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Background Proteinuria is a well-known risk factor for progressive kidney impairment. Recently, C-terminal cubilin (CUBN) variants have been associated with isolated proteinuria without progression of kidney disease. Methods Genetic testing of 347 families with proteinuria of suspected monogenic cause was performed by next-generation sequencing of a custom-designed kidney disease gene panel. Families with CUBN biallelic proteinuria-causing variants were studied at the clinical, genetic, laboratory and pathologic levels. Results Twelve families (15 patients) bearing homozygous or compound heterozygous proteinuria-causing variants in the C-terminal CUBN gene were identified, representing 3.5% of the total cohort. We identified 14 different sequence variants, five of which were novel. The median age at diagnosis of proteinuria was 4 years (range 9 months to 44 years), and in most cases proteinuria was detected incidentally. Thirteen patients had moderate to severe proteinuria at diagnosis without nephrotic syndrome. These patients showed lack of response to angiotensin-converting enzyme inhibitor (ACEi) and angiotensin receptor blocker (ARB) treatment, normal kidney biopsy and preservation of normal kidney function over time. The two remaining patients presented a more severe phenotype, likely caused by associated comorbidities. Conclusions Identification of C-terminal pathogenic CUBN variants is diagnostic of an entity characterized by glomerular proteinuria, normal kidney histology and lack of response to ACEi/ARB treatment. This study adds evidence and increases awareness about albuminuria caused by C-terminal variants in the CUBN gene, which is a benign condition usually diagnosed in childhood with preserved renal function until adulthood.

Focal segmental glomerulosclerosis (FSGS) is a histological lesion with many causes, including inherited genetic defects, with significant proteinuria being the predominant clinical finding at presentation. FSGS is considered as a podocyte disease due to the fact that in the majority of patients with FSGS, the lesion results from defects in the podocyte structure. However, FSGS does not result exclusively from podocyte-associated genes. In this study, we used a genetic approach based on targeted next-generation sequencing (NGS) of 242 genes to identify the genetic cause of FSGS in seven Tunisian families. The sequencing results revealed the presence of eight distinct mutations including seven newly discovered ones: the c.538G>A (p.V180M) in NPHS2, c.5186G>A (p.R1729Q) in PLCE1 and c.232A>C (p.I78L) in PAX2 and five novel mutations in COL4A3 and COL4A4 genes. Four mutations (c.209G>A (p.G70D), c.725G>A (p.G242E), c.2225G>A (p.G742E), and c. 1681_1698del) were detected in COL4A3 gene and one mutation (c.1424G>A (p.G475D)) was found in COL4A4. In summary, NGS of a targeted gene panel is an ideal approach for the genetic testing of FSGS with multiple possible underlying etiologies. We have demonstrated that not only podocyte genes but also COL4A3/4 mutations should be considered in patients with FSGS.

Although the evolutionary history of the X chromosome indicates its specialization in male fitness, its role in spermatogenesis has largely been unexplored. Currently only three X chromosome genes are considered of moderate-definitive diagnostic value. We aimed to provide a comprehensive analysis of all X chromosome-linked protein-coding genes in 2,354 azoospermic/cryptozoospermic men from four independent cohorts. Genomic data were analyzed and compared with data in normozoospermic control individuals and gnomAD. While updating the clinical significance of known genes, we propose 21 recurrently mutated genes strongly associated with and 34 moderately associated with azoospermia/cryptozoospermia not previously linked to male infertility (novel). The most frequently affected prioritized gene, RBBP7, was found mutated in ten men across all cohorts, and our functional studies in Drosophila support its role in germ stem cell maintenance. Collectively, our study represents a significant step towards the definition of the missing genetic etiology in idiopathic severe spermatogenic failure and significantly reduces the knowledge gap of X-linked genetic causes of azoospermia/cryptozoospermia contributing to the development of future diagnostic gene panels., This work was funded by Spanish Ministry of Health Instituto Carlos III-FIS (grant numbers PI17/01822 and PI20/01562) and the Fanconi Research Fund awarded to C.K. and A.R.-E.; the German Research Foundation Clinical Research Unit “Male Germ Cells” (DFG CRU326), grants to F.T. and C.F.; the National Institutes of Health (R01HD078641), awarded to D.F.C., L.N., and K.I.A.; the Netherlands Organisation for Scientific Research (918-15-667) as well as an Investigator Award in Science from the Wellcome Trust (209451) to J.A.V.; and the MICINN (BFU2015-65082-P and PGC2018-094538-B-I00), the Generalitat de Catalunya (SGR2009-1023 and SGR2014-204), and the European Community FEDER program to F.A.

Purpose Azoospermia affects 1% of men and it can be the consequence of spermatogenic maturation arrest (MA). Although the etiology of MA is likely to be of genetic origin, only 13 genes have been reported as recurrent potential causes of MA. Methods Exome sequencing in 147 selected MA patients (discovery cohort and two validation cohorts). Results We found strong evidence for five novel genes likely responsible for MA (ADAD2,TERB1,SHOC1,MSH4, andRAD21L1), for which mouse knockout (KO) models are concordant with the human phenotype. Four of them were validated in the two independent MA cohorts. In addition, nine patients carried pathogenic variants in seven previously reported genes-TEX14,DMRT1,TEX11,SYCE1,MEIOB,MEI1, andSTAG3-allowing to upgrade the clinical significance of these genes for diagnostic purposes. Our meiotic studies provide novel insight into the functional consequences of the variants, supporting their pathogenic role. Conclusion Our findings contribute substantially to the development of a pre-testicular sperm extraction (TESE) prognostic gene panel. If properly validated, the genetic diagnosis of complete MA prior to surgical interventions is clinically relevant. Wider implications include the understanding of potential genetic links between nonobstructive azoospermia (NOA) and cancer predisposition, and between NOA and premature ovarian failure.

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 Inherited kidney diseases are one of the leading causes of chronic kidney disease (CKD) that manifests before the age of 30 years. Precise clinical diagnosis of early-onset CKD is complicated due to the high phenotypic overlap, but genetic testing is a powerful diagnostic tool. We aimed to develop a genetic testing strategy to maximize the diagnostic yield for patients presenting with early-onset CKD and to determine the prevalence of the main causative genes. Methods We performed genetic testing of 460 patients with early-onset CKD of suspected monogenic cause using next-generation sequencing of a custom-designed kidney disease gene panel in addition to targeted screening for c.428dupC MUC1. Results We achieved a global diagnostic yield of 65% (300/460), which varied depending on the clinical diagnostic group: 77% in cystic kidney diseases, 76% in tubulopathies, 67% in autosomal dominant tubulointerstitial kidney disease, 61% in glomerulopathies and 38% in congenital anomalies of the kidney and urinary tract. Among the 300 genetically diagnosed patients, the clinical diagnosis was confirmed in 77%, a specific diagnosis within a clinical diagnostic group was identified in 15%, and 7% of cases were reclassified. Of the 64 causative genes identified in our cohort, 7 (COL4A3, COL4A4, COL4A5, HNF1B, PKD1, PKD2 and PKHD1) accounted for 66% (198/300) of the genetically diagnosed patients. Conclusions Two-thirds of patients with early-onset CKD in this cohort had a genetic cause. Just seven genes were responsible for the majority of diagnoses. Establishing a genetic diagnosis is crucial to define the precise aetiology of CKD, which allows accurate genetic counselling and improved patient management.

Background: Integrating demography and adaptive evolution is pivotal to understanding the evolutionary history and conservation of great apes. However, little is known about the adaptive evolution of our closest relatives, in particular if and to what extent adaptions to environmental differences have occurred. Here, we used whole-genome sequencing data from critically endangered orangutans from North Sumatra (Pongo abelii) and Borneo (P. pygmaeus) to investigate adaptive responses of each species to environmental differences during the Pleistocene. Results: Taking into account the markedly disparate demographic histories of each species after their split ~ 1 Ma ago, we show that persistent environmental differences on each island had a strong impact on the adaptive evolution of the genus Pongo. Across a range of tests for positive selection, we find a consistent pattern of between-island and species differences. In the more productive Sumatran environment, the most notable signals of positive selection involve genes linked to brain and neuronal development, learning, and glucose metabolism. On Borneo, however, positive selection comprised genes involved in lipid metabolism, as well as cardiac and muscle activities. Conclusions: We find strikingly different sets of genes appearing to have evolved under strong positive selection in each species. In Sumatran orangutans, selection patterns were congruent with well-documented cognitive and behavioral differences between the species, such as a larger and more complex cultural repertoire and higher degrees of sociality. However, in Bornean orangutans, selective responses to fluctuating environmental conditions appear to have produced physiological adaptations to generally lower and temporally more unpredictable food supplies. This work was financially supported by University of Zurich Forschungskredit grants FK-10 (MPMG), FK-15-103 (AN), and FK-14-094 (TBS), Swiss National Science Foundation grants 3100A-116848 (MK, CvS) and P300PA_177852 (AN), Leakey Foundation (MPMG), UZH Research Priority Program “Evolution in Action” (MK), MINECO/FEDER UE BFU2017-86471-P (TMB), U01 MH106874 (TMB), Howard Hughes International Early Career (TMB), Obra Social “La Caixa” and Secretaria d’Universitats i Recerca and CERCA Programme del Departament d’Economia i Coneixement de la Generalitat de Catalunya (TMB), Julius–Klaus Foundation (MK), Ministerio de Economía y Competitividad grant BFU2013-43726-P (JB, MP), Gates Cambridge Trust (TD), A.H. Schultz Foundation grants (MK, MPMG), and the Department of Anthropology at the University of Zurich.

Rationale & Objective: Alport syndrome is a common genetic kidney disease accounting for approximately 2% of patients receiving kidney replacement therapy (KRT). It is caused by pathogenic variants in the gene COL4A3, COL4A4, or COL4A5. The aim of this study was to evaluate the clinical and genetic spectrum of patients with autosomal dominant Alport syndrome (ADAS). Study Design: Retrospective cohort study. Setting & Participants: 82 families (252 patients) with ADAS were studied. Clinical, genetic, laboratory, and pathology data were collected. Observations: A pathogenic DNA variant in COL4A3 was identified in 107 patients (35 families), whereas 133 harbored a pathogenic variant in COL4A4 (43 families). Digenic/complex inheritance was observed in 12 patients. Overall, the median kidney survival was 67 (95% CI, 58-73) years, without significant differences across sex (P = 0.8), causative genes (P = 0.6), or type of variant (P = 0.9). Microhematuria was the most common kidney manifestation (92.1%), and extrarenal features were rare. Findings on kidney biopsies ranged from normal to focal segmental glomerulosclerosis. The slope of estimated glomerular filtration rate change was -1.46 (-1.66 to -1.26) mL/min/1.73 m(2) per year for the overall group, with no significant differences between ADAS genes (P = 0.2). Limitations: The relatively small size of this series from a single country, potentially limiting generalizability. Conclusions: Patients with ADAS have a wide spectrum of clinical presentations, ranging from asymptomatic to kidney failure, a pattern not clearly related to the causative gene or type of variant. The diversity of ADAS phenotypes contributes to its underdiagnosis in clinical practice.

The study of segmental duplications (SDs) and copy-number variants (CNVs) is of great importance in the fields of genomics and evolution. However, SDs and CNVs are usually excluded from genome-wide scans for natural selection. Because of high identity between copies, SDs and CNVs that are not included in reference genomes are prone to be collapsed-that is, mistakenly aligned to the same region-when aligning sequence data from single individuals to the reference. Such collapsed duplications are additionally challenging because concerted evolution between duplications alters their site frequency spectrum and linkage disequilibrium patterns. To investigate the potential effect of collapsed duplications upon natural selection scans we obtained expectations for four summary statistics from simulations of duplications evolving under a range of interlocus gene conversion and crossover rates. We confirm that summary statistics traditionally used to detect the action of natural selection on DNA sequences cannot be applied to SDs and CNVs since in some cases values for known duplications mimic selective signatures. As a proof of concept of the pervasiveness of collapsed duplications, we analyzed data from the 1,000 Genomes Project. We find that, within regions identified as variable in copy number, diversity between individuals with the duplication is consistently higher than between individuals without the duplication. Furthermore, the frequency of single nucleotide variants (SNVs) deviating from Hardy-Weinberg Equilibrium is higher in individuals with the duplication, which strongly suggests that higher diversity is a consequence of collapsed duplications and incorrect evaluation of SNVs within these CNV regions. This work has been supported by Ministerio de Ciencia e Innovación, Spain (BFU2015-68649-P, MINECO/FEDER, UE), the Direcció General de Recerca, Generalitat de Catalunya (2014SGR1311 and 2014SGR866), the Spanish National Institute of Bioinformatics (PT13/0001/0026) of the Instituto de Salud Carlos III, grant MDM-2014-0370 through the “María de Maeztu” Programme for Units of Excellence in R&D to UPF’s Department of Experimental and Health Sciences; a grant to D.A.H. from Conacyt; and by the Fondo Europeo de Desarrollo Regional (FEDER) and the Fondo Social Europeo (FSE).

Summary B cells thwart antigenic aggressions by releasing immunoglobulin M (IgM), IgG, IgA, and IgE, which deploy well-understood effector functions. In contrast, the role of secreted IgD remains mysterious. We found that some B cells generated IgD-secreting plasma cells following early exposure to external soluble antigens such as food proteins. Secreted IgD targeted basophils by interacting with the CD44-binding protein galectin-9. When engaged by antigen, basophil-bound IgD increased basophil secretion of interleukin-4 (IL-4), IL-5, and IL-13, which facilitated the generation of T follicular helper type 2 cells expressing IL-4. These germinal center T cells enhanced IgG1 and IgE but not IgG2a and IgG2b responses to the antigen initially recognized by basophil-bound IgD. In addition, IgD ligation by antigen attenuated allergic basophil degranulation induced by IgE co-ligation. Thus, IgD may link B cells with basophils to optimize humoral T helper type 2-mediated immunity against common environmental soluble antigens.

Summary Secretory immunoglobulin A (SIgA) enhances host-microbiota symbiosis, whereas SIgM remains poorly understood. We found that gut IgM+ plasma cells (PCs) were more abundant in humans than mice and clonally related to a large repertoire of memory IgM+ B cells disseminated throughout the intestine but rare in systemic lymphoid organs. In addition to sharing a gut-specific gene signature with memory IgA+ B cells, memory IgM+ B cells were related to some IgA+ clonotypes and switched to IgA in response to T cell-independent or T cell-dependent signals. These signals induced abundant IgM which, together with SIgM from clonally affiliated PCs, recognized mucus-embedded commensals. Bacteria recognized by human SIgM were dually coated by SIgA and showed increased richness and diversity compared to IgA-only-coated or uncoated bacteria. Thus, SIgM may emerge from pre-existing memory rather than newly activated naive IgM+ B cells and could help SIgA to anchor highly diverse commensal communities to mucus., Graphical Abstract, Highlights • IgM+ PCs generating SIgM are relatively abundant in human but not mouse gut • IgM+ PCs clonally relate to a large gut repertoire of memory IgM+ B cells • Gut memory IgM+ B cells express a tissue-specific signature and can switch to IgA • Human but not mouse SIgM binds a highly diverse microbiota dually coated by SIgA, Magri et al. found that the human gut includes a large memory IgM+ B cell repertoire clonally related to plasma cells mounting SIgM responses against mucus-embedded commensals co-targeted by SIgA. Dually coated bacteria are detected in humans but not mice and show increased diversity and richness compared to SIgA-only-coated or uncoated bacteria.

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.

This work was financially supported by University of Zurich (UZH) Forschungskredit grants FK-10 (M.P.M.-G.), FK-15-103 (A. Nater), and FK-14-094 (T.B.S.), Swiss National Science Foundation grant 3100A-116848 (M.K.and C.P.v.S.), the Leakey Foundation (M.P.M.-G.), the A.H. Schultz Foundation (M.K. and M.P.M.-G.), UZH Research Priority Program “Evolution in Action” (M.K.), Arcus Foundation grant G-PGM-1411-1112 (E.M.), Australian National University (ANU) research fund (A. Nurcahyo), an ANU Vice Chancellor Travel Grant (A. Nurcahyo), Australia Awards Scholarship-DFAT (A. Nurcahyo), ERC Starting Grant 260372 (T.M.-B.), EMBOYIP 2013 (T.M.-B.), MINECOBFU2014-55090-P, BFU2015-7116-ERC, BFU2015-6215-ERCU01, and MH106874 (T.M.-B.), Fundacio Zoo Barcelona (T.M.-B.), Julius–Klaus Foundation (M.K.), MINECO/FEDERBFU2016-77961-P (J.B. and M.P.), Gates Cambridge Trust (T.D.), and the Department of Anthropology at the University of Zurich. Six extant species of non-human great apes are currently recognized: Sumatran and Bornean orangutans, eastern and western gorillas, and chimpanzees and bonobos [1]. However, large gaps remain in our knowledge of fine-scale variation in hominoid morphology, behavior, and genetics, and aspects of great ape taxonomy remain in flux. This is particularly true for orangutans (genus: Pongo), the only Asian great apes and phylogenetically our most distant relatives among extant hominids [1]. Designation of Bornean and Sumatran orangutans, P. pygmaeus (Linnaeus 1760) and P. abelii (Lesson 1827), as distinct species occurred in 2001 [1, 2]. Here, we show that an isolated population from Batang Toru, at the southernmost range limit of extant Sumatran orangutans south of Lake Toba, is distinct from other northern Sumatran and Bornean populations. By comparing cranio-mandibular and dental characters of an orangutan killed in a human-animal conflict to those of 33 adult male orangutans of a similar developmental stage, we found consistent differences between the Batang Toru individual and other extant Ponginae. Our analyses of 37 orangutan genomes provided a second line of evidence. Model-based approaches revealed that the deepest split in the evolutionary history of extant orangutans occurred ∼3.38 mya between the Batang Toru population and those to the north of Lake Toba, whereas both currently recognized species separated much later, about 674 kya. Our combined analyses support a new classification of orangutans into three extant species. The new species, Pongo tapanuliensis, encompasses the Batang Toru population, of which fewer than 800 individuals survive. Postprint

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).

Purging through inbreeding occurs when consanguineous marriages increases the rate at which deleterious alleles are present in a homozygous state. In this study we carried out low-read depth (4-10x) whole-genome sequencing in 568 individuals from three Italian founder populations, and compared it to data from other Italian and European populations from the 1000 Genomes Project. We show extended consanguinity and depletion of homozygous genotypes at potentially detrimental sites in the founder populations compared to outbred populations. However these patterns are not compatible with the hypothesis of consanguinity driving the purging of highly deleterious mutations according to simulations. Therefore we conclude that genetic drift and the founder effect should be responsible for the observed purging of deleterious variants.

International audience; The unique inheritance pattern of the X chromosome exposes it to natural selection in a way that is different from that of the autosomes, potentially resulting in accelerated evolution. We perform a comparative analysis of X chromosome polymorphism in 10 great ape species, including humans. In most species, we identify striking megabase-wide regions, where nucleotide diversity is less than 20% of the chromosomal average. Such regions are found exclusively on the X chromosome. The regions overlap partially among species, suggesting that the underlying targets are partly shared among species. The regions have higher proportions of singleton SNPs, higher levels of population differentiation, and a higher nonsynonymous-to-synonymous substitution ratio than the rest of the X chromosome. We show that the extent to which diversity is reduced is incompatible with direct selection or the action of background selection and soft selective sweeps alone, and therefore, we suggest that very strong selective sweeps have independently targeted these specific regions in several species. The only genomic feature that we can identify as strongly associated with loss of diversity is the location of testis-expressed ampliconic genes, which also have reduced diversity around them. We hypothesize that these genes may be responsible for selective sweeps in the form of meiotic drive caused by an intragenomic conflict in male meiosis.

Genes vary in their likelihood to undergo adaptive evolution. The genomic factors that determine adaptability, however, remain poorly understood. Genes function in the context of molecular networks, with some occupying more important positions than others and thus being likely to be under stronger selective pressures. However, how positive selection distributes across the different parts of molecular networks is still not fully understood. Here, we inferred positive selection using comparative genomics and population genetics approaches through the comparison of 10 mammalian and 270 human genomes, respectively. In agreement with previous results, we found that genes with lower network centralities are more likely to evolve under positive selection (as inferred from divergence data). Surprisingly, polymorphism data yield results in the opposite direction than divergence data: Genes with higher centralities are more likely to have been targeted by recent positive selection during recent human evolution. Our results indicate that the relationship between centrality and the impact of adaptive evolution highly depends on the mode of positive selection and/or the evolutionary time-scale., This work was funded by the “Ministerio de Ciencia y Tecnología” (Spain) (grant BFU2013-43726-P), and the “Direcció General de Recerca, Generalitat de Catalunya (Grup de Recerca Consolidat 2009 SGR 1101)” awarded to J.B. P.L. was supported by a Ph.D. fellowship from “Acción Estratégica de Salud, en el marco del Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica 2008–2011” from Instituto de Salud Carlos III. D.A.-P. was a “Juan de la Cierva” fellow from the “Ministerio de Economía y Competitividad” (Spain) (JCI-2011-11089). M.A.F. was supported by a Principal Investigator grant from Science Foundation Ireland (12/IP/1673) and a project from the “Ministerio de Economía y Competitividad” (grant number BFU2012-36346).

