Gene-by-environment interactions in urban populations modulate risk phenotypes

Favé, Marie Julie; Lamaze, Fabien C.; Soave, David; Hodgkinson, Alan; Gauvin, Héloïse; Bruat, Vanessa; Grenier, Jean; Gbeha, Elias; Skead, Kimberly; Smargiassi, Audrey; Johnson, Markey; Idaghdour, Youssef; Awadalla, Philip

doi:10.1038/s41467-018-03202-2

Cited by 98 publications

(81 citation statements)

References 69 publications

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“…While the three island populations differ substantially in terms of genetic composition, we have previously shown that there is a high degree of genetic similarity within islands 13 . Therefore, we may expect that intra-island differences in either DNA methylation or gene expression profiles, if they exist, are likely to reflect local environmental differences 45 . To test this hypothesis, we took advantage of the fact that we collected samples across multiple villages in both Sumba and Mentawai.…”

Section: Resultsmentioning

confidence: 99%

Genome-wide DNA methylation and gene expression patterns reflect genetic ancestry and environmental differences across the Indonesian archipelago

Natri

Bobowik

Kusuma

et al. 2019

Preprint

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34Indonesia is the world's fourth most populous country, host to striking levels of human diversity, regional 35 patterns of admixture, and varying degrees of introgression from both Neanderthals and Denisovans. 36 However, it has been largely excluded from the human genomics sequencing boom of the last decade. 37 To serve as a benchmark dataset of molecular phenotypes across the region, we generated genome-wide 38 CpG methylation and gene expression measurements in over 100 individuals from three locations that 39 capture the major genomic and geographical axes of diversity across the Indonesian archipelago. 40Investigating between-and within-island differences, we find up to 10% of tested genes are differentially 41 expressed between the islands of Mentawai (Sumatra) and New Guinea. Variation in gene expression is 42 closely associated with DNA methylation, with expression levels of 9.7% of genes strongly correlating 43 with nearby CpG methylation, and many of these genes being differentially expressed between islands. 44Genes identified in our differential expression and methylation analyses are enriched in pathways 45 involved in immunity, highlighting Indonesia tropical role as a source of infectious disease diversity and 46 the strong selective pressures these diseases have exerted on humans. Finally, we identify robust within-47 island variation in DNA methylation and gene expression, likely driven by very local environmental 48 differences across sampling sites. Together, these results strongly suggest complex relationships between 49 DNA methylation, transcription, archaic hominin introgression and immunity, all jointly shaped by the 50 environment. This has implications for the application of genomic medicine, both in critically 51 understudied Indonesia and globally, and will allow a better understanding of the interacting roles of 52 genomic and environmental factors shaping molecular and complex phenotypes. 53 54 55 56 57 58 59 60 61 Modern human genomics does not equitably represent the full breadth of humanity. While genome 62 sequences for people of European descent now number a million or more, most of the world is deeply 63 understudied 1 . This is particularly true of Indonesia 2 , a country geographically as large as continental 64 Europe and the world's fourth largest by population. Genomic diversity in Indonesia is strikingly 65 different to other well-characterized East Asian populations, such as Han Chinese and Japanese, but this 66 diversity is not captured in large global datasets like the 1000 Genomes Project 3 or the Simons Genome 67 Diversity Project 4 . The first Indonesian genome sequences were only reported in 2016 5 with the first 68 representative survey of diversity across the archipelago only appearing in 2019 6 . This extreme lack of 69 representation extends to molecular phenotypes. To our knowledge, only one genome-wide gene 70 expression study has been published 7 from the region, focused exclusively on host-pathogen interactions 71 with P. falciparum. There are...

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Section: Resultsmentioning

confidence: 99%

Genome-wide DNA methylation and gene expression patterns reflect genetic ancestry and environmental differences across the Indonesian archipelago

Natri

Bobowik

Kusuma

et al. 2019

Preprint

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“…The idea that gene-environment interactions (GxE), not the genotype (G) alone, underpin the expression of the phenotype is now well established [1][2][3]. Based on this GxE→P idea, we and others developed a more general concept based on systems biology stating that G is an inheritance system that includes other interacting and heritable components including the epigenome and cytoplasmic components such as mitochondria, Wolbachia, and viruses [4][5][6][7].…”

