Digest Lactose Research Articles

Editors’ Pick: milk sugar, migration and pastoralism in Africa

Lactose persistence (LP), the ability to digest milk sugar (lactose), is one of the best examples of selection-based evolutionary change in humans from milk-drinking cultures. LP has been documented in populations with northern European ancestry and those originating in Central Asia, Middle East, the Arabian Peninsula, and Africa. Based on molecular genetic studies, it has been estimated that the selective change in the ability to digest lactose beyond childhood occurred within approximately the past 5,000-10,000 years [1]. The estimation is consistent with an advantage to LP in dairy farming-based subsistence, which came to prominence in certain geographical areas around the same time. The important enzyme in the breakdown of milk sugar, lactase (or more specifically lactase-phlorizin hydrolase (LPH)), is coded by the LCT gene. The molecular genetic data reported in recent years show several interesting aspects of LP. The first genetic variation described for European LP was not in the LCT gene, but in the in the intron 13 of the MCM6 gene, residing ~14 kb upstream of MCM6 [2]. However, it soon was realized that the MCM6 intron 13 T-13910 allele, which explained most LP in Europe, was absent in Africa [3,4]. Instead, three other SNPs in the same intron, C-14010, G-13907 and G-13915, were associated with lactase persistence in Africa. Also, these SNPs originated on different haplotype backgrounds from the European T-13910 allele and from each other providing a major model of convergent evolution in LP due to strong selective pressure [3,5]. To date, several SNPs associated with LP are known. In Europe, in addition to MCM6 intron 13 T-13910, intron 9 G-22018 is significantly associated with the LP trait. In Africa and the Arabian Peninsula, four SNPs (those above and G-14009), which are all located within 100 bp of T-13910 have been shown to be associated with the LP predominantly in pastoralist populations. Those variants do not, however, account for all the phenotypic variance of LP in Africa, implying that additional genetic variation may play a role. A new study by Ranciaro et al. in American Journal of Human Genetics[6] sought out new genetic variants associated with LP in Africa. They studied 819 individuals from 63 African populations, and 154 individuals from non-African populations from Europe, the Middle East and Asia. The authors sequenced MCM6 gene introns 9 and 13 and ~2 kb of the LCT gene promoter region in these samples. Additionally, in an effort to reconstruct the origin and spread of LP-associated alleles in Africa, four microsatellites were genotyped in a ~198 kb region in a subset of 252 individuals. The participants’ LP status was tested using a standardized blood test that tracks lactose digestion. With the new larger data set, and sampling from outside Africa, the authors confirmed the earlier observed association between the LP trait in Africa and three variants in intron 13, and they also found two additional LP-associated SNPs, one in intron 13 (G-12962) and one in the LCT promoter region (T-956). Further functional studies are naturally needed to prove whether these new SNPs are causative or just merely in linkage disequilibrium with the earlier identified variants. Ranciaro et al. [6] then used allele frequency and long-range linkage disequilibrium based neutrality tests to detect any signatures of selection. They found evidence for recent positive selection in eastern African populations and the Fulani from central Africa. While looking for the new variants for LP within Africa, the study by Ranciaro et al. [6] also considered that if LP patterns coincide with the rise in pastoralism, the LP-related alleles found in present-day populations should reveal past migrations of those populations. In order to do that, they analyzed a subset of 252 study participants using four microsatellites and combined these with the SNPs to create haplotypes. The haplotype analysis has some interesting insights about the migration of pastoralism groups in Africa. For example, the haplotype analysis supported an eastern African origin (Kenya and Tanzania) of the C-14010 LP-associated mutation now found in southern Africa in Bantu-speaking Xhosa and the hunter-gatherer San population. Also, the presence of Middle Eastern origin G-13915 allele in North African populations suggests migration between these regions. Interestingly, the data are supported by known historical interactions between these populations. Some of the data in Ranciaro et al. [6] is in agreement with earlier findings of distinct genetic LP variants that have arisen in various parts of Africa through convergent evolution. For example, the G-13907 was almost exclusively restricted to northern Kenya, Ethiopia and northern Sudan, as reported earlier. Last but not least, the authors also detected the traditionally European LP haplotype background in some West-and North-Central African populations. But, even with these new data from Ranciaro et al. [6], the genetic variants found and analyzed in various populations to date, are far from fully explaining LP in Africa.

