Etienne Patin

Natural selection has driven population differentiation in modern humans

The considerable range of observed phenotypic variation in human populations may reflect, in part, distinctive processes of natural selection and adaptation to variable environmental conditions. Although recent genome-wide studies have identified candidate regions under selection, it is not yet clear how natural selection has shaped population differentiation. Here, we have analyzed the degree of population differentiation at 2.8 million Phase II HapMap single-nucleotide polymorphisms. We find that negative selection has globally reduced population differentiation at amino acid–altering mutations, particularly in disease-related genes. Conversely, positive selection has ensured the regional adaptation of human populations by increasing population differentiation in gene regions, primarily at nonsynonymous and 5′-UTR variants. Our analyses identify a fraction of loci that have contributed, and probably still contribute, to the morphological and disease-related phenotypic diversity of current human populations.

Evolutionary dynamics of human Toll-like receptors and their different contributions to host defense.

Infectious diseases have been paramount among the threats to health and survival throughout human evolutionary history. Natural selection is therefore expected to act strongly on host defense genes, particularly on innate immunity genes whose products mediate the direct interaction between the host and the microbial environment. In insects and mammals, the Toll-like receptors (TLRs) appear to play a major role in initiating innate immune responses against microbes. In humans, however, it has been speculated that the set of TLRs could be redundant for protective immunity. We investigated how natural selection has acted upon human TLRs, as an approach to assess their level of biological redundancy. We sequenced the ten human TLRs in a panel of 158 individuals from various populations worldwide and found that the intracellular TLRs—activated by nucleic acids and particularly specialized in viral recognition—have evolved under strong purifying selection, indicating their essential non-redundant role in host survival. Conversely, the selective constraints on the TLRs expressed on the cell surface—activated by compounds other than nucleic acids—have been much more relaxed, with higher rates of damaging nonsynonymous and stop mutations tolerated, suggesting their higher redundancy. Finally, we tested whether TLRs have experienced spatially-varying selection in human populations and found that the region encompassing TLR10-TLR1-TLR6 has been the target of recent positive selection among non-Africans. Our findings indicate that the different TLRs differ in their immunological redundancy, reflecting their distinct contributions to host defense. The insights gained in this study foster new hypotheses to be tested in clinical and epidemiological genetics of infectious disease.

Maternal traces of deep common ancestry and asymmetric gene flow between Pygmy hunter–gatherers and Bantu-speaking farmers

Two groups of populations with completely different lifestyles—the Pygmy hunter–gatherers and the Bantu-speaking farmers—coexist in Central Africa. We investigated the origins of these two groups and the interactions between them, by analyzing mtDNA variation in 1,404 individuals from 20 farming populations and 9 Pygmy populations from Central Africa, with the aim of shedding light on one of the most fascinating cultural transitions in human evolution (the transition from hunting and gathering to agriculture). Our data indicate that this region was colonized gradually, with an initial L1c-rich ancestral population ultimately giving rise to current-day farmers, who display various L1c clades, and to Pygmies, in whom L1c1a is the only surviving clade. Detailed phylogenetic analysis of complete mtDNA sequences for L1c1a showed this clade to be autochthonous to Central Africa, with its most recent branches shared between farmers and Pygmies. Coalescence analyses revealed that these two groups arose through a complex evolutionary process characterized by (i) initial divergence of the ancestors of contemporary Pygmies from an ancestral Central African population no more than ≈70,000 years ago, (ii) a period of isolation between the two groups, accounting for their phenotypic differences, (iii) long-standing asymmetric maternal gene flow from Pygmies to the ancestors of the farming populations, beginning no more than ≈40,000 years ago and persisting until a few thousand years ago, and (iv) enrichment of the maternal gene pool of the ancestors of the farming populations by the arrival and/or subsequent demographic expansion of L0a, L2, and L3 carriers.

IL28B alleles associated with poor hepatitis C virus (HCV) clearance protect against inflammation and fibrosis in patients infected with non-1 HCV genotypes.

