Professional Education

  • Doctor of Philosophy, Universitat Pompeu Fabra (2010)
  • Master of Science, Universität für Bodenkultur, Vienna, Biotechnology (2004)

Stanford Advisors


Journal Articles

  • Melanesian Blond Hair Is Caused by an Amino Acid Change in TYRP1 SCIENCE Kenny, E. E., Timpson, N. J., Sikora, M., Yee, M., Moreno-Estrada, A., Eng, C., Huntsman, S., Burchard, E. G., Stoneking, M., Bustamante, C. D., Myles, S. 2012; 336 (6081): 554-554


    Naturally blond hair is rare in humans and found almost exclusively in Europe and Oceania. Here, we identify an arginine-to-cysteine change at a highly conserved residue in tyrosinase-related protein 1 (TYRP1) as a major determinant of blond hair in Solomon Islanders. This missense mutation is predicted to affect catalytic activity of TYRP1 and causes blond hair through a recessive mode of inheritance. The mutation is at a frequency of 26% in the Solomon Islands, is absent outside of Oceania, represents a strong common genetic effect on a complex human phenotype, and highlights the importance of examining genetic associations worldwide.

    View details for DOI 10.1126/science.1217849

    View details for Web of Science ID 000303498800036

    View details for PubMedID 22556244

  • Network Evolution: Rewiring and Signatures of Conservation in Signaling PLOS COMPUTATIONAL BIOLOGY Sun, M. G., Sikora, M., Costanzo, M., Boone, C., Kim, P. M. 2012; 8 (3)


    The analysis of network evolution has been hampered by limited availability of protein interaction data for different organisms. In this study, we investigate evolutionary mechanisms in Src Homology 3 (SH3) domain and kinase interaction networks using high-resolution specificity profiles. We constructed and examined networks for 23 fungal species ranging from Saccharomyces cerevisiae to Schizosaccharomyces pombe. We quantify rates of different rewiring mechanisms and show that interaction change through binding site evolution is faster than through gene gain or loss. We found that SH3 interactions evolve swiftly, at rates similar to those found in phosphoregulation evolution. Importantly, we show that interaction changes are sufficiently rapid to exhibit saturation phenomena at the observed timescales. Finally, focusing on the SH3 interaction network, we observe extensive clustering of binding sites on target proteins by SH3 domains and a strong correlation between the number of domains that bind a target protein (target in-degree) and interaction conservation. The relationship between in-degree and interaction conservation is driven by two different effects, namely the number of clusters that correspond to interaction interfaces and the number of domains that bind to each cluster leads to sequence specific conservation, which in turn results in interaction conservation. In summary, we uncover several network evolution mechanisms likely to generalize across peptide recognition modules.

    View details for DOI 10.1371/journal.pcbi.1002411

    View details for Web of Science ID 000302244000019

    View details for PubMedID 22438796

  • A Targeted Association Study of Immunity Genes and Networks Suggests Novel Associations with Placental Malaria Infection PLOS ONE Sikora, M., Laayouni, H., Menendez, C., Mayor, A., Bardaji, A., Sigauque, B., Netea, M. G., Casals, F., Bertranpetit, J. 2011; 6 (9)


    A large proportion of the death toll associated with malaria is a consequence of malaria infection during pregnancy, causing up to 200,000 infant deaths annually. We previously published the first extensive genetic association study of placental malaria infection, and here we extend this analysis considerably, investigating genetic variation in over 9,000 SNPs in more than 1,000 genes involved in immunity and inflammation for their involvement in susceptibility to placental malaria infection. We applied a new approach incorporating results from both single gene analysis as well as gene-gene interactions on a protein-protein interaction network. We found suggestive associations of variants in the gene KLRK1 in the single gene analysis, as well as evidence for associations of multiple members of the IL-7/IL-7R signalling cascade in the combined analysis. To our knowledge, this is the first large-scale genetic study on placental malaria infection to date, opening the door for follow-up studies trying to elucidate the genetic basis of this neglected form of malaria.

