Search

The occurrence of natural variation in human microRNAs has been the focus of numerous studies during the last 20 years. Most of them have been focused on the role of specific mutations in disease, while a minor proportion seek to analyse microRNA diversity in the genomes of human populations. We analyse the latest human microRNA annotations in the light of the most updated catalogue of genetic variation provided by the 1000 Genomes Project. By means of the in silico analysis of microRNA genetic variation we show that the level of evolutionary constraint of these sequences is governed by the interplay of different factors, like their evolutionary age or genomic location. The role of mutations in the shaping of microRNA-driven regulatory interactions is emphasized with the acknowledgement that, while the whole microRNA sequence is highly conserved, the seed region shows a pattern of higher genetic diversity that appears to be caused by the dramatic frequency shifts of a fraction of human microRNAs. We highlight the participation of these microRNAs in population-specific processes by identifying that not only the seed, but also the loop, are particularly differentiated regions among human populations. The quantitative computational comparison of signatures of population differentiation showed that candidate microRNAs with the largest differences are enriched in variants implicated in gene expression levels (eQTLs), selective sweeps and pathological processes. We explore the implication of these evolutionary-driven microRNAs and their SNPs in human diseases, such as different types of cancer, and discuss their role in population-specific disease risk., This study has been possible thanks to the Chilean Agencia Nacional de Investigación y Desarrollo—ANID (FONDECYT regular nº 1170446), the Chilean Ministry of Education (MAG-1995), grant PID2019-110933 GB-I00/AEI/10. 13039/501100011033 awarded by the Spanish Agencia Estatal de Investigación (AEI), Ministerio de Ciencia, Innovación y Universidades (MCIU, Spain), the support of Secretaria d’Universitats i Recerca del Departament d’Economia i Coneixement de la Generalitat de Catalunya (GRC 2017 SGR 702), part of the “Unidad de Excelencia María de Maeztu”, funded by the AEI (CEX2018-000792-M). P.V-M is supported by an FPI PhD fellowship (FPI-BES-2016-077706) part of the “Unidad de Excelencia María de Maeztu” funded by MINECO (ref: MDM-2014-0370).

Natural selection targets a heritable trait that provides greater or lower chances for an organism to reproduce, and/or to survive, in a given environment. This evolutionary process is therefore directional: while an advantageous trait will be selected for and, thus, increase in frequency in the population, a prejudicial phenotype will be selected against and purged from the population. This concept, introduced in 1858 simultaneously by Charles R. Darwin and Alfred Wallace ((Darwin and Wallace J Proc Linnean Soc London 3:46–50, 1858); (Darwin On the origin of species by means of natural selection, or the preservation of favoured races in the struggle for life. John Murray, London, 1859)), has been at the core of the study of evolution and biological research. However, since then there has been passionate debate concerning its relative importance among other evolutionary processes, the prevalence of adaptive traits, and how they are originated in natural populations.

Background Despite its pervasiveness, the genetic basis of adaptation resulting in variation directly or indirectly related to temperature (climatic) gradients is poorly understood. By using 3-fold replicated laboratory thermal stocks covering much of the physiologically tolerable temperature range for the temperate (i.e., cold tolerant) species Drosophila subobscura we have assessed whole-genome transcriptional responses after three years of thermal adaptation, when the populations had already diverged for inversion frequencies, pre-adult life history components, and morphological traits. Total mRNA from each population was compared to a reference pool mRNA in a standard, highly replicated two-colour competitive hybridization experiment using cDNA microarrays. Results A total of 306 (6.6%) cDNA clones were identified as 'differentially expressed' (following a false discovery rate correction) after contrasting the two furthest apart thermal selection regimes (i.e., 13°C vs . 22°C), also including four previously reported candidate genes for thermotolerance in Drosophila (Hsp26, Hsp68, Fst, and Treh). On the other hand, correlated patterns of gene expression were similar in cold- and warm-adapted populations. Analysis of functional categories defined by the Gene Ontology project point to an overrepresentation of genes involved in carbohydrate metabolism, nucleic acids metabolism and regulation of transcription among other categories. Although the location of differently expressed genes was approximately at random with respect to chromosomes, a physical mapping of 88 probes to the polytene chromosomes of D. subobscura has shown that a larger than expected number mapped inside inverted chromosomal segments. Conclusion Our data suggest that a sizeable number of genes appear to be involved in thermal adaptation in Drosophila, with a substantial fraction implicated in metabolism. This apparently illustrates the formidable challenge to understanding the adaptive evolution of complex trait variation. Furthermore, some clustering of genes within inverted chromosomal sections was detected. Disentangling the effects of inversions will be obviously required in any future approach if we want to identify the relevant candidate genes.

The Roma people are the largest transnational ethnic minority in Europe and can be considered the last human migration of South Asian origin into the continent. They left Northwest India approximately 1,000 years ago, reaching the Balkan Peninsula around the twelfth century and Romania in the fourteenth century. Here, we analyze whole-genome sequencing data of 40 Roma and 40 non-Roma individuals from Romania. We performed a genome-wide scan of selection comparing Roma, their local host population, and a Northwestern Indian population, to identify the selective pressures faced by the Roma mainly after they settled in Europe. We identify under recent selection several pathways implicated in immune responses, among them cellular metabolism pathways known to be rewired after immune stimulation. We validated the interaction between PIK3-mTOR-HIF-1α and cytokine response influenced by bacterial and fungal infections. Our results point to a significant role of these pathways for host defense against the most prevalent pathogens in Europe during the last millennium., Tis study has been funded by a Spinoza grant of the Netherlands Organization for Scientifc Research (MN), and by BFU2016-77961-P (JB and EBo), PID2019-110933GB-I00 (JB and EBo) and CGL2016-75389-P (DC) (AEI/ FEDER, UE) awarded by the Agencia Estatal de Investigación, CEX2018-000792-M, Unidad de Excelencia María de Maeztu (JB, DC and EBo), and GRC 2017 SGR 702 of Secretaria d’Universitats i Recerca de la Generalitat de Catalunya (JB, EBo and DC). BD is supported by FPU grant FPU13/06813 from the Ministerio de Educación, Cultura y Deporte (Spain). MM was supported by the European Union through the European Regional Development Fund (Project No. 2014-2020.4.01.16-0030)

After diverging, each chimpanzee subspecies has been the target of unique selective pressures. Here, we employ a machine learning approach to classify regions as under positive selection or neutrality genome-wide. The regions determined to be under selection reflect the unique demographic and adaptive history of each subspecies. The results indicate that effective population size is important for determining the proportion of the genome under positive selection. The chimpanzee subspecies share signals of selection in genes associated with immunity and gene regulation. With these results, we have created a selection map for each population that can be displayed in a genome browser (www.hsb.upf.edu/chimp_browser). This study is the first to use a detailed demographic history and machine learning to map selection genome-wide in chimpanzee. The chimpanzee selection map will improve our understanding of the impact of selection on closely related subspecies and will empower future studies of chimpanzee., Agencia Estatal de Investigacion (Spain) [PID2019- ´ 110933GB-I00, CEX2018-000792-M, in part]; Secretaria d’Universitats i Recerca del Departament d’Economia i Coneixement de la Generalitat de Catalunya [GRC 2017 SGR 702]; Agency for Management of University and Research Grants [FI-DGR 2015 to J.N.]; Part of the “Unidad de Excelencia Mar´ıa de Maeztu” [MDM-2014- 0370], funded by the Ministerio de Econom´ıa, Industria y Competividad (MINECO, Spain).

Nucleotide variants in microRNA regions have been associated with disease; nevertheless, few studies still have addressed the allele-dependent effect of these changes. We studied microRNA genetic variation in human populations and found that while low-frequency variants accumulate indistinctly in microRNA regions, the mature and seed regions tend to be depleted of high-frequency variants, probably as a result of purifying selection. Comparison of pairwise population fixation indexes among regions showed that the seed had higher population fixation indexes than the other regions, suggesting the existence of local adaptation in the seed region. We further performed functional studies of three microRNA variants associated with cancer (rs2910164:C > G in MIR146A, rs11614913:C > T in MIR196A2, and rs3746444:A > G in both MIR499A and MIR499B). We found differences in the expression between alleles and in the regulation of several genes involved in cancer, such as TP53, KIT, CDH1, CLH, and TERT, which may result in changes in regulatory networks related to tumorigenesis. Furthermore, luciferase-based assays showed that MIR499A could be regulating the cadherin CDH1 and the cell adhesion molecule CLH1 in an allele-dependent fashion. A better understanding of the effect of microRNA variants associated with disease could be key in our way to a more personalized medicine., Contract grant sponsors: Spanish National Institute for Bioinformatics (www.inab.org); “Ministerio de Ciencia e Innovación de España” (BFU2010-18477, CGL2009-09013 and FPI-MINECO); European Union Seventh Framework Programme (PIOF-GA-2009-236836 and PIRSES-GA-2013-612583); “Direcció general de Recerca de la Generalitat de Catalunya; Agencia de Gestió d'Ajuts Universitaris de Recerca” (2014SGR-866, 2014SGR-1311); “Ministerio de Educación, Cultura y Deporte de España” (FPU-MEC, FPU13/06813); FEDER European Regional Development Fund “A way to build Europe”; Ministerio de Economia y Competitividad, Spain (grant no. BFU2013-43726-P).

[Background] Determining the factors involved in the likelihood of a gene being under adaptive selection is still a challenging goal in Evolutionary Biology. Here, we perform an evolutionary analysis of the human metabolic genes to explore the associations between network structure and the presence and strength of natural selection in the genes whose products are involved in metabolism. Purifying and positive selection are estimated at interspecific (among mammals) and intraspecific (among human populations) levels, and the connections between enzymatic reactions are differentiated between incoming (in-degree) and outgoing (out-degree) links., [Results] We confirm that purifying selection has been stronger in highly connected genes. Long-term positive selection has targeted poorly connected enzymes, whereas short-term positive selection has targeted different enzymes depending on whether the selective sweep has reached fixation in the population: genes under a complete selective sweep are poorly connected, whereas those under an incomplete selective sweep have high out-degree connectivity. The last steps of pathways are more conserved due to stronger purifying selection, with long-term positive selection targeting preferentially enzymes that catalyze the first steps. However, short-term positive selection has targeted enzymes that catalyze the last steps in the metabolic network. Strong signals of positive selection have been found for metabolic processes involved in lipid transport and membrane fluidity and permeability., [Conclusions] Our analysis highlights the importance of analyzing the same biological system at different evolutionary timescales to understand the evolution of metabolic genes and of distinguishing between incoming and outgoing links in a metabolic network. Short-term positive selection has targeted enzymes with a different connectivity profile depending on the completeness of the selective sweep, while long-term positive selection has targeted genes with fewer connections that code for enzymes that catalyze the first steps in the network., This study has been possible thanks to grant BFU2016–77961-P (AEI/FEDER, UE) awarded by the Agencia Estatal de Investigación (Ministerio de Ciencia, Innovación y Universidades, Spain) and with the support of Secretaria d’Universitats i Recerca del Departament d’Economia i Coneixement de la Generalitat de Catalunya (GRC 2017 527 SGR 702) to JB. Part of the “Unidad de Excelencia María de Maeztu” (MDM-2014-0370), funded by the Ministerio de Economía, Industria y Competividad (MINECO, Spain). JP work is supported in part by the Agencia Estatal de Investigación (Ministerio de Ciencia, Innovación y Universidades, Spain) Helios grant reference: BIO2015–66960-C3–1-R (co-financed by FEDER) and by the European Union through the BioRoboost project (H2020-NMBP-TR-IND-2018-2020/BIOTEC-01-2018 (CSA), Project ID 210491758). BD is supported by F.P.U. grant FPU13/06813 from the Ministerio de Educación, Cultura y Deporte (Spain).

Gineau, L. et al., © 2015 Macmillan Publishers Limited. Human leukocyte antigen-G (HLA-G) has well-recognized immunosuppressive properties modulating the activity of many immune system cells, and polymorphisms observed at the HLA-G 5′ upstream regulatory region (5′URR) may influence gene transcriptional regulation. In this study, we characterized the sequence variation and haplotype structure of the HLA-G 5′URR in worldwide populations to investigate the evolutionary history of the HLA-G promoter and shed some light into the mechanisms that may underlie HLA-G expression control. A 1.4-kb region, encompassing the known HLA-G regulatory elements, was sequenced in three African populations from Senegal, Benin and Congo, and data were combined with those available in the literature, resulting in a total of 1411 individuals from 21 worldwide populations. High levels of nucleotide and haplotype diversities, excess of intermediate-frequency variants and reduced population differentiation were observed at this locus when compared with the background genomic variation. These features support a strong molecular signature of balancing selection at HLA-G 5′URR, probably as a result of the competing needs to maintain both a maternal-fetal immune tolerance and an efficient host immune response to invading pathogens during human evolution. An extended analysis of a 300-kb region surrounding HLA-G revealed that this region is not involved in a hitchhiking effect and may be the direct target of selection., This work was supported by the binational collaborative research program CAPES-COFECUB (grant #653/09) and by the Spanish National Institute for Bioinformatics (www.inab.org). LG was supported by grants from Région Ile-de-France. PL was supported by a PhD fellowship from ‘Acción Estratrégica de Salud, en el Marco del Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica 2008–2011’ from Instituto de Salud Carlos III. BP was supported by a PhD fellowship from the doctoral program in Public Health from Paris Sud University. ECC was supported by the Brazilian Council for Scientific and Technological Development—CNPq (grant # 304471/2013-5). EAD was supported by the Brazilian Council for Scientific and Technological Development—CNPq Project (grant # 476036/2013-5).

Indian demographic history includes special features such as founder effects, interpopulation segregation, complex social structure with a caste system and elevated frequency of consanguineous marriages. It also presents a higher frequency for some rare mendelian disorders and in the last two decades increased prevalence of some complex disorders. Despite the fact that India represents about one-sixth of the human population, deep genetic studies from this terrain have been scarce. In this study, we analyzed high-density genotyping and whole-exome sequencing data of a North and a South Indian population. Indian populations show higher differentiation levels than those reported between populations of other continents. In this work, we have analyzed its consequences, by specifically assessing the transferability of genetic markers from or to Indian populations. We show that there is limited genetic marker portability from available genetic resources such as HapMap or the 1,000 Genomes Project to Indian populations, which also present an excess of private rare variants. Conversely, tagSNPs show a high level of portability between the two Indian populations, in contrast to the common belief that North and South Indian populations are genetically very different. By estimating kinship from mates and consanguinity in our data from trios, we also describe different patterns of assortative mating and inbreeding in the two populations, in agreement with distinct mating preferences and social structures. In addition, this analysis has allowed us to describe genomic regions under recent adaptive selection, indicating differential adaptive histories for North and South Indian populations. Our findings highlight the importance of considering demography for design and analysis of genetic studies, as well as the need for extending human genetic variation catalogs to new populations and particularly to those with particular demographic histories., International fellowship funded by Center for Neurogenomics and Cognitive Research (CNCR), VU, Amsterdam, The Netherlands to GJ; Research grant from J C Bose fellowship to BKT; grant # BT/01/COE/07/UDSC to BKT and salary support to GJ are gratefully acknowledged. FC was supported by a Beatriu de Pinós (2010-BP- B-00128) fellowship and MM by a PhD grant both from AGAUR (Generalitat de Catalunya). Funding to FC by grant SAF2012-35025 from the Ministerio de Economía y Competitividad (Spain); Funding to JB by grants BFU2010-19443 from the Ministerio de Ciencia y Tecnología (Spain), PRI-PIBIN-2011-0942 from the Ministerio de Economía y Competitividad (Spain), and from the Direcció General de Recerca, Generalitat de Catalunya (Grup de Recerca Consolidat 2009 SGR 1101).

We present 42 new Y-chromosomal sequences from diverse Indian tribal and non-tribal populations, including the Jarawa and Onge from the Andaman Islands, which are analysed within a calibrated Y-chromosomal phylogeny incorporating South Asian (in total 305 individuals) and worldwide (in total 1286 individuals) data from the 1000 Genomes Project. In contrast to the more ancient ancestry in the South than in the North that has been claimed, we detected very similar coalescence times within Northern and Southern non-tribal Indian populations. A closest neighbour analysis in the phylogeny showed that Indian populations have an affinity towards Southern European populations and that the time of divergence from these populations substantially predated the Indo-European migration into India, probably reflecting ancient shared ancestry rather than the Indo-European migration, which had little effect on Indian male lineages. Among the tribal populations, the Birhor (Austro-Asiatic-speaking) and Irula (Dravidian-speaking) are the nearest neighbours of South Asian non-tribal populations, with a common origin in the last few millennia. In contrast, the Riang (Tibeto-Burman-speaking) and Andamanese have their nearest neighbour lineages in East Asia. The Jarawa and Onge shared haplogroup D lineages with each other within the last ~7000 years, but had diverged from Japanese haplogroup D Y-chromosomes ~53000 years ago, most likely by a split from a shared ancestral population. This analysis suggests that Indian populations have complex ancestry which cannot be explained by a single expansion model. Funding was provided by the joint Spain–India bilateral grant PRI-PIBIN-2011-0942 and BFU2016-77961-P (AEI/ FEDER, UE) both awarded by the Ministerio de Economía y Competitividad (Spain) and with the support of Secretaria d’Universitats i Recerca del Departament d’Economia i Coneixement de la Generalitat de Catalunya (GRC 2014 SGR 866). Anders Bergström, YaliXue and Chris Tyler-Smith were supported by The Wellcome Trust (Grant 098051)

Prado-Martinez, Javier et al., Most great ape genetic variation remains uncharacterized1,2; however, its study is critical for understanding population history3–6, recombination7, selection8 and susceptibility to disease9,10.Herewe sequence to high coverage a total of 79 wild- and captive-born individuals representing all six great ape species and seven subspecies and report 88.8 million single nucleotide polymorphisms. Our analysis provides support for genetically distinct populations within each species, signals of gene flow, and the split of common chimpanzees into two distinct groups: Nigeria–Cameroon/western and central/ eastern populations.Wefind extensive inbreeding in almost all wild populations, with eastern gorillas being the most extreme. Inferred effective population sizes have varied radically over timein different lineages and this appears to have a profound effect on the genetic diversity at, or close to, genes in almost all species. We discover and assign 1,982 loss-of-function variants throughout the human and great ape lineages, determining that the rate of gene loss has not been different in the human branch compared to other internal branches in the great ape phylogeny. This comprehensive catalogue of great ape genomediversity provides a framework for understanding evolution and a resource for more effective management of wild and captive great ape populations., We thank the following funding agencies: ERC Starting Grant (260372) to T.M.-B.; NIH grants HG002385 to E.E.E., R01_HG005226 to K.R.V., A.E.W., M.F.H., L.S. and J.D.W., GM100233 and NSF HOMINID grant 1032255 to D.R. and He.Li.;MICINN(Spain)BFU2011-28549to T.M.-B.,BFU2010-19443to Ja.Be.,Spanish Government and FEDER for grants BFU2009-13409-C02-02 and BFU2012-38236 to A.N. and J.P.-M., Direccio´ General de Recerca, Generalitat de Catalunya (Grup de Recerca Consolidat 2009 SGR 1101) to Ja.Be., D.C., A.N. and T.M.-B.; ERC Advanced Grant (233297) and Max Planck Society to S. Paabo; Danish Council for Independent Research Natural Sciences to H.S.; Spanish Grant (CGL-2010-20170) and Zoo de Barcelona (Beca PRIC) to A.R.-H.; EUPRIM-Net to BPRC; DP1ES022577-04 NIH grant to S.A.T.; NSF Grant 0755823 to M.K.G.; P.G. is supported by the G. Harold and Leila Y. Mathers Foundation. A.N. and T.M.-B. are ICREA Research Investigators (Institut Catala d’Estudis i RecercaAvancats delaGeneralitat deCatalunya). J.P.-M. is supported by the Zoo de Barcelona and l’Ajuntament de Barcelona.

5 páginas, 3 figuras., The Basques are a culturally isolated population, living across the western border between France and Spain and speaking a non-Indo-European language. They show outlier allele frequencies in the ABO, RH, and HLA loci. To test whether Basques are a genetic isolate with the features that would make them good candidates in genetic association studies, we genotyped 123 SNPs in a 1-Mb region in chromosome 22 in Basque samples from France and Spain, as well as in samples from northern and southern Spain, and in three North African samples. Both Basque samples showed similar levels of heterozygosity to the other populations, and the decay of linkage disequilibrium with physical distance was not different between Basques and non-Basques. Thus, Basques do not show the genetic properties expected in population isolates.

To shed light on the peopling of South Asia and the origins of the morphological adaptations found there, we analyzed whole-genome sequences from 10 Andamanese individuals and compared them with sequences for 60 individuals from mainland Indian populations with different ethnic histories and with publicly available data from other populations. We show that all Asian and Pacific populations share a single origin and expansion out of Africa, contradicting an earlier proposal of two independent waves of migration1, 2, 3, 4. We also show that populations from South and Southeast Asia harbor a small proportion of ancestry from an unknown extinct hominin, and this ancestry is absent from Europeans and East Asians. The footprints of adaptive selection in the genomes of the Andamanese show that the characteristic distinctive phenotypes of this population (including very short stature) do not reflect an ancient African origin but instead result from strong natural selection on genes related to human body size., Our main funding was provided by the joint Spain–India bilateral grant PRI-PIBIN-2011-0942 from the Ministerio de Economía y Competitividad (Spain). Complementary funding was provided by grant BFU2013-43726-P from the Ministerio de Economía y Competitividad (Spain), with the support of Secretaria d'Universitats i Recerca, Departament d'Economia i Coneixement de la Generalitat de Catalunya (GRC 2014 SGR866).

Trabajo presentado en la XV Jornada de Biología Evolutiva, celebrada en Barcelona el 23 de junio de 2015., East Africa is a strategic region to study human genetic diversity due to the presence of ethnically, linguistically, and geographically diverse populations. Here, we provide new insight into the genetic history of populations living in the Sudanese region of East Africa by analysing nine ethnic groups belonging to three African linguistic families: Niger-Kordofanian, Nilo-Saharan and Afro-Asiatic. A total of 500 individuals were genotyped for 200,000 single-nucleotide polymorphisms. Principal component analysis, clustering analysis using ADMIXTURE, FST statistics, and the three*population test were used to investigate the underlying genetic structure and ancestry of the different ethnolinguistic groups. Our analyses revealed a genetic component for Sudanese Nilo*Saharan speaking groups (Darfurians and part of Nuba populations) related to Nilotes of South Sudan, but not to other Sudanese populations or other sub*Saharan populations. Populations inhabiting the North of the region showed close genetic affinities with North Africa, with a component that could be remnant of North Africans before the migrations of Arabs from Arabia. In addition, we found very low genetic distances between populations in genes important for anti*malarial and anti-bacterial host defence, suggesting similar selective pressures on these genes and stressing the importance of considering functional pathways to understand the evolutionary history of populations.

Inversions are portions of a chromosome where the gene order is reversed relative to a standard reference orientation. Because of reduced levels of recombination in heterokaryotypes, inversions have a potentially important effect on patterns of nucleotide variability in those genomic regions close to, or included in, the inverted fragments. Here we report sequence variation at three anonymous regions (STSs) located at different positions in relation to second-chromosome inversion breakpoints in 29 isochromosomal lines derived from an Argentinean population of Drosophila buzzatii. In agreement with previous findings in Drosophila, gene flux (crossing over and/or gene conversion) between arrangements seems to appreciably increase as we approach the middle sections of inversion 2j, and patterns of nucleotide variability within, as well as genetic differentiation between chromosome arrangements, are comparable to those observed at the molecular marker outside the inverted fragments. On the other hand, nucleotide diversity near the proximal breakpoint of inversion 2j is reduced when contrasted with that found at the other regions, particularly in the case of derived inverted chromosomes. Using the data from the breakpoint, we estimate that the inversion polymorphism is approximately 1.63 N generations old, where N is the effective population size. An excess of low-frequency segregating polymorphisms is detected; mostly in the ancestral 2st arrangement and probably indicating a population expansion that predates the coalescent time of inversion 2j. Heterogeneity in mutation rates between the markers linked to the inversions may be sufficient to explain the different levels of nucleotide diversity observed. When considered in the context of other studies on patterns of variation relative to physical distance to inversion breakpoints, our data appear to be consistent with the conclusion that inversions are unlikely to be "long-lived" balanced polymorphisms.

[Background] 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., [Results] 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., [Conclusions] 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).

[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).

Studies of large sets of single nucleotide polymorphism (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 2841 SNPs in 12 sub-Saharan African populations, including a previously unsampled region of southeastern Africa (Mozambique). We show that robust results in a world-wide perspective can be obtained when analyzing only 1000 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 southeastern Bantu population from Mozambique, which suggests an assimilation of a pre-Bantu substrate by Bantu speakers in the region., Esta investigación ha sido financiada por la Dirección General de Investigación, Ministerio de Ciencia y Tecnología, España (becas SAF2007-63.171, BFU2007-63657) y la Direcció General de Recerca de la Generalitat de Catalunya (2009 SGR 1101). MS fue financiado por una beca de doctorado del Programa de becas FPU del Ministerio de Educación y Ciencia, España (AP2005-3982).

11 páginas, 2 figuras, 3 tablas., Because pathogens are powerful selective agents, host-cell surface molecules used by pathogens as identification signals can reveal the signature of selection. Most of them are oligosaccharides, synthesized by glycosyltransferases. One known example is balancing selection shaping ABO evolution as a consequence of both, A and B antigens being recognized as receptors by some pathogens, and anti-A and/or anti-B natural antibodies produced by hosts conferring protection against the numerous infectious agents expressing A and B motifs. These antigens can also be found in tissues other than blood if there is activity of another enzyme, FUT2, a fucosyltransferase responsible for ABO biosynthesis in body fluids. Homozygotes for null variants at this locus present the nonsecretor phenotype (se), because they cannot express ABO antigens in secretions. Multiple independent mutations have been shown to be responsible for the nonsecretor phenotype, which is coexisting with the secretor phenotype in most populations. In this study, we have resequenced the coding region of FUT2 in 732 individuals from 39 worldwide human populations. We report a complex pattern of natural selection acting on the gene. Although frequencies of secretor and nonsecretor phenotypes are similar in different populations, the point mutations at the base of the phenotypes are different, with some variants showing a long history of balancing selection among Eurasian and African populations, and one recent variant showing a fast spread in East Asia, likely due to positive selection. Thus, a convergent phenotype composition has been achieved through different mutations with different evolutionary histories., This research was funded by grants BFU2005-00243 and SAF-2007-63171 awarded by Ministerio de Educación y Ciencia (Spain) and by the Direcció General de Recerca of Generalitat de Catalunya (Grup de Recerca Consolidat 2005SGR/00608). Funds were also from the Etablissement Francxais du Sang (EFS) Centre Atlantique, and fromthe Ministère Francxais de la Recherche (EA3034). All the sequencing was done at the Genomic Service, Universitat Pompeu Fabra; we thank Stéphanie Plaza and Roger Anglada for their help. Computational analysis was helped by the National Institute for Bioinformatics (www.inab.org), and SNP genotyping services were provided by the Spanish ‘‘Centro Nacional de Genotipado’’ (CEGEN; www.cegen.org); both are platforms of Genoma Espan˜a. A.F.-A. is supported by a PhDfellowship from UPF and M.S. from the Programa de becas FPU del Ministerio de Educación y Ciencia, Spain (AP2005-3982).

From the detection of population structure to the reconstruction of population history: the historical reading of the human genome

Natural selection is crucial for the adaptation of populations to their environments. Here, we present the first global study of natural selection in the Hominidae (humans and great apes) based on genome-wide information from population samples representing all extant species (including most subspecies). Combining several neutrality tests we create a multi-species map of signatures of natural selection covering all major types of natural selection. We find that the estimated efficiency of both purifying and positive selection varies between species and is significantly correlated with their long-term effective population size. Thus, even the modest differences in population size among the closely related Hominidae lineages have resulted in differences in their ability to remove deleterious alleles and to adapt to changing environments. Most signatures of balancing and positive selection are species-specific, with signatures of balancing selection more often being shared among species. We also identify loci with evidence of positive selection across several lineages. Notably, we detect signatures of positive selection in several genes related to brain function, anatomy, diet and immune processes. Our results contribute to a better understanding of human evolution by putting the evidence of natural selection in humans within its larger evolutionary context. The global map of natural selection in our closest living relatives is available as an interactive browser at http://tinyurl.com/nf8qmzh., This work was supported by funding from the Max Planck Society to K.P. and A.M.A.; by grants from the Ministerio de Economía y Competitividad in Spain (grant BFU2013-43726-P) and the Secretaria d’Universitats i Recerca de la Generalitat de Catalunya (grant GRC 2014 SGR 866) to J.B.; by an European Research Council Advanced Grant (233297) to S.Pääbo and European Research Council Starting Grant (260372) to T.M.B.; and by European Molecular Biology Organization Young Investigator Award and Ministerio de Ciencia e Innovación in Spain (BFU2014-55090-P) to T.M.B.

9 pages, 2 figures, 4 additional files., [Background] It is well known that the pattern of linkage disequilibrium varies between human populations, with remarkable geographical stratification. Indirect association studies routinely exploit linkage disequilibrium around genes, particularly in isolated populations where it is assumed to be higher. Here, we explore both the amount and the decay of linkage disequilibrium with physical distance along 211 gene regions, most of them related to complex diseases, across 39 HGDP-CEPH population samples, focusing particularly on the populations defined as isolates. Within each gene region and population we use r2 between all possible single nucleotide polymorphism (SNP) pairs as a measure of linkage disequilibrium and focus on the proportion of SNP pairs with r2 greater than 0.8., [Results] Although the average r2 was found to be significantly different both between and within continental regions, a much higher proportion of r2 variance could be attributed to differences between continental regions (2.8% vs. 0.5%, respectively). Similarly, while the proportion of SNP pairs with r2 > 0.8 was significantly different across continents for all distance classes, it was generally much more homogenous within continents, except in the case of Africa and the Americas. The only isolated populations with consistently higher LD in all distance classes with respect to their continent are the Kalash (Central South Asia) and the Surui (America). Moreover, isolated populations showed only slightly higher proportions of SNP pairs with r2 > 0.8 per gene region than non-isolated populations in the same continent. Thus, the number of SNPs in isolated populations that need to be genotyped may be only slightly less than in non-isolates., [Conclusion] The "isolated population" label by itself does not guarantee a greater genotyping efficiency in association studies, and properties other than increased linkage disequilibrium may make these populations interesting in genetic epidemiology., This research was supported by "Fundación Genoma España" (proyectos piloto CEGEN 2004–2005), Dirección General de Investigación, Ministerio de Educación y Ciencia of Spain (grants BFU2005-00243, BFU2006-01235, BFU2006-15413-CO2-01, SEJ2006-13537) and Direcció General de Recerca, Generalitat de Catalunya (2005SGR00608). SNP genotyping services were provided by the Spanish "Centro Nacional de Genotipado"