notyet-weaned) caprines and cattle was more frequent in Near Eastern archaeozoological sites dated to around 10,500 years before present (BP) onwards, than in earlier (Late-Mesolithic)

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Fig 1

(a) Interpolated map of Old World LP phenotype frequencies. Colors and color key show the frequencies of the phenotype estimated by surface interpolation, where collection locations are represented by dots. (b) Distribution of the allele 213,910*T, associated to LP. Dots represent sample data taken from the literature (46,72–76); crosses and diamonds correspond to locations where data have recently been tested and added, respectively (57). Up-to-date versions of these maps and listing of the literature used are available on the global LP association database (http://www.ucl.ac.uk/macelab/resources/glad).

sites (11,14–16). This suggests that more female animals were kept alive to be milked after 10,500 years BP. The immunological detection of milk proteins (e.g., bovine a-casein) in potsherds has provided evidence of milk processing in potsherds from the Scottish Atlantic coast in archaeological sites dated to the Iron Age (17). However, immunological-based methods have been largely abandoned, with the preferred approach for inferring milk processing in pottery vessels being the detection of dairy fat residues using a compound-specific stable carbon isotope, as developed by Dudd and Evershed (18). The lipid residue approach to detecting signatures of dairying in the past is based on the fact that during processing in ceramic vessels, lipids from foodstuffs such as milk or other liquid or liquefied components become trapped and preserved into the pores of the clay wall of “cooking” vessels (19). These absorbed residues are invisible to the naked eye and even by traditional microscopic observations. Nevertheless, they can be readily extracted using organic solvents and identified using gas chromatographic and mass spectrometric methods. These

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determinations have allowed the detection of lipids, ranging from 0 to 100% of the sherds analyzed from a given archaeological site; recoveries vary depending on the use of pottery vessel, the burial conditions/history, and fabric type. The presence of diagnostic lipid biomarkers and specific distributions (chemical “fingerprint”) of compounds allow commodities, such as plant oils and waxes, beeswax, resins, tars, and animal fats, to be identified (19). The most common organic compounds detected in archaeological ceramics are palmitic (C16:0) and stearic (C18:0) acids due to their ubiquitous occurrence in oils and fats (Fig. 2a). In the case of well-preserved organic residues, milk and adipose fat residues can be distinguished based on the presence of low-molecular weight triacylglycerols (building blocks of fats, consisting of glycerol and fatty acids) only present in milk residues (18). However, the fatty acid composition of organic residues is rarely specific enough to identify the nature of animal fat processed in a ceramic pot. Since the late 1990s, the identification of archaeological lipid residues, particularly the distinction of ruminant and non-ruminant fats, has been made possible by compound-specific carbon isotopic analysis of individual fatty acids (C16:0 and C18:0 fatty acids (18)). Briefly, the differences in metabolism (ruminant vs. nonruminant animals) and fat source (adipose vs. milk fats) lead to a difference in the stable carbon isotope composition (13C/12C ratio or d13C values) of the different fats. The d13C values of palmitic and stearic acid are determined by gas chromatography-combustion-isotope ratio-mass spectrometry (GC-C-IRMS (18,20)). In order to remove exogenous factors linked to the environment and to highlight the metabolic and biosynthetic characteristics of the fat source, the D13C (5d13C18:0 2 d13C16:0) value is calculated (20,21). The D13C value obtained for each animal fat preserved in an archaeological potsherd is then compared to values obtained for modern reference fats and the fat source identified (Fig. 2b). The identification of dairy fat residues in archaeological potsherds in this way has informed on the use of milk and the emergence of dairying across Europe and the Near East in prehistory (Fig. 3). This approach has shown dairy products were used extensively in the northwest of present day Turkey around the sea of Marmara as early as 8,500 years BP, correlating with the presence of cattle remains at archaeological sites (22). Furthermore, milk residues have been detected in potsherds from the Libyan Sahara between 7,150 and 5,750 years BP (21), at Neolithic sites in Romania and Hungary around 7,900–7,150 years BP (22,23), around 6,100 years BP in Britain (24) and one millennium later in Scandinavia (25). The earliest evidence for cheese-making come from sieves from the region of Kuyavia in Poland dating between 7,150 and 6,750 years BP. Perforated vessels were identified as cheese-strainers by the presence of milk residues due to their typological similarity to those used by modern-day cheese producers (26). All these dates lie near or at the time when farming developed or arrived in their

