Dahlquist:Evo-Ed Evolution of Lactase Persistence

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Annotated Bibliography

Reviews

  • Amiri, M., et al. (2015). The Diverse Forms of Lactose Intolerance and the Putative Linkage to Several Cancers. Nutrients, 7(9), 7209-7230. doi:10.3390/nu7095332 (Nutrients)
    • Structure & function of LPH heavily defined & detailed, including how it is created & matured step by step and how it is transported to the luminal surface of the epithelial cells. The chemistry of digestion is explained on what type of cleavage occurs and what is hydrolyzed, which enables glucose & galactose to be absorbed into the enterocytes.
  • Anguita-Ruiz, A., Aguilera, C. M., & Gil, Á. (2020). Genetics of Lactose Intolerance: An Updated Review and Online Interactive World Maps of Phenotype and Genotype Frequencies. Nutrients, 12(9). https://doi.org/10.3390/nu12092689 (Full text)
    • Created two online interactive resources, which constitute an upgrade over previously published static world maps, and allow users a personalized data exploration, while at the same time accessing complete reports by population or ethnicity
  • Bayless, T. M., Brown, E., & Paige, D. M. (2017). Lactase Non-persistence and Lactose Intolerance. Current Gastroenterology Reports, 19(5), 23. https://doi.org/10.1007/s11894-017-0558-9
    • Current and historical information on lactase genetics, downregulation of lactase in adults, thresholds for lactose intolerance symptoms, and adaptation to lactose ingestion in lactase non-persistent individuals. Relation to public health, synthesized conclusions from the 2010 NIH Consensus Conference on lactose intolerance.
  • Beal, T. & Ervin, D. (2018). The Geography of Malnutrition. The Professional Geographer, 70(1), 47-59. doi: 10. 1080/00330124.2017.1310623 (Full text)
  • Blanchard, C. (2017). A history into genetic and epigenetic evolution of food tolerance. Current Opinion in Allergy and Clinical Immunology, 17(6), 460-464. doi: 10.1097/aci.0000000000000397 Ingenta])
    • Behind paywall
  • Bouwman, A. & Rühli, F. (2016). Archaeogenetics in evolutionary medicine. Journal of Molecular Medicine, 94(9), 971-977. doi:10.1007/s00109-016-1438-8 (Full text)
    • Gives brief history of emergence of LP
  • Cerny, V., Kulichova, I., Poloni, E. S., Nunes, J. M., Pereira, L., Mayor, A., & Sanchez-Mazas, A. (2018). Genetic history of the African Sahelian populations. Hla, 91(3), 153-166. doi: 10.1111/tan.13189 (Wiley)
    • Figure 2 shows allele frequencies of different SNPs associated with lactase persistence on map
  • Deng, Y., et al. (2015). Lactose Intolerance in Adults: Biological Mechanism and Dietary Management. Nutrients, 7(9), 8020-8035. doi:10.3390/nu7095380 (Nutrients)
    • The article defines why lactose is important to newborn mammals and how lactase activity usually decreases post-weaning, the exception being the mutations in the human LCT gene that arose independently in different parts of the world. The article also illustrates how lactose malabsorption and lactose intolerance are different. They outline how lactose intolerance symptoms arise physiologically and how environmental and physiological factors can affect the severity of these symptoms, proving that genetics alone do not determine phenotype.
  • Fan, S., Hansen, M. E., Lo, Y., & Tishkoff, S. A. (2016). Going global by adapting local: A review of recent human adaptation. Science, 354(6308), 54-59. doi:10.1126/science.aaf5098 (PubMed Central)
  • Fassio, F., Facioni, M., & Guagnini, F. (2018). Lactose Maldigestion, Malabsorption, and Intolerance: A Comprehensive Review with a Focus on Current Management and Future Perspectives. Nutrients, 10. doi: 10.3390/nu10111599 (Nutrients)
    • Information regarding where lactase is found and expressed, how the expression of lactase changes across time, what happens when there is a lactase deficiency, and the molecular make-up of LPH. The definitions of congenital lactase deficiency, primary lactase deficiency, and secondary hypolactasia are given, as well as clinical conditions that can cause secondary hypolactasia.
  • Gerbault, P. (2013). The onset of lactase persistence in Europe. Human heredity, 76(3-4), 154-161. doi:10.1159/000360136 (Human Heredity)
  • Goldman, A. S. (2019). Future Research in the Immune System of Human Milk. The Journal of Pediatrics, 206, 274-279. doi: 10.1016/j.jpeds.2018.11.024 (Full text)
  • Goodrich, J. K., Davenport, E. R., Clark, A. G., & Ley, R. E. (2017). The Relationship Between the Human Genome and Microbiome Comes into View. Annual Review of Genetics, 51, 413-433. doi: 10.1146/annurev-genet-110711-155532 (Full text)
    • The CC genotype of the C/T-13910 SNP was associated with increased levels of Bifidobacteria compared to those with the LP phenotype, which indicates that individuals who are LNP yet still eat dairy can increase their levels of lactose-digesting bacteria, enabling them to consume lactose with less symptoms. This information shows that genotype does not always correlate with expected phenotype, as the gut microbiome can influence this outcome. The article also speculates that even though the relationship between Bifidobacteria and genotype has only been found in the European SNP so far, it is not unlikely that this phenomenon is present in other SNPs.
  • Grand, R. J., Montgomery, R. K., Chitkara, D. K., & Hirschhorn, J. N. (2003). Changing genes; losing lactase. Gut, 52(5), 617-619. doi: 10.1136/gut.52.5.617 (Gut)
  • Hall, A. B., Tolonen, A. C., & Xavier, R. J. (2017). Human genetic variation and the gut microbiome in disease. Nature Reviews Genetics, 18(11), 690-699. doi: 10.1038/nrg.2017.63 (Nature)
  • Hartwig, F. P., et al. (2016). Association of lactase persistence genotype with milk consumption, obesity and blood pressure: a Mendelian randomization study in the 1982 Pelotas (Brazil) Birth Cohort, with a systematic review and meta-analysis. International journey of epidemiology, 45(5), 1573-1587. doi:10.1093/ije/dyw074 (Int J Epidemiol)
  • Heine, R. G., et al. (2017). Lactose intolerance and gastrointestinal cow's milk allergy in infants and children - common misconceptions revisited. World Allergy Organization Journal, 10. doi: 10.1186/s40413-017-0173-0 (WAO)
  • Ibrahim, S., Gyawali, R., Awaisheh, S., Ayivi, R., Silva, R., Subedi, K., . . . Krastanov, A. (2021). Fermented foods and probiotics: An approach to lactose intolerance. Journal of Dairy Research, 88(3), 357-365. doi:10.1017/S0022029921000625
    • Provides overview of lactose intolerance and describes various types of lactose intolerance, the how probiotics may alleviate the gastrointestinal symptoms associated with lactose non persistence
