Lactase Persistence

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Eric Sibley - One of the best experts on this subject based on the ideXlab platform.

  • The human Lactase Persistence-associated SNP -13910*T enables in vivo functional Persistence of Lactase promoter-reporter transgene expression.
    Human genetics, 2012
    Co-Authors: Lin Fang, Jong Kun Ahn, Dariusz Wodziak, Eric Sibley
    Abstract:

    Lactase is the intestinal enzyme responsible for digestion of the milk sugar lactose. Lactase gene expression declines dramatically upon weaning in mammals and during early childhood in humans (Lactase nonPersistence). In various ethnic groups, however, Lactase persists in high levels throughout adulthood (Lactase Persistence). Genetic association studies have identified that Lactase Persistence in northern Europeans is strongly associated with a single nucleotide polymorphism (SNP) located 14 kb upstream of the Lactase gene: −13910*C/T. To determine whether the −13910*T SNP can function in vivo to mediate Lactase Persistence, we generated transgenic mice harboring human DNA fragments with the −13910*T SNP or the ancestral −13910*C SNP cloned upstream of a 2-kb rat Lactase gene promoter in a luciferase reporter construct. We previously reported that the 2-kb rat Lactase promoter directs a post-weaning decline of luciferase transgene expression similar to that of the endogenous Lactase gene. In the present study, the post-weaning decline directed by the rat Lactase promoter is impeded by addition of the −13910*T SNP human DNA fragment, but not by addition of the −13910*C ancestral SNP fragment. Persistence of transgene expression associated with the −13910*T SNP represents the first in vivo data in support of a functional role for the −13910*T SNP in mediating the human Lactase Persistence phenotype.

  • the human Lactase Persistence associated snp 13910 t enables in vivo functional Persistence of Lactase promoter reporter transgene expression
    Human Genetics, 2012
    Co-Authors: Lin Fang, Jong Kun Ahn, Dariusz Wodziak, Eric Sibley
    Abstract:

    Lactase is the intestinal enzyme responsible for digestion of the milk sugar lactose. Lactase gene expression declines dramatically upon weaning in mammals and during early childhood in humans (Lactase nonPersistence). In various ethnic groups, however, Lactase persists in high levels throughout adulthood (Lactase Persistence). Genetic association studies have identified that Lactase Persistence in northern Europeans is strongly associated with a single nucleotide polymorphism (SNP) located 14 kb upstream of the Lactase gene: −13910*C/T. To determine whether the −13910*T SNP can function in vivo to mediate Lactase Persistence, we generated transgenic mice harboring human DNA fragments with the −13910*T SNP or the ancestral −13910*C SNP cloned upstream of a 2-kb rat Lactase gene promoter in a luciferase reporter construct. We previously reported that the 2-kb rat Lactase promoter directs a post-weaning decline of luciferase transgene expression similar to that of the endogenous Lactase gene. In the present study, the post-weaning decline directed by the rat Lactase promoter is impeded by addition of the −13910*T SNP human DNA fragment, but not by addition of the −13910*C ancestral SNP fragment. Persistence of transgene expression associated with the −13910*T SNP represents the first in vivo data in support of a functional role for the −13910*T SNP in mediating the human Lactase Persistence phenotype.

  • Lactase Persistence SNPS IN AFRICAN POPULATIONS REGULATE PROMOTER ACTIVITY IN INTESTINAL CELL CULTURE
    2011
    Co-Authors: Eric Sibley, Jong Kun Ahn
    Abstract:

    Lactase-phlorizin hydrolase, Lactase, is the intestinal enzyme responsible for the digestion of the milk sugar lactose. The majority of the world’s human population experiences a decline in expression of the Lactase gene by late childhood (Lactase non-Persistence). Individuals with Lactase Persistence, however, continue to express high levels of the Lactase gene throughout adulthood. Lactase Persistence is a heritable autosomal dominant condition and has been strongly correlated with several single nucleotide polymorphisms (SNPs) located 14 kb upstream of the Lactase gene in different ethnic populations: -13910*T in Europeans and -13907*G, -13915*G, and -14010*C in several African populations. The coincidence of the four SNPs clustering within 100 bp strongly suggests that this region mediates the Lactase non-Persistence/Persistence phenotype. Having previously characterized the European SNP, we aimed to determine whether the African SNPs similarly mediate a functional role in regulating the Lactase promoter. Human intestinal Caco-2 cells were transfected with Lactase SNP/promoter-reporter constructs and assayed for promoter activity. The -13907*G and -13915*G SNPs result in a significant enhancement of Lactase promoter activity relative to the ancestral Lactase non-Persistence genotype. Such differential regulation by the SNPs is consistent with a causative role in the mechanism specifying the Lactase Persistence phenotype.

