Evolutionary analysis of genes of two pathways involved in placental malaria infection

Placental malaria is a special form of malaria that causes up to 200,000 maternal and infant deaths every year. Previous studies show that two receptor molecules, hyaluronic acid and chondroitin sulphate A, are mediating the adhesion of parasite-infected erythrocytes in the placenta of patients, which is believed to be a key step in the pathogenesis of the disease. In this study, we aimed at identifying sites of malaria-induced adaptation by scanning for signatures of natural selection in 24 genes in the complete biosynthesis pathway of these two receptor molecules. We analyzed a total of 24 Mb of publicly available polymorphism data from the International HapMap project for three human populations with European, Asian and African ancestry, with the African population from a region of presently and historically high malaria prevalence. Using the methods based on allele frequency distributions, genetic differentiation between populations, and on long-range haplotype structure, we found only limited evidence for malaria-induced genetic adaptation in this set of genes in the African population; however, we identified one candidate gene with clear evidence of selection in the Asian population. Although historical exposure to malaria in this population cannot be ruled out, we speculate that it might be caused by other pathogens, as there is growing evidence that these molecules are important receptors in a variety of host-pathogen interactions. We propose to use the present methods in a systematic way to help identify candidate regions under positive selection as a consequence of malaria

A genomic analysis identifies a novel component in the genetic structure of sub-Saharan African populations

Studies of large sets of SNP data have proven to be a powerful tool in the analysis of the genetic structure of human populations. In this work, we analyze genotyping data for 2,841 SNPs in 12 Sub-Saharan African populations, including a previously unsampled region of south-eastern Africa (Mozambique). We show that robust results in a world-wide perspective can be obtained when analyzing only 1,000 SNPs. Our main results both confirm the results of previous studies, and show new and interesting features in Sub-Saharan African genetic complexity. There is a strong differentiation of Nilo-Saharans, much beyond what would be expected by geography. Hunter-gatherer populations (Khoisan and Pygmies) show a clear distinctiveness with very intrinsic Pygmy (and not only Khoisan) genetic features. Populations of the West Africa present an unexpected similarity among them, possibly the result of a population expansion. Finally, we find a strong differentiation of the south-eastern Bantu population from Mozambique, which suggests an assimilation of a pre-Bantu substrate by Bantu speakers in the region.This research was supported by Dirección General de Investigación, Ministerio de Ciencia y Tecnología, Spain (grants SAF2007-63171, BFU2007-63657) and Direcció General de Recerca, Generalitat de Catalunya (2009 SGR 1101). SNP genotyping services were provided by the Spanish "Centro Nacional de Genotipado" (CEGEN; http://www.cegen.org); Bioinformatic services were kindly provided by the Genomic Diversity node, Spanish Bioinformatic Institute (www.inab.org). MS was supported by a PhD fellowship from the Programa de becas FPU del Ministerio de Educación y Ciencia, Spain (AP2005-3982)

Distribution of events of positive selection and population differentiation in a metabolic pathway: the case of asparagine N-glycosylation