  • Ingram, C.J., Mulcare, C.A., Itan, Y., Thomas, M.G. & Swallow, D.M. (2009). Lactose digestion and the evolutionary genetics of lactase persistence. Hum. Genet. 124, 579–591. (Human Genetics)
  • Janiak, M. C. (2016). Digestive enzymes of human and nonhuman primates. Evolutionary Anthropology: Issues, News, and Reviews, 25(5). doi:10.1002/evan.21498 (Full text)
    • Good information
  • Jones, B. L. & Swallow, D. M. (2011). The impact of cis-acting polymorphisms on the human phenotype. Human genome organization, 5(1-4), 13–23. doi:10.1007/s11568-011-9155-4 (HUGO J)
  • Kimura, R. (2018). Global Landscapes of Human Phenotypic Variation in Inherited Traits. Evolution of the Human Genome I Evolutionary Studies, 217-239. doi: 10.1007/978-4-431-56603-8_11 (Full text)
  • Laland, K. N. (2015). On evolutionary causes and evolutionary processes. Behavioural Processes, 117, 97-104. doi:10.1016/j.beproc.2014.05.008 (Full text)
  • Lapides, R. & Savaiano, D. (2018). Gender, age, race and lactose intolerance: Is there evidence to support a differential symptom response? A scoping review. Nutrients, 10(12), 1956. doi:10.3390/nu10121956 (Nutrients)
  • Lomer, M. C. E., Parkes, G. C., & Sanderson, J. D. (2008). Lactose intolerance in clinical practice–myths and realities. Alimentary pharmacology & therapeutics, 27(2), 93-103. doi:10.1111/j.1365-2036.2007.03557.x (APT)
  • Lukito, W., et al. (2015). From 'lactose intolerance' to 'lactose nutrition'. Asian pacific journal of clinical nutrition, 24(1), S1-S8. doi:10.6133/apjcn.2015.24.s1.01 (PubMed Central)
  • Marciniak, S. & Perry, G. H. (2017). Harnessing ancient genomes to study the history of human adaptation. Nature Reviews Genetics, 18, 659-674. doi: 10.1038/nrg.2017.65 (Nature)
  • Melnik, B. & Schmitz, G. (2017). Milk’s Role as an Epigenetic Regulator in Health and Disease. Diseases, 5(1), 12. doi:10.3390/diseases5010012 (Diseases)
  • Misselwitz, B., et al. (2013). Lactose malabsorption and intolerance: pathogenesis, diagnosis and treatment. United European Gastroenterology Journal, 1(3) 151-159. doi:10.1177/2050640613484463 (PubMed Central)
  • Montinaro, F. & Capelli, C. (2018). The evolutionary history of Southern Africa. Current Opinion in Genetics & Development, 53, 157-164. doi: 10.1016/j.gde.2018.11.003 (Full text)
  • Montgomery, R. K., et al. (2007). Lactose and lactase--who is lactose intolerant and why?. Journal of pediatric gastroenterology and nutrition, 45(2). doi:10.1097/mpg.0b013e31812e68f6 (JPGN)
  • O'Brien, M. J. & Bentley, R. A. (2015). The role of food storage in human niche construction: An example from Neolithic Europe. Environmental Archaeology, 20(4), 364-378. doi:10.1179/1749631414y.0000000053 (Taylor and Francis)
  • Pennacchio, L. A., Bickmore, W., Dean, A., Nobrega, M. A., & Bejerano, G. (2013). Enhancers: five essential questions. Nature Reviews Genetics, 14(4), 288-295. doi:10.1038/nrg3458 (Nature)
  • Schlebusch, C. M. & Jakobsson, M. (2018). Tales of Human Migration, Admixture, and Selection in Africa. Annual Review of Genomics and Human Genetics, 19, 405-428. doi: 10.1146/annurev-genom-083117-021759 (Annual Review)
  • Segurel, L. & Bon, C. (2017). On the Evolution of Lactase Persistence in Humans. Annual Review of Genomics and Human Genetics, 18(1), 297-319. doi:10.1146/annurev-genom-091416-035340 (Annual Reviews)
    • new SNPs: G-13907 (rs41525747), C-13913 (rs41456145), G-14009 (rs869051967)
  • Shrier, I., et al. (2008). Impact of lactose containing foods and the genetics of lactase on diseases: an analytical review of population data. Nutrition and cancer, 60(3), 292-300. 10.1080/01635580701745301 (PubMed Central)
  • Siggers, T. & Gordân, R. (2013). Protein–DNA binding: complexities and multi-protein codes. Nucleic acids research, gkt1112. doi: 10.1093/nar/gkt1112 (Nucleic Acids Research)
  • Storhaug, C. L., Fosse, S. K., & Fadnes, L. T. (2017). Country, regional, and global estimates for lactose malabsorption in adults: A systematic review and meta-analysis. The Lancet Gastroenterology & Hepatology, 2(10), 738-746. doi: 10.1016/s2468-1253(17)30154-1 (Full text)
    • Important figure illustrating percentage of LP globally
    • This review focuses on the prevalence of lactose malabsorption in adults across the regions of the world. Patterns for symptom management stresses the importance in updating national health and population data.
    • new SNP: C-13910 (rs4988235)
  • Szilagyi, Andrew. (2015). Adaptation to Lactose in Lactase Non Persistent People: Effects on Intolerance and the Relationship between Dairy Food Consumption and Evalution of Diseases. Nutrients, 7(8), 6751-6779. doi:10.3390/nu7085309 (Nutrients)
  • Szilagyi, A. & Ishayek, N. (2018). Lactose Intolerance, Dairy Avoidance, and Treatment Options. Nutrients, 10(12), 1994. doi:10.3390/nu10121994 (Nutrients)
    • The article details the three forms of lactose intolerance (congenital, primary, and secondary) and introduces a fourth, which pertains to premature newborns who may not have fully developed intestinal lactase, and also defines many important terms so as to clarify and distinguish between similar terms. They state that lactose challenge tests with resulting symptoms do not accurately reflect normal consumption of lactose since it is generally combined with other foods, and that some people have symptoms that are not related to lactose, showing that different tests need to be developed. Finally, they created a guide for people to help them manage LI and a list of non-dairy substitutes with a nutrient profile comparison to that of milk.
  • Troelsen, J. T. (2005). Adult-type hypolactasia and regulation of lactase expression. Biochimica et Biophysica Acta (BBA)-General Subjects, 1723(1), 19-32. doi: 10.1016/j.bbagen.2005.02.003 (Full text)
    • Behind paywall
  • Voss, J. D., Goodson, M. S., & Leon, J. C. (2018). Phenotype diffusion and one health: A proposed framework for investigating the plurality of obesity epidemics across many species. Zoonoses and Public Health, 65(3), 279-290. doi: 10.1111/zph.12445 (Wiley)
    • Discusses how humans benefited from milk exposure despite being exposed to the pathogens in milk
  • Wanes, D., et al. (2019). Congenital Lactase Deficiency: Mutations, Functional and Biochemical Implications, and Future Perspectives. Nutrients, 11(2), 461. doi:10.3390/nu11020461 (MDPI)
  • Wiley, A. S. (2018). The Evolution of Lactase Persistence: Milk Consumption, Insulin-Like Growth Factor I, and Human Life-History Parameters. The Quarterly Review of Biology, 93(4), 319-345. doi: 10.1086/700768 (Journals)
  • Zhang, J., Lu, Y., Wang, Y., Ren, X., & Han, J. (2018). The impact of the intestinal microbiome on bone health. Intractable & Rare Diseases Research, 7(3), 148-155. doi: 10.5582/irdr. 2018.01055 (Jstage)
    • Discusses how SNPs affect intestinal microbes

