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In humans the ability to digest milk lactose is conferred by a β-galactosidase enzyme called lactase-phlorizin hydrolase (LPH). While in some humans (approximately two-thirds of humankind) the levels of this enzyme decline drastically after the weaning phase (a trait known as lactase non-persistence (LNP)), some other individuals are capable of maintaining high levels of LPH lifelong (lactase persistence (LP)), thus being able to digest milk during adulthood. Both lactase phenotypes in humans present a complex genetic basis and have been widely investigated during the last decades. The distribution of lactase phenotypes and their associated single nucleotide polymorphisms (SNPs) across human populations has also been extensively studied, though not recently reviewed. All available information has always been presented in the form of static world maps or large dimension tables, so that it would benefit from the newly available visualization tools, such as interactive world maps. Taking all this into consideration, the aims of the present review were: (1) to gather and summarize all available information on LNP and LP genetic mechanisms and evolutionary adaptation theories, and (2) to create online interactive world maps, including all LP phenotype and genotype frequency data reported to date. As a result, we have 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.

The maritime expansion of Scandinavian populations during the Viking Age (about ad  750–1050) was a far-flung transformation in world history 1 , 2 . Here we sequenced the genomes of 442 humans from archaeological sites across Europe and Greenland (to a median depth of about 1×) to understand the global influence of this expansion. We find the Viking period involved gene flow into Scandinavia from the south and east. We observe genetic structure within Scandinavia, with diversity hotspots in the south and restricted gene flow within Scandinavia. We find evidence for a major influx of Danish ancestry into England; a Swedish influx into the Baltic; and Norwegian influx into Ireland, Iceland and Greenland. Additionally, we see substantial ancestry from elsewhere in Europe entering Scandinavia during the Viking Age. Our ancient DNA analysis also revealed that a Viking expedition included close family members. By comparing with modern populations, we find that pigmentation-associated loci have undergone strong population differentiation during the past millennium, and trace positively selected loci—including the lactase-persistence allele of LCT and alleles of ANKA that are associated with the immune response—in detail. We conclude that the Viking diaspora was characterized by substantial transregional engagement: distinct populations influenced the genomic makeup of different regions of Europe, and Scandinavia experienced increased contact with the rest of the continent. Ancient DNA analyses reveal that Viking Age migrations from Scandinavia resulted in differential influxes of ancestry to different parts of Europe, and the increased presence of non-local ancestry within Scandinavia.

ObjectiveTryptophan can be catabolised to various metabolites through host kynurenine and microbial indole pathways. We aimed to examine relationships of host and microbial tryptophan metabolites with incident type 2 diabetes (T2D), host genetics, diet and gut microbiota.MethodWe analysed associations between circulating levels of 11 tryptophan metabolites and incident T2D in 9180 participants of diverse racial/ethnic backgrounds from five cohorts. We examined host genome-wide variants, dietary intake and gut microbiome associated with these metabolites.ResultsTryptophan, four kynurenine-pathway metabolites (kynurenine, kynurenate, xanthurenate and quinolinate) and indolelactate were positively associated with T2D risk, while indolepropionate was inversely associated with T2D risk. We identified multiple host genetic variants, dietary factors, gut bacteria and their potential interplay associated with these T2D-relaetd metabolites. Intakes of fibre-rich foods, but not protein/tryptophan-rich foods, were the dietary factors most strongly associated with tryptophan metabolites. The fibre-indolepropionate association was partially explained by indolepropionate-associated gut bacteria, mostly fibre-using Firmicutes. We identified a novel association between a host functional LCT variant (determining lactase persistence) and serum indolepropionate, which might be related to a host gene-diet interaction on gut Bifidobacterium, a probiotic bacterium significantly associated with indolepropionate independent of other fibre-related bacteria. Higher milk intake was associated with higher levels of gut Bifidobacterium and serum indolepropionate only among genetically lactase non-persistent individuals.ConclusionHigher milk intake among lactase non-persistent individuals, and higher fibre intake were associated with a favourable profile of circulating tryptophan metabolites for T2D, potentially through the host–microbial cross-talk shifting tryptophan metabolism toward gut microbial indolepropionate production.

Lactase persistence (LP) is common among people of European ancestry, but with the exception of some African, Middle Eastern and southern Asian groups, is rare or absent elsewhere in the world. Lactase gene haplotype conservation around a polymorphism strongly associated with LP in Europeans (-13,910 C/T) indicates that the derived allele is recent in origin and has been subject to strong positive selection. Furthermore, ancient DNA work has shown that the--13,910*T (derived) allele was very rare or absent in early Neolithic central Europeans. It is unlikely that LP would provide a selective advantage without a supply of fresh milk, and this has lead to a gene-culture coevolutionary model where lactase persistence is only favoured in cultures practicing dairying, and dairying is more favoured in lactase persistent populations. We have developed a flexible demic computer simulation model to explore the spread of lactase persistence, dairying, other subsistence practices and unlinked genetic markers in Europe and western Asia's geographic space. Using data on--13,910*T allele frequency and farming arrival dates across Europe, and approximate Bayesian computation to estimate parameters of interest, we infer that the--13,910*T allele first underwent selection among dairying farmers around 7,500 years ago in a region between the central Balkans and central Europe, possibly in association with the dissemination of the Neolithic Linearbandkeramik culture over Central Europe. Furthermore, our results suggest that natural selection favouring a lactase persistence allele was not higher in northern latitudes through an increased requirement for dietary vitamin D. Our results provide a coherent and spatially explicit picture of the coevolution of lactase persistence and dairying in Europe.

Abstract Coexistence and cooperation between dogs and humans over thousands of years have supported convergent evolutionary processes in the two species. Previous studies found that Eurasian dogs evolved into a distinct geographic cluster. In this study, we used the genomes of 242 European dogs, 38 Southeast Asian indigenous (SEAI) dogs, and 41 gray wolves to identify adaptation of European dogs . We report 86 unique positively selected genes in European dogs, among which is LCT (lactase). LCT encodes lactase, which is fundamental for the digestion of lactose. We found that an A-to-G mutation (chr19:38,609,592) is almost fixed in Middle Eastern and European dogs. The results of two-dimensional site frequency spectrum (2D SFS) support that the mutation is under soft sweep . We inferred that the onset of positive selection of the mutation is shorter than 6,535 years and behind the well-developed dairy economy in central Europe. It increases the expression of LCT by reducing its binding with ZEB1, which would enhance dog’s ability to digest milk-based diets. Our study uncovers the genetic basis of convergent evolution between humans and dogs with respect to diet, emphasizing the import of the dog as a biomedical model for studying mechanisms of the digestive system.

Background and aims: The mechanism of the developmental downregulation of the lactase-phlorizin hydrolase (LPH) gene underlying adult-type hypolactasia is unknown. We have determined the functional significance of the recently identified two single nucleotide polymorphisms (SNPs), C/T−13910 and G/A−22018, associated with adult-type hypolactasia by studying LPH mRNA levels in intestinal biopsy samples with different genotypes. Methods: Intestinal biopsy samples were taken from 52 patients with abdominal complaints. Hypolactasia was diagnosed by determining lactase and sucrase activities and calculating their ratio (L/S ratio). The functional effect of the C/T−13910 and G/A−22018 genotype on expression of LPH mRNA was demonstrated in patients heterozygous for the C/T−13910 and G/A−22018 polymorphism and an informative expressed SNP located in the coding region of the LPH mRNA. Reverse transcription-polymerase chain reaction followed by solid phase minisequencing was used for accessing the relative expression levels of the LPH alleles using informative SNPs located in exons 1, 2, 6, 10, 13, or 17 as markers. Results: Statistically significant differences between the three different genotypes CC−13910 GG−22018, CT−13910 GA−22018, and TT−13910 AA-22018 and their respective L/S ratios were observed. Relative quantitation of the expressed LPH alleles showed that the persistent allele represented 92 (6)% (mean (SEM), range 78–99%; n=14) of the expressed LPH mRNA. The patient with the homozygous persistent TT−13910 AA−22018, as well as hypolactasic patients with CC−13910 GG−22018, showed equal expression of both alleles (47 (1)%; n=7). Conclusions: Expression of LPH mRNA in the intestinal mucosa in individuals with T−13910 A−22018 alleles is several times higher than that found in individuals with C−13910, G−22018 alleles. These findings suggest that the two SNPs, C/T−13910 and G/A−22018, associated with adult-type hypolactasia, are associated with the transcriptional regulation of the LPH gene. The presence of the T−13910 A−22018 allele also shows significant elevation of the L/S ratio.