    View details for DOI 10.1371/journal.pone.0024996

    View details for Web of Science ID 000295257900043

    View details for PubMedID 21949827

  • Molecular evidence for a single evolutionary origin of domesticated rice PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Molina, J., Sikora, M., Garud, N., Flowers, J. M., Rubinstein, S., Reynolds, A., Huang, P., Jackson, S., Schaal, B. A., Bustamante, C. D., Boyko, A. R., Purugganan, M. D. 2011; 108 (20): 8351-8356


    Asian rice, Oryza sativa, is one of world's oldest and most important crop species. Rice is believed to have been domesticated ?9,000 y ago, although debate on its origin remains contentious. A single-origin model suggests that two main subspecies of Asian rice, indica and japonica, were domesticated from the wild rice O. rufipogon. In contrast, the multiple independent domestication model proposes that these two major rice types were domesticated separately and in different parts of the species range of wild rice. This latter view has gained much support from the observation of strong genetic differentiation between indica and japonica as well as several phylogenetic studies of rice domestication. We reexamine the evolutionary history of domesticated rice by resequencing 630 gene fragments on chromosomes 8, 10, and 12 from a diverse set of wild and domesticated rice accessions. Using patterns of SNPs, we identify 20 putative selective sweeps on these chromosomes in cultivated rice. Demographic modeling based on these SNP data and a diffusion-based approach provide the strongest support for a single domestication origin of rice. Bayesian phylogenetic analyses implementing the multispecies coalescent and using previously published phylogenetic sequence datasets also point to a single origin of Asian domesticated rice. Finally, we date the origin of domestication at ?8,200-13,500 y ago, depending on the molecular clock estimate that is used, which is consistent with known archaeological data that suggests rice was first cultivated at around this time in the Yangtze Valley of China.

    View details for DOI 10.1073/pnas.1104686108

    View details for Web of Science ID 000290719600056

    View details for PubMedID 21536870

  • A genomic analysis identifies a novel component in the genetic structure of sub-Saharan African populations EUROPEAN JOURNAL OF HUMAN GENETICS Sikora, M., Laayouni, H., Calafell, F., Comas, D., Bertranpetit, J. 2011; 19 (1): 84-88


    Studies of large sets of single nucleotide polymorphism (SNP) data have proven to be a powerful tool in the analysis of the genetic structure of human populations. In this work, we analyze genotyping data for 2841 SNPs in 12 sub-Saharan African populations, including a previously unsampled region of southeastern Africa (Mozambique). We show that robust results in a world-wide perspective can be obtained when analyzing only 1000 SNPs. Our main results both confirm the results of previous studies, and show new and interesting features in sub-Saharan African genetic complexity. There is a strong differentiation of Nilo-Saharans, much beyond what would be expected by geography. Hunter-gatherer populations (Khoisan and Pygmies) show a clear distinctiveness with very intrinsic Pygmy (and not only Khoisan) genetic features. Populations of the West Africa present an unexpected similarity among them, possibly the result of a population expansion. Finally, we find a strong differentiation of the southeastern Bantu population from Mozambique, which suggests an assimilation of a pre-Bantu substrate by Bantu speakers in the region.

    View details for DOI 10.1038/ejhg.2010.141

    View details for Web of Science ID 000285139600014

    View details for PubMedID 20736976

  • A variant in the gene FUT9 is associated with susceptibility to placental malaria infection HUMAN MOLECULAR GENETICS Sikora, M., Ferrer-Admetlla, A., Laayouni, H., Menendez, C., Mayor, A., Bardaji, A., Sigauque, B., Mandomando, I., Alonso, P. L., Bertranpetit, J., Casals, F. 2009; 18 (16): 3136-3144


    Malaria in pregnancy forms a substantial part of the worldwide burden of malaria, with an estimated annual death toll of up to 200 000 infants, as well as increased maternal morbidity and mortality. Studies of genetic susceptibility to malaria have so far focused on infant malaria, with only a few studies investigating the genetic basis of placental malaria, focusing only on a limited number of candidate genes. The aim of this study therefore was to identify novel host genetic factors involved in placental malaria infection. To this end we carried out a nested case-control study on 180 Mozambican pregnant women with placental malaria infection, and 180 controls within an intervention trial of malaria prevention. We genotyped 880 SNPs in a set of 64 functionally related genes involved in glycosylation and innate immunity. A single nucleotide polymorphism (SNP) located in the gene FUT9, rs3811070, was significantly associated with placental malaria infection (odds ratio = 2.31, permutation P-value=0.028). Haplotypic analysis revealed a similarly strong association of a common haplotype of four SNPs including rs3811070. FUT9 codes for a fucosyl-transferase that is catalyzing the last step in the biosynthesis of the Lewis-x antigen, which forms part of the Lewis blood group-related antigens. These results therefore suggest an involvement of this antigen in the pathogenesis of placental malaria infection.

    View details for DOI 10.1093/hmg/ddp240

    View details for Web of Science ID 000268330900018

    View details for PubMedID 19460885

  • Evolutionary analysis of genes of two pathways involved in placental malaria infection HUMAN GENETICS Sikora, M., Ferrer-Admetlla, A., Mayor, A., Bertranpetit, J., Casals, F. 2008; 123 (4): 343-357


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

    View details for DOI 10.1007/s00439-008-0483-y

    View details for Web of Science ID 000254959600003

    View details for PubMedID 18317811

  • Pulling out the 1%: Whole-Genome Capture for the Targeted Enrichment of Ancient DNA Sequencing Libraries AMERICAN JOURNAL OF HUMAN GENETICS Carpenter, M. L., Buenrostro, J. D., Valdiosera, C., Schroeder, H., Allentoft, M. E., Sikora, M., Rasmussen, M., Gravel, S., Guillen, S., Nekhrizov, G., Leshtakov, K., Dimitrova, D., Theodossiev, N., Pettener, D., Luiselli, D., Sandoval, K., Moreno-Estrada, A., Li, Y., Wang, J., Gilbert, M. T., Willerslev, E., Greenleaf, W. J., Bustamante, C. D. 2013; 93 (5): 852-864
  • Analysis of the genetic basis of disease in the context of worldwide human relationships and migration. PLoS genetics Corona, E., Chen, R., Sikora, M., Morgan, A. A., Patel, C. J., Ramesh, A., Bustamante, C. D., Butte, A. J. 2013; 9 (5)


    Genetic diversity across different human populations can enhance understanding of the genetic basis of disease. We calculated the genetic risk of 102 diseases in 1,043 unrelated individuals across 51 populations of the Human Genome Diversity Panel. We found that genetic risk for type 2 diabetes and pancreatic cancer decreased as humans migrated toward East Asia. In addition, biliary liver cirrhosis, alopecia areata, bladder cancer, inflammatory bowel disease, membranous nephropathy, systemic lupus erythematosus, systemic sclerosis, ulcerative colitis, and vitiligo have undergone genetic risk differentiation. This analysis represents a large-scale attempt to characterize genetic risk differentiation in the context of migration. We anticipate that our findings will enable detailed analysis pertaining to the driving forces behind genetic risk differentiation.

    View details for DOI 10.1371/journal.pgen.1003447

    View details for PubMedID 23717210

  • Distribution of events of positive selection and population differentiation in a metabolic pathway: the case of asparagine N-glycosylation BMC EVOLUTIONARY BIOLOGY Marco Dall'Olio, G., Laayouni, H., Luisi, P., Sikora, M., Montanucci, L., Bertranpetit, J. 2012; 12


    Asparagine N-Glycosylation is one of the most important forms of protein post-translational modification in eukaryotes. This metabolic pathway can be subdivided into two parts: an upstream sub-pathway required for achieving proper folding for most of the proteins synthesized in the secretory pathway, and a downstream sub-pathway required to give variability to trans-membrane proteins, and involved in adaptation to the environment and innate immunity. Here we analyze the nucleotide variability of the genes of this pathway in human populations, identifying which genes show greater population differentiation and which genes show signatures of recent positive selection. We also compare how these signals are distributed between the upstream and the downstream parts of the pathway, with the aim of exploring how forces of population differentiation and positive selection vary among genes involved in the same metabolic pathway but subject to different functional constraints.Our results show that genes in the downstream part of the pathway are more likely to show a signature of population differentiation, while events of positive selection are equally distributed among the two parts of the pathway. Moreover, events of positive selection are frequent on genes that are known to be at bifurcation points, and that are identified as being in key position by a network-level analysis such as MGAT3 and GCS1.These findings indicate that the upstream part of the Asparagine N-Glycosylation pathway has lower diversity among populations, while the downstream part is freer to tolerate diversity among populations. Moreover, the distribution of signatures of population differentiation and positive selection can change between parts of a pathway, especially between parts that are exposed to different functional constraints. Our results support the hypothesis that genes involved in constitutive processes can be expected to show lower population differentiation, while genes involved in traits related to the environment should show higher variability. Taken together, this work broadens our knowledge on how events of population differentiation and of positive selection are distributed among different parts of a metabolic pathway.

    View details for DOI 10.1186/1471-2148-12-98

    View details for Web of Science ID 000307937900001

    View details for PubMedID 22731960

  • Network-Level and Population Genetics Analysis of the Insulin/TOR Signal Transduction Pathway Across Human Populations MOLECULAR BIOLOGY AND EVOLUTION Luisi, P., Alvarez-Ponce, D., Marco Dall'Olio, G., Sikora, M., Bertranpetit, J., Laayouni, H. 2012; 29 (5): 1379-1392


    Genes and proteins rarely act in isolation, but they rather operate as components of complex networks of interacting molecules. Therefore, for understanding their evolution, it may be helpful to take into account the interaction networks in which they participate. It has been shown that selective constraints acting on genes depend on the position that they occupy in the network. Less understood is how the impact of local adaptation at the intraspecific level is affected by the network structure. Here, we analyzed the patterns of molecular evolution of 67 genes involved in the insulin/target of rapamycin (TOR) signal transduction pathway. This well-characterized pathway plays a key role in fundamental processes such as energetic metabolism, growth, reproduction, and aging and is involved in metabolic disorders such as obesity, insulin resistance, and diabetes. For that purpose, we combined genotype data from worldwide human populations with current knowledge of the structure and function of the pathway. We identified the footprint of recent positive selection in nine of the studied genomic regions. Most of the adaptation signals were observed among Middle East and North African, European, and Central South Asian populations. We found that positive selection preferentially targets the most central elements in the pathway, in contrast to previous observations in the whole human interactome. This observation indicates that the impact of positive selection on genes involved in the insulin/TOR pathway is affected by the pathway structure.

    View details for DOI 10.1093/molbev/msr298

    View details for Web of Science ID 000303603300008

    View details for PubMedID 22135191

  • Type 2 Diabetes Risk Alleles Demonstrate Extreme Directional Differentiation among Human Populations, Compared to Other Diseases PLOS GENETICS Chen, R., Corona, E., Sikora, M., Dudley, J. T., Morgan, A. A., Moreno-Estrada, A., Nilsen, G. B., Ruau, D., Lincoln, S. E., Bustamante, C. D., Butte, A. J. 2012; 8 (4): 100-115