Molecular Biology

  • Arnold, J. W., et al. (2018). Prebiotics for Lactose Intolerance: Variability in Galacto-Oligosaccharide Utilization by Intestinal Lactobacillus rhamnosus. Nutrients, 10(10), 1517. doi:10.3390/nu10101517 (Nutrients)
  • Boll, W., et al. (1991). Structure of the Chromosomal Gene and cDNAs Coding for Lactase-Phlorizin Hydrolase in Humans with Adult-Type Hypolactasia or Persistence of Lactase. American Journal of Human Genetics, 48(5), 889-902. (PubMed Central)
  • Boyd, M., Bressendorff, S., Møller, J., Olsen, J., & Troelsen, J. T. (2009). Mapping of HNF4α target genes in intestinal epithelial cells. BMC gastroenterology, 9(1), 68. doi: 10.1186/1471-230X-9-68 (BMC Gastroenterology)
  • Brasen, C. L., Frischknecht, L., Ørnskov, D., Andreasen, L., & Madsen, J. S. (2017). Combination of real-time PCR and sequencing to detect multiple clinically relevant genetic variations in the lactase gene. Scandinavian Journal of Clinical and Laboratory Investigation, 77(1), 60-65. doi:10.1080/00365513.2016.1261408 (Taylor and Francis)
    • Behind paywall
  • Diekmann, L., et al. (2015). Congenital lactose intolerance is triggered by severe mutations on both alleles of the lactase gene. BMC Gastroenterology, 15(36). doi:10.1186/s12876-015-0261-y (BMC)
  • Elliott, G., et al. (2015). Intermediate DNA methylation is a conserved signature of genome regulation. Nat. Commun. 6, 6363. (Nature Comm.)
  • Escher, J. C., et al. (1992). Molecular basis of lactase levels in adult humans. Journal of clinical investigation, 89(2), 480-483. doi:10.1172/jci115609 (JCI)
  • Fajardo, O., et al. (1994). The polymorphic expression of lactase in adults is regulated at the messenger RNA level. Gastroenterology, 106(5), 1233-1241. doi:10.1016/0016-5085(94)90014-0 (Science Direct)
  • Fang, R., Santiago, N. A., Olds, L. C., & Sibley, E. (2000). The homeodomain protein Cdx2 regulates lactase gene promoter activity during enterocyte differentiation. Gastroenterology, 118(1), 115-127. doi:10.1016/S0016-5085(00)70420-3 (Gastroenterology)
    • Behind paywall
  • Fang, R., Olds, L.C. & Sibley, E. (2006). Spatio-temporal patterns of intestine-specific transcription factor expression during postnatal mouse gut development. Gene Expr. Patterns 6, 426–432. (ScienceDirect)
  • Fitzgerald, K., et al. (1998). GATA-6 stimulates a cell line-specific activation element in the human lactase promoter. American journal of physiology-gastrointestinal and liver physiology, 274(2), 314-324. doi:10.1152/ajpgi.1998.274.2.g314 (Am J Physiology)
  • Gerstein, M. B., et al. (2012). Architecture of the human regulatory network derived from ENCODE data. Nature, 489(7414), 91-100. (Nature)
  • Goda, T., Yasutake, H., Tanaka, T. & Takase, S. (1999). Lactase-phlorizin hydrolase and sucrase-isomaltase genes are expressed differently along the villus-crypt axis of rat jejunum. J. Nutr. 129, 1107–1113. (JN)
  • Grand, R. J., et al. (2003). Changing genes; losing lactase. Gut, 52(5), 617–619. doi:10.1136/gut.52.5.617 (Gut)
  • Harvey, W. B., et al. (1995). Studies on the expression of intestinal lactase in different individuals. Gut, 36(1), 28-33. doi:10.1136/gut.36.1.28 (BMJ)
  • Huang, M., et al. (2016). Evolutionary triangulation: Informing genetic association studies with evolutionary evidence. BioData Mining, 9. doi:10.1186/s13040-016-0091-7 (BioData Mining)
  • Kuranuki, S., et al. (2007). The possible roles of homeobox protein, Cdx-2 for the expression of LPH gene during postnatal development. Life sciences, 80(8), 795-799. doi:10.1016/j.lfs.2006.11.007 (Science Direct)
  • Labrie, V., et al. (2016). Lactase non-persistence is directed by DNA variation-dependent epigenetic aging. Nature structural & molecular biology, 23(6), 566-573. doi:10.1038/nsmb.3227 (NSMB)
    • Discusses aging as a factor
    • Epigenetic modifications target specific regulatory elements in lactase mRNA levels, such as the LNP haplotype silencing regulatory elements in MCM6 and LCT, which accounts for the variation in LCT expression after infancy in mammals. Both haplotypes had different epigenetic aging, of which genetic factors enable an accumulation of epigenetic change with age that can influence phenotype, indicating that age does play a role in whether someone is LNP or LP regardless of genetics.
  • Lacey, S. W., et al. (1994). Expression of lactase-phlorizin hydrolase in sheep is regulated at the RNA level. Biochemical journal, 302(3), 929-935. doi:10.1042/bj3020929 (BMC)
  • Leseva, M. N., et al. (2018). Differences in DNA Methylation and Functional Expression in Lactase Persistent and Non-persistent Individuals. Scientific Reports, 8(1). doi:10.1038/s41598-018-23957-4 (Scientific Reports)
  • Lewinsky, R. H., Jensen, T. G., Møller, J., Stensballe, A., Olsen, J., & Troelsen, J. T. (2005). T− 13910 DNA variant associated with lactase persistence interacts with Oct-1 and stimulates lactase promoter activity in vitro. Human Molecular Genetics, 14(24), 3945-3953. doi:10.1093/hmg/ddi418 (Human Molecular Genetics)
    • LNP is explained to be caused by transcriptional down-regulation of LCT gene, and it was noted that the T-13910 variant of the European SNP has increased enhancer activity, which would prevent the post-weaning decline of LPH and result in LP. The article studied transcriptional factors that bind to the LPH promotor, affecting promotor and enhancer activity, specifically Oct-1 mediated enhancer activity since increased activity of it causes LP. It was found that Oct-1 is the transcription factor that binds more strongly to T-13910 than to C-13910, which correlates with increased enhancer activity, thereby explaining the molecular cause for LP in the European SNP and hinting that other SNPs may result in LP for similar reasons.
  • Linnell, J., Mott, R., Field, S., Kwiatkowski, D. P., Ragoussis, J., & Udalova, I. A. (2004). Quantitative high‐throughput analysis of transcription factor binding specificities. Nucleic Acids Research, 32(4), e44-e44. doi:10.1093/nar/gnh042 (Nucleic Acids Research)
  • Motohashi, Y., et al. (1997). Lactase decline in weaning rats is regulated at the transcriptional level and not caused by termination of milk ingestion. The journal of nutrition, 127(9), 1737-43. doi:10.1093/jn/127.9.1737 (JN)
  • Olds, L.C. & Sibley, E. (2003). Lactase persistence DNA variant enhances lactase promoter activity in vitro: functional role as a cis regulatory element. Hum. Mol. Genet. 12, 2333–2340. (HMG)
    • Analyzed differences in DNA-protein interactions between C-13910 and T-13910 alleles on intestinal cell nuclear proteins. A gel shift revealed distinct binding patterns that suggest this interaction could be involved in phenotypic outcome. Specifically, the T-13910 allele may create a transactivating protein that can enhance lactase transcription, preventing its decline. However, the C nucleotide in LNP individuals may disrupt transactivating binding site, preventing long-term lactase transcription.
  • Perissinato, A. G., et al. (2018). Simple Strategy to Protect Lactase Activity in Solid Formulation. Current Drug Delivery, 15(2), 215-218. doi:10.2174/1567201814666170518125802 (PubMed Central)
    • Behind paywall
  • Roder, P. V., et al. (2014). The Role of SGLT1 and GLUT2 in Intestinal Glucose Transport and Sensing. PLoS ONE, 9(2). doi:10.1371/journal.pone.0089977 (PLoS)
  • Rossi, M., et al. (1997). Lactase persistence versus decline in human adults: multifactorial events are involved in down-regulation after weaning. Gastroenterology, 112(5), 1506–1514. doi:10.1016/s0016-5085(97)70031-3 (Gastroenterology)
    • The article addresses the causes for lactase persistence in 65% of human adults, with lactase biosynthesis determined to be at a higher rate in hypolactasic subjects. It also discusses how there are different types of adult-type hypolactasia, since some individuals have high LPH mRNA levels and low enzymatic activity while others have low LPH mRNA levels and high enzymatic activity. The article reported that the decline of intestinal lactase was caused by transcriptional and posttranscriptional factors, which would explain the variations in adult-type hypolactasia, and that LP individuals had a high rate of lactase biosynthesis. This information could explain how different SNPs can cause LP independently due to different changes in transcriptional and posttranscriptional regulation. Furthermore, the results can be used in relation to lactase mRNA levels and the connection between genotype/phenotype in LP people.
  • Schrider, D. R. & Kern, A. D. (2016). S/HIC: Robust Identification of Soft and Hard Sweeps Using Machine Learning. PLOS Genetics, 12(3). doi:10.1371/journal.pgen.1005928 (PLOS Genetics)
    • Brief mention of lactase
  • Stegmann, A., et al. (2006). Metabolome, transcriptome, and bioinformatic cis-element analyses point to HNF-4 as a central regulator of gene expression during enterocyte differentiation. Physiological Genomics, 27(2), 141-155. doi:10.1152/physiolgenomics.00314.200 (Physiol Genomics)
  • Strand, H., et al. Lactase persistence genotyping: rapid detection of seven sequence variants in a single tube with melting curve analyses. Clinical chemistry and laboratory medicine, 52(9). doi: 10.1515/cclm-2014-0123 (PubMed Central)
  • Swallow, D. M. & Troelsen, J. T. (2016). Escape from epigenetic silencing of lactase expression is triggered by a single-nucleotide change. Nature Structural & Molecular Biology, 23(6), 505-507. doi:10.1038/nsmb.3238 (Nature)
    • Behind paywall
  • Tjalling, B., et al. (2007). Gata4 and Hnf1alpha are partially required for the expression of specific intestinal genes during development. American journal of physiology-gastrointestinal and liver physiology, 292(5), 1302-1314. doi:10.1152/ajpgi.00418.2006 (Am J Physiology)
  • Troelsen, J.T., Olsen, J., Møller, J. & Sjöström, H. (2003). An upstream polymorphism associated with lactase persistence has increased enhancer activity. Gastroenterology 125, 1686–1694. (ScienceDirect)
  • Troelsen, J., Mitchelmore, C., Spodsberg, N., Jensen, A., Noren, O., & Sjostrom, H. (1997). Regulation of lactase–phlorizin hydrolase gene expression by the caudal-related homoeodomain protein Cdx-2. Biochem. J, 322, 833-838. doi: 10.1042/bj3220833 (PubMedCentral)
  • Wang, Z., Fang, R., Olds, L. C., & Sibley, E. (2004). Transcriptional regulation of the lactase-phlorizin hydrolase promoter by PDX-1. American Journal of Physiology-Gastrointestinal and Liver Physiology, 287(3), G555-G561. doi: 10.1152/ajpgi.00011.2004 (Physiology)
  • Wering, H. M. V., et al. (2002). Novel interaction at the Cdx-2 binding sites of the lactase-phlorizin hydrolase promoter. Biochemical and biophysical research communications, 299(4), 587-593. doi:10.1016/s0006-291x(02)02697-9 (Science Direct)
  • Yeh, K.Y., Yeh, M. & Holt, P.R. (1991). Intestinal lactase expression and epithelial cell transit in hormone-treated suckling rats. Am. J. Physiol. 260, G379–G384. (AJPGI)
    • Behind paywall

