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Peru hosts extremely diverse ecosystems which can be broadly classified into the following three major ecoregions: the Pacific desert coast, the Andean highlands, and the Amazon rainforest. Since its initial peopling approximately 12,000 years ago, the populations inhabiting such ecoregions might have differentially adapted to their contrasting environmental pressures. Previous studies have described several candidate genes underlying adaptation to hypobaric hypoxia among Andean highlanders. However, the adaptive genetic diversity of coastal and rainforest populations has been less studied. Here, we gathered genome-wide single-nucleotide polymorphism-array data from 286 Peruvians living across the three ecoregions and analyzed signals of recent positive selection through population differentiation and haplotype-based selection scans. Among highland populations, we identify candidate genes related to cardiovascular function (TLL1, DUSP27, TBX5, PLXNA4, SGCD), to the Hypoxia-Inducible Factor pathway (TGFA, APIP), to skin pigmentation (MITF), as well as to glucose (GLIS3) and glycogen metabolism (PPP1R3C, GANC). In contrast, most signatures of adaptation in coastal and rainforest populations comprise candidate genes related to the immune system (including SIGLEC8, TRIM21, CD44, and ICAM1 in the coast; CBLB and PRDM1 in the rainforest; and BRD2, HLA-DOA, HLA-DPA1 regions in both), possibly as a result of strong pathogen-driven selection. This study identifies candidate genes related to human adaptation to the diverse environments of South America., This work was supported by the Ministerio de Ciencia e Innovación and the Agencia Estatal de Investigación (AEI) (PID2019-110933GB-I00/AEI/10.13039/501100011033 to E.B.); the Unidad de Excelencia María de Maeztu funded by the Ministerio de Ciencia e Innovación and the Agencia Estatal de Investigación (DOI: 10.13039/501100011033; ref: CEX2018-000792-M to E.B. and R.C.-C.); the National Science Foundation (NSF) SBE (Postdoctoral Research Fellowship Award No. 1711982 to M.A.N.-C.), NSF-BCS (BCS-0242958 to A.C.S.) and NSF-Research Experience for Undergraduates (BCS-0242958 to A.C.S.); the Mexican National Council for Science and Technology (CONACYT) (FONCICYT/50/2016 to A.M.-E.); and the International Center for Genetic Engineering and Biotechnology (ICGEB, Italy) (CRP/MEX15-04_EC to A.M.-E.). The PEGEN-BC study was supported by the National Cancer Institute at the National Institutes of Health (R01CA204797 to L.F.) and the Instituto Nacional de Enfermedades Neoplásicas in Lima, Peru.

SLC30A9encodes a ubiquitously zinc transporter (ZnT9) and has been consistently suggested as a candidate for positive selection in humans. However, no direct adaptive molecular phenotype has been demonstrated to date. Our results provide evidence for directional selection operating in two major complementary haplotypes in Africa and East Asia. These haplotypes are associated with differential gene expression but also differ in the Met50Val substitution (rs1047626) in ZnT9, which we show was adaptively introgressed from archaic humans. Although we found no significant differences in systemic zinc content between individuals with different rs1047626 genotypes, we demonstrate that the expression of the derived isoform (ZnT9 50Val) in HEK293 cells shows a gain of function when compared with the ancestral (ZnT9 50Met) variant. In particular, the ZnT9 50Val variant was found to avoid zinc overload in the endoplasmic reticulum and mitochondria, with an impact on mitochondrial metabolism. Overall, our results show that this adaptatively introgressed variant, which is prevalent in East Asians and present at intermediate-high frequencies in other non-African populations, is associated with functional differences in zinc handling by the mitochondria and endoplasmic reticulum. Given the essential role of the mitochondria in both skeletal muscle and brain, and that of zinc in glutamatergic neurotransmission, we propose that archaic adaptation to cold may have driven this selection event, while also impacting susceptibility to neuropsychiatric disorders in modern humans.

[Aim] To investigate DDR1 methylation in the brains of bipolar disorder (BD) patients and its association with DDR1 mRNA levels and comethylation with myelin genes., [Materials & methods] Genome-wide profiling of DNA methylation (Infinium MethylationEPIC BeadChip) corrected for glial composition and DDR1 gene expression analysis in the occipital cortices of individuals with BD (n = 15) and healthy controls (n = 15) were conducted., [Results] DDR1 5-methylcytosine levels were increased and directly associated with DDR1b mRNA expression in the brains of BD patients. We also observed that DDR1 was comethylated with a group of myelin genes., [Conclusion] DDR1 is hypermethylated in BD brain tissue and is associated with isoform expression. Additionally, DDR1 comethylation with myelin genes supports the role of this receptor in myelination.

BackgroundIndividuals with a first episode of psychosis (FEP) show rapid weight gain during the first months of treatment, which is associated with reduction in psychiatric and physical health. Although genetics is assumed to be a significant contributor to this weight gain, its exact role is unknown.MethodsReference GWAS from BMI and SCZ were obtained to evaluate the pleiotropic landscape between both traits using the pleioFDR software. In parallel, we gathered a population-based FEP cohort of 381 individuals and BMI Polygenic risk-scores (PRS) were evaluated on a sample of 224 individuals. Subsequently, the PRSs obtained from both BMI and the variants shared between the two traits were incorporated into risk models that included demographic and clinical variable to predict BMI increase (ΔBMI) on an independent sample of 157 patients.ResultsBMI PRS significantly improved the prediction of absolute BMI and ΔBMI during the first 12 months after the onset of psychotic symptoms. This improvement, was mainly explained by shared variants between SCZ and BMI. In contrast, absolute BMI was predicted mainly by non-shared variants.ConclusionsWe validated, for the first time, that genetic factors play a key in the determination of both BMI and ΔBMI in FEP. This finding has important clinical implications in identifying individuals who require specific treatment strategies. Improved risk classification may help prevent associated adverse metabolic events, and reduce overtreatment and costs for both individuals and the healthcare system. It also highlights the importance of studying genetic pleiotropy in the context of medically important comorbidities.

