LeCHE  
Lactase persistence and the early Cultural History of Europe  
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UNIVERSITY COLLEGE LONDON

UCLUCL is one of the UK's top research universities and has had a long history of excellence in Human Genetics, which includes Biochemical and Molecular Genetics, Cytogenetics, Developmental Biology, Biometry, Statistical and Population Genetics. Colleagues with a high public profile include Professor Steve Jones, Professor Linda Partridge FRS. Professor Ziheng Yang FRS. UCL also has world leading Archeology and Anthropology Departments, which include eminent researchers in the fields in the field of Human Evolution (eg Professor Ruth Mace) and cultural evolution (eg Professor Stephen Shennan). There thus are multiple cross faculty interactions which include UCL hospitals.

Two projects are running at UCL:-
ESR3 Genetics of modern humans
ESR12 Modelling the spread of dairying and LP

ESR3 Genetics of modern humans
Prof. Dallas Swallow, Prof. Jesper Troelsen (Copenhagen) and Dr Mark Thomas
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The geographic cline of LP across Europe agrees with that predicted from the distribution of the -13.910*T carrying genotypes (right). However -13.910*T is absent in many milk drinking pastoralist groups in Africa (Mulcare, et al., 2004 Am.J.Hum.Genet. 74:1102). We and others have identified several new alleles associated with LP in Africa. These occur on different haplotype backgrounds from -13.910*T and appear to have been subject to strong positive selection like -13.910*T. These nucleotide substitutions, are located within a 100 base pair region in intron 13 of the adjacent gene, in region that has been shown in vitro by Jesper Toelsen (JT) (2005, Hum Mol.Genet 14:3945) to have enhancer function.
It is not known how far the 'African' alleles penetrate into Europe nor how widespread -13.910*T is outside Europe (Ingram et al Hum.Genet. 2007).  ESR3 will examine the fine-scale distribution of gene variants associated with LP in Europe and the Middle East. The major aim will be to describe LCT allelic distributions in south-eastern Europe and the Near East and define the south eastern edges of the distribution of -13.910*T and the north western edges of other functional alleles. This will involve resequencing of the lactase gene enhancer regions in several thousand selected DNA samples. SNPs in the vicinity of LCT will be tested to construct haplotypes to provide data to place the origin of -13.910*T and for the dating and selection studies to be done by ESR12. These studies will help to identify populations for lactose tolerance testing. We shall then contact members of the consortium and our wide network of contacts to arrange lactose tolerance testing, followed by more extensive sequencing in individuals who have been lactose tolerance tested (regions to be selected based on ongoing work in the lab of Associate Partner (JT) and in collaborative work between JT and UCL. To obtain a full understanding of functional aspects the student will take part in some functional experimental work in the lab of JT. The student will thus have the opportunity to obtain wide training in molecular and population genetics, and will link with principally with ESR4, ESR5, ESR6, will provide data for ESR12 but also with proteomics ESR9, diagenesis, ESR13, and will be guided by ER1 and report to ER2.

ESR12 Modelling the spread of dairying and LP
Mark Thomas
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This ESRwill further develop and adapt a flexible demic forward computer simulation model (see Figure) to explore the spread of LP, dairying, other subsistence practices, and unlinked genetic markers, using gene-culture co-evolutionary dynamics in geographic space. Key components of this simulation model include: (i) a three layer intra-deme population structure: hunter-gatherers, non-dairying farmers and dairying farmers. (ii) Population genetic simulation of a LP allele under selection, and an undrifted allele signifying general genetic background. (iii) Intra and inter-deme gene flow and sporadic longer distance migration (following a Gaussian random walk process). (iv) Paramaterizable logistic growth (to allow the potential for incorporating data on past climate and ecological factors). (v) The potential for subsistence practice change through a cultural demic diffusion process. The major advantages of this approach are that: 1) demographic, stochastic and natural selection processes can be easily integrated. 2) Parameter estimation can be achieved by comparing simulation outcomes, using standard goodness-of-fit statistics, to various sources of data (modern and aDNA, archaeological data). 3) The approach can be made semi-realistic by integrating various sources of information from LeCHE into the model itself.
Data relating to the spread of farming, dairying, milk processing (butter fat, yoghurt and cheese manufacture - from pottery), and LP (distribution and estimates of strength of natural selection - from genetics) can be used for parameter estimation or integrated into the model itself. In addition, data on human population densities, palaeo-climate and physical geography can be integrated into a parameter heavy model (full parameter space exploration at this level is unfeasible but comparisons with simulation outcomes from simpler models will be performed). Parameter estimation will employ an Approximate Bayesian Computation (ABC) approach (Genetics, 2002, 162: 2025). Preliminary results have already both shown that the modern LP frequency distribution (high in NW Europe; see Fig. 1) can arise if LP originated in SE Europe, and indicated that a disproportionately high component of European ancestry may trace back to Europe’s earliest lactase persistent dairying group(s). This early work has also indicated that LP allele homogeneity in Europe is a rare product of both strong natural selection and specific demographic processes which contrasts with the greater LP allele heterogeneity found elsewhere (Africa, the Middle East and southern and western Asia). This project will draw data from all the other projects, initially from ER1 , but latterly from the different ESRs. Simulation runs will also guide the selection of samples for analysis by ESR3, ESR4 & ESR6 in the latter part of the project.

 
STAFF
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Professor Dallas Swallow is a Professor of Human Genetics. Her group in UCL has made major contributions to the field of lactase molecular and population genetics, e.g. being the first to show: that LCT SNP allele frequencies differed markedly across Europe. She has supervised more than ten students who have completed their PhDs, including 4 working on lactase, and has experience of acting as PI/coordinator for an EU Concerted action.

Dr Mark Thomas is a senior lecturer in Human Evolutionary Genetics. He has published widely on inferring the demographic history of various human groups using population genetic approaches (e.g. Thomas et al., Nature 1998. 394, 138-140). He was one of the first working on aDNA (e.g. Hagelberg et al., Nature 1994, 370, 333-334) and continues to work in this field (e.g. Barnes et al., Nature 2005, 438, 850). Recently he has pioneered the integration of modern and aDNA data with archaeological information using computer simulation models of the movement and people and genes (Thomas et al., Proc. Roy. Soc. Lond. B 2006, 273, 2651-2657; Burger et al., PNAS, 2007, 104, 3736-3741).

 
FACILITIES
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The molecular biology labs are equipped with high throughput sequencers (ABI3100) and real Time PCR equipment. They own/have access to over 33,000 human DNA samples from around the World, including Africa, the Middle East and Europe and through a good professional relationship with Prof. Yang FRS, access to computer facilities for very cpu intensive simulations.  The Department of Biology has several internationally renowned research scientists with expertise of relevance to this programme (see above) also houses The Centre for Genetic Anthropology (TCGA), to which Thomas has strong links. Thomas is also an active member of the UCL AHRC Centre for the Evolution of Cultural Diversity. This centre supports one of his PhD students who works partly on computer simulation modelling, and will be available to advise ESR12.

 
REFERENCES
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1. Hollox EJ, et al., Lactase haplotype diversity in the Old World. (2001) Am. J. Hum. Genet. 68:160

2. Ingram CJ et al., A novel polymorphism associated with lactose tolerance in Africa: multiple causes for lactase persistence? (2007) Hum. Genet. 120:779-788

3. Mulcare CA, et al.,  The T allele of a single-nucleotide polymorphism 13.9 kb upstream of the lactase gene (LCT) (C-13.9kbT) does not predict or cause the lactase-persistence phenotype in Africans. (2004) Am. J. Hum. Genet. 74:1102.

5. Ceiridwen J. Edwards, Ruth Bollongino, Amelie Scheu, Andrew Chamberlain, Anne Tresset, Jean-Denis Vigne, Jillian F. Baird, Greger Larson, Simon Y. W. Ho, Tim H. Heupink, Beth Shapiro, Abigail R. Freeman, Mark G. Thomas, Rose-Marie Arbogast, Betty Arndt, László Bartosiewicz, Norbert Benecke, Mihael Budja, Louis Chaix, Alice M. Choyke, Eric Coqueugniot, Hans-Jürgen Döhle, Holger Göldner, Sönke Hartz, Daniel Helmer, Barabara Herzig, Hitomi Hongo, Marjan Mashkour, Mehmet Özdogan, Erich Pucher, Georg Roth, Sabine Schade-Lindig, Ulrich Schmölcke, Rick J. Schulting, Elisabeth Stephan, Hans-Peter Uerpmann, István Vörös, Barbara Voytek, Daniel G. Bradley, Joachim Burger (2007) Mitochondrial DNA analysis shows a Near Eastern Neolithic origin for domestic cattle and no indication of domestication of European aurochs. Proc. Roy. Soc. Lond. B. 274: pp1377-1385.

6. J. Burger, M. Kirchner, B. Bramanti, W. Haak, M. G. Thomas (2007) Absence of the Lactase-Persistence associated allele in early Neolithic Europeans. Proceedings of the National Academy of Science USA 104: pp3736-3741