Physiology

  • Abildgaard, A., Tovbjerg, S. K., Giltay, A., Detemmerman, L., & Nissen, P. H. (2018). Lactase persistence genotyping on whole blood by loop-mediated isothermal amplification and melting curve analysis. Clinica Chimica Acta, 482, 50-56. doi: 10.1016/j.cca.2018.03.029 (Full text)
  • Blekhman, R., Goodrich, J. K., Huang, K., Sun, Q., Bukowski, R., Bell, J. T., . . . Clark, A. G. (2015). Host genetic variation impacts microbiome composition across human body sites. Genome Biology, 16. doi:10.1186/s13059-015-0759-1 (GenomeBiology)
  • Bonder, M. J., et al. (2016). The effect of host genetics on the gut microbiome. Nature Genetics, 48, 1407-1412. doi:10.1038/ng.3663 (Nature Genetics)
  • Buning, C., et al. (2005). Introducing Genetic Testing for Adult-Type Hypolactasia. Digestion, 71(4), 245-250. doi:10.1159/000087050 (Karger)
  • Davenport, E. R., Goodrich, J. K., Bell, J. T., Spector, T. D., Ley, R. E., & Clark, A. G. (2016). ABO antigen and secretor statuses are not associated with gut microbiota composition in 1,500 twins. BMC Genomics, 17. doi:10.1186/s12864-016-3290-1 (BMC Genomics)
  • Fang, L., Ahn, J. K., Wodziak, D., & Sibley, E. (2012). The human lactase persistence-associated SNP− 13910* T enables in vivo functional persistence of lactase promoter–reporter transgene expression. Human genetics, 131(7), 1153-1159. doi: 10.1007/s00439-012-1140-z (PubMedCentral)
  • Gencdal, G., Salman, E., Ozutemiz, O., & Akarca, U. S. (2017). Association of LCT-13910 C/T Polymorphism and Colorectal Cancer. Annals of Coloproctology, 33(5), 169-172. doi: 10.3393/ac.2017.33.5.169 (Coloproctol)
  • Hoang, T. T., et al. (2019). Maternal Lactase Polymorphism (rs4988235) Is Associated with Neural Tube Defects in Offspring in the National Birth Defects Prevention Study. The Journal of Nutrition, 149(2), 295-303. doi: 10.1093/jn/nxy246 (Academic)
  • Malek, A. J., et al. Associations of the lactase persistence allele and lactose intake with body composition among multiethnic children. Genes & nutrition, 8(5), 487-494. doi:10.1007/s12263-013-0335-9 (PubMed Central)
    • Discusses LP allele with obesity in children in America; Hispanic Americans, African Americans, and European Americans.
    • This paper links childhood obesity in the US with lactase persistence, to compare the results against ethnicity, age, socio-economic status, and energy intake. The positive correlation found between lactose consumption and fat mass index can be used to mark the significance in altering the US dietary guidelines.
  • Manco, L., Dias, H., Muc, M., & Padez, C. (2016). The lactase −13910CT polymorphism (rs4988235) is associated with overweight/obesity and obesity-related variables in a population sample of Portuguese young adults. European Journal of Clinical Nutrition, 71, 21-24. doi:10.1038/ejcn.2016.164 (Nature)
    • Behind paywall
  • Mattar, R., de Campos Mazo, D. F., & Carrilho, F. J. (2012). Lactose intolerance: diagnosis, genetic, and clinical factors. PubMedCentral, NCBI, 5, 113. doi:10.2147/CEG.S32368 (PubMedCentral)
    • Table 1 has countries and populations as well as the 13910 allele frequency for each and the reference in which they got the data
    • Table 2 has frequencies of 13910 allele in African countries
    • Table 3 has countries and populations as well as the frequency of other LP alleles and references in which they got the data
      • new SNPs: G-13907 (rs41525747), C-13910 (rs4988235), G-13914, G-13915 (rs41380347), C-14010 (rs145946881)
      • this article cited a separate article where they got their US data (Utah only) from
        • Enattah, N. S., et al. (2007). Evidence of Still-Ongoing Convergence Evolution of the Lactase Persistence T-13910 Alleles in Humans. The American Journal of Human Genetics, 81(3), 615–625. doi: 10.1086/520705 ([1])
          • Examined 37 countries and took 1,611 samples total; the places did not have a uniform number of samples taken, meaning the data could be under or over-represented in some areas
  • Oh, E., et al. (2017). Transcriptional heterogeneity in the lactase gene within cell-type is linked to the epigenome. Scientific Reports, 7. doi: 10.1038/srep41843 (Nature)
  • Petruski-Ivleva, N., et al. (2017). Milk Intake at Midlife and Cognitive Decline over 20 Years. The Atherosclerosis Risk in Communities (ARIC) Study. Nutrients, 9. doi: 10.3390/nu9101134 (Nutrients)
  • Physicians Committee for Responsible Medicine. (2019). Health Concerns About Dairy: Avoid the Dangers of Dairy with a Plant-Based Diet. (Physicians Committee for Responsible Medicine)
  • Pruimboom, L., Fox, T., & Muskiet, F. A. (2014). Lactase persistence and augmented salivary alpha-amylase gene copy numbers might have been selected by the combined toxic effects of gluten and (food born) pathogens. Medical Hypotheses, 82(3), 326-334. doi:10.1016/j.mehy.2013.12.020 (Science Direct)
  • Rusynyk, R. A. & Still, C. D. (2001). Lactose Intolerance. The Journal of American Osteopathic Association 101: S10-S12. (JAOA)
  • Sahi, T., Launiala, K., & Laitinen, H. (1983). Hypolactasia in a fixed cohort of young Finnish adults: a follow-up study. Scand. J. Gastroenterol., 18, 865–870. (Taylor and Francis)
  • Smith, C. E., et al. (2017). Genome-wide association studies of body mass index. Molecular Nutrition Food Research, 62(3), 69-78. doi: 10.1017/cbo9781107337459.007 (Wiley)
    • Table 2 has a list of 26 SNPs that they considered, but selected 6 to test that they put in table 3
  • Stegmann, A., et al. (2006). Metabolome, transcriptome, and bioinformatic cis-element analyses point to HNF-4 as a central regulator of gene expression during enterocyte differentiation. Physiological genomics, 27(2), 141-155. doi: 10.1152/physiolgenomics.00314.2005 (Physiology)
  • Wang, Z., Maravelias, C., & Sibley, E. (2006). Lactase gene promoter fragments mediate differential spatial and temporal expression patterns in transgenic mice. DNA and cell biology, 25(4), 215-222. doi:10.1089/dna.2006.25.215 (Liebert)
    • Behind paywall
  • Wilt, T. J., et al. (2007). Lactose intolerance and health. Evidence Reports/Technology Assessments, No. 192 (NCBI)
    • The article establishes the difference between LNP, LI, and lactose malabsorption, what the prevalence of LI is and how it differs across race, ethnicity, and age, what daily dose of lactose is tolerated by LI individuals of varying age and ethnicity, and ways to manage LI. They highlight the notion that people on dairy exclusion diets are more prone to certain health conditions and are lacking nutrients. Specifically, the article examines the effects of lactose intolerance on bone health on relation to the age and race of the subject. They found evidence in the U.S. that suggests that LI rates are very low in young children and will remain low in adults of European descent while the rates of LI in young adults of African American, Hispanic, Asian, and American Indian populations are often higher. Due to the multiple diagnostic and clinical tests, the symptomatic data will be important to reference when discussing alternatives to dairy products. Non-dairy options included probiotics, enzyme replacements, non-dairy milk, and an increasing ingestion of lactose over time.
  • U.S. National Library of Medicine (NIH). (2019). Lactose Intolerance. (NIH)
  • Zheng, X., Chu, H., Cong, Y., Deng, Y., Long, Y., Zhu, Y., . . . Fox, M. (2015). Self-reported lactose intolerance in clinic patients with functional gastrointestinal symptoms: Prevalence, risk factors, and impact on food choices. Neurogastroenterology & Motility, 27(8), 1138-1146. doi:10.1111/nmo.12602 (Full text)
    • This cohort study examined patients in China with self-reported lactose intolerance in order to compare phenotype with the corresponding genotype. It was proposed that the presence of the food intolerance has an overall negative impact on an individual’s quality of life.