Genetic polymorphisms near IL28B are associated with spontaneous and treatment‐induced clearance of hepatitis C virus (HCV), two processes that require the appropriate activation of the host immune responses. Intrahepatic inflammation is believed to mirror such activation, but its relationship with IL28B polymorphisms has yet to be fully appreciated. We analyzed the association of IL28B polymorphisms with histological and follow‐up features in 2335 chronically HCV‐infected Caucasian patients. Assessable phenotypes before any antiviral treatment included necroinflammatory activity (n = 1,098), fibrosis (n = 1,527), fibrosis progression rate (n = 1,312), and hepatocellular carcinoma development (n = 1,915). Associations of alleles with the phenotypes were evaluated by univariate analysis and multivariate logistic regression, accounting for all relevant covariates. The rare G allele at IL28B marker rs8099917—previously shown to be at risk of treatment failure—was associated with lower activity (P = 0.04), lower fibrosis (P = 0.02) with a trend toward lower fibrosis progression rate (P = 0.06). When stratified according to HCV genotype, most significant associations were observed in patients infected with non‐1 genotypes (P = 0.003 for activity, P = 0.001 for fibrosis, and P = 0.02 for fibrosis progression rate), where the odds ratio of having necroinflammation or rapid fibrosis progression for patients with IL28B genotypes TG or GG versus TT were 0.48 (95% confidence intervals 0.30‐0.78) and 0.56 (0.35‐0.92), respectively. IL28B polymorphisms were not predictive of the development of hepatocellular carcinoma. Conclusion: In chronic hepatitis C, IL28B variants associated with poor response to interferon therapy may predict slower fibrosis progression, especially in patients infected with non‐1 HCV genotypes. (HEPATOLOGY 2012)

Positively selected G6PD-Mahidol mutation reduces Plasmodium vivax density in Southeast Asians.

Ghosts of Selection Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common enzyme deficiency of humans, and it has been long suspected to exert an effect on Plasmodium falciparum malaria in Africa. Likewise, the increase in prevalence of the G6PD-Mahidol 487A allele among Karen people in Thailand, who only in the past few thousand years have migrated into malarious zones, may be the result of selection by Plasmodium vivax malaria. P. vivax has recently been implicated in more severe disease than previously suspected, providing both a direct selective effect through mortality and an indirect selective effect through morbidity and reproductive failure. Louicharoen et al. (p. 1546) link population-genetic evidence for positive selection in an 8-year family-based study of 3000 Karen individuals and reveal that there is an association between the presence of the G6PD-Mahidol 487A allele and a reduction in the density of P. vivax parasites circulating in the bloodstreams of infected individuals. The mutation appears to exert its effect on the physiology of immature red blood cells, which are the preferred niche for P. vivax but not of P. falciparum. Positive selection acts on a hemolytic anemia–causing mutation that affects the proliferation of a blood parasite in humans. Glucose-6-phosphate dehydrogenase (G6PD) deficiency—the most common known enzymopathy—is associated with neonatal jaundice and hemolytic anemia usually after exposure to certain infections, foods, or medications. Although G6PD-deficient alleles appear to confer a protective effect against malaria, the link with clinical protection from Plasmodium infection remains unclear. We investigated the effect of a common G6PD deficiency variant in Southeast Asia—the G6PD-Mahidol487A variant—on human survival related to vivax and falciparum malaria. Our results show that strong and recent positive selection has targeted the Mahidol variant over the past 1500 years. We found that the G6PD-Mahidol487A variant reduces vivax, but not falciparum, parasite density in humans, which indicates that Plasmodium vivax has been a driving force behind the strong selective advantage conferred by this mutation.

Ribosomal Protein SA Haploinsufficiency in Humans with Isolated Congenital Asplenia

Spleen Knockout Explained Isolated congenital asplenia (ICA) is a rare disorder where patients are born without a spleen and are at increased risk of bacterial infection but have no other developmental abnormalities. Through sequence analysis of familial and sporadic cases, Bolze et al. (p. 976, published online 11 April) found that ICA patients carry mutations in the gene encoding ribosomal protein SA and as a result express about half the normal amount of this protein. The mechanism by which reduced expression of a housekeeping protein causes an organ-specific defect remains unclear. A rare human disorder, characterized by the absence of a spleen at birth, is associated with mutations in a ribosomal protein. Isolated congenital asplenia (ICA) is characterized by the absence of a spleen at birth in individuals with no other developmental defects. The patients are prone to life-threatening bacterial infections. The unbiased analysis of exomes revealed heterozygous mutations in RPSA in 18 patients from eight kindreds, corresponding to more than half the patients and over one-third of the kindreds studied. The clinical penetrance in these kindreds is complete. Expression studies indicated that the mutations carried by the patients—a nonsense mutation, a frameshift duplication, and five different missense mutations—cause autosomal dominant ICA by haploinsufficiency. RPSA encodes ribosomal protein SA, a component of the small subunit of the ribosome. This discovery establishes an essential role for RPSA in human spleen development.

The heritage of pathogen pressures and ancient demography in the human innate-immunity CD209/CD209L region.

The innate immunity system constitutes the first line of host defense against pathogens. Two closely related innate immunity genes, CD209 and CD209L, are particularly interesting because they directly recognize a plethora of pathogens, including bacteria, viruses, and parasites. Both genes, which result from an ancient duplication, possess a neck region, made up of seven repeats of 23 amino acids each, known to play a major role in the pathogen-binding properties of these proteins. To explore the extent to which pathogens have exerted selective pressures on these innate immunity genes, we resequenced them in a group of samples from sub-Saharan Africa, Europe, and East Asia. Moreover, variation in the number of repeats of the neck region was defined in the entire Human Genome Diversity Panel for both genes. Our results, which are based on diversity levels, neutrality tests, population genetic distances, and neck-region length variation, provide genetic evidence that CD209 has been under a strong selective constraint that prevents accumulation of any amino acid changes, whereas CD209L variability has most likely been shaped by the action of balancing selection in non-African populations. In addition, our data point to the neck region as the functional target of such selective pressures: CD209 presents a constant size in the neck region populationwide, whereas CD209L presents an excess of length variation, particularly in non-African populations. An additional interesting observation came from the coalescent-based CD209 gene tree, whose binary topology and time depth (∼2.8 million years ago) are compatible with an ancestral population structure in Africa. Altogether, our study has revealed that even a short segment of the human genome can uncover an extraordinarily complex evolutionary history, including different pathogen pressures on host genes as well as traces of admixture among archaic hominid populations.

Evolutionary genetic dissection of human interferons

As revealed by population genetic analyses, different human interferon genes evolved under distinct selective constraints and signatures of positive selection vary according to geographic region, suggesting that some sequence changes may have conferred an advantage by increasing resistance to viral infection.

Formulating a Historical and Demographic Model of Recent Human Evolution Based on Resequencing Data from Noncoding Regions

Background Estimating the historical and demographic parameters that characterize modern human populations is a fundamental part of reconstructing the recent history of our species. In addition, the development of a model of human evolution that can best explain neutral genetic diversity is required to identify confidently regions of the human genome that have been targeted by natural selection. Methodology/Principal Findings We have resequenced 20 independent noncoding autosomal regions dispersed throughout the genome in 213 individuals from different continental populations, corresponding to a total of ∼6 Mb of diploid resequencing data. We used these data to explore and co-estimate an extensive range of historical and demographic parameters with a statistical framework that combines the evaluation of multiple models of human evolution via a best-fit approach, followed by an Approximate Bayesian Computation (ABC) analysis. From a methodological standpoint, evaluating the accuracy of the parameter co-estimation allowed us to identify the most accurate set of statistics to be used for the estimation of each of the different historical and demographic parameters characterizing recent human evolution. Conclusions/Significance Our results support a model in which modern humans left Africa through a single major dispersal event occurring ∼60,000 years ago, corresponding to a drastic reduction of ∼5 times the effective population size of the ancestral African population of ∼13,800 individuals. Subsequently, the ancestors of modern Europeans and East Asians diverged much later, ∼22,500 years ago, from the population of ancestral migrants. This late diversification of Eurasians after the African exodus points to the occurrence of a long maturation phase in which the ancestral Eurasian population was not yet diversified.

Genome-Wide Association Study Identifies Variants Associated with Progression of Liver Fibrosis from HCV Infection

BACKGROUND & AIMS Polymorphisms in IL28B were shown to affect clearance of hepatitis C virus (HCV) infection in genome-wide association (GWA) studies. Only a fraction of patients with chronic HCV infection develop liver fibrosis, a process that might also be affected by genetic factors. We performed a 2-stage GWA study of liver fibrosis progression related to HCV infection. METHODS We studied well-characterized HCV-infected patients of European descent who underwent liver biopsies before treatment. We defined various liver fibrosis phenotypes on the basis of METAVIR scores, with and without taking the duration of HCV infection into account. Our GWA analyses were conducted on a filtered primary cohort of 1161 patients using 780,650 single nucleotide polymorphisms (SNPs). We genotyped 96 SNPs with P values <5 × 10(-5) from an independent replication cohort of 962 patients. We then assessed the most interesting replicated SNPs using DNA samples collected from 219 patients who participated in separate GWA studies of HCV clearance. RESULTS In the combined cohort of 2342 HCV-infected patients, the SNPs rs16851720 (in the total sample) and rs4374383 (in patients who received blood transfusions) were associated with fibrosis progression (P(combined) = 8.9 × 10(-9) and 1.1 × 10(-9), respectively). The SNP rs16851720 is located within RNF7, which encodes an antioxidant that protects against apoptosis. The SNP rs4374383, together with another replicated SNP, rs9380516 (P(combined) = 5.4 × 10(-7)), were linked to the functionally related genes MERTK and TULP1, which encode factors involved in phagocytosis of apoptotic cells by macrophages. CONCLUSIONS Our GWA study identified several susceptibility loci for HCV-induced liver fibrosis; these were linked to genes that regulate apoptosis. Apoptotic control might therefore be involved in liver fibrosis.