Asparagine N-Glycosylation is one of the most important forms of protein post-translational modification in eukaryotes. This metabolic pathway can be subdivided into two parts: an upstream sub-pathway required for achieving proper folding for most of the proteins synthesized in the secretory pathway, and a downstream sub-pathway required to give variability to trans-membrane proteins, and involved in adaptation to the environment and innate immunity. Here we analyze the nucleotide variability of the genes of this pathway in human populations, identifying which genes show greater population differentiation and which genes show signatures of recent positive selection. We also compare how these signals are distributed between the upstream and the downstream parts of the pathway, with the aim of exploring how forces of population differentiation and positive selection vary among genes involved in the same metabolic pathway but subject to different functional constraints. Our results show that genes in the downstream part of the pathway are more likely to show a signature of population differentiation, while events of positive selection are equally distributed among the two parts of the pathway. Moreover, events of positive selection are frequent on genes that are known to be at bifurcation points, and that are identified as being in key position by a network-level analysis such as MGAT3 and GCS1. These findings indicate that the upstream part of the Asparagine N-Glycosylation pathway has lower diversity among populations, while the downstream part is freer to tolerate diversity among populations. Moreover, the distribution of signatures of population differentiation and positive selection can change between parts of a pathway, especially between parts that are exposed to different functional constraints. Our results support the hypothesis that genes involved in constitutive processes can be expected to show lower population differentiation, while genes involved in traits related to the environment should show higher variability. Taken together, this work broadens our knowledge on how events of population differentiation and of positive selection are distributed among different parts of a metabolic pathway.This work was funded by grant BFU2010-19443 (subprogram BMC) awarded to JB by Ministerio de Ciencia y Tecnología (Spain), and the Direcció General de Recerca, Generalitat de Catalunya (Grup de Recerca Consolidat 2009 SGR 1101). GMD is supported by a FPI fellowship (BES-2009-017731) from the Ministerio de Ciencia y Tecnología, (Spain). PL is supported by a PhD fellowship from “Acción Estratégica de Salud, 2008-2011” from Instituto de Salud Carlos III and LM is supported by a postdoctoral fellowship from the Juan de la Cierva Program of the Spanish Ministry of Science and Innovation (MICINN)

Distribution of events of positive selection and population differentiation in a metabolic pathway: the case of asparagine N-glycosylation

Asparagine N-Glycosylation is one of the most important forms of protein post-translational modification in eukaryotes. This metabolic pathway can be subdivided into two parts: an upstream sub-pathway required for achieving proper folding for most of the proteins synthesized in the secretory pathway, and a downstream sub-pathway required to give variability to trans-membrane proteins, and involved in adaptation to the environment and innate immunity. Here we analyze the nucleotide variability of the genes of this pathway in human populations, identifying which genes show greater population differentiation and which genes show signatures of recent positive selection. We also compare how these signals are distributed between the upstream and the downstream parts of the pathway, with the aim of exploring how forces of population differentiation and positive selection vary among genes involved in the same metabolic pathway but subject to different functional constraints. Our results show that genes in the downstream part of the pathway are more likely to show a signature of population differentiation, while events of positive selection are equally distributed among the two parts of the pathway. Moreover, events of positive selection are frequent on genes that are known to be at bifurcation points, and that are identified as being in key position by a network-level analysis such as MGAT3 and GCS1. These findings indicate that the upstream part of the Asparagine N-Glycosylation pathway has lower diversity among populations, while the downstream part is freer to tolerate diversity among populations. Moreover, the distribution of signatures of population differentiation and positive selection can change between parts of a pathway, especially between parts that are exposed to different functional constraints. Our results support the hypothesis that genes involved in constitutive processes can be expected to show lower population differentiation, while genes involved in traits related to the environment should show higher variability. Taken together, this work broadens our knowledge on how events of population differentiation and of positive selection are distributed among different parts of a metabolic pathway.This work was funded by grant BFU2010-19443 (subprogram BMC) awarded to JB by Ministerio de Ciencia y Tecnología (Spain), and the Direcció General de Recerca, Generalitat de Catalunya (Grup de Recerca Consolidat 2009 SGR 1101). GMD is supported by a FPI fellowship (BES-2009-017731) from the Ministerio de Ciencia y Tecnología, (Spain). PL is supported by a PhD fellowship from “Acción Estratégica de Salud, 2008-2011” from Instituto de Salud Carlos III and LM is supported by a postdoctoral fellowship from the Juan de la Cierva Program of the Spanish Ministry of Science and Innovation (MICINN)