Summary: Given a set of extant haplotypes IRiS first detects high confidence recombination events in their shared genealogy. Next using the local sequence topology defined by each detected event, it integrates these recombinations into an ancestral recombination graph. While the current system has been calibrated for human population data, it is easily extendible to other species as well. Availability: IRiS (Identification of Recombinations in Sequences) binary files are available for non-commercial use in both Linux and Microsoft Windows, 32 and 64 bit environments from https://researcher.ibm.com/researcher/view_project.php?id = 2303 Contact: parida@us.ibm.com

Background: Population differentiation has proved to be effective for identifying loci under geographically-localized positive selection, and has the potential to identify loci subject to balancing selection. We have previously investigated the pattern of genetic differentiation among human populations at 36.8 million genomic variants to identify sites in the genome showing high frequency differences. Here, we extend this dataset to include additional variants, survey sites with low levels of differentiation, and evaluate the extent to which highly differentiated sites are likely to result from selective or other processes. Results: We demonstrate that while sites of low differentiation represent sampling effects rather than balancing selection, sites showing extremely high population differentiation are enriched for positive selection events and that one half may be the result of classic selective sweeps. Among these, we rediscover known examples, where we actually identify the established functional SNP, and discover novel examples including the genes ABCA12, CALD1 and ZNF804, which we speculate may be linked to adaptations in skin, calcium metabolism and defense, respectively. Conclusions: We have identified known and many novel candidate regions for geographically restricted positive selection, and suggest several directions for further research.

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.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited., Searching for Darwinian selection in natural populations has been the focus of a multitude of studies over the last decades. Here we present the 1000 Genomes Selection Browser 1.0 (http://hsb.upf.edu) as a resource for signatures of recent natural selection in modern humans. We have implemented and applied a large number of neutrality tests as well as summary statistics informative for the action of selection such as Tajima's D, CLR, Fay and Wu's H, Fu and Li's F* and D*, XPEHH, ΔiHH, iHS, FST, ΔDAF and XPCLR among others to low coverage sequencing data from the 1000 genomes project (Phase 1; release April 2012). We have implemented a publicly available genome-wide browser to communicate the results from three different populations of West African, Northern European and East Asian ancestry (YRI, CEU, CHB). Information is provided in UCSC-style format to facilitate the integration with the rich UCSC browser tracks and an access page is provided with instructions and for convenient visualization. We believe that this expandable resource will facilitate the interpretation of signals of selection on different temporal, geographical and genomic scales. © 2013 The Author(s). Published by Oxford University Press., Ministerio de Ciencia y Tecnología (Spain); Direcció General de Recerca, Generalitat de Catalunya (Grup de Recerca Consolidat 2009 SGR 1101); Subprogram BMC [BFU2010-19443 awarded to J.B.]; Post-doctoral scholarship from the Volkswagenstiftung [Az: I/85 198 to J.E.]; Spanish government [BFU-2008-01046; SAF2011-29239]; The Spanish government FPI scholarships [BES-2009-017731 and BES-2011-04502 to G.M.D. and M.P., respectively]; PhD fellowship from ‘Acción Estratégica de Salud, en el marco del Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica 2008-2011’ from Instituto de Salud Carlos III (to P.L.). Funding for open access charge: Prof. Jaume Bertranpetit.

From The Eleventh Asia Pacific Bioinformatics Conference (APBC 2013) Vancouver, Canada. 21-24 January 2013, [Background] Reconstructability of population history, from genetic information of extant individuals, is studied under a simulation setting. We do not address the issue of accuracy of the reconstruction algorithms: we assume the availability of the theoretical best algorithm. On the other hand, we focus on the fraction (1 - f) of the common genetic history that is irreconstructible or impenetrable. Thus the fraction, f, gives an upper bound on the extent of estimability. In other words, there exists no method that can reconstruct a fraction larger than f of the entire common genetic history. For the realization of such a study, we first define a natural measure of the amount of genetic history. Next, we use a population simulator (from literature) that has at least two features. Firstly, it has the capability of providing samples from different demographies, to effectively reflect reality. Secondly, it also provides the underlying relevant genetic history, captured in its entirety, where such a measure is applicable. Finally, to compute f, we use an information content measure of the relevant genetic history. The simulator of choice provided the following demographies: Africans, Europeans, Asians and Afro-Americans., [Results] We observe that higher the rate of recombination, lower the value of f, while f is invariant over varying mutation rates, in each of the demographies. The value of f increases with the number of samples, reaching a plateau and suggesting that in all the demographies at least about one-third of the relevant genetic history is impenetrable. The most surprising observation is that the the sum of the reconstructible history of the subsegments is indeed larger than the reconstructible history of the whole segment. In particular, longer the chromosomal segment, smaller the value of f, in all the demographies., [Conclusions] We present the very first framework for measuring the fraction of the relevant genetic history of a population that is mathematically elusive. Our observed results on the tested demographies suggest that it may be better to aggregate the analysis of smaller chunks of chromosomal segments than fewer large chunks. Also, no matter the richness of samples in a population, at least one-third of the population genetic history is impenetrable. The framework also opens up possible new lines of investigation along the following. Given the characteristics of a population, possibly derived from observed extant individuals, to estimate the (1) optimal sample size and (2) optimal sequence length for the most informative analysis. © 2013 Utro et al.; licensee BioMed Central Ltd.

The dispersal of the human population to all the continents of the globe is a compelling story that can possibly be unravelled from the genetic landscape of the current populations. Indeed, a grasp on this strengthens the understanding of relationship between populations for anthropological as well as medical applications. While the collective genomes is believed to have captured its own “evolution”, undoubtedly, a lot is irrecoverably lost. It is important to try to estimate what fraction of past events become unreconstructable. We used a published population simulation algorithm which includes parameter sets that simulate modern regional human demographics: it reflects the out-of-Africa expansion events, isolation during the Last Glacial Period, Neolithic expansion of agriculture, and the industrial revolution for African, African–American, European, and Asian populations. This simulation tool was used to provide complete genetic histories unavailable in real human population data. Next we used the minimal descriptor device which is an algorithm-independent means to explore the (potential) recoverable genetic events from the final extant population data. We found that, on average, around 65 % of the total number of genetic events are recoverable, with substantial variations among histories. We also found that increases of sequence length tended to yield diminishing returns in new information yield. Lastly, even with a substantial fraction of events unrecoverable, and even for different population history simulations, the recoverable events do yield similar resolution of the whole record of demographic, climatic, and other population events.

Melé, Marta et al.-- The Genographic Consortium, The information left by recombination in our genomes can be used to make inferences on our recent evolutionary history. Specifically, the number of past recombination events in a population sample is a function of its effective population size (Ne). We have applied a method, IRiS, to detect specific past recombination events in 30 Old World populations to infer their Ne. We have found that Sub-Saharan African populations have an Ne that is ∼ 4 times greater than those of non-African populations and that outside of Africa, South Asian populations had the largest Ne. We also observe that the patterns of recombinational diversity of these populations correlate with distance out of Africa if that distance is measured along a path crossing South Arabia. No such correlation is found through a Sinai route, suggesting that anatomically modern humans first left Africa through the Bab-el-Mandeb strait rather than through present Egypt., Funding for this project was provided by National Geographic and IBM within the Genographic Project initiative and by the Spanish Ministry of Science and Innovation project BFU2010-19443 (subprogram BMC). M.M. was supported by grant AP2006-03268. Genotyping and bioinformatic services were provided respectively by CEGEN (Centro Nacional de Genotipado) and INB (National Bioinformatics Insitute), Spain.

13 páginas.-- Javed, Asif et al., We have analyzed human genetic diversity in 33 Old World populations including 23 populations obtained through Genographic Project studies. A set of 1,536 SNPs in five X chromosome regions were genotyped in 1,288 individuals (mostly males). We use a novel analysis employing subARG network construction with recombining chromosomal segments. Here, a subARG is constructed independently for each of five gene-free regions across the X chromosome, and the results are aggregated across them. For PCA, MDS and ancestry inference with STRUCTURE, the subARG is processed to obtain feature vectors of samples and pairwise distances between samples. The observed population structure, estimated from the five short X chromosomal segments, supports genome-wide frequency-based analyses: African populations show higher genetic diversity, and the general trend of shared variation is seen across the globe from Africa through Middle East, Europe, Central Asia, Southeast Asia, and East Asia in broad patterns. The recombinational analysis was also compared with established methods based on SNPs and haplotypes. For haplotypes, we also employed a fixed-length approach based on information-content optimization. Our recombinational analysis suggested a southern migration route out of Africa, and it also supports a single, rapid human expansion from Africa to East Asia through South Asia., This research is part of the Genographic Project, funded by National Geographic and IBM. Additional funding was provided by the Spanish Ministry of Science and Innovation projects BFU2007-63657, BFU2007-63171, and BFU2010-19443; MM was supported by grant AP2006-03268, Generalitat de Catalunya; OB was supported by Russian Foundation for Basic Research (grants 10-06-00451, 10-04-01603) and by the Presidium RAS Programme “Molecular and Cell Biology”.

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.

Sánchez-Quinto, Federico et al.-- Data can be downloaded from http://www.ibe.upf-csic.es/ibe/research/research-groups/lalueza-fox.html, The genetic background of the European Mesolithic and the extent of population replacement during the Neolithic [1-10] is poorly understood, both due to the scarcity of human remains from that period [11-18] and the inherent methodological difficulties of ancient DNA research. However, advances in sequencing technologies are both increasing data yields and providing supporting evidence for data authenticity, such as nucleotide misincorporation patterns [19-22]. We use these methods to characterize both the mitochondrial DNA genome and generate shotgun genomic data from two exceptionally well-preserved 7,000-year-old Mesolithic individuals from La Braña-Arintero site in León (Northwestern Spain) [23]. The mitochondria of both individuals are assigned to U5b2c1, a haplotype common among the small number of other previously studied Mesolithic individuals from Northern and Central Europe. This suggests a remarkable genetic uniformity and little phylogeographic structure over a large geographic area of the pre-Neolithic populations. Using Approximate Bayesian Computation, a model of genetic continuity from Mesolithic to Neolithic populations is poorly supported. Furthermore, analyses of 1.34% and 0.53% of their nuclear genomes, containing about 50,000 and 20,000 ancestry informative SNPs, respectively, show that these two Mesolithic individuals are not related to current populations from either the Iberian Peninsula or Southern Europe. © 2012 Elsevier Ltd All rights reserved., C.L.-F., O.R., and F.S.-Q. are supported by a grant from the Ministerio de Ciencia e Innovación of Spain (BFU2009-06974). H.S., L.O., M.C.A.-A., and M.T.P.G acknowledge the Marie Curie Actions, Danish National Research Foundation, and Danish Council for Independent Research for support.

[Motivation] Detecting positive selection in genomic regions is a recurrent topic in natural population genetic studies. However, there is little consistency among the regions detected in several genome-wide scans using different tests and/or populations. Furthermore, few methods address the challenge of classifying selective events according to specific features such as age, intensity or state (completeness)., [Results] We have developed a machine-learning classification framework that exploits the combined ability of some selection tests to uncover different polymorphism features expected under the hard sweep model, while controlling for population-specific demography. As a result, we achieve high sensitivity toward hard selective sweeps while adding insights about their completeness (whether a selected variant is fixed or not) and age of onset. Our method also determines the relevance of the individual methods implemented so far to detect positive selection under specific selective scenarios. We calibrated and applied the method to three reference human populations from The 1000 Genome Project to generate a genome-wide classification map of hard selective sweeps. This study improves detection of selective sweep by overcoming the classical selection versus no-selection classification strategy, and offers an explanation to the lack of consistency observed among selection tests when applied to real data. Very few signals were observed in the African population studied, while our method presents higher sensitivity in this population demography., This work was supported by Ministerio de Economía y Competitividad (Spain) [grants BFU2010-19443, BFU2013-43726-P]; and the Secretaria d’Universitats i Recerca del Departament d’Economia i Coneixement de la Generalitat de Catalunya [GRC 2014 SGR 866] to J.B. M.P. and G.D. have been supported by a grant of the FPI program, Ministerio de Economia y Competitividad; P.L. by a grant from the Instituto de Salud Carlos III; J.E. was supported through a Postdoc scholarship from the Volkswagenstiftung [Az: I/85 198].