Section: Introductionmentioning

confidence: 99%

The Cytoplasm Affects the Epigenome in Drosophila melanogaster

et al. 2018

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Cytoplasmic components and their interactions with the nuclear genome may mediate patterns of phenotypic expression to form a joint inheritance system. However, proximate mechanisms underpinning these interactions remain elusive. To independently assess nuclear genetic and epigenetic cytoplasmic effects, we created a full-factorial design in which representative cytoplasms and nuclear backgrounds from each of two geographically disjunct populations of Drosophila melanogaster were matched together in all four possible combinations. To capture slowly-accumulating epimutations in addition to immediately occurring ones, these constructed populations were examined one year later. We found the K4 methylation of histone H3, H3K4me3, an epigenetic marker associated with transcription start-sites had diverged across different cytoplasms. The loci concerned mainly related to metabolism, mitochondrial function, and reproduction. We found little overlap (<8%) in sites that varied genetically and epigenetically, suggesting that epigenetic changes have diverged independently from any cis-regulatory sequence changes. These results are the first to show cytoplasm-specific effects on patterns of nuclear histone methylation. Our results highlight that experimental nuclear-cytoplasm mismatch may be used to provide a platform to identify epigenetic candidate loci to study the molecular mechanisms of cyto-nuclear interactions.

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“…Most human traits are polygenic and their phenotypes are typically influenced by numerous genes and environmental factors, and possibly by their interactions, e.g. genotype-environment (G×E) interaction 1-4 . These traits have been termed as “complex traits”, which are distinguished from Mendelian traits that are shaped by a single or few major genes 5 .…”

Section: Introductionmentioning

confidence: 99%

Detecting genotype-population interaction effects by ancestry principal components

Werf³

et al. 2019

Preprint

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26Heterogeneity in the phenotypic mean and variance across populations is often observed for 27 complex traits. One way to understand heterogeneous phenotypes lies in uncovering 28 heterogeneity in genetic effects. Previous studies on genetic heterogeneity across populations 29 were typically based on discrete groups of population stratified by different countries or 30 cohorts, which ignored the difference of population characteristics for the individuals within 31 each group and resulted in loss of information. Here we introduce a novel concept of 32 genotype-by-population (G×P) interaction where population is defined by the first and second 33 ancestry principal components (PCs), which are less likely to be confounded with 34 country/cohort-specific factors. We applied a reaction norm model fitting each of 70 complex 35 traits with significant SNP-heritability and the PCs as covariates to examine G×P interactions 36 across diverse populations including white British and other white Europeans from the UK 37 Biobank (N = 22,229). Our results demonstrated a significant population genetic 38 heterogeneity for behavioural traits such as age first had sexual intercourse and qualifications. 39 Our approach may shed light on the latent genetic architecture of complex traits that underlies 40 the modulation of genetic effects across different populations. 41 42 43 44 45 46 47 48 49 50 51Most human traits are polygenic and their phenotypes are typically influenced by numerous 52 genes and environmental factors, and possibly by their interactions, e.g. genotype-53 environment (G×E) interaction 1-4 . These traits have been termed as "complex traits", which 54 are distinguished from Mendelian traits that are shaped by a single or few major genes 5 . 55 Genome-wide association studies (GWAS) have successfully discovered thousands of 56 associations between single-nucleotide polymorphisms (SNPs) and complex traits, which 57 have revolutionized our understanding of the polygenic architecture of complex traits 6-8 . 58Subsequently, in order to increase the power and precision to identify more causal variants, 59 there have been numerous follow-up studies using meta-analyses of GWAS summary 60 statistics or mega-analyses of multiple GWAS by combining diverse data sources that usually 61 span across different nations or populations 9, 10 . However, many human complex traits (e.g., 62height and body mass index (BMI)) are substantially differentiated among diverse 63 populations 11 . For instance, the mean height across European nations generally increases 64 with latitude 12 . Although across-population differences in the mean values are often 65 observed for the phenotypes of complex traits, the underlying genetic and environmental 66 bases remain largely unknown 12 . 68One way to understand such phenotypic heterogeneity lies in uncovering genetic 69 differentiation for the traits captured by common variants across populations. Some studies 12-70 15 have focused on examining population genetic differentiation f...

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Gene-by-environment interactions in urban populations modulate risk phenotypes

Cited by 98 publications

References 69 publications

Genome-wide DNA methylation and gene expression patterns reflect genetic ancestry and environmental differences across the Indonesian archipelago

Genome-wide DNA methylation and gene expression patterns reflect genetic ancestry and environmental differences across the Indonesian archipelago

The Cytoplasm Affects the Epigenome in Drosophila melanogaster

Detecting genotype-population interaction effects by ancestry principal components

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