Prevalence of Lactose Intolerance in Primary School Children in Qena Governorate , Egypt

Most people are born with the ability to digest lactose. Approximately 75% of the general population loses this ability, to some extent, going into adulthood (adult hypolactasia), while others retain such ability. The aim of the present study was to determine the prevalence of lactose intolerance, and its correlation with gastrointestinal symptoms, in primary school children aged 6-12 years in Qena Governorate, Egypt. A cross-sectional study was carried out on 300 school children with clinical suspicion of lactose intolerance. Biological and clinical data were obtained from children’s parents or guardians. The history of diarrheal attacks especially following ingestion of milk or dairy products, as well as the incidence of diabetes in the children or family history of such diseases was also obtained. The children were instructed to maintain a low fiber diet without lactose for 48 hours prior to the day of examination. After 12 hours of fasting lactose tolerance test was carried out. The data obtained revealed that 74% of the participants in the study were intolerant to lactose. However, only 56.8% of lactose-intolerant children had positive clinical history of abdominal pain, abdominal distension or diarrheal attacks following ingestion of milk or dairy products. The prevalence of lactose intolerance in the studied cohort increased with age. Such genetically determined intolerance was 58% at 6-7 years of age and increased to 90% by the age of 11-12.

Lactose avoidance for young children with acute diarrhoea.

Young children with acute diarrhoea, typically due to infectious gastroenteritis, may temporarily stop producing lactase, the intestinal enzyme that digests lactose. This means they may not digest lactose, the main sugar in milk, and this may worsen or prolong the diarrhoeal illness. However, there is uncertainty whether avoiding lactose-containing milk or milk products helps young children recover from acute diarrhoea more quickly. To assess if avoiding or reducing intake of lactose-containing milk or milk products shortens the duration and severity of illness in young children with acute diarrhoea. We also sought other indicators of morbidity and overall mortality. We searched the Cochrane Infectious Diseases Group Specialized Register (14 May 2013), Cochrane Central Register of Controlled Trials (CENTRAL) published in The Cochrane Library (Issue 4, 2013), MEDLINE (1996 to 14 May 2013), EMBASE (1974 to 14 May 2013), and LILACS (1982 to 14 May 2013), and the reference lists of potentially relevant trials, key conference proceedings, and wrote to individuals and organizations in the field. Randomized or quasi-randomized controlled trials that assessed the effects of avoiding or reducing exposure to lactose in young children under five years with acute diarrhoea. We extracted data using the standard methods of the Cochrane Infectious Diseases Group, and two review authors independently evaluated trial quality and data extraction. Continuous outcomes were compared using mean difference (MD), and dichotomous outcomes using the risk ratio (RR). We presented all results with 95% confidence intervals (CI) and assessed the quality of evidence using the GRADE approach. We included 33 trials enrolling 2973 children with acute diarrhoea. Twenty-nine trials were exclusively conducted on inpatients, all from high- or middle-income countries. Fifteen trials included children aged below 12 months, and 22 excluded children who were being breast-fed.Compared to lactose-containing milk, milk products, or foodstuffs, lactose-free products may reduce the duration of diarrhoea by an average of about 18 hours (MD -17.77, 95% CI -25.32 to -10.21, 16 trials, 1467 participants, low quality evidence). Lactose-free products probably also reduce treatment failure (defined variously as continued or worsening diarrhoea or vomiting, the need for additional rehydration therapy, or continuing weight loss) by around a half (RR 0.52, 95% CI 0.39 to 0.68, 18 trials, 1470 participants, moderate quality evidence).Diluted lactose-containing milk has not been shown to reduce the duration of diarrhoea compared to undiluted milk or milk products (five trials, 417 participants, low quality evidence), but may reduce the risk of treatment failure (RR 0.65, 95% CI 0.45 to 0.94, nine trials, 687 participants, low quality evidence). In young children with acute diarrhoea who are not predominantly breast-fed, change to a lactose-free diet may result in earlier resolution of acute diarrhoea and reduce treatment failure. Diluting lactose-containing formulas may also have some benefits but further trials are required to have confidence in this finding. There are no trials from low-income countries, where mortality for diarrhoea is high, and malnutrition is more common.