Background Congenital lactase deficiency (CLD) is a rare severe autosomal recessive disorder, with symptoms like watery diarrhea, meteorism and malnutrition, which start a few days after birth by the onset of nursing. The most common rationales identified for this disorder are missense mutations or premature stop codons in the coding region of the lactase-phlorizin hydrolase (LPH) gene. Recently, two heterozygous mutations, c.4419C > G (p.Y1473X) in exon 10 and c.5387delA (p.D1796fs) in exon 16, have been identified within the coding region of LPH in a Japanese infant with CLD. Methods Here, we investigate the influence of these mutations on the structure, biosynthesis and function of LPH. Therefore the mutant genes were transiently expressed in COS-1 cells. Results We show that both mutant proteins are mannose-rich glycosylated proteins that are not capable of exiting the endoplasmic reticulum. These mutant proteins are misfolded and turnover studies show that they are ultimately degraded. The enzymatic activities of these mutant forms are not detectable, despite the presence of lactase and phlorizin active sites in the polypeptide backbone of LPH-D1796fs and LPH-Y1473X respectively. Interestingly, wild type LPH retains its complete enzymatic activity and intracellular transport competence in the presence of the pathogenic mutants suggesting that heterozygote carriers presumably do not show symptoms related to CLD. Conclusions Our study strongly suggests that the onset of severe forms of CLD is elicited by mutations in the LPH gene that occur in either a compound heterozygous or homozygous pattern of inheritance.

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.

In European and many African, Middle Eastern and southern Asian populations, lactase persistence (LP) is the most strongly selected monogenic trait to have evolved over the past 10,000 years 1 . Although the selection of LP and the consumption of prehistoric milk must be linked, considerable uncertainty remains concerning their spatiotemporal configuration and specific interactions 2 , 3 . Here we provide detailed distributions of milk exploitation across Europe over the past 9,000 years using around 7,000 pottery fat residues from more than 550 archaeological sites. European milk use was widespread from the Neolithic period onwards but varied spatially and temporally in intensity. Notably, LP selection varying with levels of prehistoric milk exploitation is no better at explaining LP allele frequency trajectories than uniform selection since the Neolithic period. In the UK Biobank 4 , 5 cohort of 500,000 contemporary Europeans, LP genotype was only weakly associated with milk consumption and did not show consistent associations with improved fitness or health indicators. This suggests that other reasons for the beneficial effects of LP should be considered for its rapid frequency increase. We propose that lactase non-persistent individuals consumed milk when it became available but, under conditions of famine and/or increased pathogen exposure, this was disadvantageous, driving LP selection in prehistoric Europe. Comparison of model likelihoods indicates that population fluctuations, settlement density and wild animal exploitation—proxies for these drivers—provide better explanations of LP selection than the extent of milk exploitation. These findings offer new perspectives on prehistoric milk exploitation and LP evolution. Examination of archaeological pottery residues and modern genes suggest that environmental conditions, subsistence economics and pathogen exposure may explain selection for lactase persistence better than prehistoric consumption of milk.