Long and Zhang1 present empirical and conceptual objections to our results2. Concerning data, they observe that a single disease provides nearly all the support for mutation accumulation (MA). On a more theoretical note, they find no evidence for a putative prediction of antagonistic pleiotropy (AP): that at ‘each’ antagonistic pleiotropic single nucleotide polymorphism (SNP), the risk allele frequencies (RAFs) should be lower for early-onset rather than late-onset diseases., This work was supported by Ministerio de Ciencia e Innovación, Spain (with project grants BFU2015-68649-P, BFU2016-77961-P and PGC2018-101927-B-I00, MINECO/AEI/FEDER, UE), the Spanish National Institute of Bioinformatics (PT17/0009/0020), Direcció General de Recerca, Generalitat de Catalunya (2017SGR702, 2017SGR880) and the “Unidad de Excelencia María de Maeztu”, funded by the MINECO (ref: MDM-2014-0370).

Demographic history plays a major role in shaping the distribution of genomic variation. Yet the interaction between different demographic forces and their effects in the genomes is not fully resolved in human populations. Here, we focus on the Roma population, the largest transnational ethnic minority in Europe. They have a South Asian origin and their demographic history is characterized by recent dispersals, multiple founder events, and extensive gene flow from non-Roma groups. Through the analyses of new high-coverage whole exome sequences and genome-wide array data for 89 Iberian Roma individuals together with forward simulations, we show that founder effects have reduced their genetic diversity and proportion of rare variants, gene flow has counteracted the increase in mutational load, runs of homozygosity show ancestry-specific patterns of accumulation of deleterious homozygotes, and selection signals primarily derive from preadmixture adaptation in the Roma population sources. The present study shows how two demographic forces, bottlenecks and admixture, act in opposite directions and have long-term balancing effects on the Roma genomes. Understanding how demography and gene flow shape the genome of an admixed population provides an opportunity to elucidate how genomic variation is modeled in human populations., This study was supported by the Spanish Ministry of Science, Innovation and Universities (MCIU) and the Agencia Estatal de Investigación (AEI) (grant numbers CGL2016-75389-P, PID2019-106485GB-I00/AEI/10.13039/501100011033) and “Unidad de Excelencia María de Maeztu” (AEI, CEX2018-000792-M). N.F.-P. was supported by a FPU17/03501 fellowship., With funding from the Spanish government through the "Severo Ochoa Centre of Excellence" accreditation (CEX2018-000792-M).

Psychiatric disorders such as Schizophrenia (SCZ) and Bipolar Disorder (BD) represent an evolutionary paradox, as they exhibit strong negative effects on fitness, such as decreased fecundity and early mortality, yet they persist at a worldwide prevalence of approximately 1%. Molecular mechanisms affecting lifespan, which may be widely common among complex diseases with fitness effects, can be studied by the integrated analysis of data from genome-wide association studies (GWAS) of human longevity together with any disease of interest. Here, we report the first of such studies, focusing on the genetic overlap—pleiotropy—between two psychiatric disorders with shortened lifespan, SCZ and BD, and human parental lifespan (PLS) as a surrogate of life expectancy. Our results are twofold: first, we demonstrate extensive polygenic overlap between SCZ and PLS and to a lesser extent between BD and PLS. Second, we identified novel loci shared between PLS and SCZ (n = 39), and BD (n = 8). Whereas most of the identified SCZ (66%) and BD (62%) pleiotropic risk alleles were associated with reduced lifespan, we also detected some antagonistic protective alleles associated to shorter lifespans. In fact, top-associated SNPs with SCZ seems to explain longevity variance explained (LVE) better than many other life-threatening diseases, including Type 2 diabetes and most cancers, probably due to a high overlap with smoking-related pathways. Overall, our study provides evidence of a genetic burden driven through premature mortality among people with SCZ, which can have profound implications for understanding, and potentially treating, the mortality gap associated with this psychiatric disorder., This work was supported by Ministerio de Ciencia e Innovación, Spain, the Agencia Estatal de Investigación (AEI) and the Fondo Europeo de Desarrollo Regional (FEDER) with project grants BFU2016-77961-P and PGC2018-101927-B-I00 to EB and AN, respectively, by the Spanish National Institute of Bioinformatics (PT17/0009/0020 to AN), the Direcció General de Recerca, the Generalitat de Catalunya (2017SGR444 to EV, 2017SGR702 to EB and 2017SGR880 to AN) and the “Unidad de Excelencia María de Maeztu”, funded by the AEI (CEX2018-000792-M).

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)

Genome-wide association studies and meta-analysis have contributed to the identification of more than 200 loci associated with multiple sclerosis (MS). However, a proportion of MS heritability remains unknown. We aimed to uncover new genetic variants associated with MS and determine their functional effects. For this, we resequenced the exons and regulatory sequences of 14 MS risk genes in a cohort of MS patients and healthy individuals (n = 1070) and attempted to validate a selection of signals through genotyping in an independent cohort (n = 5138). We identified three new MS-associated variants at C-X-C motif chemokine receptor 5 (CXCR5), Ts translation elongation factor, mitochondrial (TSFM) and cytochrome P450 family 24 subfamily A member 1 (CYP24A1). Rs10892307 resulted in a new signal at the CXCR5 region that explains one of the associations with MS within the locus. This polymorphism and three others in high linkage disequilibrium mapped within regulatory regions. Of them, rs11602393 showed allele-dependent enhancer activity in the forward orientation as determined by luciferase reporter assays. Immunophenotyping using peripheral blood mononuclear cells from MS patients associated the minor allele of rs10892307 with increased percentage of regulatory T cells expressing CXCR5. This work reports a new signal for the CXCR5 MS risk locus and points to rs11602393 as the causal variant. The expansion of CXCR5+ circulating regulatory T cells induced by this variant could cause its MS association., The genotyping service was carried out at CEGEN-PRB2-ISCIII and was supported by grant PT13/0001, ISCIII-SGEFI/FEDER. This work was also supported by the following grants: BFU2016-77961-P (AEI/FEDER); 2017-SGR-00702 (Direcció General de Recerca, Generalitat de Catalunya); Unidad de Excelencia María de Maeztu funded by the MINECO (MDM-2014-0370); Proyectos de Investigación en Salud (FIS PI12/02229, PI15/00587, PI16/01259); Red Española de Esclerosis Múltiple (RD16/0015/0004 to M.C., RD16/0015/0002; RD16/0015/0005 to K.V.; RD16/0015/0016) integrated in the Plan Estatal I+D+I and cofunded by Instituto de Salud Carlos III and the Fondo Europeo de Desarrollo Regional (FEDER; “Otra forma de hacer Europa”); SAF2016-80595-C2-1-P (Ministerio de Economía, Industria y Competitividad).

Genome-wide association studies and meta-analysis have contributed to the identification of more than 200 loci associated with multiple sclerosis (MS). However, a proportion of MS heritability remains unknown. We aimed to uncover new genetic variants associated with MS and determine their functional effects. For this, we resequenced the exons and regulatory sequences of 14 MS risk genes in a cohort of MS patients and healthy individuals (n = 1070) and attempted to validate a selection of signals through genotyping in an independent cohort (n = 5138). We identified three new MS-associated variants at C-X-C motif chemokine receptor 5 (CXCR5), Ts translation elongation factor, mitochondrial (TSFM) and cytochrome P450 family 24 subfamily A member 1 (CYP24A1). Rs10892307 resulted in a new signal at the CXCR5 region that explains one of the associations with MS within the locus. This polymorphism and three others in high linkage disequilibrium mapped within regulatory regions. Of them, rs11602393 showed allele-dependent enhancer activity in the forward orientation as determined by luciferase reporter assays. Immunophenotyping using peripheral blood mononuclear cells from MS patients associated the minor allele of rs10892307 with increased percentage of regulatory T cells expressing CXCR5. This work reports a new signal for the CXCR5 MS risk locus and points to rs11602393 as the causal variant. The expansion of CXCR5+ circulating regulatory T cells induced by this variant could cause its MS association.

Although genome-wide association studies have identified a number of common variants associated with multiple sclerosis (MS) susceptibility, little is known about the relevance of rare variants. Here, we aimed to explore the role of rare variants in 14 MS risk genes (FCRL1, RGS1, TIMMDC1, HHEX, CXCR5, LTBR, TSFM, GALC, TRAF3, STAT3, TNFSF14, IFI30, CD40, and CYP24A1) by targeted resequencing in an Iberian population of 524 MS cases and 546 healthy controls. Four rare variants-enriched regions within CYP24A1, FCRL1, RGS1, and TRAF3 were identified as significantly associated with MS. Functional studies revealed significantly decreased regulator of G protein signaling 1 (RGS1) gene expression levels in peripheral blood mononuclear cells from MS patients with RGS1 rare variants compared to noncarriers, whereas no significant differences in gene expression were observed for CYP24A1, FCRL1, and TRAF3 between rare variants carriers and noncarriers. Immunophenotyping showed significant decrease in RGS1 expression in peripheral blood B lymphocytes from MS patients with RGS1 rare variants relative to noncarriers. Lastly, peripheral blood mononuclear cell from MS patients carrying RGS1 rare variants showed significantly lower induction of RGS1 gene expression by interferon-β compared to MS patients lacking RGS1 variants. The presence of rare variants in RGS1 reinforce the ideas of high genetic heterogeneity and a role of rare variants in MS pathogenesis., This work was supported by grants from the Fondo de Investigación Sanitaria (FIS; grant number PI12/02229; Ministry of Science and Innovation, Spain), Agencia Estatal de Investigación (AEI) and Fondo Europeo de Desarollo Regional (FEDER; grant number BFU2016‐77961‐P), Direcció General de Recerca ‐ Generalitat de Catalunya (2017‐SGR‐00702), Unidad de Excelencia María de Maeztu (MINECO; MDM‐2014‐0370), and Vall d'Hebrón Institut de Recerca (predoctoral grants program 2014).

TRPP3 (also called PKD2L1) is a nonselective, cation-permeable channel activated by multiple stimuli, including extracellular pH changes. TRPP3 had been considered a candidate for sour sensor in humans, due to its high expression in a subset of tongue receptor cells detecting sour, along with its membership to the TRP channel family known to function as sensory receptors. Here, we describe the functional consequences of two non-synonymous genetic variants (R278Q and R378W) found to be under strong positive selection in an Ethiopian population, the Gumuz. Electrophysiological studies and 3D modelling reveal TRPP3 loss-of-functions produced by both substitutions. R278Q impairs TRPP3 activation after alkalinisation by mislocation of H binding residues at the extracellular polycystin mucolipin domain. R378W dramatically reduces channel activity by altering conformation of the voltage sensor domain and hampering channel transition from closed to open state. Sour sensitivity tests in R278Q/R378W carriers argue against both any involvement of TRPP3 in sour detection and the role of such physiological process in the reported evolutionary positive selection past event., Tis work was funded by the Spanish Ministry of Science and Innovation, the State Research Agency (AEI, Agencia Estatal de Investigación) and FEDER Funds (Fondo Europeo de Desarrollo Regional): Grants BFU2016-77961-P to J.B. and E.B., RTI2018-094809-B-I00 to J.M.F.F., PID2019-110933GB-I00/AEI/10.13039/501100011033 to E.B. and J.B., and CEX2018-000792-M through the “María de Maeztu” Programme for Units of Excellence in R&D to “Departament de Ciències Experimentals i de la Salut”. With the support of Secretaria d’Universitats i Recerca del Departament d’Economia i Coneixement de la Generalitat de Catalunya (GRC 2017 SGR 702). S.W. has had a F.P.I. grant (BES-2014-068994) and M.I.-S. a “Juan de la Cierva-Incorporación” Fellowship funded by the Spanish Ministry of Science and Innovation.

25 p.-5 fig.-5 fig. supl.-2 tab. supl., MHCII in antigen-presenting cells (APCs) is a key regulator of adaptive immune responses. Expression of MHCII genes is controlled by the transcription coactivator CIITA, itself regulated through cell type-specific promoters. Here we show that the transcription factor NFAT5 is needed for expression of Ciita and MHCII in macrophages, but not in dendritic cells and other APCs. NFAT5-deficient macrophages showed defective activation of MHCII-dependent responses in CD4(+) T lymphocytes and attenuated capacity to elicit graft rejection in vivo. Ultrasequencing analysis of NFAT5-immunoprecipitated chromatin uncovered an NFAT5-regulated region distally upstream of Ciita. This region was required for CIITA and hence MHCII expression, exhibited NFAT5-dependent characteristics of active enhancers such as H3K27 acetylation marks, and required NFAT5 to interact with Ciita myeloid promoter I. Our results uncover an NFAT5-regulated mechanism that maintains CIITA and MHCII expression in macrophages and thus modulates their T lymphocyte priming capacity., This work was supported by the Spanish Ministry of Economy and Competitiveness (MINECO), Agencia Estatal de Investigación, and European Regional Development Fund(SAF2012-36535, SAF2015-71363-R, and BFU2016-77961-P), and Fundació la Marató de TV3 (1225-30 and 201619-30). We also acknowledge funding support from Generalitat de Catalunya(2014SGR1153, 2017SGR888, and 2017SGR702) and MINECO through the “Unidad de Excelencia María de Maeztu” funded by MINECO (MDM-2014-0370). H. Huerga Encabo was supported by a predoctoral fellowship of the Spanish Ministerio de Educación, Cultura y Deporte (FPU13/01798). M. Tellechea was supported by fellowships from Fundació Catalunya-La Pedrera(2011) and Generalitat de Catalunya (FI-DGR program 2013). C. López-Rodríguez is a recipient of an ICREA Acadèmia award from Institució Catalana de Recerca i Estudis Avançats (ICREA,Generalitat de Catalunya)

The analysis of geographically specific regions and the characterization of fine-scale patterns of genetic diversity may facilitate a much better understanding of the microevolutionary processes affecting local human populations. Here we generated genome-wide high-density SNP genotype data in 425 individuals from six geographical regions in Lithuania and combined our dataset with available ancient and modern data to explore genetic population structure, ancestry components and signatures of natural positive selection in the Lithuanian population. Our results show that Lithuanians are a homogenous population, genetically differentiated from neighbouring populations but within the general expected European context. Moreover, we not only confirm that Lithuanians preserve one of the highest proportions of western, Scandinavian and eastern hunter-gather ancestry components found in European populations but also that of an steppe Early to Middle Bronze Age pastoralists, which together configure the genetic distinctiveness of the Lithuanian population. Finally, among the top signatures of positive selection detected in Lithuanians, we identified several candidate genes related with diet (PNLIP, PPARD), pigmentation (SLC24A5, TYRP1 and PPARD) and the immune response (BRD2, HLA-DOA, IL26 and IL22)., This study was supported by LITGEN project, which was approved by the Vilnius Regional Research Ethics Committee No. 158200-05-329-79, date: 2011-05-03, and by Direcció General de Recerca, Generalitat de Catalunya (2017SGR702), Agencia Estatal de Investigación (AEI) and Fondo Europeo de Desarrollo Regional (FEDER) with project grants BFU2016-77961-P and CGL2016-75389-P, and the Unidad de Excelencia María de Maeztu”, funded by the MINECO (ref: MDM-2014-0370). EB is the recipient of an ICREA Academia Award.

Background The analysis of coverage depth in next-generation sequencing data allows the detection of gene dose alterations. We explore the frequency of such structural events in a Spanish cohort of sporadic PD cases. Methods Gene dose alterations were detected with the eXome-Hidden Markov Model (XHMM) software from depth of coverage in resequencing data available for 38 Mendelian and other risk PD loci in 394 individuals (249 cases and 145 controls) and subsequently validated by quantitative PCR. Results We identified 10 PD patients with exon dosage alterations in PARK2, GBA-GBAP1, and DJ1. Additional functional variants, including 2 novel nonsense mutations (p.Arg1552Ter in LRRK2 and p.Trp90Ter in PINK1), were confirmed by Sanger sequencing. This combined approach disclosed the genetic cause of 12 PD cases. Conclusions Gene dose alterations related to PD can be correctly identified from targeting resequencing data. This approach substantially improves the detection rate of cases with causal genetic alterations. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Basques show specific cultural, demographic, and genetic characteristics that have placed them as an isolated and unique population within Europe, such as their non-Indo-European language, Euskara. They have historically lived along the Western Pyrenees, between Spain and France, in one of the most important European glacial refugia during the Last Glacial Maximum. The most striking genetic characteristic is their highest frequency of the RhD blood group negative allele, a variant related to the hemolytic disease of the newborn. Both demographic and adaptive processes have been suggested as possible causes of the high frequency of RhD negative in Basques, but neither hypothesis has been clearly demonstrated. While previous studies on the Rh system in Basques have been mostly focused on serological and genotyping diversity, in this work we analyze genotyping and next generation sequencing data in order to provide a general framework of the genetic scenario of the system in Basques. In particular, we genotyped the most relevant variants of the system (D/d, E/e, and C/c), and sequenced three ~6 kb flanking regions surrounding the Rh genes in Basques and also in other populations for comparison. Our results are in agreement with previous studies, with Basques presenting the highest frequency of the RHD deletion (47.2%). Haplotype analyses of D/d, E/e, and C/c variants confirmed an association between the RhC allele, previously suggested to be under positive selection, and the RhD positive variant in non-sub-Saharan populations, including Basques. We also found extreme differentiation for the C/c variant when comparing sub-Saharan to non-sub-Saharan populations.

Engelken, Johannes et al., Essential trace elements possess vital functions at molecular, cellular, and physiological levels in health and disease, and they are tightly regulated in the human body. In order to assess variability and potential adaptive evolution of trace element homeostasis, we quantified 18 trace elements in 150 liver samples, together with the expression levels of 90 genes and abundances of 40 proteins involved in their homeostasis. Additionally, we genotyped 169 single nucleotide polymorphism (SNPs) in the same sample set. We detected significant associations for 8 protein quantitative trait loci (pQTL), 10 expression quantitative trait loci (eQTLs), and 15 micronutrient quantitative trait loci (nutriQTL). Six of these exceeded the false discovery rate cutoff and were related to essential trace elements: 1) one pQTL for GPX2 (rs10133290); 2) two previously described eQTLs for HFE (rs12346) and SELO (rs4838862) expression; and 3) three nutriQTLs: The pathogenic C282Y mutation at HFE affecting iron (rs1800562), and two SNPs within several clustered metallothionein genes determining selenium concentration (rs1811322 and rs904773). Within the complete set of significant QTLs (which involved 30 SNPs and 20 gene regions), we identified 12 SNPs with extreme patterns of population differentiation (FST values in the top 5% percentile in at least one HapMap population pair) and significant evidence for selective sweeps involving QTLs at GPX1, SELENBP1, GPX3, SLC30A9, and SLC39A8. Overall, this detailed study of various molecular phenotypes illustrates the role of regulatory variants in explaining differences in trace element homeostasis among populations and in the human adaptive response to environmental pressures related to micronutrients., This work was supported by Ministerio de Ciencia e Innovación, Spain (grants BFU2008-01046 and SAF2011-29239) and by Direcció General de Recerca, Generalitat de Catalunya (2009SGR-1101 and 2014SGR-866). The CRG/UPF Proteomics Unit is part of the “Plataforma de Recursos Biomoleculares y Bioinformáticos (ProteoRed)” supported by grant PT13/0001 of the Instituto de Salud Carlos III (ISCIII). J.E. was supported by a Postdoctoral scholarship from the Volkswagenstiftung (Az: I/85 198).

Santpere, Gabriel et al., We set out to investigate potential differences and similarities between the selective forces acting upon the coding and noncoding regions of five different sets of genes defined according to functional and evolutionary criteria: 1) two reference gene sets presenting accelerated and slow rates of protein evolution (the Complement and Actin pathways); 2) a set of genes with evidence of accelerated evolution in at least one of their introns; and 3) two gene sets related to neurological function (Parkinson’s and Alzheimer’s diseases). To that effect, we combine human–chimpanzee divergence patterns with polymorphism data obtained from target resequencing 20 central chimpanzees, our closest relatives with largest long-term effective population size. By using the distribution of fitness effect-alpha extension of the McDonald–Kreitman test, we reproduce inferences of rates of evolution previously based only on divergence data on both coding and intronic sequences and also obtain inferences for other classes of genomic elements (untranslated regions, promoters, and conserved noncoding sequences). Our results suggest that 1) the distribution of fitness effect-alpha method successfully helps distinguishing different scenarios of accelerated divergence (adaptation or relaxed selective constraints) and 2) the adaptive history of coding and noncoding sequences within the gene sets analyzed is decoupled., This work was supported by Ministerio de Ciencia e Innovación, Spain (SAF2011-29239 to E.B. and BFU2012-38236 to A.N.), Direcció General de Recerca, Generalitat de Catalunya (2014SGR1311 and 2014SGR866), the Spanish National Institute of Bioinfomatics of the Instituto de Salud Carlos III (PT13/0001/0026), and FEDER (Fondo Europeo de Desarrollo Regional)/FSE (Fondo Social Europeo).

Senescence has long been a public health challenge as well as a fascinating evolutionary problem. There is neither a universally accepted theory for its ultimate causes, nor a consensus about what may be its impact on human health. Here we test the predictions of two evolutionary explanations of senescence-mutation accumulation and antagonistic pleiotropy-which postulate that genetic variants with harmful effects in old ages can be tolerated, or even favoured, by natural selection at early ages. Using data from genome-wide association studies (GWAS), we study the effects of genetic variants associated with diseases appearing at different periods in life, when they are expected to have different impacts on fitness. Data fit theoretical expectations. Namely, we observe higher risk allele frequencies combined with large effect sizes for late-onset diseases, and detect a significant excess of early-late antagonistically pleiotropic variants that, strikingly, tend to be harboured by genes related to ageing. Beyond providing systematic, genome-wide evidence for evolutionary theories of senescence in our species and contributing to the long-standing question of whether senescence is the result of adaptation, our approach reveals relationships between previously unrelated pathologies, potentially contributing to tackling the problem of an ageing population.

Complex diseases and GWAS Complex or multifactorial diseases are, by definition, determined by a number of genetic and environmental factors. Unlike the mutations that underlie Mendelian diseases, which involve single mutations with strong phenotypic effects, complex diseases are believed to be caused by multiple genetic variants along the genome, implying that each of them has a weak effect on its own. The most common strategy for identifying such risk alleles has been through association studies, in which allele frequencies from patients and controls were initially compared in candidate genes, although now this is usually done on a genome-wide scale, in the so-called genome-wide association studies (GWASs). In the last years, GWASs have successfully identified hundreds of common risk variants associated with the most common human diseases such as diabetes, Alzheimer's, Parkinson's, Crohn's disease, schizophrenia, and various types of cancer. This notable achievement was not reached until it became possible to compare, in large cohorts of patients and controls (more recently in the range of tens of thousands individuals), the allele frequencies at several hundred thousand single nucleotide polymorphisms (SNPs) which are assayed on arrays that are able to capture the most common variations in the human genome (usually those with minor allele frequencies, or MAF, > 5%). Although GWASs have remarkably facilitated insights into understanding complex disease, it is clearly recognized that most of the disease-associated SNPs identified in GWASs usually imply a very small increase in risk and explain only a modest fraction of the genetic component (commonly referred as heritability) of most complex traits (Manolio et al ., 2009). Many factors have been suggested to explain such “missing heritability”: the existence of much larger numbers of still-undetected small-effect variants; the possible involvement of structural variants, inadequately picked up by SNP arrays; potential gene–gene interactions; and heritability overestimates due to gene–environment correlations. GWASs may have also partially failed because the common variant–common disease model was uncritically assumed, and rarer variants (those with MAF

Parkinson's disease (PD) can be divided into familial (Mendelian) and sporadic forms. A number of causal genes have been discovered for the Mendelian form, which constitutes 10-20% of the total cases. Genome-wide association studies have successfully uncovered a number of susceptibility loci for sporadic cases but those only explain a small fraction (6-7%) of PD heritability. It has been observed that some genes that confer susceptibility to PD through common risk variants also contain rare causing mutations for the Mendelian forms of the disease. These results suggest a possible functional link between Mendelian and sporadic PD and led us to investigate the role that rare and low-frequency variants could have on the sporadic form. Through a targeting approach, we have resequenced at 49× coverage the exons and regulatory regions of 38 genes (including Mendelian and susceptibility PD genes) in 249 sporadic PD patients and 145 unrelated controls of European origin. Unlike susceptibility genes, Mendelian genes show a clear general enrichment of rare functional variants in PD cases, observed directly as well as with Tajima's D statistic and several collapsing methods. Our f This work was supported by Ministerio de Ciencia e Innovación, Spain (SAF2011-29239 to E.B. and BFU2012-38236 to A.N.), by Direcció General de Recerca, Generalitat de Catalunya (2009SGR-1101 and 2014SGR-866), by the Spanish National Institute of Bioinfomatics of the Instituto de Salud Carlos III (PT13/0001/0026), CIBERNED and by FEDER (Fondo Europeo de Desarrollo Regional)/FSE (Fondo Social Europeo).

The Y-chromosomal binary marker P25 is a paralogous sequence variant, rather than a SNP: three copies of the P25 sequence lie within the giant palindromic repeats on Yq, and one copy has undergone a C to A transversion to define haplogroup R1b (designated C/C/A). Since gene conversion is known to be active in the palindromic repeats, we reasoned that P25 might be liable to back-mutation by gene conversion, yielding the ancestral state C/C/C. Through analysis of a set of binary markers in Y-chromosomes in two large samples from Great Britain and the Iberian Peninsula we show that such conversion events have occurred at least twice, and provide preliminary evidence that the reverse conversion event (yielding C/A/A) has also occurred. Because of its inherent instability, we suggest that P25 be used with caution in forensic studies, and perhaps replaced with the more reliable binary marker M269.

Since Thor Heyerdahl asserted that Polynesia was first colonized from the Americas (Heyerdahl 1950), geneticists have sought--but have not found--any evidence to support his theories. Here, Native American Y chromosomes are detected on the Polynesian island of Rapa. However, this, together with other odd features of the island's Y-chromosomal gene pool, is best explained as the genetic impact of a 19th century Peruvian slave trade in Polynesia. These findings underscore the need to account for history before turning to prehistory and the value of archival research to understanding modern genetic diversity. Although the impact of the Atlantic slave trade on the distribution of modern genetic diversity has been well appreciated, this represents the first study investigating the impact of this underappreciated episode on genetic diversity in the Pacific.

A number of alternative hypotheses seek to explain the origins of the three groups of Pacific populations—Melanesians, Micronesians, and Polynesians—who speak languages belonging to the Oceanic subfamily of Austronesian languages. To test these various hypotheses at the genetic level, we assayed diversity within the nonrecombining portion of the Y chromosome, which contains within it a relatively simple record of the human past and represents the most informative haplotypic system in the human genome. High-resolution haplotypes combining binary, microsatellite, and minisatellite markers were generated for 390 Y chromosomes from 17 Austronesian-speaking populations in southeast Asia and the Pacific. Nineteen paternal lineages were defined and a Bayesian analysis of coalescent simulations was performed upon the microsatellite diversity within lineages to provide a temporal aspect to their geographical distribution. The ages and distributions of these lineages provide little support for the dominant archeo-linguistic model of the origins of Oceanic populations that suggests that these peoples represent the Eastern fringe of an agriculturally driven expansion initiated in southeast China and Taiwan. Rather, most Micronesian and Polynesian Y chromosomes appear to originate from different source populations within Melanesia and Eastern Indonesia. The Polynesian outlier, Kapingamarangi, is demonstrated to be an admixed Micronesian/Polynesian population. Furthermore, it is demonstrated that a geographical rather than linguistic classification of Oceanic populations best accounts for their extant Y chromosomal diversity.

Do genes presenting variation that has been linked to human disease have different biological properties than genes that have never been related to disease? What is the relationship between disease and fitness? Are the evolutionary pressures that affect genes linked to Mendelian diseases the same to those acting on genes whose variation contributes to complex disorders? The answers to these questions could shed light on the architecture of human genetic disorders and may have relevant implications when designing mapping strategies in future genetic studies. Here we show that, relative to non-disease genes, human disease (HD) genes have specific evolutionary profiles and protein network properties. Additionally, our results indicate that the mutation-selection balance renders an insufficient account of the evolutionary history of some HD genes and that adaptive selection could also contribute to shape their genetic architecture. Notably, several biological features of HD genes depend on the type of pathology (complex or Mendelian) with which they are related. For example, genes harbouring both causal variants for Mendelian disorders and risk factors for complex disease traits (Complex-Mendelian genes), tend to present higher functional relevance in the protein network and higher expression levels than genes associated only with complex disorders. Moreover, risk variants in Complex-Mendelian genes tend to present higher odds ratios than those on genes associated with the same complex disorders but with no link to Mendelian diseases. Taken together, our results suggest that genetic variation at genes linked to Mendelian disorders plays an important role in driving susceptibility to complex disease. This work was supported by Ministerio de Ciencia e Innovación, Spain (SAF2011-29239 to EB and BFU2012-38236 to AN), by Direcció General de Recerca, Generalitat de Catalunya (2014SGR1311 and 2014SGR866), by the Spanish National Institute of Bioinfomatics of the Instituto de Salud Carlos III (PT13/0001/0026) and by FEDER (Fondo Europeo de Desarrollo Regional)/FSE (Fondo Social Europeo). Funding to pay the Open Access publication charges for this article was provided by the ICREA Award granted to EB by the Institució Catalana de Recerca i Estudis Avançats (Generalitat de Catalunya).

Engelken, Johannes et al., Extreme differences in allele frequency between West Africans and Eurasians were observed for a leucine-to-valine substitution (Leu372Val) in the human intestinal zinc uptake transporter, ZIP4, yet no further evidence was found for a selective sweep around the ZIP4 gene (SLC39A4). By interrogating allele frequencies in more than 100 diverse human populations and resequencing Neanderthal DNA, we confirmed the ancestral state of this locus and found a strong geographical gradient for the derived allele (Val372), with near fixation in West Africa. In extensive coalescent simulations, we show that the extreme differences in allele frequency, yet absence of a classical sweep signature, can be explained by the effect of a local recombination hotspot, together with directional selection favoring the Val372 allele in Sub-Saharan Africans. The possible functional effect of the Leu372Val substitution, together with two pathological mutations at the same codon (Leu372Pro and Leu372Arg) that cause acrodermatitis enteropathica (a disease phenotype characterized by extreme zinc deficiency), was investigated by transient overexpression of human ZIP4 protein in HeLa cells. Both acrodermatitis mutations cause absence of the ZIP4 transporter cell surface expression and nearly absent zinc uptake, while the Val372 variant displayed significantly reduced surface protein expression, reduced basal levels of intracellular zinc, and reduced zinc uptake in comparison with the Leu372 variant. We speculate that reduced zinc uptake by the ZIP4-derived Val372 isoform may act by starving certain pathogens of zinc, and hence may have been advantageous in Sub-Saharan Africa. Moreover, these functional results may indicate differences in zinc homeostasis among modern human populations with possible relevance for disease risk. © 2014 Engelken et al.

Cénit, M.C. et al., CD5 plays a crucial role in autoimmunity and is a well-established genetic risk factor of developing RA. Recently, evidence of positive selection has been provided for the CD5 Pro224-Val471 haplotype in East Asian populations. The aim of the present work was to further analyze the functional relevance of non-synonymous CD5 polymorphisms conforming the ancestral and the newly derived haplotypes (Pro224-Ala471 and Pro224-Val471, respectively) as well as to investigate the potential role of CD5 on the development of SLE and/or SLE nephritis, This work was supported by grants from the Spanish Ministerio de Economía y Competitividad [SAF2010-19717 to FL, SAF2009-11110 to JM, SAF2011-29239, and BFU2008-01046 to EB], Generalitat de Catalunya [2009SGR00252 to FL, and 2009SGR1101 to EB], Junta de Andalucía [CTS-4977], and Instituto de Salud Carlos III and Fondo Europeo de Desarrollo Regional/FEDER [RD12/0009/0004 to JM].

The reference database of highly informative Y-chromosomal short tandem repeat (STR) haplotypes (YHRD), available online at http://ystr.charite.de, represents the largest collection of male-specific genetic profiles currently available for European populations. By September 2000, YHRD contained 4688 9-locus (so-called "minimal") haplotypes, 40% of which have been extended further to include two additional loci. Establishment of YHRD has been facilitated by the joint efforts of 31 forensic and anthropological institutions. All contributing laboratories have agreed to standardize their Y-STR haplotyping protocols and to participate in a quality assurance exercise prior to the inclusion of any data. In view of its collaborative character, and in order to put YHRD to its intended use, viz. the support of forensic caseworkers in their routine decision-making process, the database has been made publicly available via the Internet in February 2000. Online searches for complete or partial Y-STR haplotypes from evidentiary or non-probative material can be performed on a non-commercial basis, and yield observed haplotype counts as well as extrapolated population frequency estimates. In addition, the YHRD website provides information about the quality control test, genotyping protocols, haplotype formats and informativity, population genetic analysis, literature references, and a list of contact addresses of the contributing laboratories.

In the present study we have analyzed 44 Y-chromosome biallelic polymorphisms in population samples from northwestern (NW) Africa and the Iberian Peninsula, which allowed us to place each chromosome unequivocally in a phylogenetic tree based on >150 polymorphisms. The most striking results are that contemporary NW African and Iberian populations were found to have originated from distinctly different patrilineages and that the Strait of Gibraltar seems to have acted as a strong (although not complete) barrier to gene flow. In NW African populations, an Upper Paleolithic colonization that probably had its origin in eastern Africa contributed 75% of the current gene pool. In comparison, ∼78% of contemporary Iberian Y chromosomes originated in an Upper Paleolithic expansion from western Asia, along the northern rim of the Mediterranean basin. Smaller contributions to these gene pools (constituting 13% of Y chromosomes in NW Africa and 10% of Y chromosomes in Iberia) came from the Middle East during the Neolithic and, during subsequent gene flow, from Sub-Saharan to NW Africa. Finally, bidirectional gene flow across the Strait of Gibraltar has been detected: the genetic contribution of European Y chromosomes to the NW African gene pool is estimated at 4%, and NW African populations may have contributed 7% of Iberian Y chromosomes. The Islamic rule of Spain, which began in a.d. 711 and lasted almost 8 centuries, left only a minor contribution to the current Iberian Y-chromosome pool. The high-resolution analysis of the Y chromosome allows us to separate successive migratory components and to precisely quantify each historical layer.

Clinal patterns of autosomal genetic diversity within Europe have been interpreted in previous studies in terms of a Neolithic demic diffusion model for the spread of agriculture; in contrast, studies using mtDNA have traced many founding lineages to the Paleolithic and have not shown strongly clinal variation. We have used 11 human Y-chromosomal biallelic polymorphisms, defining 10 haplogroups, to analyze a sample of 3,616 Y chromosomes belonging to 47 European and circum-European populations. Patterns of geographic differentiation are highly nonrandom, and, when they are assessed using spatial autocorrelation analysis, they show significant clines for five of six haplogroups analyzed. Clines for two haplogroups, representing 45% of the chromosomes, are continentwide and consistent with the demic diffusion hypothesis. Clines for three other haplogroups each have different foci and are more regionally restricted and are likely to reflect distinct population movements, including one from north of the Black Sea. Principal-components analysis suggests that populations are related primarily on the basis of geography, rather than on the basis of linguistic affinity. This is confirmed in Mantel tests, which show a strong and highly significant partial correlation between genetics and geography but a low, nonsignificant partial correlation between genetics and language. Genetic-barrier analysis also indicates the primacy of geography in the shaping of patterns of variation. These patterns retain a strong signal of expansion from the Near East but also suggest that the demographic history of Europe has been complex and influenced by other major population movements, as well as by linguistic and geographic heterogeneities and the effects of drift. Z.H.R. was supported by a BBSRC Studentship, T.Z. by a Wellcome Trust Bioarchaeology Studentship, M.E.H. by an MRC Studentship, F.R.S. by the Leverhulme Trust, and L.P. by Ph.D. grant PRAXIS XXI/BD/13632/97 from Fundacao para a Ciencia e a Tecnologia. D.C.R. is a Glaxo Wellcome Research Fellow. C.T.-S. is supported by the CRC, and M.A.J. is a Wellcome Trust Senior Fellow in Basic Biomedical Science, supported by grant 057559. Iberian sample collection was partially funded by multidisciplinary project grant PR182/96 6745 from Complutense University.

The 13 short tandem repeat (STR) loci D3S1358, vWA, FGA, D16S539, TH01, TPOX, CSF1PO, D8S1179, D21S11, D18S51, D5S818, D13S317 and D7S820 as well as the amelogenin locus, contained in AmpFlSTR Profiler Plus and/or AmpFlSTR Cofiler and/or AmpFlSTR Green I PCR amplification kits, were studied in four populations from the Iberian Peninsula, Basques, Catalans, Andalusians and Portuguese and two North African populations (Moroccan Arabs and Berbers). The aim of the study was to obtain accurate allele frequency data and other genetic parameters of forensic interest on the main representative human groups living in Iberia and Morocco using an automated method and commercial amplification kits.

Eleven biallelic polymorphisms and seven short-tandem-repeat (STR) loci mapping on the nonrecombining portion of the human Y chromosome have been typed in men from northwestern Africa. Analysis of the biallelic markers, which represent probable unique events in human evolution, allowed us to characterize the stable backgrounds or haplogroups of Y chromosomes that prevail in this geographic region. Variation in the more rapidly mutating genetic markers (STRs) has been used both to estimate the time to the most recent common ancestor for STR variability within these stable backgrounds and to explore whether STR differentiation among haplogroups still retains information about their phylogeny. When analysis of molecular variance was used to study the apportionment of STR variation among both genetic backgrounds (i.e., those defined by haplogroups) and population backgrounds, we found STR variability to be clearly structured by haplogroups. More than 80% of the genetic variance was found among haplogroups, whereas only 3.72% of the genetic variation could be attributed to differences among populations—that is, genetic variability appears to be much more structured by lineage than by population. This was confirmed when two population samples from the Iberian Peninsula were added to the analysis. The deep structure of the genetic variation in old genealogical units (haplogroups) challenges a population-based perspective in the comprehension of human genome diversity. A population may be better understood as an association of lineages from a deep and population-independent gene genealogy, rather than as a complete evolutionary unit.