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

Uncovering the interaction between genomes and the environment is a principal challenge of modern genomics and preventive medicine. While theoretical models are well defined, little is known of the G × E interactions in humans. We used an integrative approach to comprehensively assess the interactions between 1.6 million data points, encompassing a range of environmental exposures, health, and gene expression levels, coupled with whole-genome genetic variation. From ∼1000 individuals of a founder population in Quebec, we reveal a substantial impact of the environment on the transcriptome and clinical endophenotypes, overpowering that of genetic ancestry. Air pollution impacts gene expression and pathways affecting cardio-metabolic and respiratory traits, when controlling for genetic ancestry. Finally, we capture four expression quantitative trait loci that interact with the environment (air pollution). Our findings demonstrate how the local environment directly affects disease risk phenotypes and that genetic variation, including less common variants, can modulate individual's response to environmental challenges.

Relaxed Selection During a Recent Human Expansion.

Humans have colonized the planet through a series of range expansions, which deeply impacted genetic diversity in newly settled areas and potentially increased the frequency of deleterious mutations on expanding wave fronts. To test this prediction, we studied the genomic diversity of French Canadians who colonized Quebec in the 17th century. We used historical information and records from ∼4000 ascending genealogies to select individuals whose ancestors lived mostly on the colonizing wave front and individuals whose ancestors remained in the core of the settlement. Comparison of exomic diversity reveals that: (i) both new and low-frequency variants are significantly more deleterious in front than in core individuals, (ii) equally deleterious mutations are at higher frequencies in front individuals, and (iii) front individuals are two times more likely to be homozygous for rare very deleterious mutations present in Europeans. These differences have emerged in the past six to nine generations and cannot be explained by differential inbreeding, but are consistent with relaxed selection mainly due to higher rates of genetic drift on the wave front. Demographic inference and modeling of the evolution of rare variants suggest lower effective size on the front, and lead to an estimation of selection coefficients that increase with conservation scores. Even though range expansions have had a relatively limited impact on the overall fitness of French Canadians, they could explain the higher prevalence of recessive genetic diseases in recently settled regions of Quebec.

A haplotype-based normalization technique for the analysis and detection of allele specific expression.

BACKGROUND: Allele specific expression (ASE) has become an important phenotype, being utilized for the detection of cis-regulatory variation, nonsense mediated decay and imprinting in the personal genome, and has been used to both identify disease loci and consider the penetrance of damaging alleles. The detection of ASE using high throughput technologies relies on aligning short-read sequencing data, a process that has inherent biases, and there is still a need to develop fast and accurate methods to detect ASE given the unprecedented growth of sequencing information in big data projects. RESULTS: Here, we present a new approach to normalize RNA sequencing data in order to call ASE events with high precision in a short time-frame. Using simulated datasets we find that our approach dramatically improves reference allele quantification at heterozygous sites versus default mapping methods and also performs well compared to existing techniques for ASE detection, such as filtering methods and mapping to parental genomes, without the need for complex and time consuming manipulation. Finally, by sequencing the exomes and transcriptomes of 96 well-phenotyped individuals of the CARTaGENE cohort, we characterise the levels of ASE across individuals and find a significant association between the proportion of sites undergoing ASE within the genome and smoking. CONCLUSIONS: The correct treatment and analysis of RNA sequencing data is vital to control for mapping biases and detect genuine ASE signals. By normalising RNA sequencing information after mapping, we show that this approach can be used to identify biologically relevant signals in personal genomes.

Comparative Analysis of Iron Homeostasis in Sub-Saharan African Children with Sickle Cell Disease and Their Unaffected Siblings.

Iron is an essential trace element subject to tight regulation to ensure adequate running of biological processes. In sub-Saharan Africa where hemoglobinopathies are common, iron homeostasis is likely to be impaired by these conditions. Here, we assessed and compared key serum proteins associated with iron metabolism between sub-Saharan African children with sickle cell disease (SCD) and their unaffected siblings. Complete blood counts and serum concentrations of four key proteins involved in iron regulation (ferritin, transferrin, sTfR, and hepcidin) were measured for 73 children with SCD and 68 healthy siblings in Benin, West Africa. We found significant differences in concentration of transferrin, sTfR, and ferritin between the two groups. Hepcidin concentrations were found at unusually high concentrations but did not differ among the two groups. We found a significant negative correlation between hepcidin levels and both MCH and MCV in the SCD group and report that sTfR concentrations show a correlation with MCV and MHC in opposite directions in the two groups. These results highlight the unusually high levels of hepcidin in the Beninese population and the patterns of differential iron homeostasis taking place under SCD status. These results lay the foundation for a systematic evaluation of the underlying mechanisms deregulating iron homeostasis in populations with SCD or high prevalence of iron deficiency.

Recombination affects accumulation of damaging and disease-associated mutations in human populations.

Many decades of theory have demonstrated that, in non-recombining systems, slightly deleterious mutations accumulate non-reversibly, potentially driving the extinction of many asexual species. Non-recombining chromosomes in sexual organisms are thought to have degenerated in a similar fashion; however, it is not clear the extent to which damaging mutations accumulate along chromosomes with highly variable rates of crossing over. Using high-coverage sequencing data from over 1,400 individuals in the 1000 Genomes and CARTaGENE projects, we show that recombination rate modulates the distribution of putatively deleterious variants across the entire human genome. Exons in regions of low recombination are significantly enriched for deleterious and disease-associated variants, a signature varying in strength across worldwide human populations with different demographic histories. Regions with low recombination rates are enriched for highly conserved genes with essential cellular functions and show an excess of mutations with demonstrated effects on health, a phenomenon likely affecting disease susceptibility in humans.

High-resolution genomic analysis of human mitochondrial RNA sequence variation.

Mutations in the mitochondrial genome are associated with multiple diseases and biological processes; however, little is known about the extent of sequence variation in the mitochondrial transcriptome. By ultra-deeply sequencing mitochondrial RNA (>6000×) from the whole blood of ~1000 individuals from the CARTaGENE project, we identified remarkable levels of sequence variation within and across individuals, as well as sites that show consistent patterns of posttranscriptional modification. Using a genome-wide association study, we find that posttranscriptional modification of functionally important sites in mitochondrial transfer RNAs (tRNAs) is under strong genetic control, largely driven by a missense mutation in MRPP3 that explains ~22% of the variance. These results reveal a major nuclear genetic determinant of posttranscriptional modification in mitochondria and suggest that tRNA posttranscriptional modification may affect cellular energy production.

Genomic architecture of sickle cell disease in West African children.

Sickle cell disease (SCD) is a congenital blood disease, affecting predominantly children from sub-Saharan Africa, but also populations world-wide. Although the causal mutation of SCD is known, the sources of clinical variability of SCD remain poorly understood, with only a few highly heritable traits associated with SCD having been identified. Phenotypic heterogeneity in the clinical expression of SCD is problematic for follow-up (FU), management, and treatment of patients. Here we used the joint analysis of gene expression and whole genome genotyping data to identify the genetic regulatory effects contributing to gene expression variation among groups of patients exhibiting clinical variability, as well as unaffected siblings, in Benin, West Africa. We characterized and replicated patterns of whole blood gene expression variation within and between SCD patients at entry to clinic, as well as in follow-up programs. We present a global map of genes involved in the disease through analysis of whole blood sampled from the cohort. Genome-wide association mapping of gene expression revealed 390 peak genome-wide significant expression SNPs (eSNPs) and 6 significant eSNP-by-clinical status interaction effects. The strong modulation of the transcriptome implicates pathways affecting core circulating cell functions and shows how genotypic regulatory variation likely contributes to the clinical variation observed in SCD.

Whole-exome sequencing reveals a rapid change in the frequency of rare functional variants in a founding population of humans.

Whole-exome or gene targeted resequencing in hundreds to thousands of individuals has shown that the majority of genetic variants are at low frequency in human populations. Rare variants are enriched for functional mutations and are expected to explain an important fraction of the genetic etiology of human disease, therefore having a potential medical interest. In this work, we analyze the whole-exome sequences of French-Canadian individuals, a founder population with a unique demographic history that includes an original population bottleneck less than 20 generations ago, followed by a demographic explosion, and the whole exomes of French individuals sampled from France. We show that in less than 20 generations of genetic isolation from the French population, the genetic pool of French-Canadians shows reduced levels of diversity, higher homozygosity, and an excess of rare variants with low variant sharing with Europeans. Furthermore, the French-Canadian population contains a larger proportion of putatively damaging functional variants, which could partially explain the increased incidence of genetic disease in the province. Our results highlight the impact of population demography on genetic fitness and the contribution of rare variants to the human genetic variation landscape, emphasizing the need for deep cataloguing of genetic variants by resequencing worldwide human populations in order to truly assess disease risk.

Evidence for additive and interaction effects of host genotype and infection in malaria.

The host mechanisms responsible for protection against malaria remain poorly understood, with only a few protective genetic effects mapped in humans. Here, we characterize a host-specific genome-wide signature in whole-blood transcriptomes of Plasmodium falciparum-infected West African children and report a demonstration of genotype-by-infection interactions in vivo. Several associations involve transcripts sensitive to infection and implicate complement system, antigen processing and presentation, and T-cell activation (i.e., SLC39A8, C3AR1, FCGR3B, RAD21, RETN, LRRC25, SLC3A2, and TAPBP), including one association that validated a genome-wide association candidate gene (SCO1), implicating binding variation within a noncoding regulatory element. Gene expression profiles in mice infected with Plasmodium chabaudi revealed and validated similar responses and highlighted specific pathways and genes that are likely important responders in both hosts. These results suggest that host variation and its interplay with infection affect children's ability to cope with infection and suggest a polygenic model mounted at the transcriptional level for susceptibility.

An X-linked haplotype of Neandertal origin is present among all non-African populations.

Recent work on the Neandertal genome has raised the possibility of admixture between Neandertals and the expanding population of Homo sapiens who left Africa between 80 and 50 Kya (thousand years ago) to colonize the rest of the world. Here, we provide evidence of a notable presence (9% overall) of a Neandertal-derived X chromosome segment among all contemporary human populations outside Africa. Our analysis of 6,092 X-chromosomes from all inhabited continents supports earlier contentions that a mosaic of lineages of different time depths and different geographic provenance could have contributed to the genetic constitution of modern humans. It indicates a very early admixture between expanding African migrants and Neandertals prior to or very early on the route of the out-of-Africa expansion that led to the successful colonization of the planet.

Ethnic differences in the frequency of the cardioprotective C679X PCSK9 mutation in a West African population.

PCSK9 is a liver-secreted blood protein that promotes the degradation of low-density lipoprotein receptors, leading to reduced hepatic uptake of plasma cholesterol. Nucleotide variations in its gene have been linked to hypo- and hyper-cholesterolemia. Two nonsense mutations, Y142X and C679X, are associated to lifelong hypocholesterolemia and a remarkable protection against coronary heart disease (CHD) in African Americans. The aim of this study was to determine the frequency of these cardioprotective mutations in West Africans. Subjects (n = 520) from different ethnic groups were recruited in Burkina-Faso, Benin, and Togo. Only the C679X mutation was detected. All carriers were heterozygous. The overall heterozygosity frequency was 3.3%. It varied significantly among ethnic groups, ranging from 0% to 6.9%. The overall high frequency of the cardioprotective C679X mutation in Africa may contribute to the lower incidence of CHD on this continent. The interethnic frequency differences may reflect historical settlement and migration patterns in the region, possibly combined with positive selection for the mutation driven by yet-unknown environmental factors.