Brief communication: Effect of nomadic subsistence practices on lactase persistence associated genetic variation in Kuwait

Lactase persistence (LP)-the ability to digest lactose in adulthood-is paradigmatic of Holocenic dietary change affecting the evolutionary trajectory of specific populations. Kuwait represents one location of high LP where the variation in associated genomic regions has not been examined. Here, we present new sequence data from a 427 bp amplicon 14 kb upstream of the LCT (lactase) gene for two Bedouin tribal populations, the Ajman and Mutran. We estimate the frequency of known LP associated alleles and discuss the impact of nomadic-pastoralism on the associated genetic variation. We observe high frequency (56% on average) of the -13,915*G allele in both tribes, which is consistent with the high prevalence of LP in Kuwait. Whilst LP associated alleles occur in Kuwait at a similar frequency to other regional populations, we suggest that the -13,915*G allele frequency among the Kuwaiti Bedouin may be higher than among non-Bedouin Kuwaitis, possibly due to greater historical reliance on milk consumption or genetic drift.

Lactase treated feeds to promote growth and feeding tolerance in preterm infants

Successful transition from parenteral nutrition to full enteral feedings during the immediate neonatal period is associated with improved growth in preterm infants. Lactase is the last of the major intestinal disaccharidases to develop in preterm infants. Because of inadequate lactase activity, preterm infants are unable to digest lactose. Lactase preparations could potentially be used to hydrolyse lactose in formulas and breast milk to minimize lactose malabsorption in preterm infants. To assess the effectiveness and safety of the addition of lactase to milk compared to placebo or no intervention for the promotion of growth and feeding tolerance in preterm infants. weight gain expressed as grams/kg/day, growth expressed as weight, length and head circumference percentile for postmenstrual age (PMA), assessed at birth and at 40 weeks PMA, days to achieve full enteral feeds. several common outcomes associated with preterm birth, and adverse effects. Electronic and manual searches were conducted in January 2005 of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, 2004, Issue 4), MEDLINE (1966 to Jan 2005), EMBASE (1980 to Jan 2005) and CINAHL (1982 to Jan 2005), personal files, bibliographies of identified trials and abstracts by the Pediatric Academic Societies' Meetings and the European Society of Pediatric Research Meetings published in Pediatric Research. The searches were repeated in May 2012 of The Cochrane Library, MEDLINE, EMBASE and CINAHL and abstracts from the Pediatric Academic Societies' Annual Meetings from 2000 to 2012 (Abstracts2View). The Web of Science was searched using the only previously identified trial by Erasmus 2002 as the starting point to search for additional trials that cited this trial. Types of studies: randomized or quasi-randomized controlled trials. preterm infants < 37 weeks PMA. addition of lactase to milk versus placebo or no intervention. The standard methods of the Cochrane Neonatal Review Group were followed independently by the review authors to assess study quality and report outcomes. Treatment effects, calculated using Review Manager 5, included risk ratio (RR), risk difference (RD) and mean difference (MD), all with 95% confidence intervals (CI). A fixed-effect model was used for meta-analyses. We did not perform heterogeneity tests as only one study was identified. The repeat searches conducted in May 2012 did not identify any additional studies for inclusion. One study enrolling 130 infants of 26 to 34 weeks PMA (mean postnatal age at entry 11 days) was identified and no identified study was excluded. The study was a double blind randomized controlled trial of high quality. Lactase treated feeds were initiated when enteral feedings provided > 75% of daily intake. None of the primary outcomes outlined in the protocol for this review and only one of the secondary outcomes, necrotizing enterocolitis (NEC) were reported on. The RR for NEC was 0.32 (95% CI 0.01 to 7.79); the RD was -0.02 (95% CI -0.06 to 0.03) (a reduction which was not statistically significant). There was a statistically significant increase in weight gain at study day 10 in the lactase treated feeds group but not at any other time points. Overall, there was not a statistically significant effect on weight gain. No adverse effects were noted. The only randomized trial to date provides no evidence of significant benefit to preterm infants from adding lactase to their feeds. Further research regarding effectiveness and safety are required before practice recommendations can be made. Randomized controlled trials comparing lactase versus placebo treated feeds and enrolling infants when enteral feeds are introduced are required. The primary and secondary outcomes for effectiveness and safety should include those identified in this review.

Stronger signal of recent selection for lactase persistence in Maasai than in Europeans

Continued ability to digest lactose after weaning provides a possible selective advantage to individuals who have access to milk as a food source. The lactase persistence (LP) phenotype exists at varying frequencies in different populations and SNPs that modulate the regulation of the LCT gene have been identified in many of these populations. Very strong positive selection for LP has been illustrated for a single SNP (rs4988235) in northwestern European populations, which has become a textbook example of the effect of recent selective sweeps on genetic variation and linkage disequilibrium. In this study, we employed two different methods to detect signatures of positive selection in an East African pastoralist population in the HapMap collection, the Maasai from Kenya, and compared results with other HapMap populations. We found that signatures of recent selection coinciding with the LCT gene are the strongest across the genome in the Maasai population. Furthermore, the genome-wide signal of recent positive selection on haplotypic variation and population differentiation around the LCT gene is greater in the Maasai than in the CEU population (northwestern European descent), possibly due to stronger selection pressure, but it could also be an indication of more recent selection in Maasai compared with the Central European group or more efficient selection in the Maasai due to less genetic drift for their larger effective population size. This signal of recent selection is driven by a putative East African LP haplotype that is different from the haplotype that contributes to the LP phenotype in northwestern Europe.

Lactose intolerance: diagnosis, genetic, and clinical factors

Most people are born with the ability to digest lactose, the major carbohydrate in milk and the main source of nutrition until weaning. Approximately 75% of the world’s population loses this ability at some point, while others can digest lactose into adulthood. This review discusses the lactase-persistence alleles that have arisen in different populations around the world, diagnosis of lactose intolerance, and its symptomatology and management.

Analysis of a SNP linked to lactase persistence: An exercise for teaching molecular biology techniques to undergraduates

Recent experimental evidence indicates that the ability of adults to tolerate milk, cheese, and other lactose-containing dairy products is an autosomal dominant trait that co-evolved with dairy farming in Central Europe about 7,500 years ago. Among persons of European descent, this trait is strongly associated with a C to T substitution at a polymorphic site 13,910 bp upstream of the lactase gene. This mutation results in the persistent expression of lactase into adulthood enabling individuals carrying a T(-13,910) allele to digest lactose as adults. In this report, we describe a laboratory exercise for an undergraduate molecular biology course in which students determine their own genotype at the -13,910 polymorphic site and correlate this with their ability to tolerate dairy products. The exercise is used as a tool to teach basic molecular biology procedures such as agarose gel electrophoresis, PCR1, and DNA sequencing. Students are actively engaged in the learning process, not only by analyzing their own DNA but also by applying their knowledge and skills to answer an authentic question. The exercise is also integrated with lecture material on the control of gene expression at the transcriptional level, in particular, how transcription factors can influence the activity of a promoter by binding to cis-acting DNA regulatory elements located within the proximal promoter of a gene or distant enhancer regions.

Frequency of lactase persistence genotype in a healthy Polish population

Abstract The majority of mammals are unable to digest lactose due to post-weaning deactivation of the LCT gene, which is responsible for encoding the enzyme lactase (i.e., adult-type hypolactasia). A substitution of C with T at position −13910 bp upstream of the LCT gene has been linked to the lactase persistence phenotype in European populations. We investigated the frequency of LCT-13910C&gt;T polymorphism in 223 blood donors from central Poland. All samples were genotyped by polymerase chain reaction and direct sequencing. The LCT-13910 T allele (lactase persistence) was present in 51% of individuals sampled from the Polish population. We did not find any non-European variants associated with lactase persistence (LCT-13907C&gt;G, LCT-13913T&gt;C, LCT-13915T&gt;G), or any new polymorphisms within the sequenced region. Allele frequencies obtained are in agreement with results from other countries and confirm the unique pattern of distribution of the LCT-13910C&gt;T genotype in Europe.

Novel formulation of neutral lactase improves digestion of dairy products in case of lactose intolerance

Background Lactose intolerance is the insufficient ability to digest lactose, a sugar commonly found in dairy products. It is caused by a deficiency of the enzyme lactase, which is resident in the small intestine. Lactase breaks down lactose into glucose and galactose, which are readily absorbed into the bloodstream. Lactase deficiency develops slowly over time, most persons concerned do not experience symptoms of lactose intolerance until late adolescence or adulthood. Typical symptoms are abdominal pain, bloating, diarrhea and nausea.