African signatures of recent positive selection in human FOXI1

Background: The human FOXI1 gene codes for a transcription factor involved in the physiology of the inner ear, testis, and kidney. Using three interspecies comparisons, it has been suggested that this may be a gene under/nhuman-specific selection. We sought to confirm this finding by using an extended set of orthologous sequences./nAdditionally, we explored for signals of natural selection within humans by sequencing the gene in 20 Europeans,/n20 East Asians and 20 Yorubas and by analysing SNP variation in a 2 Mb region centered on FOXI1 in 39/nworldwide human populations from the HGDP-CEPH diversity panel./nResults: The genome sequences recently available from other primate and non-primate species showed that FOXI1/ndivergence patterns are compatible with neutral evolution. Sequence-based neutrality tests were not significant in/nEuropeans, East Asians or Yorubas. However, the Long Range Haplotype (LRH) test, as well as the iHS and XP-Rsb/nstatistics revealed significantly extended tracks of homozygosity around FOXI1 in Africa, suggesting a recent/nepisode of positive selection acting on this gene. A functionally relevant SNP, as well as several SNPs either on the/nputatively selected core haplotypes or with significant iHS or XP-Rsb values, displayed allele frequencies strongly/ncorrelated with the absolute geographical latitude of the populations sampled./nConclusions: We present evidence for recent positive selection in the FOXI1 gene region in Africa. Climate might/nbe related to this recent adaptive event in humans. Of the multiple functions of FOXI1, its role in kidney-mediated/nwater-electrolyte homeostasis is the most obvious candidate for explaining a climate-related adaptation.This research was funded by grant BFU2005-00243 awarded by Dirección General de Investigación, Ministerio de Educación y Ciencia (Spain), by grant BFU2008-01046/BMC awarded by Subdirección General de Proyectos de Investigación, Ministerio de Ciencia e Innovación (Spain), and by the Direcció General de Recerca, Generalitat de Catalunya (2009SGR1101). AME was supported by a CONACYT fellowship from the Mexican government (grant 179339), MS by a PhD fellowship from the Programa de becas FPU del Ministerio de Educación y Ciencia, Spain (AP2005-3982) and JE by a Volkswagenstiftung scholarship (I/82 750). SNP genotyping services were provided by the Spanish “Centro Nacional de Genotipado” (http://www.cegen.org)

African signatures of recent positive selection in human FOXI1

Background: The human FOXI1 gene codes for a transcription factor involved in the physiology of the inner ear, testis, and kidney. Using three interspecies comparisons, it has been suggested that this may be a gene under/nhuman-specific selection. We sought to confirm this finding by using an extended set of orthologous sequences./nAdditionally, we explored for signals of natural selection within humans by sequencing the gene in 20 Europeans,/n20 East Asians and 20 Yorubas and by analysing SNP variation in a 2 Mb region centered on FOXI1 in 39/nworldwide human populations from the HGDP-CEPH diversity panel./nResults: The genome sequences recently available from other primate and non-primate species showed that FOXI1/ndivergence patterns are compatible with neutral evolution. Sequence-based neutrality tests were not significant in/nEuropeans, East Asians or Yorubas. However, the Long Range Haplotype (LRH) test, as well as the iHS and XP-Rsb/nstatistics revealed significantly extended tracks of homozygosity around FOXI1 in Africa, suggesting a recent/nepisode of positive selection acting on this gene. A functionally relevant SNP, as well as several SNPs either on the/nputatively selected core haplotypes or with significant iHS or XP-Rsb values, displayed allele frequencies strongly/ncorrelated with the absolute geographical latitude of the populations sampled./nConclusions: We present evidence for recent positive selection in the FOXI1 gene region in Africa. Climate might/nbe related to this recent adaptive event in humans. Of the multiple functions of FOXI1, its role in kidney-mediated/nwater-electrolyte homeostasis is the most obvious candidate for explaining a climate-related adaptation.This research was funded by grant BFU2005-00243 awarded by Dirección General de Investigación, Ministerio de Educación y Ciencia (Spain), by grant BFU2008-01046/BMC awarded by Subdirección General de Proyectos de Investigación, Ministerio de Ciencia e Innovación (Spain), and by the Direcció General de Recerca, Generalitat de Catalunya (2009SGR1101). AME was supported by a CONACYT fellowship from the Mexican government (grant 179339), MS by a PhD fellowship from the Programa de becas FPU del Ministerio de Educación y Ciencia, Spain (AP2005-3982) and JE by a Volkswagenstiftung scholarship (I/82 750). SNP genotyping services were provided by the Spanish “Centro Nacional de Genotipado” (http://www.cegen.org)