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Fig 2

(a) Typical partial gas chromatogram of total lipid extract from prehistoric potsherds. The extract is dominated by palmitic (C16:0) and stearic (C18:0) acids (fatty acids FA). Such high preservation of triacylglycerols (TAGs), diacylglycerols (DAGs), and monoacylglycerols (MAGs) is rare in archaeological samples, and most of the degraded animal fats detected in potsherds only contain fatty acids. An internal standard (IS) is added to the extract for quantification. (b) D13C values (5 d13C18:0 2 d13C16:0) of different extracts plotted against d13C16:0 values from early Neolithic cooking pots (grey) and sieves (black) from the region of Kuyavia (Poland). The ranges show the mean 6 1 s.d. of the D13C values for a global database comprising modern reference animal fats from Europe, Asia, and Africa (21). Dairy fats were detected in most of the sieves, while ruminant adipose fats were detected in cooking pots (26).

respective regions, indicating that dairying was an early feature of Neolithic subsistence. An outstanding question is which came first dairying or LP? This can be addressed using population genetics approaches.

Lactase Persistence in Modern and Ancient Populations LP is inherited in an autosomal dominant manner (27–29). A single gene (LCT) located at chromosome 2q21 codes for lactase. Although more gene variants have been identified, just five of them so far (213,907*G, 213,910*T, 213,915*G, 214,009*G, and 214,010*C), located about 14 kb upstream the LCT promoter, have been found to associate with LP (30– 35). The genomic region surrounding LCT contains various transcription factor binding sites (6). In vitro studies have reported these five substitutions enhance lactase expression (33,35–39), while the in vivo effect has only recently been confirmed for one of them (213,910*T) (40). The 213,910*T allele is the only one found in indigenous Europeans, in contrast to Africa where all five alleles segregate (Fig. 1b). The presence of the 213,910*T allele associated with LP in populations of European ancestry has been investigated in ancient DNA (aDNA) from various populations (Fig. 4). The earliest evidence for the presence of this allele in European populations is in late Scandinavian hunter–gatherers (frequency of 5%) dating from 5,400–3,400 BP (41), and at about the same time (between 5,000 and 4,500 BP (frequency of 26% and 11%) in Neolithic farmers from northwestern Spain (42). Whilst the allele is absent from contemporaneous early Neolithic farmers

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from other regions (43–45), it has been found later, in Medieval individuals, in northeastern Europe, carried by a single heterozygous individual dated to 400–600 years AD (43), and in southeastern Europe, where the allele frequency reached 11% in population samples dated to 1,012–1,112 years AD (46). This aDNA evidence of the low frequency/rarity of 213,910*T allele during the Neolithic together with the archaeological evidence of the spread of dairying both suggest that dairying was practiced before LP arose or became common.

Drinking Milk: An Advantageous Trait? By studying patterns of genetic variation in regions surrounding the alleles associated with LP, age estimates of the most frequent alleles in Europe (213,910*T) and Africa (214,010*C) can be made. For 213,910*T, estimates obtained using extended haplotype homozygosity (EHH) statistics range between 2,188 and 20,650 years ago (47), matching those obtained using variation at closely linked microsatellites, that is between 7,450 and 12,300 (48) and between 7,475 and 10,250 years BP (49). Age estimates obtained for 214,010*C using EHH range between 1,200 and 23,200 years ago (33). All these estimates bracket the dates for the domestication of milkable animals and the spread of agriculture and herding. These age estimates are remarkably young for alleles found at such high frequencies in multiple populations. This rapid increase in frequency is unlikely to have occurred through genetic drift alone, but requires the extra boost of natural selection. The genomic region surrounding LCT has indeed been widely cited as containing a striking genetic signature of

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Fig 3

Locations of Neolithic sites from which lipid residue analyses were performed on potsherds (with the detection of dairy residues based on isotopic analyses or molecular criteria for well-preserved residues) and results of the analyses. *Milk fats undetectable, †,‡ 30% of milk fats detected in sherds providing lipid residues, respectively. Data from 1Copley et al. (24), 2 Berstan et al. (77), 3Mirabaud et al. (78), 4Spangenberg et al. (79), 5Spangenberg et al. (80), 6Craig et al. (23), 7Salque et al.  (81,82), 8Salque et al. (26), 9Soberl et al. (83), 10Evershed et al. (19), 11Craig et al. (25), 12Gregg et al. (84), and 13Copley et al. (85).

natural selection on European genomes based on extended haplotype lengths (47,50–52), linked microsatellite variation (48), and population differentiation-based tests (53,54). The strength of natural selection can be estimated by measuring the extent of haplotype conservation of the chromosomal region carrying LP associated alleles, together with the frequency of the allele itself. The selection strengths needed to explain the distribution of the 213,910*T and the 214,010*C alleles range between 0.8 and 19% (47,55,56) and between 1 and 15% (33), respectively. Even though these selection coefficients are amongst the highest estimated for any human genes in the last 30,000 years (51), the reasons why LP would have been favored are still subject to debate (57). Consideration of the substrates of LPH may provide some insight into the benefits of expressing it in adulthood. For

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example, some of the substrates of LPH b-glucosidase activity may have known health benefits (such as flavonoids (5)), but the relationship between the consumption of substrates requiring this activity in lactase persistent individuals versus nonpersistent individuals has been little studied. Moreover, another intestinal enzyme, the cytosolic b-glucosidase (CBG), performs the same deglycosylation (5,58,59), and therefore the necessity of expressing lactase is not clear and needs further investigation. In contrast, LPH is the only enzyme in mammals that has the ability to cleave lactose into its constituent monosaccharides, which can then be transported across epithelial cell membranes. Lactose is a major constituent of most mammalian milk and can cause undesirable symptoms when consumed but not broken down by LPH in the small-intestine. In

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Fig 4

Frequency of the 213,910*T allele (black) associated with LP in Europe in aDNA from prehistoric farmers. The time of sampling is given in years Before Present (BP) and color-coded, going from red (for older samples) to cream (most recent samples), and represents the ancestral allele 213,910*C frequency. References where this data comes from are printed horizontally at the bottom of the Figure. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

lactase non-persistent adults, when lactose reaches the colon, colonic bacteria ferment it to produce various gasses, particularly hydrogen. The production of gasses, plus the osmotic effects of undigested lactose often cause symptoms such as bloating, abdominal cramps, flatulence, and diarrhea (60), although the severity of these symptoms can vary between non-persistent individuals (31,57). While lactase non-persistent individuals may lose fluids and minerals when drinking fresh milk because of lactose intolerance symptoms, lactase persistent individuals drinking fresh milk can fully benefit from the source of carbohydrates and the many other nutrients it contains. Before LP became common, the use of sieves would have allowed the manufacture of reduced-lactose milk prod-

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ucts (19,26), such as cheese, thereby permitting the consumption of dairy products by lactase non-persistent individuals while minimizing lactose intolerance symptoms. The advantages of expressing lactase throughout life are still open to debate. In Europe, the most commonly cited selection mechanism is the calcium assimilation hypothesis (60). In northern Europe, at least, a shift to cereal-based diets would have entailed less dietary vitamin D, and at such high latitudes UVB-light would have been insufficient to photoconverts 7dehydrocholesterol into cholecalciferol (vitamin D3) in the skin for much of the year. Milk, which contains large amounts of calcium and small amount of vitamin D, may thus have been an essential nutritional supplement in early Neolithic societies,

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providing protection against rickets. However, despite the possibility that the selective advantage conferred to lactase persistent individuals may not have been constant over time and space (55), there is little evidence in the archaeological record to support a higher proportion of rickets in early Neolithic individuals when compared to Mesolithic ones.

Conclusion The correlation between the cultural trait of dairying and the occurrence of LP in human populations provides a model example of the type of dietary adaptation the Neolithic entailed (61), as well as one of the most clear-cut examples of human niche construction and, more specifically, gene-culture co-evolution (62,63). With the intensification of agriculture and domestication, the dietary breadth of farming populations would have become narrower in comparison to that of hunter– gatherers (64,65). Thus, and as suggested by most of the hypotheses to explain the selective advantage of LP (57), the consumption of milk and dairy products is likely to have provided valuable nutritional components to the diet of farmers (66). Once domestic animal breeding stopped being seasonal (67), milk would have provided a reliable supply of nutrients to lactase persistent people, protecting against food shortages brought about by the seasonality of crops (68). What makes the evolution of LP even more interesting is the ever-increasing availability of evidence from diverse scientific fields. A powerful tool for integrating various types of data is simulation modeling coupled with an approximate Bayesian computation (69,70). Recently, such an approach has been used for investigating the origin of LP in Europe. This spatially explicit computer simulation study (56) inferred the LP associated 213,910*T allele is likely to have started to be positively selected in Central Europe, between 8,683 and 6,256 years ago. This places the origins of LP-dairying co-evolution among the progenitors of the Neolithic Linearbandkeramik (LBK) culture, associated with a preponderance of cattle remains in archaeological sites (71). As yet no definitive conclusions have been drawn about why LP was so advantageous, but this challenging issue will only benefit from cross-disciplinary research.

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Consumption of Milk and Dairy Products

How long have adult humans been consuming milk?

Lactase is the enzyme that breaks down the milk sugar lactose, and in most mammals, including most humans, lactase activity is down-regulated after th...
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