Guidelines for the Diagnosis and Management of Food Allergy in the United States: Summary of the NIAID-Sponsored Expert Panel Report

Guidelines for the Diagnosis and Management of Food Allergy in the United States: Summary of the NIAID-Sponsored Expert Panel Report

191 Variation of intrinsic cetuximab sensitivity in head and neck squamous cell carcinomas

Adult-type hypolactasia is a genetically determined inability to digest lactose after weaning. Two single-nucleotide polymorphisms (C-13910T, G-22018A) located upstream of the lactase gene (LCT) within the gene MCM6 are associated with the lactase persistence/non-persistence trait in patients of European descent. Therefore, the genotyping of these SNPs has been established as a diagnostic tool for adult-type hypolactasia. We have recently shown that several novel allelic variants located in close proximity to the C-13910T SNP interfere with the diagnostic accuracy of real-time PCR-based genotyping methods.We describe here the validation of a comprehensive reverse-hybridization teststrip-based assay for the detection of common and novel LCT SNPs (C-13907G, C-13910T, T-13913C, G-13914A, T-13915G, and G-22018A). This assay is based on multiplex DNA amplification and ready-to-use membrane teststrips containing variant-specific oligonucleotide probes immobilized as an array of parallel lines.We evaluated the novel reverse-hybridization StripAssay on 125 DNA samples in comparison to LightCycler analysis and sequencing. The outcome of StripAssay genotyping was found to be completely concordant with that obtained by sequencing.The StripAssay represents an accurate and robust screening tool to identify multiple LCT/MCM6 variants in a rapid manner. It overcomes diagnostic pitfalls that were reported and allows the simultaneous genotyping of closely spaced LCT variant sites in a single-step diagnostic approach.

National Institutes of Health Consensus Development Conference: Lactose Intolerance and Health

National Institutes of Health (NIH) consensus and stateof-the-science statements are prepared by independent panels of health professionals and public representatives on the basis of 1) the results of a systematic literature review prepared under contract with the Agency for Healthcare Research and Quality; 2) presentations by investigators working in areas relevant to the conference questions during a 2-day public session; 3) questions and statements from conference attendees during open discussion periods that are part of the public session; and 4) closed deliberations by the panel during the remainder of the second day and morning of the third. This statement is an independent report of the panel and is not a policy statement of the National Institutes of Health or the U.S. government. The following statement is an abridged version of the panel’s report, which is available in full at http: //consensus.nih.gov/2010/lactosestatement.htm. Lactose intolerance is the syndrome of diarrhea, abdominal pain, flatulence, or bloating occurring after lactose ingestion. These symptoms, which are produced by malabsorption of lactose, a sugar found in milk and other dairy products, often cause afflicted individuals to avoid dairy products in their diets. Lactose malabsorption is caused by a decreased ability to digest lactose that is due to a deficiency in the levels of the enzyme lactase. Lactase breaks lactose down into 2 simpler sugars, glucose and galactose, which are readily absorbed into the bloodstream. This enzyme is produced by expression of the lactase‐phlorizin hydrolase gene in the cells lining the small intestine. All infants produce lactase and successfully digest lactose provided by human milk or by infant formulas. However, sometime after weaning, a genetically programmed decrease in lactase (lactase nonpersistence) occurs in most children worldwide. The symptoms of lactose intolerance result from bacterial fermentation of undigested lactose in the colon. Lactose malabsorption can be diagnosed by having individuals ingest a standard dose of lactose after fasting and measuring breath hydrogen; elevated breath hydrogen levels are caused by bacterial fermentation of undigested lactose in the colon. Other diagnostic tools include measuring lactase activity in an intestinal biopsy sample or genetic testing for the common polymorphism that is linked to lactase nonpersistence. The demonstration of lactose malabsorption does not necessarily indicate that an individual will have symptoms. Many variables determine whether a person who malabsorbs lactose develops symptoms, including the dose of lactose ingested, the residual intestinal lactase activity, the ingestion of food along with lactose, the ability of the colonic flora to ferment lactose, and individual sensitivity to the products of lactose fermentation.

Nutrition and bone health. Lactose and bone

Lactose, a disaccharide in milk or dairy products, is known to promote calcium absorption. The enzyme lactase is needed to digest lactose. Although lactase is secreted normally in childhood, the secretion is decreased with growth, and the activity becomes lower in adulthood. When the activity of lactase is low, lactose passes intact the small intestine and reaches the large intestine, could cause unpleasantness such as diarrhea and stomach ache. This is called lactose intolerance. In this paper, we discuss promotion of calcium absorption by lactose, lactose intolerance, and bone health.

Differential Impact of Lactose/Lactase Phenotype on Colonic Microflora

The ability to digest lactose divides the world's population into two phenotypes that may be risk variability markers for several diseases. Prebiotic effects likely favour lactose maldigesters who experience lactose spilling into their colon. To evaluate the effects of fixed-dose lactose solutions on fecal bifidobacteria and lactobacilli in digesters and maldigesters, and to determine whether the concept of a difference in ability to digest lactose is supported. A four-week study was performed in 23 lactose maldigesters and 18 digesters. Following two weeks of dairy food withdrawal, subjects ingested 25 g of lactose twice a day for two weeks. Stool bifidobacteria and lactobacilli counts pre- and postintervention were measured as the primary outcome. For secondary outcomes, total anaerobes, Enterobacteriaceae, beta-galactosidase and N-acetyl-beta-D-glucosaminidase activity in stool, as well as breath hydrogen and symptoms following lactose challenge tests, were measured. Lactose maldigesters had a mean change difference (0.72 log10 colony forming unitsg stool; P=0.04) in bifidobacteria counts compared with lactose digesters. Lactobacilli counts were increased, but not significantly. Nevertheless, reduced breath hydrogen after lactose ingestion correlated with lactobacilli (r=-0.5; P<0.001). Reduced total breath hydrogen and symptom scorestogether, with a rise in fecal enzymes after intervention, were appropriate, but not significant. Despite failure to achieve full colonic adaptation, the present study provided evidence for a differential impact of lactose on microflora depending on genetic lactase status. A prebiotic effect was evident in lactose maldigesters but not in lactose digesters. This may play a role in modifying the mechanisms of certain disease risks related to dairy food consumption between the two phenotypes.

Update to Holden and Mace's “Phylogenetic Analysis of the Evolution of Lactose Digestion in Adults” (1997): Revisiting the Coevolution of Human Cultural and Biological Diversity

In 1997, Clare Holden and I used a formal phylogenetic comparative method to show that high levels of the ability to digest lactose in adulthood were coevolving with a history of dairying at the population level (Holden and Mace 1997). This not only confirmed what was already suspected—that lactase persistence was an adaptation to pastoralism—but also allowed us to show statistically the direction of the change: Dairying preceded the evolution of lactose tolerance, providing stronger evidence in favor of the route of causation. Any model in which the evolution of lactose tolerance either was independent of pastoralism or preceded the cultural evolution of pastoralism was far less likely than models in which pas-toralism evolved first, which then caused lactase persistence to be selected for. Since 1997, when we wrote our paper, I am happy to say that we still agree with the conclusions of our study, and in fact, had we to do it over again, we would not do it in any substantively different way. However, there have been a number of exciting developments in the field, and I am delighted to take the opportunity to report them here.First, when we examined the coevolution of lactose tolerance and milk drinking, although the association was known (Simoons 1978), little was known about the genetic basis of the persistence of the ability to digest lactose into adult-hood. This is no longer the case, and the story is intriguing (Ingram et al. 2009). Several candidate genes have been identified that appear to be highly correlated with lactase persistence. One of the tightest correlations is with the -

Phylogenetic Analysis of the Evolution of Lactose Digestion in Adults

In most of the world's population the ability to digest lactose declines sharply after infancy. High lactose digestion capacity in adults is common only in populations of European and circum-Mediterranean origin and is thought to be an evolutionary adaptation to millennia of drinking milk from domestic livestock. Milk can also be consumed in a processed form, such as cheese or soured milk, which has a reduced lactose content. Two other selective pressures for drinking fresh milk with a high lactose content have been proposed: promotion of calcium uptake in high-latitude populations prone to vitamin-D deficiency and maintainance of water and electrolytes in the body in highly and environments. These three hypotheses are all supported by the geographic distribution of high lactose digestion capacity in adults. However, the relationships between environmental variables and adult lactose digestion capacity are highly confounded by the shared ancestry of many populations whose lactose digestion capacity has been tested. The three hypotheses for the evolution of high adult lactose digestion capacity are tested here using a comparative method of analysis that takes the problem of phylogenetic confounding into account. This analysis supports the hypothesis that high adult lactose digestion capacity is an adaptation to dairying but does not support the hypotheses that lactose digestion capacity is additionally selected for either at high latitudes or in highly arid environments. Furthermore, methods using maximum likelihood are used to show that the evolution of milking preceded the evolution of high lactose digestion.

Effect of dairy and non-dairy calcium on fecal fat excretion in lactose digester and maldigester obese adults

BackgroundThe effect of dietary calcium on fecal fat excretion in lactose maldigestion is not known.ObjectiveTo investigate the effect of dairy and nondairy dietary calcium on fecal fat excretion in lactose digesters and maldigesters during moderate energy restriction.DesignA randomized cross-over trial comparing the effect of 500 mg vs. 1500 mg dairy and nondairy calcium on fecal fat excretion in 34 healthy adults during moderate (− 30%) energy restriction diet-induced weight loss for 12 weeks. The participants were classified as lactose digester or maldigester on the basis of breath hydrogen test.MeasurementsAnthropometric parameters and body composition, resting energy expenditure, energy and nutrient intake, fecal fat, physical activity, blood pressure, blood and urine sampling for pertinent measurements.ResultsFecal fat loss expressed as percent of fat intake was significantly higher with 1500 mg (high-Ca) compared to 500 mg (low-Ca) calcium intake per day (mean: 3.0%; the 95% CI: 2.3 to 3.7%; P <0.001) independent of calcium source and lactose digestion status.ConclusionsDuring moderate energy restriction induced weight loss a high-Ca diet causes an increase in fecal fat excretion independent of calcium source. Calcium intake related fecal fat loss is also independent of the ability to digest lactose and it is not diminished over time.

Update to Terwilliger and Göring's "Gene Mapping in the 20th and 21st Centuries" (2000): Gene Mapping When Rare Variants Are Common and Common Variants Are Rare

Update to Terwilliger and Göring's "Gene Mapping in the 20th and 21st Centuries" (2000):Gene Mapping When Rare Variants Are Common and Common Variants Are Rare Joseph D. Terwilliger and Harald H. H. Göring Keywords Gene Mapping, Common Variant/Common Disease (CVCD) Hypothesis, Complex Disease Genetics, Study Design Our Lasker Prize winning article from 2000 was a discussion of the myriad factors that influence the success or failure of gene mapping studies, and in it we suggested that the reasons we geneticists have had so little success in unraveling the etiology of complex traits had more to do with biology than technology and that many of the decisions about future strategies were being made based on unrealistic and untested assumptions. At the time, the common variant/common disease (CVCD) hypothesis (Reich and Lander 2001) was widely believed to provide a plausible model for complex disease genetics, in which common alleles [defined at the time as greater than 0.10 MAF (minor allele frequency)] with high attributable fractions, such as APOE4 and Alzheimer disease, would dominate trait etiology (Fallin et al. 2001; Pennisi 1998). As argued by Risch and Merikangas (1996: 1516), "Despite the small effects of such genes, the magnitude of their attributable risk may be large because they are quite frequent in the population, making them of public health significance." The discussions at the time proposed that such alleles should be ubiquitous across world populations, predating the expansion of human populations out of Africa (Goldstein and Weale 2001; Lander 1996). We argued that this was inconsistent with what we know about the nature of the evolution of genetic variation (Terwilliger 2001; Terwilliger and Weiss 1998; Weiss and Terwilliger 2000) and "that a larger number of less common alleles is likely to be involved in the etiology of complex disease" (Terwilliger and Göring 2000: 122) with individually trivial attributable fractions. At the time, we were accused of being naysayers and extremists for suggesting that genome-wide association studies would not be uncovering APOE-like effects for schizophrenia and most other complex traits (Brookes 1999; Emahazion et al. 2001; Pennisi 1998). Leading proponents of the CVCD hypothesis predicted in 1998 that "it would be surprising if most of the major genetic factors involved in human disease were not defined over the next 5–10 years" (Bell 1998: 618) and that "the widespread redefinition [End Page 729] of disease through genetics will be accompanied by the use of genetics for prediction and diagnosis and to optimize treatment in most common diseases. This is likely to occur within the next decade" (Bell 1998: 620). Ten years and billions of taxpayer dollars later, our once "extreme" position has replaced the mainstream opinion of a decade ago, as the recent flood of empirical data from genome-wide association studies consistently yields results that are inconsistent with the CVCD hypothesis and rosy scenarios about personalized medicine. In recent months, papers have been trumpeting the success of genome-wide association studies in finding new rare (i.e., p < 0.1) variants with individually minuscule attributable risks, forcing investigators to admit that their results effectively prove that there must be hundreds or thousands of alleles of small effect influencing schizophrenia and bipolar disorder (Purcell et al. 2009), height (Aulchenko et al. 2009), hypertension (Levy et al. 2009), type 2 diabetes (Zeggini et al. 2007), and virtually every other complex trait examined. Perhaps the only common variant of high attributable fraction that has proven to be a useful predictor of disease in the past decade is the lactase-persistence allele identified through family studies in Finland (Enattah et al. 2002), and the allelic simplicity of this locus has more to do with the fact that the new mutation added a useful function—ability to digest lactose in adulthood—rather than making a gene work less efficiently, as most random mutations tend to do. Even the most trumpeted "success stories" in genome-wide association studies, such as Crohn's disease (Barrett et al. 2008), end up implicating tens of specific rare variants, which put together explain only a few percent of the overall genetic contribution to the disease, putting the promised personalized medicine and "gene-chip...