A targeted association study of immunity genes and networks suggests novel associations with placental malaria infection

A large proportion of the death toll associated with malaria is a consequence of malaria infection during pregnancy, causing up to 200,000 infant deaths annually. We previously published the first extensive genetic association study of placental malaria infection, and here we extend this analysis considerably, investigating genetic variation in over 9,000 SNPs in more than 1,000 genes involved in immunity and inflammation for their involvement in susceptibility to placental malaria infection. We applied a new approach incorporating results from both single gene analysis as well as gene-gene interactions/non a protein-protein interaction network. We found suggestive associations of variants in the gene KLRK1 in the single gene/nanalysis, as well as evidence for associations of multiple members of the IL-7/IL-7R signalling cascade in the combined analysis. To our knowledge, this is the first large-scale genetic study on placental malaria infection to date, opening the door for follow-up studies trying to elucidate the genetic basis of this neglected form of malaria.This work was supported by grant SAF-2007-63171 awarded by Ministerio de Educación y Ciencia (Spain) to JB and the CIBERESP (CIBER of Epidemiology and Public Health, Ministry of Health). Funds were also obtained from Dirreció General de Recerca of Generalitat de Catalunya (Grup de Recerca Consolidat 2005SGR/00608) and from Banco de Bilbao, Vizcaya, Argentaria Foundation (grant number BBVA 02-0). The CISM receives core support from the Spanish Agency for International Cooperation and Development (AECID). All the genotyping was provided by the Spanish “Centro Nacional de Genotipado” (CEGEN; www.cegen.org); support for computations was provided by the National Institute for Bioinformatics (www.inab.org); both are platforms of Genoma España. MGN was supported by a Vici grant of the Netherlands Organization for Scientific Research. AM was supported by the Spanish Ministry of Health (Program for the Promotion of Biomedical Research and Health Sciences, Instituto de Salud Carlos III, CP-04/00220). MS was supported by a PhD fellowship from the Programa de becas FPU del Ministerio de Educación y Ciencia, Spain (AP2005-3982). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

A variant in the gene FUT9 is associated with susceptibility to placental malaria infection

Malaria in pregnancy forms a substantial part of the worldwide burden of malaria, with an estimated annual death toll of up to 200,000 infants, as well as increased maternal morbidity and mortality. Studies of genetic susceptibility to malaria have so far focused on infant malaria, with only a few studies investigating the genetic basis of placental malaria, focusing only on a limited number of candidate genes. The aim of this study therefore was to identify novel host genetic factors involved in placental malaria infection. To this end we carried out a nested case-control study on 180 Mozambican pregnant women with placental malaria infection, and 180 controls within an intervention trial of malaria prevention. We genotyped 880 SNPs in a set of 64 functionally related genes involved in glycosylation and innate immunity. A SNP located in the gene FUT9, rs3811070, was significantly associated with placental malaria infection (OR = 2.31, permutation p-value = 0.028). Haplotypic analysis revealed a similarly strong association of a common haplotype of four SNPs including rs3811070. FUT9 codes for a fucosyl-transferase that is catalyzing the last step in the biosynthesis of the Lewis-x antigen, which forms part of the Lewis blood group-related antigens. These results therefore suggest an involvement of this antigen in the pathogenesis of placental malaria infection.This work was supported by grant SAF-2007-63171 awarded by Ministerio de Educación y Ciencia (Spain) to JB and the CIBERESP (CIBER of Epidemiology and Public Health, Ministry of Health). Funds were also obtained from Direcció General de Recerca of Generalitat de Catalunya (Grup de Recerca Consolidat 2005SGR/00608) and from Banco de Bilbao, Vizcaya, Argentaria Foundation (grant number BBVA 02-0). The CISM receives core support from the Spanish Agency for International Cooperation and Development (AECID). All the genotyping was provided by the Spanish "Centro Nacional de Genotipado" (CEGEN; www.cegen.org); Support for computations was provided by the National Institute for Bioinformatics (www.inab.org); both are platforms of Genoma España. MS is supported by a PhD fellowship from the Programa de becas FPU del Ministerio de Educación y Ciencia, Spain (AP2005-3982)