SNPs and Population Genetics

  • Antelope, C. X., Marnetto, D., Casey, F., & Huerta-Sanchez, E. (2017). Leveraging Multiple Populations across Time Helps Define Accurate Models of Human Evolution: A Reanalysis of the Lactase Persistence Adaptation. Human Biology, 89(1). doi: 10.13110/humanbiology.89.1.05 (MUSE)
  • Baffour-Awuah, N. Y., et al. (2015). Functional significance of single nucleotide polymorphisms in the lactase gene in diverse US patients and evidence for a novel lactase persistence allele at -13909 in those of European ancestry. Journal of pediatric gastroenterology and nutrition, 60(2), 182-191. doi:10.1097/mpg.0000000000000595 (PubMed Central)
    • -13909C>A SNP (European ancestry)
  • Bayoumi, R., et al. (2016). Positive selection of lactase persistence among people of Southern Arabia. American Journal of Physical Anthropology, 161(4). doi:10.1002/ajpa.23072 (Full text)
    • −13,915G SNP (Arabian LP‐related variation was found in Dhofaris and Yemenis)
  • Bersaglieri, T., et al. (2004). Genetic Signatures of Strong Recent Positive Selection at the Lactase Gene. American journal of human genetics, 74(6), 1111–1120. doi:10.1086/421051 (PubMed Central)
  • Blant, A., Kwong, M., Szpiech, Z. A., & Pemberton, T. J. (2017). Weighted likelihood interference of genomic autozygosity patterns in dense genotype data. BMC Genomics, 18(1). doi: 10.1186/s12864-017-4312-3 (BMC)
    • Discusses autozygosity hotspots in relation to lactase persistence
  • Boschmann, S. E., et al. (2015). The Frequency of the LCT*-13910C>T Polymorphism Associated with Lactase Persistence Diverges among Euro-Descendant Groups from Brazil. Medical Principles and Practice, 25(1), 18–20. doi:10.1159/000440807 (MPP)
  • Brasen, C. L., et al. (2016). Combination of real-time PCR and sequencing to detect multiple clinically relevant genetic variations in the lactase gene. Scandinavian journal of clinical and laboratory investigation, 77(1), 60-65. doi:10.1080/00365513.2016.1261408 (PubMed Central)
  • Burger, J., et al. (2007). Absence of the lactase-persistence-associated allele in early Neolithic Europeans. Proceedings of the National Academy of Sciences, 104(10). doi:10.1073/pnas.0607187104 (PNAS)
  • Burger, J., et al. (2020). Low Prevalence of Lactase Persistence in Bronze Age Europe Indicates Ongoing Strong Selection over the Last 3,000 Years. Current Biology, 30(21), 4307-4315.e13. https://doi.org/10.1016/j.cub.2020.08.033
    • update on 2007 paper by the same author (above).
  • Charati, H., et al. (2019). The evolutionary genetics of lactase persistence in seven ethnic groups across the Iranian plateau. Human Genomics, 13(7). doi: 10.1186/s40246-019-0195-5 (Human Genomics)
    • new SNPs: C-13910 (rs4988235), G-13915 (rs41380347), A-22018 (rs182549)
  • Chin, E. L., et al. (2019). Association of Lactase Persistence Genotypes (rs4988235) and Ethnicity with Dairy Intake in a Healthy U.S. Population. Nutrients, 11(8), 1860. doi: 10.3390/nu11081860 (Nutrients)
    • Discussed how ethnic background can influence diet and therefore dairy consumption, which is seen in the statistics that illustrate that in the US, non-Hispanic Whites meet the Dietary Guidelines of milk consumption more often than non-Hispanic Blacks and Mexican-Americans. They focuesed on lactase persistence genotypes and corresponding ethnicities to determine levels of dairy consumption in the US. They found that genotype of rs4988235 and ethnic background did not influence whether an individual drank milk but did influence how much milk they consumed. However, since they only used one SNP, some of the subjects could have a different SNP that was not tested for that makes them LP, especially in the African American subjects.The data concluded that culture and diet should be evaluated when determining which SNP is present in an individual.
  • Corella, D., et al. (2010). Association of the LCT-13910C>T polymorphism with obesity and its modulation by dairy products in a Mediterranean population. Obesity, 19(8), 1707-1714. doi:10.1038/oby.2010.320 (Wiley)
  • De Luca, P., et al. (2021). Development of a novel SNP assay to detect lactase persistence associated genetic variants. Molecular Biology Reports, 1-7. doi:10.1007/s11033-021-06698-y (Full text)
    • New SNPs: rs4988236 (Far East) rs773131166 (East Europe)
  • Enattah, N. S., et al. (2007). Evidence of still-ongoing convergence evolution of the lactase persistence T-13910 alleles in humans. The American journal of human genetics, 81(3), 615-625. doi:10.1086/520705 (Science Direct)
    • SNP frequencies analyzed in 37 worldwide populations
    • This paper examines multiple SNP frequencies from around the world. The T-13910 variant was found to have evolved independently in different populations, which suggests that the -13910 DNA region is important area for this mutation.
    • new SNPs identified: T-8540 (rs3754686), C-8630 (rs3769005), T-15239 (rs4954493), C-20077 (rs3099181), T-27312 (rs4988183), C-27807 (rs3087343)
  • Enattah, N. S., et al. (2008). Independent Introduction of Two Lactase-Persistence Alleles into Human Populations Reflects Different History of Adaptation to Milk Culture. The American journal of human genetics, 82(1), 57-72. doi:10.1016/j.ajhg.2007.09.012 (AJHG)
    • Analyzed 124 samples from Saudi Arabia looking for European SNP
      • G-13915 has complete co-occurence with C-3712
      • Determined that A/G-12962 is NOT an LP causative SNP
  • Enattah, N. S., Sahi, T., Savilahti, E., Terwilliger, J. D., Peltonen, L., & Järvelä, I. (2002). Identification of a variant associated with adult-type hypolactasia. Nature genetics, 30(2), 233-237. doi: 10.1038/ng826 (Nature)
  • Fanti, S. D., et al. (2015). Inferring the genetic history of lactase persistence along the Italian peninsula from a large genomic interval surrounding the LCT gene. American journal of physical anthropology, 158(4), 708-18. doi:10.1002/ajpa.22814 (Wiley)
  • Fernández, C. I. & Flores, S. V. (2014). Brief Communication: Lactase persistence and dairy intake in Mapuche and Mestizo populations from southern Chile. American journal of physical anthropology, 155(3), 482-487. doi:10.1002/ajpa.22594 (AJPA)
  • Fernández, C. I., Montalva, N., Arias, M., Hevia, M., Moraga, M. L., & Flores, S. V. (2015). Lactase non-persistence and general patterns of dairy intake in indigenous and mestizo chilean populations. American Journal of Human Biology, 28(2), 213-219. doi:10.1002/ajhb.22775 (Full text)
  • Friedrich, D. C., et al. (2012). Several Different Lactase Persistence Associated Alleles and High Diversity of the Lactase Gene in the Admixed Brazilian Population. PLoS ONE, 8(10). doi:10.1371/journal.pone.0046520 (PLoS)
  • Gallego Romero, I., et al. (2012). Herders of Indian and European cattle share their predominant allele for lactase persistence. Mol. Biol. Evol. 29, 249–260. (MBE)
  • Fung, M., Xue, X., & Szilagyi, A. (2020). Estimating Lactase Nonpersistence Distributions in the Multi-Ethnic Canadian Demographic: A Population-Based Study. Journal of the Canadian Association of Gastroenterology, 3(3), 103–110. https://doi.org/10.1093/jcag/gwy068 (Full text)
    • Used the latest 2016 population census into our sampled population and used Storhaug data of global LNP prevalence to derive LNP estimation rates for the Canadian demographic
  • Gamba, C., et al. (2014). Genome flux and stasis in a five millennium transect of European prehistory. Nat. Commun. 5, 5257. (Nature Communications)