  • 13915 g dna polymorphism associated with Lactase Persistence in africa interacts with oct 1
    Human Genetics, 2011
    Co-Authors: Lynne C. Olds, Jong Kun Ahn, Eric Sibley
    Abstract:

    Lactase gene expression declines with aging (Lactase non-Persistence) in the majority of humans worldwide. Lactase Persistence is a heritable autosomal dominant condition and has been strongly correlated with several single nucleotide polymorphisms (SNPs) located ~14-kb upstream (−13907, −13910 and −13915) of the Lactase gene in different ethnic populations. In contrast to the −13907*G and −13910*T SNPs, the −13915*G SNP was previously believed not to interact with Oct-1. In the present study, however, Oct-1 is shown to interact with the −13915*G SNP region DNA sequence by EMSAs and gel supershift. In addition, Oct-1 is capable of enhancing promoter activity of a Lactase promoter–reporter construct harboring the 13915*G SNP sequence in cell culture. Oct-1 binding to the −13907 to −13915 SNP region therefore remains a candidate interaction involved in Lactase Persistence.

  • Theodore E. Woodward Award: Lactase Persistence SNPs in African populations regulate promoter activity in intestinal cell culture.
    Transactions of the American Clinical and Climatological Association, 2011
    Co-Authors: Eric Sibley, Jong Kun Ahn
    Abstract:

    Lactase-phlorizin hydrolase, Lactase, is the intestinal enzyme responsible for the digestion of the milk sugar lactose. The majority of the world's human population experiences a decline in expression of the Lactase gene by late childhood (Lactase non-Persistence). Individuals with Lactase Persistence, however, continue to express high levels of the Lactase gene throughout adulthood. Lactase Persistence is a heritable autosomal dominant condition and has been strongly correlated with several single nucleotide polymorphisms (SNPs) located ∼14 kb upstream of the Lactase gene in different ethnic populations: -13910*T in Europeans and -13907*G, -13915*G, and -14010*C in several African populations. The coincidence of the four SNPs clustering within 100 bp strongly suggests that this region mediates the Lactase non-Persistence/Persistence phenotype. Having previously characterized the European SNP, we aimed to determine whether the African SNPs similarly mediate a functional role in regulating the Lactase promoter. Human intestinal Caco-2 cells were transfected with Lactase SNP/promoter-reporter constructs and assayed for promoter activity. The -13907*G and -13915*G SNPs result in a significant enhancement of Lactase promoter activity relative to the ancestral Lactase non-Persistence genotype. Such differential regulation by the SNPs is consistent with a causative role in the mechanism specifying the Lactase Persistence phenotype.

Irma Järvelä - One of the best experts on this subject based on the ideXlab platform.

  • Lactase Persistence genotypes and malaria susceptibility in Fulani of Mali
    Malaria journal, 2011
    Co-Authors: A. Inkeri Lokki, Irma Järvelä, Elisabeth Israelsson, Bakary Maiga, Marita Troye-blomberg, Amagana Dolo, Ogobara K. Doumbo, Seppo Meri, Ville Holmberg
    Abstract:

    Background: Fulani are a widely spread African ethnic group characterized by lower susceptibility to Plasmodium falciparum, clinical malaria morbidity and higher rate of Lactase Persistence compared to sympatric tribes. Lactase non-Persistence, often called lactose intolerance, is the normal condition where Lactase activity in the intestinal wall declines after weaning. Lactase Persistence, common in Europe, and in certain African people with traditions of raising cattle, is caused by polymorphisms in the enhancer region approximately 14 kb upstream of the Lactase gene. Methods: To evaluate the relationship between malaria and Lactase Persistence genotypes, a 400 bp region surrounding the main European C/T-13910 polymorphism upstream of the Lactase gene was sequenced. DNA samples used in the study originated from 162 Fulani and 79 Dogon individuals from Mali. Results: Among 79 Dogon only one heterozygote of the Lactase enhancer polymorphism was detected, whereas all others were homozygous for the ancestral C allele. Among the Fulani, the main European polymorphism at locus C/T-13910 was by far the most common polymorphism, with an allele frequency of 37%. Three other singlenucleotide polymorphisms were found with allele frequencies of 3.7%, 1.9% and 0.6% each. The novel DNA polymorphism T/C-13906 was seen in six heterozygous Fulani. Among the Fulani with Lactase non-Persistence CC genotypes at the C/T-13910 locus, 24% had malaria parasites detectable by microscopy compared to 18% for Lactase persistent genotypes (P = 0.29). Pooling the Lactase enhancer polymorphisms to a common presumptive genotype gave 28% microscopy positives for non-persistent and 17% for others (P = 0.11). Conclusions: Plasmodium falciparum parasitaemia in asymptomatic Fulani is more common in individuals with Lactase non-Persistence genotypes, but this difference is not statistically significant. The potential immunoprotective properties of dietary cow milk as a reason for the partial malaria resistance of Fulani warrant further investigation.

  • The T/G−13915 variant upstream of the Lactase gene (LCT) is the founder allele of Lactase Persistence in an urban Saudi population
    Journal of medical genetics, 2007
    Co-Authors: Faiqa Imtiaz, Erkki Savilahti, A Sarnesto, D Trabzuni, K Al-kahtani, I Kagevi, Mohamed S. Rashed, Brian F. Meyer, Irma Järvelä
    Abstract:

    Background: The prevalence of Lactase Persistence is high in Saudi Arabia. Objective: To identify a DNA variant for the Lactase Persistence/non-Persistence trait in adult Arabs in Saudi Arabia. Methods: We sequenced DNA from 432 anonymous neonatal blood donors from five different regions of Saudi Arabia to cover the 400 bp region surrounding the previously identified Lactase Persistence/non-Persistence variant C/T−13910 residing in intron 13 of the MCM6 gene. Results: Two anonymous blood donors carried the C/T−13910 genotype. One variant, T/G −13915, residing 5 bp upstream of the C/T−13910 variant, was present in 332 of 432 (76.9%) of the neonatal samples, compatible with previous prevalence figures of Lactase Persistence in urban Saudi populations. Determination of disaccharidase activities in 25 intestinal biopsy samples showed a highly significant correlation between Lactase activity and the T/G−13915 genotypes (p Conclusion: The T/G−13915 variant is the founder mutation of Lactase Persistence in an urban Saudi population. The results obtained here have implications for genetic testing of adult-type hypolactasia and to analysis of human evolution, the origin of cattle domestication and migrations of the populations in the Arabian peninsula.

  • the t g 13915 variant upstream of the Lactase gene lct is the founder allele of Lactase Persistence in an urban saudi population
    Journal of Medical Genetics, 2007
    Co-Authors: Faiqa Imtiaz, Erkki Savilahti, A Sarnesto, D Trabzuni, I Kagevi, Mohamed S. Rashed, Brian F. Meyer, K Alkahtani, Irma Järvelä
    Abstract:

    Background: The prevalence of Lactase Persistence is high in Saudi Arabia. Objective: To identify a DNA variant for the Lactase Persistence/non-Persistence trait in adult Arabs in Saudi Arabia. Methods: We sequenced DNA from 432 anonymous neonatal blood donors from five different regions of Saudi Arabia to cover the 400 bp region surrounding the previously identified Lactase Persistence/non-Persistence variant C/T−13910 residing in intron 13 of the MCM6 gene. Results: Two anonymous blood donors carried the C/T−13910 genotype. One variant, T/G −13915, residing 5 bp upstream of the C/T−13910 variant, was present in 332 of 432 (76.9%) of the neonatal samples, compatible with previous prevalence figures of Lactase Persistence in urban Saudi populations. Determination of disaccharidase activities in 25 intestinal biopsy samples showed a highly significant correlation between Lactase activity and the T/G−13915 genotypes (p Conclusion: The T/G−13915 variant is the founder mutation of Lactase Persistence in an urban Saudi population. The results obtained here have implications for genetic testing of adult-type hypolactasia and to analysis of human evolution, the origin of cattle domestication and migrations of the populations in the Arabian peninsula.

  • Lactase Persistence and ovarian carcinoma risk in Finland, Poland and Sweden.
    International journal of cancer, 2005
    Co-Authors: Mikko Kuokkanen, Ralf Bützow, Heli Rasinperä, Krzysztof Mędrek, Mef Nilbert, Susanne Malander, Jan Lubinski, Irma Järvelä
    Abstract:

    Ovarian carcinoma is the fourth most common cause of cancer death in women. The cause and pathogenesis of this disease has remained obscure. Galactose, the hydrolyzing product of the milk sugar lactose, has been hypothesized to be toxic to ovarian epithelial cells and consumption of dairy products and Lactase Persistence has been suggested to be a risk factor for ovarian carcinoma. In adults, downregulation of Lactase depends on a variant C/T-13910 at the 5' end of the Lactase gene. To explore whether Lactase Persistence is related to the risk of ovarian carcinoma we determined the C/T-13910 genotype in a cohort of 782 women with ovarian carcinoma. The C/T-13910 genotype was defined by solid phase minisequencing from 327 Finnish, 303 Polish, 152 Swedish patients and 938 Finnish, 296 Polish and 97 Swedish healthy individuals served as controls. Lactase Persistence did not associate significantly with increased risk for ovarian carcinoma in the Finnish (odds ratio [OR]=0.77, 95% confidence interval [CI]=0.57-1.05, p=0.097), in the Polish (OR=0.95, 95% CI=0.68-1.33, p=0.75), or in the Swedish populations (OR=1.63, 95% CI=0.65-4.08, p=0.29). Our results do not support the hypothesis that Lactase Persistence increases the ovarian carcinoma risk. On the contrary, Lactase Persistence may decrease the ovarian carcinoma risk at least in the Finnish population.

Torbjörn K. Nilsson - One of the best experts on this subject based on the ideXlab platform.

Dallas M. Swallow - One of the best experts on this subject based on the ideXlab platform.

  • population genetics of Lactase Persistence and lactose intolerance
    eLS, 2012
    Co-Authors: Catherine J. E. Ingram, Anke Liebert, Dallas M. Swallow
    Abstract:

    Variation in the ability of adult humans to digest the lactose in milk is a genetically determined trait that has excited the interest of many for the past 50 years. The trait seems to have risen to high frequencies by one of the strongest selection pressures ever described. This section describes the phenotypic polymorphism and the evidence that the genetic trait involves regulation of expression of the Lactase gene and is caused by multiple independent mutations that have reached high frequencies in different populations, because of the benefits of drinking milk. The evolutionary history in Europe and Africa are rather different; there being a single high-frequency allele in Europe, in contrast to multiple alleles in Africa. Also the selective forces, which are likely to include both the nutritional and water content of milk, may have been different in these regions. Key Concepts: The enzyme, Lactase, is restricted to the small intestine where it digests lactose in the milk of suckling mammals. Lactase persists into adult life in some, but not all, people. Lactase Persistence is a genetic trait, which varies in frequency in different populations of the world. Mutations in an enhancer sequence, at a distance from the Lactase gene, appear to be responsible for Lactase Persistence. These alleles arose in the last few thousand years and have been under strong positive selection. The selection may be attributable to one of the nutrients or water in fresh milk and/or its calorific value. Keywords: lactose; milk; Lactase; selection; Persistence; tolerance

  • eLS - Population Genetics of Lactase Persistence and Lactose Intolerance
    eLS, 2012
    Co-Authors: Catherine J. E. Ingram, Anke Liebert, Dallas M. Swallow
    Abstract:

    Variation in the ability of adult humans to digest the lactose in milk is a genetically determined trait that has excited the interest of many for the past 50 years. The trait seems to have risen to high frequencies by one of the strongest selection pressures ever described. This section describes the phenotypic polymorphism and the evidence that the genetic trait involves regulation of expression of the Lactase gene and is caused by multiple independent mutations that have reached high frequencies in different populations, because of the benefits of drinking milk. The evolutionary history in Europe and Africa are rather different; there being a single high-frequency allele in Europe, in contrast to multiple alleles in Africa. Also the selective forces, which are likely to include both the nutritional and water content of milk, may have been different in these regions. Key Concepts: The enzyme, Lactase, is restricted to the small intestine where it digests lactose in the milk of suckling mammals. Lactase persists into adult life in some, but not all, people. Lactase Persistence is a genetic trait, which varies in frequency in different populations of the world. Mutations in an enhancer sequence, at a distance from the Lactase gene, appear to be responsible for Lactase Persistence. These alleles arose in the last few thousand years and have been under strong positive selection. The selection may be attributable to one of the nutrients or water in fresh milk and/or its calorific value. Keywords: lactose; milk; Lactase; selection; Persistence; tolerance

  • The −14010*C variant associated with Lactase Persistence is located between an Oct-1 and HNF1α binding site and increases Lactase promoter activity
    Human Genetics, 2011
    Co-Authors: Tine G. K. Jensen, Dallas M. Swallow, Anke Liebert, Rikke Lewinsky, Jørgen Olsen, Jesper T. Troelsen
    Abstract:

    In most people worldwide intestinal Lactase expression declines in childhood. In many others, particularly in Europeans, Lactase expression persists into adult life. The Lactase Persistence phenotype is in Europe associated with the −13910*T single nucleotide variant located 13,910 bp upstream the Lactase gene in an enhancer region that affects Lactase promoter activity. This variant falls in an Oct-1 binding site and shows greater Oct-1 binding than the ancestral variant and increases enhancer activity. Several other variants have been identified very close to the −13910 position, which are associated with Lactase Persistence in the Middle East and Africa. One of them, the −14010*C, is associated with Lactase Persistence in Africa. Here we show by deletion analysis that the −14010 position is located in a 144 bp region that reduces the enhancer activity. In transfections the −14010*C allele shows a stronger enhancer effect than the ancestral −14010*G allele. Binding sites for Oct-1 and HNF1α surrounding the −14010 position were identified by gel shift assays, which indicated that −14010*C has greater binding affinity to Oct-1 than −14010*G.

  • Evolution of Lactase Persistence: an example of human niche construction
    Philosophical transactions of the Royal Society of London. Series B Biological sciences, 2011
    Co-Authors: Pascale Gerbault, Yuval Itan, Dallas M. Swallow, Anke Liebert, Adam Powell, Mathias Currat, Joachim Burger, Mark G. Thomas
    Abstract:

    Niche construction is the process by which organisms construct important components of their local environment in ways that introduce novel selection pressures. Lactase Persistence is one of the clearest examples of niche construction in humans. Lactase is the enzyme responsible for the digestion of the milk sugar lactose and its production decreases after the weaning phase in most mammals, including most humans. Some humans, however, continue to produce Lactase throughout adulthood, a trait known as Lactase Persistence. In European populations, a single mutation (−13910*T) explains the distribution of the phenotype, whereas several mutations are associated with it in Africa and the Middle East. Current estimates for the age of Lactase Persistence-associated alleles bracket those for the origins of animal domestication and the culturally transmitted practice of dairying. We report new data on the distribution of −13910*T and summarize genetic studies on the diversity of Lactase Persistence worldwide. We review relevant archaeological data and describe three simulation studies that have shed light on the evolution of this trait in Europe. These studies illustrate how genetic and archaeological information can be integrated to bring new insights to the origins and spread of Lactase Persistence. Finally, we discuss possible improvements to these models.

  • the 14010 c variant associated with Lactase Persistence is located between an oct 1 and hnf1α binding site and increases Lactase promoter activity
    Human Genetics, 2011
    Co-Authors: Tine G. K. Jensen, Dallas M. Swallow, Anke Liebert, Jørgen H. Olsen, Rikke H. Lewinsky, Jesper T. Troelsen
    Abstract:

    In most people worldwide intestinal Lactase expression declines in childhood. In many others, particularly in Europeans, Lactase expression persists into adult life. The Lactase Persistence phenotype is in Europe associated with the −13910*T single nucleotide variant located 13,910 bp upstream the Lactase gene in an enhancer region that affects Lactase promoter activity. This variant falls in an Oct-1 binding site and shows greater Oct-1 binding than the ancestral variant and increases enhancer activity. Several other variants have been identified very close to the −13910 position, which are associated with Lactase Persistence in the Middle East and Africa. One of them, the −14010*C, is associated with Lactase Persistence in Africa. Here we show by deletion analysis that the −14010 position is located in a 144 bp region that reduces the enhancer activity. In transfections the −14010*C allele shows a stronger enhancer effect than the ancestral −14010*G allele. Binding sites for Oct-1 and HNF1α surrounding the −14010 position were identified by gel shift assays, which indicated that −14010*C has greater binding affinity to Oct-1 than −14010*G.

Mark G. Thomas - One of the best experts on this subject based on the ideXlab platform.

  • Diversity of Lactase Persistence in African milk drinkers.
    Human genetics, 2015
    Co-Authors: Bryony L. Jones, Mark G. Thomas, Anke Liebert, Endashaw Bekele, Tamiru Oljira, Pawel Zmarz, Nicolas Montalva, Ayele Tarekeyn, Rosemary Ekong, Neil Bradman
    Abstract:

    The genetic trait of Lactase Persistence is attributable to allelic variants in an enhancer region upstream of the Lactase gene, LCT. To date, five different functional alleles, −13910*T, −13907*G, −13915*G, −14009*G and −14010*C, have been identified. The co-occurrence of several of these alleles in Ethiopian lactose digesters leads to a pattern of sequence diversity characteristic of a ‘soft selective sweep’. Here we hypothesise that throughout Africa, where multiple functional alleles co-exist, the enhancer diversity will be greater in groups who are traditional milk drinkers than in non-milk drinkers, as the result of this sort of parallel selection. Samples from 23 distinct groups from 10 different countries were examined. Each group was classified ‘Yes ‘or ‘No’ for milk-drinking, and ethnicity, language spoken and geographic location were recorded. Predicted Lactase Persistence frequency and enhancer diversity were, as hypothesised, higher in the milk drinkers than the non-milk-drinkers, but this was almost entirely accounted for by the Afro-Asiatic language speaking peoples of east Africa. The other groups, including the ‘Nilo-Saharan language speaking’ milk-drinkers, show lower frequencies of LP and lower diversity, and there was a north-east to south-west decline in overall diversity. Amongst the Afro-Asiatic (Cushitic) language speaking Oromo, however, the geographic cline was not evident and the southern pastoralist Borana showed much higher LP frequency and enhancer diversity than the other groups. Together these results reflect the effects of parallel selection, the stochastic processes of the occurrence and spread of the mutations, and time depth of milk drinking tradition.

  • The evolution of Lactase Persistence in Europe. A synthesis of archaeological and genetic evidence
    International Dairy Journal, 2012
    Co-Authors: Michela Leonardi, Mark G. Thomas, Pascale Gerbault, Joachim Burger
    Abstract:

    Lactase Persistence, the ability to digest the milk sugar lactose in adulthood, is highly associated with a T allele situated 13,910 bp upstream from the actual Lactase gene in Europeans. The frequency of this allele rose rapidly in Europe after transition from hunter–gatherer to agriculturalist lifestyles and the introduction of milkable domestic species from Anatolia some 8000 years ago. Here we first introduce the archaeological and historic background of early farming life in Europe, then summarize what is known of the physiological and genetic mechanisms of Lactase Persistence. Finally, we compile the evidence for a co-evolutionary process between dairying culture and Lactase Persistence. We describe the different hypotheses on how this allele spread over Europe and the main evolutionary forces shaping this process. We also summarize three different computer simulation approaches, which offer a means of developing a coherent and integrated understanding of the process of spread of Lactase Persistence and dairying.

  • Evolution of Lactase Persistence: an example of human niche construction
    Philosophical transactions of the Royal Society of London. Series B Biological sciences, 2011
    Co-Authors: Pascale Gerbault, Yuval Itan, Dallas M. Swallow, Anke Liebert, Adam Powell, Mathias Currat, Joachim Burger, Mark G. Thomas
    Abstract:

    Niche construction is the process by which organisms construct important components of their local environment in ways that introduce novel selection pressures. Lactase Persistence is one of the clearest examples of niche construction in humans. Lactase is the enzyme responsible for the digestion of the milk sugar lactose and its production decreases after the weaning phase in most mammals, including most humans. Some humans, however, continue to produce Lactase throughout adulthood, a trait known as Lactase Persistence. In European populations, a single mutation (−13910*T) explains the distribution of the phenotype, whereas several mutations are associated with it in Africa and the Middle East. Current estimates for the age of Lactase Persistence-associated alleles bracket those for the origins of animal domestication and the culturally transmitted practice of dairying. We report new data on the distribution of −13910*T and summarize genetic studies on the diversity of Lactase Persistence worldwide. We review relevant archaeological data and describe three simulation studies that have shed light on the evolution of this trait in Europe. These studies illustrate how genetic and archaeological information can be integrated to bring new insights to the origins and spread of Lactase Persistence. Finally, we discuss possible improvements to these models.

  • A worldwide correlation of Lactase Persistence phenotype and genotypes
    BMC evolutionary biology, 2010
    Co-Authors: Yuval Itan, Bryony L. Jones, Catherine J. E. Ingram, Dallas M. Swallow, Mark G. Thomas
    Abstract:

    The ability of adult humans to digest the milk sugar lactose - Lactase Persistence - is a dominant Mendelian trait that has been a subject of extensive genetic, medical and evolutionary research. Lactase Persistence is common in people of European ancestry as well as some African, Middle Eastern and Southern Asian groups, but is rare or absent elsewhere in the world. The recent identification of independent nucleotide changes that are strongly associated with Lactase Persistence in different populations worldwide has led to the possibility of genetic tests for the trait. However, it is highly unlikely that all Lactase Persistence-associated variants are known. Using an extensive database of Lactase Persistence phenotype frequencies, together with information on how those data were collected and data on the frequencies of Lactase Persistence variants, we present a global summary of the extent to which current genetic knowledge can explain Lactase Persistence phenotype frequency. We used surface interpolation of Old World Lactase Persistence genotype and phenotype frequency estimates obtained from all available literature and perform a comparison between predicted and observed trait frequencies in continuous space. By accommodating additional data on sample numbers and known false negative and false positive rates for the various Lactase Persistence phenotype tests (blood glucose and breath hydrogen), we also apply a Monte Carlo method to estimate the probability that known Lactase Persistence-associated allele frequencies can explain observed trait frequencies in different regions. Lactase Persistence genotype data is currently insufficient to explain Lactase Persistence phenotype frequency in much of western and southern Africa, southeastern Europe, the Middle East and parts of central and southern Asia. We suggest that further studies of genetic variation in these regions should reveal additional nucleotide variants that are associated with Lactase Persistence.

  • Multiple Rare Variants as a Cause of a Common Phenotype: Several Different Lactase Persistence Associated Alleles in a Single Ethnic Group
    Journal of Molecular Evolution, 2009
    Co-Authors: Catherine J. E. Ingram, Mark G. Thomas, Mohamed F. Elamin, Michael E. Weale, Ayele Tarekegn, Tamiru Oljira Raga, Endashaw Bekele, Neil Bradman, Sarah L. Browning, Dallas M. Swallow
    Abstract:

    Persistence of intestinal Lactase into adulthood allows humans to use milk from other mammals as a source of food and water. This genetic trait has arisen by convergent evolution and the derived alleles of at least three different single nucleotide polymorphisms ( –13910C>T , –13915T>G , –14010G>C ) are associated with Lactase Persistence in different populations. Each allele occurs on an extended haplotype, consistent with positive directional selection. The SNPs are located in an ‘enhancer’ sequence in an intron of a neighboring gene ( MCM6 ) and modulate Lactase transcription in vitro. However, a number of Lactase persistent individuals carry none of these alleles, but other low-frequency single nucleotide polymorphisms have been observed in the same region. Here we examine a cohort of 107 milk-drinking Somali camel-herders from Ethiopia. Eight polymorphic sites are identified in the enhancer. –13915*G and –13907*G (a previously reported candidate) are each significantly associated with Lactase Persistence. A new allele, –14009*G , has borderline association with Lactase Persistence, but loses significance after correction for multiple testing. Sequence diversity of the enhancer is significantly higher in the Lactase persistent members of this and a second cohort compared with non-persistent members of the two groups ( P  = 7.7 × 10^−9 and 1.0 × 10^−3). By comparing other loci, we show that this difference is not due to population sub-structure, demonstrating that increased diversity can accompany selection. This contrasts with the well-documented observation that positive selection decreases diversity by driving up the frequency of a single advantageous allele, and has implications for association studies.

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