Genetic adaptation of the antibacterial human innate immunity network

Background: Pathogens have represented an important selective force during the adaptation of modern human populations to changing social and other environmental conditions. The evolution of the immune system has therefore been influenced by these pressures. Genomic scans have revealed that immune system is one of the functions enriched with genes under adaptive selection. Results: Here, we describe how the innate immune system has responded to these challenges, through the analysis of resequencing data for 132 innate immunity genes in two human populations. Results are interpreted in the context of the functional and interaction networks defined by these genes. Nucleotide diversity is lower in the adaptors and modulators functional classes, and is negatively correlated with the centrality of the proteins within the interaction network. We also produced a list of candidate genes under positive or balancing selection in each population detected by neutrality tests and showed that some functional classes are preferential targets for selection. Conclusions: We found evidence that the role of each gene in the network conditions the capacity to evolve or their evolvability: genes at the core of the network are more constrained, while adaptation mostly occurred at particular positions at the network edges. Interestingly, the functional classes containing most of the genes with signatures of balancing selection are involved in autoinflammatory and autoimmune diseases, suggesting a counterbalance between the beneficial and deleterious effects of the immune response.Support for this research comes from the Spanish Ministry of Innovation and Research grant SAF-2007-63171 to JB. Additional support from Direcció General de Recerca of Generalitat de Catalunya (Grup de Recerca Consolidat 2005SGR/00608) and the National Institute for Bioinformatics (http://www.inab.org). A.M. is supported by Red HERACLES (Instituto de Salut Carlos III). R.L. was supported by NIH grants HL065899, HL083069, HG004909 and HG003646. M.G.N. was supported by a Vici grant of the Netherlands Organization for Scientific Research. M.S. was supported by a PhD fellowship from the Programa de becas FPU del Ministerio de Educación y Ciencia, Spain (AP2005-3982

Similarity in recombination rate estimates highly correlates with genetic differentiation in humans

Recombination varies greatly among species, as illustrated by the poor conservation of the recombination landscape between humans and chimpanzees. Thus, shorter evolutionary time frames are needed to understand the evolution of recombination. Here, we analyze its recent evolution in humans. We calculated the recombination rates between adjacent pairs of 636,933 common single-nucleotide polymorphism loci in 28 worldwide human populations and analyzed them in relation to genetic distances between populations. We found a strong and highly significant correlation between similarity in the recombination rates corrected for effective population size and genetic differentiation between populations. This correlation is observed at the genome-wide level, but also for each chromosome and when genetic distances and recombination similarities are calculated independently from different parts of the genome. Moreover, and more relevant, this relationship is robustly maintained when considering presence/absence of recombination hotspots. Simulations show that this correlation cannot be explained by biases in the inference of recombination rates caused by haplotype sharing among similar populations. This result indicates a rapid pace of evolution of recombination, within the time span of differentiation of modern humansThis research was funded by grants BFU2007-63657, BFU2009-13409-C02-02 and SAF-2007-63171 awarded by Ministerio de Educación y Ciencia (Spain), by the Direcció General de Recerca of Generalitat de Catalunya (Grup de Recerca Consolidat 2005SGR/00608 and 2009 SGR 1101), and by the National Institute for Bioinformatics (www.inab.org), a platform of Genoma España. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscrip