The molecular basis of lactase persistence: Linking genetics and epigenetics

被引:0
作者
Cohen, Celeste E. [1 ]
Swallow, Dallas M. [1 ]
Walker, Catherine [1 ,2 ]
机构
[1] UCL, Genet Inst UGI, Dept Genet Evolut & Environm, Gower Str, London WC1E 6BT, England
[2] Univ Tokyo, Grad Sch Sci, Dept Biol Sci, Tokyo, Japan
关键词
epigenetics; gene expression; lactase persistence; methylation; multiple alleles; transcription factors; TRANSCRIPTION FACTOR; POSITIVE SELECTION; PROMOTER ACTIVITY; DNA METHYLATION; POLYMORPHISM; ALLELES; OBESITY; AFRICA; DEMETHYLATION; CONSUMPTION;
D O I
10.1111/ahg.12575
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
Lactase persistence (LP) - the genetic trait that determines the continued expression of the enzyme lactase into adulthood - has undergone recent, rapid positive selection since the advent of animal domestication and dairying in some human populations. While underlying evolutionary explanations have been widely posited and studied, the molecular basis of LP remains less so. This review considers the genetic and epigenetic bases of LP. Multiple single-nucleotide polymorphisms (SNPs) in an LCT enhancer in intron 13 of the neighbouring MCM6 gene are associated with LP. These SNPs alter binding of transcription factors (TFs) and likely prevent age-related increases in methylation in the enhancer, maintaining LCT expression into adulthood to cause LP. However, the complex relationship between the genetics and epigenetics of LP is not fully characterised, and the mode of action of methylation quantitative trait loci (meQTLs) (SNPs affecting methylation) generally remains poorly understood. Here, we examine published LP data to propose a model describing how methylation in the LCT enhancer is prevented in LP adults. We argue that this occurs through altered binding of the TF Oct-1 (encoded by the gene POU2F1) and neighbouring TFs GATA-6 (GATA6), HNF-3A (FOXA1) and c-Ets1 (ETS1) acting in concert. We therefore suggest a plausible new model for LCT downregulation in the context of LP, with wider relevance for future work on the mechanisms of other meQTLs.
引用
收藏
页数:12
相关论文
共 68 条
  • [1] The lactase persistence -13910C>T polymorphism shows indication of association with abdominal obesity among Portuguese children
    Albuquerque, David
    Nobrega, Clevio
    Manco, Licinio
    [J]. ACTA PAEDIATRICA, 2013, 102 (04) : e153 - e157
  • [2] Association of the European Lactase Persistence Variant (LCT-13910 C>T Polymorphism) with Obesity in the Canary Islands
    Almon, Ricardo
    Elisa Alvarez-Leon, Eva
    Serra-Majem, Lluis
    [J]. PLOS ONE, 2012, 7 (08):
  • [3] Methylation QTLs Are Associated with Coordinated Changes in Transcription Factor Binding, Histone Modifications, and Gene Expression Levels
    Banovich, Nicholas E.
    Lan, Xun
    McVicker, Graham
    van de Geijn, Bryce
    Degner, Jacob F.
    Blischak, John D.
    Roux, Julien
    Pritchard, Jonathan K.
    Gilad, Yoav
    [J]. PLOS GENETICS, 2014, 10 (09):
  • [4] Genetic signatures of strong recent positive selection at the lactase gene
    Bersaglieri, T
    Sabeti, PC
    Patterson, N
    Vanderploeg, T
    Schaffner, SF
    Drake, JA
    Rhodes, M
    Reich, DE
    Hirschhorn, JN
    [J]. AMERICAN JOURNAL OF HUMAN GENETICS, 2004, 74 (06) : 1111 - 1120
  • [5] The effect of host genetics on the gut microbiome
    Bonder, Marc Jan
    Kurilshikov, Alexander
    Tigchelaar, Ettje F.
    Mujagic, Zlatan
    Imhann, Floris
    Vila, Arnau Vich
    Deelen, Patrick
    Vatanen, Tommi
    Schirmer, Melanie
    Smeekens, Sanne P.
    Zhernakova, Dania V.
    Jankipersadsing, Soesma A.
    Jaeger, Martin
    Oosting, Marije
    Cenit, Maria Carmen
    Masclee, Ad A. M.
    Swertz, Morris A.
    Li, Yang
    Kumar, Vinod
    Joosten, Leo
    Harmsen, Hermie
    Weersma, Rinse K.
    Franke, Lude
    Hofker, Marten H.
    Xavier, Ramnik J.
    Jonkers, Daisy
    Netea, Mihai G.
    Wijmenga, Cisca
    Fu, Jingyuan
    Zhernakova, Alexandra
    [J]. NATURE GENETICS, 2016, 48 (11) : 1407 - 1412
  • [6] SNIP1 Recruits TET2 to Regulate c-MYC Target Genes and Cellular DNA Damage Response
    Chen, Lei-Lei
    Lin, Huai-Peng
    Zhou, Wen-Jie
    He, Chen-Xi
    Zhang, Zhi-Yong
    Cheng, Zhou-Li
    Song, Jun-Bin
    Liu, Peng
    Chen, Xin-Yu
    Xia, Yu-Kun
    Chen, Xiu-Fei
    Sun, Ren-Qiang
    Zhang, Jing-Ye
    Sun, Yi-Ping
    Song, Lei
    Liu, Bing-Jie
    Du, Rui-Kai
    Ding, Chen
    Lan, Fei
    Huang, Sheng-Lin
    Zhou, Feng
    Liu, Suling
    Xiong, Yue
    Ye, Dan
    Guan, Kun-Liang
    [J]. CELL REPORTS, 2018, 25 (06): : 1485 - +
  • [7] Microsatellite variation and evolution of human lactase persistence
    Coelho, M
    Luiselli, D
    Bertorelle, G
    Lopes, AI
    Seixas, S
    Destro-Bisol, G
    Rocha, J
    [J]. HUMAN GENETICS, 2005, 117 (04) : 329 - 339
  • [8] The lactase rs4988235 is associated with obesity related variables and diabetes mellitus in menopausal obese females
    de Luis, D. A.
    Izaola, O.
    Primo, D.
    [J]. EUROPEAN REVIEW FOR MEDICAL AND PHARMACOLOGICAL SCIENCES, 2021, 25 (02) : 932 - 940
  • [9] Independent introduction of two lactase-persistence alleles into human populations reflects different history of adaptation to milk culture
    Enattah, Nabil Sabri
    Jensen, Tine G. K.
    Nielsen, Mette
    Lewinski, Rikke
    Kuokkanen, Mikko
    Rasinpera, Heli
    El-Shanti, Hatem
    Seo, Jeong Kee
    Alifrangis, Michael
    Khalil, Insaf F.
    Natah, Abdrazak
    Ali, Ahmed
    Natah, Sirajedin
    Comas, David
    Mehdi, S. Qasim
    Groop, Leif
    Vestergaard, Else Marie
    Imtiaz, Faiqa
    Rashed, Mohamed S.
    Meyer, Brian
    Troelsen, Jesper
    Peltonen, Leena
    [J]. AMERICAN JOURNAL OF HUMAN GENETICS, 2008, 82 (01) : 57 - 72
  • [10] Identification of a variant associated with adult-type hypolactasia
    Enattah, NS
    Sahi, T
    Savilahti, E
    Terwilliger, JD
    Peltonen, L
    Järvelä, I
    [J]. NATURE GENETICS, 2002, 30 (02) : 233 - 237