Update to Holden and Mace's "Phylogenetic Analysis of the Evolution of Lactose Digestion in Adults" (1997): Revisiting the Coevolution of Human Cultural and Biological Diversity

Update to Holden and Mace's "Phylogenetic Analysis of the Evolution of Lactose Digestion in Adults" (1997):Revisiting the Coevolution of Human Cultural and Biological Diversity Ruth Mace Keywords Lactase Persistence, Lactose Tolerance, Pastoralism, Phylogenetic Trees, Language, Phylogenetic Comparative Methods In 1997, Clare Holden and I used a formal phylogenetic comparative method to show that high levels of the ability to digest lactose in adulthood were coevolving with a history of dairying at the population level (Holden and Mace 1997). This not only confirmed what was already suspected—that lactase persistence was an adaptation to pastoralism—but also allowed us to show statistically the direction of the change: Dairying preceded the evolution of lactose tolerance, providing stronger evidence in favor of the route of causation. Any model in which the evolution of lactose tolerance either was independent of pastoralism or preceded the cultural evolution of pastoralism was far less likely than models in which pastoralism evolved first, which then caused lactase persistence to be selected for. Since 1997, when we wrote our paper, I am happy to say that we still agree with the conclusions of our study, and in fact, had we to do it over again, we would not do it in any substantively different way. However, there have been a number of exciting developments in the field, and I am delighted to take the opportunity to report them here. First, when we examined the coevolution of lactose tolerance and milk drinking, although the association was known (Simoons 1978), little was known about the genetic basis of the persistence of the ability to digest lactose into adulthood. This is no longer the case, and the story is intriguing (Ingram et al. 2009). Several candidate genes have been identified that appear to be highly correlated with lactase persistence. One of the tightest correlations is with the -13910*T allele, which is a single nucleotide polymorphism (13.9 kb) located close to the lactase gene (C-13910 > T). The allele is widespread in Europe, and its high frequency combined with a long region of haplotype conservation (500 kb) suggests recent origin combined with strong selection (Bersaglieri et al. 2004). This story continues to provide not only one of the best examples of gene culture coevolution but also one of the strongest cases of recent selection on a gene being documented. Why the selection in favor of lactase persistence in Europe is so strong is not entirely clear, but it clearly enabled enhanced survival and growth [End Page 621] and provides further support for the notion that it was the Indo-Europeans' agricultural innovations that underpinned their dominance in Europe. What is intriguing, however, is that the same genes do not appear to predict lactase persistence in different regions of the world. This allele does not predict lactose tolerance in Africa, where it is actually rare and where at least three other alleles (also close to the lactase gene) have been implicated (Tishkoff et al. 2007). This suggests, as predicted by the culture historical hypothesis, that lactase persistence evolved recently after the spread of modern humans around the world, and the problem of how to digest milk has been "solved" by natural selection in a number of different ways. The independent evolution of different gene-regulating mechanisms is the best explanation, and lactase persistence may be one of the first examples of a polymorphism in a regulatory element. In addition, cultural traditions, especially curdling milk before drinking, may have contributed to relatively low levels of lactose tolerance in some populations, especially in Africa. Some have suggested that high levels of lactase persistence might have hidden costs in malarial areas, because flavins generated by milk drinking may enhance the risk of catching malaria. There is also some evidence that, among Somali nomads, a particular gut flora is enabling lactose digestion in genetically "lactose intolerant" individuals (Ingram et al. 2009). There is much more to run in this story as all these diverse mechanisms are further investigated. The reason we were able to make firm conclusions about the direction of gene-culture evolution in our 1997 paper was because the methods we were using were a considerable methodological advance on previous work in...