    Many disease-susceptible SNPs exhibit significant disparity in ancestral and derived allele frequencies across worldwide populations. While previous studies have examined population differentiation of alleles at specific SNPs, global ethnic patterns of ensembles of disease risk alleles across human diseases are unexamined. To examine these patterns, we manually curated ethnic disease association data from 5,065 papers on human genetic studies representing 1,495 diseases, recording the precise risk alleles and their measured population frequencies and estimated effect sizes. We systematically compared the population frequencies of cross-ethnic risk alleles for each disease across 1,397 individuals from 11 HapMap populations, 1,064 individuals from 53 HGDP populations, and 49 individuals with whole-genome sequences from 10 populations. Type 2 diabetes (T2D) demonstrated extreme directional differentiation of risk allele frequencies across human populations, compared with null distributions of European-frequency matched control genomic alleles and risk alleles for other diseases. Most T2D risk alleles share a consistent pattern of decreasing frequencies along human migration into East Asia. Furthermore, we show that these patterns contribute to disparities in predicted genetic risk across 1,397 HapMap individuals, T2D genetic risk being consistently higher for individuals in the African populations and lower in the Asian populations, irrespective of the ethnicity considered in the initial discovery of risk alleles. We observed a similar pattern in the distribution of T2D Genetic Risk Scores, which are associated with an increased risk of developing diabetes in the Diabetes Prevention Program cohort, for the same individuals. This disparity may be attributable to the promotion of energy storage and usage appropriate to environments and inconsistent energy intake. Our results indicate that the differential frequencies of T2D risk alleles may contribute to the observed disparity in T2D incidence rates across ethnic populations.

    View details for DOI 10.1371/journal.pgen.1002621

    View details for Web of Science ID 000303441800007

    View details for PubMedID 22511877

  • New insights into the Tyrolean Iceman's origin and phenotype as inferred by whole-genome sequencing NATURE COMMUNICATIONS Keller, A., Graefen, A., Ball, M., Matzas, M., Boisguerin, V., Maixner, F., Leidinger, P., Backes, C., Khairat, R., Forster, M., Stade, B., Franke, A., Mayer, J., Spangler, J., McLaughlin, S., Shah, M., Lee, C., Harkins, T. T., Sartori, A., Moreno-Estrada, A., Henn, B., Sikora, M., Semino, O., Chiaroni, J., Rootsi, S., Myres, N. M., Cabrera, V. M., Underhill, P. A., Bustamante, C. D., Vigl, E. E., Samadelli, M., Cipollini, G., Haas, J., Katus, H., O'Connor, B. D., Carlson, M. R., Meder, B., Blin, N., Meese, E., Pusch, C. M., Zink, A. 2012; 3


    The Tyrolean Iceman, a 5,300-year-old Copper age individual, was discovered in 1991 on the Tisenjoch Pass in the Italian part of the Ötztal Alps. Here we report the complete genome sequence of the Iceman and show 100% concordance between the previously reported mitochondrial genome sequence and the consensus sequence generated from our genomic data. We present indications for recent common ancestry between the Iceman and present-day inhabitants of the Tyrrhenian Sea, that the Iceman probably had brown eyes, belonged to blood group O and was lactose intolerant. His genetic predisposition shows an increased risk for coronary heart disease and may have contributed to the development of previously reported vascular calcifications. Sequences corresponding to ~60% of the genome of Borrelia burgdorferi are indicative of the earliest human case of infection with the pathogen for Lyme borreliosis.

    View details for DOI 10.1038/ncomms1701

    View details for Web of Science ID 000302060100039

    View details for PubMedID 22426219

  • Genetic adaptation of the antibacterial human innate immunity network BMC EVOLUTIONARY BIOLOGY Casals, F., Sikora, M., Laayouni, H., Montanucci, L., Muntasell, A., Lazarus, R., Calafell, F., Awadalla, P., Netea, M. G., Bertranpetit, J. 2011; 11


    Pathogens have represented an important selective force during the adaptation of modern human populations to changing social and other environmental conditions. The evolution of the immune system has therefore been influenced by these pressures. Genomic scans have revealed that immune system is one of the functions enriched with genes under adaptive selection.Here, we describe how the innate immune system has responded to these challenges, through the analysis of resequencing data for 132 innate immunity genes in two human populations. Results are interpreted in the context of the functional and interaction networks defined by these genes. Nucleotide diversity is lower in the adaptors and modulators functional classes, and is negatively correlated with the centrality of the proteins within the interaction network. We also produced a list of candidate genes under positive or balancing selection in each population detected by neutrality tests and showed that some functional classes are preferential targets for selection.We found evidence that the role of each gene in the network conditions the capacity to evolve or their evolvability: genes at the core of the network are more constrained, while adaptation mostly occurred at particular positions at the network edges. Interestingly, the functional classes containing most of the genes with signatures of balancing selection are involved in autoinflammatory and autoimmune diseases, suggesting a counterbalance between the beneficial and deleterious effects of the immune response.