  • Gerbault, P., et al. (2011). Evolution of lactase persistence: an example of human niche construction. Philosophical Transactions of the Royal Society B: Biological Sciences, 366(1566), 863-877. doi:10.1098/rstb.2010.0268 (Royal Society B)
    • The dates of origin for the C/T-13910 and the G/C-14010 alleles are given as supporting evidence for positive selection occurring at the time in order to give the frequencies of the alleles we see today. The dates of origin align with the emergence of domestication and dairying in Europe and pastoralism in Africa, which supports the idea of the SNPs occurring simultaneously with the change in culture. The article goes into depth on why there was such a strong positive selection to be LP.
  • Goh, L., et al. (2018). Lactase deficiency and lactose intolerance in a multiracial Asian population in Malaysia. Journal of Gastroenterology and Hepatology, 2(6), 307-310. doi:10.1002/jgh3.12089 (JGH Open)
  • Halima, Y. B., et al. (2017). Lactase persistence in Tunisia as a result of admixture with other Mediterranean populations. Genes & Nutrition, 12. doi: 10.1186/s12263-017-0573-3 (Genes & Nutrition)
    • new SNPs: C-13910 (rs4988235), A-22018 (rs182549)
  • Hassan, H. Y., et al. (2016). Genetic diversity of lactase persistence in East African populations. BMC Research Notes, 9(1). doi:10.1186/s13104-015-1833-1 (PubMed Central)
    • new SNPs: G-13907 (rs41525747), G-13915 (rs41380347)
  • Hermisson, J. & Pennings, P. S. (2017). Soft sweeps and beyond: Understanding the patterns and probabilities of selection footprints under rapid adaptation. Methods in Ecology and Evolution, 8, 700-716. doi: 10.1111/2041-210x.12808 (BES)
    • Look at Box 2
  • Hilliard, C. B. (2016). High osteoporosis risk among East Africans linked to lactase persistence genotype. BoneKEy Reports, 5. doi:10.1038/bonekey.2016.30 (PubMed Central)
  • Hollfelder, N., Babiker, H., Granehäll, L., Schlebusch, C. M., & Jakobsson, M. (2021). The genetic variation of lactase persistence alleles in Sudan and South Sudan. Genome biology and evolution, evab065. Advance online publication. https://doi.org/10.1093/gbe/evab065 (Full text)
    • Research paper that collected/sequenced frequencies of genetic variants linked to LP in Sudanese and South Sudanese populations
  • Imtiaz, F., et al. (2005). 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, 40(10). doi:10.1136/jmg.2007.051631 (PubMed Central)
    • new SNP: C-13913 (rs41456145)
  • Itan, Y., et al. (2009). The Origins of Lactase Persistence in Europe. PLoS Computational Biology, 5(8). doi:10.1371/journal.pcbi.1000491 (PLoS)
  • Itan, Y., Jones, B. L., Ingram, C. J., Swallow, D. M., & Thomas, M. G. (2010). A worldwide correlation of lactase persistence phenotype and genotypes. BMC evolutionary biology, 10(1), 36. doi:10.1186/1471-2148-10-36 (BMC)
  • Jensen, T. G., Liebert, A., Lewinsky, R., Swallow, D. M., Olsen, J., & Troelsen, J. T. (2011). 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, 130(4), 483-493. (Human Genetics)
  • Jones, B. L., et al. (2015). Diversity of lactase persistence in African milk drinkers. Human genetics, 134(8), 917-925. doi:10.1007/s00439-015-1573-2 (PubMed Central)
  • Joslin, S. E. K., Durbin-Johnson, B. P., Britton, M., Settles, M. L., Korf, I., & Lemay, D. G. (2020). Association of the Lactase Persistence Haplotype Block With Disease Risk in Populations of European Descent. Frontiers in Genetics, 11. Frontiers in Genetics
    • Notes that there is no significant association between LP haplotype block and other disease risk, contrary to existing research that suggests that cardiovascular and endocrine problems can be linked to LP allele. Further suggests that there is far more than a genetic basis to LP
  • Kasimov, S., Nazarova, G., Kasimova, D., Yunusova, Z., & Rakhmatova, M. (2015). A Single Nucleotide Polymorphism C/T - 13910 And Consumption Of Dairy Products In Uzbek Population. Journal of Evolution of Medical and Dental Sciences, 4(86), 15042-15050. doi:10.14260/jemds/2015/2134 (JEMDS)
  • Khabarova, Y., et al. (2009). Prevalence of lactase persistent/non-persistent genotypes and milk consumption in a young population in north-west Russia. World journal of gastroenterology, 15(15), 1849. doi:10.3748/wjg.15.1849 (WJG)
  • Khabarova, Y., et al. (2010). The -13914G>A variant upstream of the lactase gene (LCT) is associated with lactase persistence/non-persistence. Scandanavian journal of clinical and laboratory investigation, 70(5), 354-357. doi:10.3109/00365513.2010.491554 (PubMed Central)
    • new SNP: G-13914
  • Kuchay, R. A. H., et al. (2012). Correlation of G/A -22018 single-nucleotide polymorphism with lactase activity and its usefulness in improving the diagnosis of adult-type hypolactasia among North Indian children. Genes and nutrition, 8(1) 145-151. doi:10.1007/s12263-012-0305-7 (Springer)
    • new SNP: A-22018 (rs182549)
  • Kulichova, I., et al. (2017). Internal diversification of non-Sub-Saharan haplogroups in Sahelian populations and the spread of pastoralism beyond the Sahara. American Journal of Physical Anthropology, 164(2). doi: 10.1002/ajpa.23285 (Wiley)
  • Kuokkanen, M., Enattah, N. S., & Oksanen, et al (2003). Transcriptional regulation of the lactase-phlorizin hydrolase gene by polymorphisms associated with adult-type hypolactasia. Gut, 52(5), 647-652. (Gut)
    • Duodenum samples were isolated from patients to obtain the levels of lactase and sucrase activities as well as the ratio between the two (L/S ratio) to compare with the patients’ C/T-13910 and G/A-22018 genotypes. They found that individuals who were homozygous recessive for both alleles had low lactase activity and low L/S ratios while heterozygous individuals had much higher lactase activity and L/S ratios and homozygous dominant individuals had the highest lactase activity and L/S ratios. This information shows that lactase activity is significantly decreased in LNP individuals and that there is variation between the severity of the symptoms within each genotype based on how much the LCT gene is being repressed.
  • Laso-Jadart, R., et al. (2017). The Genetic Legacy of the Indian Ocean Slave Trade: Recent Admixture and Post-admixture Selection in the Makranis of Pakistan. The American Journal of Human Genetics, 101(6), 977-984. doi: 10.1016/j.ajhg.2017.09.025 (PubMed Central)
    • Table 1 has relevance to lactose tolerance
  • Lember, M. (2006). Lactase non-persistence and milk consumption in Estonia. World journal of gastroenterology, 12(45), 7329. doi:10.3748/wjg.v12.i45.7329 (WJG)
  • Liebert, A., et al. (2016). In vitro functional analyses of infrequent nucleotide variants in the lactase enhancer reveal different molecular routes to increased lactase promoter activity and lactase persistence. Annals of Human Genetics, 80(6), 307-318. doi: doi:10.1111/ahg.12167 (PubMed Central)
    • new SNP: T-14011 (rs4988233)
  • Liebert, A., et al. (2017). World-wide distributions of lactase persistence alleles and the complex effects of recombination and selection. Human genetics, 136(11). (PubMed Central)
    • new SNPs: C-13779 (rs527991977), G-14009 (rs869051967), C-14028 (rs759157971)
  • Montalva, N., Adhikari, K., Liebert, A., Mendoza-Revilla, J., Flores, S. V., Mace, R., & Swallow, D. M. (2018). Adaptation to milking agropastoralism in Chilean goat herders and nutritional benefit of lactase persistence. Annals of Human Genetics, 83(1), 11-22. doi: 10.1111/ahg. 12277 (Wiley)
  • Morales, E., et al. (2011). The European lactase persistence genotype determines the lactase persistence state and correlates with gastrointestinal symptoms in the Hispanic and Amerindian Chilean population: a case–control and population-based study. BMJ, 1(1), e000125. doi:10.1136/bmjopen-2011-000125 (BMJ)
    • The article discusses how LP is determined by the SNP LCT C>T-13910 and where it is located, when it likely occurred and where, and age of LNP onset, which provides essential background information. They mention how the prevalence of the LP phenotype is not well known in the Chilean region and set out to find the answer using an RFLP assays for the C>T-13910 SNP, which we used as a model for the beginning stages of our experiment. Using these assays, they noticed that these minority groups had low frequencies for being LP and that people of the CC genotype were more likely to report symptoms. Due to low prevalence of the T variant, this study is important in emphasizing the need for updated social demographic information that include genotypes with self-reported symptoms. The data can be inputted to describe the spread of European heritage and the C/T-13910 SNP.
  • Nilsson, T. K. & Olssen, L. A. (2008). Simultaneous genotyping of the three lactose tolerance-linked polymorphisms LCT -13907C>G, LCT -13910C>T and LCT -13915T>G with Pyrosequencing technology. Clinical chemistry and laboratory medicine, 46(1). doi:10.1515/cclm.2008.015 (PubMed Central)
  • Ojeda-Granados, C., et al. (2016). Association of lactase persistence genotypes with high intake of dairy saturated fat and high prevalence of lactase non-persistence among the Mexican population. Lifestyle Genomics, 9(2-4), 83-94. doi:10.1159/000446241 (Karger)
  • Olds, L. C., Ahn, J. K., & Sibley, E. (2011). − 13915* G DNA polymorphism associated with lactase persistence in Africa interacts with Oct-1. Human genetics, 129(1), 111-113. doi:10.1007/s00439-010-0898-0 (PubMedCentral)
  • Paz-Y-Miño, C., Burgos, G., López-Cortés, A., Herrera, C., Gaviria, A., Tejera, E., & Cabrera-Andrade, A. (2016). A study of the molecular variants associated with lactase persistence in different Ecuadorian ethnic groups. American Journal of Human Biology, 28(6). doi:10.1002/ajhb.22865 (Full text)
  • Peltonen, L., et al. (2018). Identification of a DNA Variant Associated with Adult-Type Hypolactasia. (U.S. Patents)
  • Pinto, J. C., et al. (2016). Food and pathogen adaptations in the Angolan Namib desert: Tracing the spread of lactase persistence and human African trypanosomiasis resistance into southwestern Africa. American Journal of Physical Anthropology, 161(3), 436-447. doi:10.1002/ajpa.23042 (Full text)
  • Plantinga, T. S., et al. (2012). Low prevalence of lactase persistence in Neolithic South-West Europe. European journal of human genetics, 20(7), 778-782. doi:10.1038/ejhg.2011.254 (PubMed Central)
  • Poulter, M., et al. (2003). The causal element for the lactase persistence/non-persistence polymorphism is located in a 1 Mb region of linkage disequilibrium in Europeans. Annals of human genetics, 67(4), 298-311. doi:10.1046/j.1469-1809.2003.00048.x (PubMed Central)
  • Priehodová, E., et al. (2017). The historical spread of Arabian Pastoralists to the eastern African Sahel evidenced by the lactase persistence −13,915*G allele and mitochondrial DNA. American Journal of Human Biology, 29(3). doi: 10.1002/ajhb.22950 (Full text)
  • Ranciaro, A., et al. (2014). Genetic Origins of Lactase Persistence and the Spread of Pastoralism in Africa. The American Journal of Human Genetics, 94(4), 496-510. doi:10.1016/j.ajhg.2014.02.009 (PubMed Central).
    • new SNP: G-12962, contradicts Enattah 2008
  • Rasinpera, H., et al. (2005). Transcriptional downregulation of the lactase (LCT) gene during childhood. Gut, 54(11), 1660–1661. doi:10.1136/gut.2005.077404 (Gut)
  • Raz, M., et al. (2013). Frequency of LCT-13910C/T and LCT-22018G/A single nucleotide polymorphisms associated with adult-type hypolactasia/lactase persistence among Israelis of different ethnic groups. Gene, 519(1), 67-70. doi:10.1016/j.gene.2013.01.049 (Science Direct)
    • new SNPs: C-13910 (rs4988235), A-22018 (rs182549)
  • Seppo, L., et al. (2008). Can primary hypolactasia manifest itself after the age of 20 years? A two-decade follow-up study. Scandinavian journal of gastroenterology, 43(9), 1082-7. doi:10.1080/00365520802095485 (PubMed Central)
  • Sibley, E. & Ahn, J. K. (2011). 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, 122, 155. (PubMedCentral)
  • Smith, G. D., et al. (2008). Lactase persistence-related genetic variant: population substructure and health outcomes. European journal of human genetics, 17(3), 357-367. doi:10.1038/ejhg.2008.156 (PubMed Central)
  • Segurel, L., et al. (2020). Why and when was lactase persistence selected for? Insights from Central Asian herders and ancient DNA. PLOS Biology, 18(6), e3000742. https://doi.org/10.1371/journal.pbio.3000742
    • Not every population with access to milk develops lactase persistence. Central asian herders have not seen significant increase in lactase perisitence over the last ~5,000 years despite dietary reliance on dairy products. Adaptation to milk comsumption has been cultural (fermentation) and/or colonical, rather than genetic.
  • Szilagyi, A. & Xue, X. (2016). Geographic associations between lactase phenotype, multiple sclerosis, and inflammatory bowel diseases; Does obesity trump geography? Medical Hypotheses, 96, 68-72. doi:10.1016/j.mehy.2016.10.001 (Full text)
  • Tishkoff, S. A., et al. (2007). Convergent adaptation of human lactase persistence in Africa and Europe. Nature genetics, 39(1), 31. doi:10.1038/ng1946 (Nature)
    • C/T-13910 SNP is determined to be the cause of LP in Europeans, however there are populations in Africa that have a low frequency of this SNP yet still exhibit LP, meaning that there must be other independent SNPs that are the cause. They identified the locations of the G/C-14010 allele, the C/G-13907 allele, and the T/G-13915 allele on the MCM6 gene as well as their prevalence in different African populations due to positive selection. The G/C-14010 allele was found to be the oldest African mutation, meaning it has had more time to become prevalent than the others.
    • new SNPs: G-13907 (rs41525747), G-13915 (rs41380347), C-14010 (rs145946881)
  • Torniainen, S., et al. (2009). Screening of variants for lactase persistence/non-persistence in populations from South Africa and Ghana. BMC genetics, 10(31). doi:10.1186/1471-2156-10-31 (PubMed Central)
    • new SNPs: A-13937 (rs4988234), C-14010 (rs145946881), T-14091, A-14107, C-14176,
  • Tournebize, R., Poncet, V., Jakobsson, M., Vigouroux, Y., & Manel, S. (2018). McSwan: A joint site frequency spectrum method to detect and date selective sweeps across multiple population genomes. Molecular Ecology Resources, 19(1), 283-295. doi: 10.1111/1755-0998.12957 (Wiley)
  • Valencia, L., et al. (2017). Identification of novel genetic variants in the mutational hotspot region 14 kb upstream of the LCT gene in a Mexican population. Scandinavian Journal of Clinical and Laboratory Investigation, 77(5), 311-314. doi:10.1080/00365513.2017.1318445 (Taylor & Francis)
    • Behind paywall
    • new SNP: T-13889 (rs865955447)
  • Williamson, S. H., Hubisz, M. J., Clark, A. G., Payseur, B. A., Bustamante, C. D., & Nielsen, R. (2007). Localizing recent adaptive evolution in the human genome. PLoS genetics, 3(6), e90. doi:10.1371/journal.pgen.0030090 (PLoS)

Education

  • Boguski, M. S., Boguski, R. M., & Berman, M. R. (2013). Personal genotypes are teachable moments. Genome medicine, 5(3), 22. doi:10.1186/gm426 (Full text
  • Daley, L. A. A., Wagner, J. K., Himmel, T. L., McPartland, K. A., Katsanis, S. H., Shriver, M. D., & Royal, C. D. (2013). Personal DNA testing in college classrooms: perspectives of students and professors. Genetic testing and molecular biomarkers, 17(6), 446-452. doi: 10.1089/gtmb.2012.0404 (Full text)
  • Garber, K. B., Hyland, K. M., & Dasgupta, S. (2016). Participatory genomic testing as an educational experience. Trends in Genetics, 32(6), 317-320.10.1016/j.tig.2016.03.008 (Full text)
  • Haga, S. B., Barry, W. T., Mills, R., Ginsburg, G. S., Svetkey, L., Sullivan, J., & Willard, H. F. (2013). Public knowledge of and attitudes toward genetics and genetic testing. Genetic testing and molecular biomarkers, 17(4), 327-335. doi: 10.1089/gtmb.2012.0350 (Full text)
  • Hill, R. W., Wyse, G. A., & Anderson, M. (2016). Nutrition, Feeding, and Digestion. In Animal Physiology (3rd ed., pp. 127-128). Sunderland, MA: Sinauer Association. (Full text)
  • Leksmono, C. S., et al. (2018). Measuring Lactase Enzymatic Activity in the Teaching Lab. Journal of Visualized Experiments, (138), 54377. doi:10.3791/54377. (Jove)
  • Mavroidopoulou, V., Xera, E., & Mollaki, V. (2015). Awareness, attitudes and perspectives of direct-to-consumer genetic testing in Greece: a survey of potential consumers. Journal of human genetics, 60(9), 515. (Full text)
  • Michigan State University. (2019). Evo Ed Project: Molecular Biology of Lactase Persistence. (Evo-Ed)
  • Ormond, K. E., Hudgins, L., Ladd, J. M., Magnus, D. M., Greely, H. T., & Cho, M. K. (2011). Medical and graduate students' attitudes toward personal genomics. Genetics in Medicine, 13(5), 400. (Full text)
  • Pearson, Y. E. & Liu-Thompkins, Y. (2012). Consuming direct-to-consumer genetic tests: the role of genetic literacy and knowledge calibration. Journal of Public Policy & Marketing, 31(1), 42-57. doi: 10.1509/jppm.10.066 (Full text)
  • Salari, K., Karczewski, K. J., Hudgins, L., & Ormond, K. E. (2013). Evidence that personal genome testing enhances student learning in a course on genomics and personalized medicine. PLoS One, 8(7), e68853. doi: 10.1371/journal.pone.0068853 (Full text)
  • Sanderson, S. C., et al. (2013). Informed decision-making among students analyzing their personal genomes on a whole genome sequencing course: a longitudinal cohort study. Genome medicine, 5(12), 113. doi:10.1186/gm518 (Full text)
  • Sanderson, S. C., et al. (2015). How do students react to analyzing their own genomes in a whole-genome sequencing course?: outcomes of a longitudinal cohort study. Genetics in Medicine, 17(11), 866. (Full text)
  • Schultheis, P. J. & Bowling, B. V. (2011). Analysis of a SNP linked to lactase persistence: An exercise for teaching molecular biology techniques to undergraduates. Biochemistry and Molecular Biology Education, 39(2), 133-140. doi:10.1002/bmb.20456 (IUBMB)
  • Stourman, N. & Moore, J. (2018). Analysis of lactase in lactose intolerance supplements. Biochemistry and Molecular Biology Education, 46(6), 652-662. doi: 10.1002/bmb.21185 (Full text)
  • Vernez, S. L., Salari, K., Ormond, K. E., & Lee, S. S. J. (2013). Personal genome testing in medical education: student experiences with genotyping in the classroom. Genome medicine, 5(3), 24. doi:10.1186/gm428 [(Full text)
  • Weinlander, K. M., Hall, D. J., & De Stasio, E. A. (2010). RFLP analysis and allelic discrimination with real‐time PCR using the human lactase persistence trait. Biochemistry and Molecular Biology Education, 38(3), 167-171. doi: 10.1002/bmb.20357 (IUBMB)

Other

  • Allentoft, M. E., et al. (2015). Population genomics of Bronze Age Eurasia. Nature, 522, 167-172. (Nature)
  • American Dairy Association. (2019). Dietary Recommendations. (Drink Milk)
  • Bleasdale, M., Richter, K. K., Janzen, A., Brown, S., Scott, A., Zech, J., Wilkin, S., Wang, K., Schiffels, S., Desideri, J., Besse, M., Reinold, J., Saad, M., Babiker, H., Power, R. C., Ndiema, E., Ogola, C., Manthi, F. K., Zahir, M., … Boivin, N. (2021). Ancient proteins provide evidence of dairy consumption in eastern Africa. Nature Communications, 12(1), 632. (Nature)
    • makes important points that there was widespread milk consumption in Africa prior to the LP allele's notable rise and spread, suggests that LP is an important but not essential indicator of dairy consumption
  • Brock, W. A., O’Brien, M. J., & Bentley, R. A. (2016). Validating niche-construction theory through path analysis. Archaeological and Anthropological Sciences, 8(4), 819-837. doi:10.1007/s12520-015-0257-0 (Full text)
    • Good path analysis and mathematics
  • Cohen, M. (2017). Animal Colonialism: The Case of Milk. AJIL Unbound, 111, 267-271. (AJIL)
  • Curry, A. (2013). Archaeology: The Milk Revolution. Nature, 500(7460). doi:10.1038/500020a (Nature)
  • Dairy Council of California. (2019). Health Benefits of Dairy. (Healthy Eating)
  • Food and Agriculture Organization. (2012). Milk and Dairy Products in Human Nutrition: Questions and Answers. FAO Milk. (FAO)
  • Food Empowerment Project. (2019). Lactose Intolerance. (FEP)
    • Article highlights that although it is easily possible to live a healthy life lactose-free, minority communities that are likely to be LNP generally have limited access to dairy alternatives and therefore may not even know they exist. Furthermore, the populations in low-income areas tend to be higher than populations in higher-income communities.
  • Food Empowerment Project. (2010). Shining a Light on the Valley of Heart’s Delight: Taking a Look at Access to Healthy Foods in Santa Clara County’s Communities of Color and Low-Income Communities. (FEP)
  • Freeman, A. (2013). The unbearable whiteness of milk: Food oppression and the USDA. UC Irvine L. Rev., 3, 1251. (HeinOnline)
    • Food oppression is discussed by mentioning how minority communities generally exhibit LNP more often than whites yet have less access to dairy alternatives. It is also brought up that referring to others as lactose intolerant gives the idea that LNP is the abnormal state, which is incorrect, and shows that it is the whites who make the decision as to what is normal or not. This belief that LP is “normal” is what has propagated the idea that dairy should be in everyone’s diet when in reality, minority communities are vastly LNP and suffer from a lack of dairy alternatives and the belief that they are yet again not up to white standards.
  • Friedman, M. (2015). Antibiotic-Resistant Bacteria: Prevalence in Food and Inactivation by Food-Compatible Compounds and Plant Extracts. Journal of Agricultural and Food Chemistry 63 (15), 3805-3822. doi: 10.1021/acs.jafc.5b00778 (ACS)
  • Gaard, G. (2013). Toward a Feminist Postcolonial Milk Studies. American Quarterly, 65(3), 595-618. doi:10.1353/aq.2013.0040 (JSTOR)
  • Hagenkord, J., Funke, B., Qian, E., Hegde, M., Jacobs, K.B., Ferber, M., Lebo, M., Buchanan, A.H., & Bick, D. 2019. Design and reporting considerations for genetic screening tests. PeerJ Preprints 7:e27922v4 https://doi.org/10.7287/peerj.preprints.27922v4
    • Preprint; may or may not be relevant
  • Henry, A. G. (2016). The Evolution of Human Diets. Ernahrungs Umschau, 63(6), M350-M358. doi:10.4455/eu.2016.030 (Ernaehrungs Umschau)
    • Abstract had to be translated and behind paywall
  • Hertzler, S., Savaiano, D. A., Dilk, A., Jackson, K. A., Bhriain, S. N., & Suarez, F. L. (2017). Nutrient Considerations in Lactose Intolerance. In A. M. Coulston, C. J. Boushey, M. G. Ferruzzi, & L. M. Delahanty (Eds.), Nutrition in the prevention and treatment of disease (4th ed., pp. 875-892). Amsterdam: Academic Press. (Full text)
    • Table denoting what percentage of different ethnic groups are LNP, which explains why the people who are lactose intolerant in the U.S. tend to fall in the ethnic groups with high LNP percentages. The synthesis of LPH is discussed, as well as the differences between congenital lactase deficiency, primary acquired hypolactasia, and secondary hypolactasia. This article also discusses how lactose intolerance symptoms arise, the dose of lactose that generally results in symptoms, and factors that lessen the symptoms when lactose is digested, which is helpful to understanding how to manage LI in the absence of dairy alternatives.
  • Jennings, K.A. Health Line. (2018). Top 15 Calcium-Rich Foods (Many Are Non-Dairy). (Calcium-Rich Foods)
  • Montalva, N., et al. (2018). Adaptation to milking agropastoralism in Chilean goat herders and nutritional benefit of lactase persistence. Annals of human genetics, 83(1), 11-22. doi:10.1111/ahg.12277 (PubMedCentral)
  • Moshfegh, A., Goldman, J., Ahuja, J., Rhodes, D., LaComb, R., US Department of Agriculture. (2009). What we eat in America, NHANES 2005-2006: Usual Intakes from Food and Water compared to 1997 Dietary Reference Intakes for Vitamin D, Calcium, Phosphorus and Magnesium. (U.S. ARS)
  • Office of Disease Prevention and Health Promotion. (2019). Dietary Guidelines for Americans 2015-2020, 8th edition. (Dietary Guidelines)


SNP Data and Human Genome Browser

Excel Sheet with SNPs

LMU Box


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