    View details for DOI 10.1186/1471-2148-11-202

    View details for Web of Science ID 000293852100001

    View details for PubMedID 21745391

  • Similarity in Recombination Rate Estimates Highly Correlates with Genetic Differentiation in Humans PLOS ONE Laayouni, H., Montanucci, L., Sikora, M., Mele, M., Marco Dall'Olio, G., Lorente-Galdos, B., McGee, K. M., Graffelman, J., Awadalla, P., Bosch, E., Comas, D., Navarro, A., Calafell, F., Casals, F., Bertranpetit, J. 2011; 6 (3)


    Recombination varies greatly among species, as illustrated by the poor conservation of the recombination landscape between humans and chimpanzees. Thus, shorter evolutionary time frames are needed to understand the evolution of recombination. Here, we analyze its recent evolution in humans. We calculated the recombination rates between adjacent pairs of 636,933 common single-nucleotide polymorphism loci in 28 worldwide human populations and analyzed them in relation to genetic distances between populations. We found a strong and highly significant correlation between similarity in the recombination rates corrected for effective population size and genetic differentiation between populations. This correlation is observed at the genome-wide level, but also for each chromosome and when genetic distances and recombination similarities are calculated independently from different parts of the genome. Moreover, and more relevant, this relationship is robustly maintained when considering presence/absence of recombination hotspots. Simulations show that this correlation cannot be explained by biases in the inference of recombination rates caused by haplotype sharing among similar populations. This result indicates a rapid pace of evolution of recombination, within the time span of differentiation of modern humans.

    View details for DOI 10.1371/journal.pone.0017913

    View details for Web of Science ID 000289053800005

    View details for PubMedID 21464928

  • African signatures of recent positive selection in human FOXI1 BMC EVOLUTIONARY BIOLOGY Moreno-Estrada, A., Aparicio-Prat, E., Sikora, M., Engelken, J., Ramirez-Soriano, A., Calafell, F., Bosch, E. 2010; 10


    The human FOXI1 gene codes for a transcription factor involved in the physiology of the inner ear, testis, and kidney. Using three interspecies comparisons, it has been suggested that this may be a gene under human-specific selection. We sought to confirm this finding by using an extended set of orthologous sequences. Additionally, we explored for signals of natural selection within humans by sequencing the gene in 20 Europeans, 20 East Asians and 20 Yorubas and by analysing SNP variation in a 2 Mb region centered on FOXI1 in 39 worldwide human populations from the HGDP-CEPH diversity panel.The genome sequences recently available from other primate and non-primate species showed that FOXI1 divergence patterns are compatible with neutral evolution. Sequence-based neutrality tests were not significant in Europeans, East Asians or Yorubas. However, the Long Range Haplotype (LRH) test, as well as the iHS and XP-Rsb statistics revealed significantly extended tracks of homozygosity around FOXI1 in Africa, suggesting a recent episode of positive selection acting on this gene. A functionally relevant SNP, as well as several SNPs either on the putatively selected core haplotypes or with significant iHS or XP-Rsb values, displayed allele frequencies strongly correlated with the absolute geographical latitude of the populations sampled.We present evidence for recent positive selection in the FOXI1 gene region in Africa. Climate might be related to this recent adaptive event in humans. Of the multiple functions of FOXI1, its role in kidney-mediated water-electrolyte homeostasis is the most obvious candidate for explaining a climate-related adaptation.

    View details for DOI 10.1186/1471-2148-10-267

    View details for Web of Science ID 000282768900002

    View details for PubMedID 20809947

  • A functional ABCA1 gene variant is associated with low HDL-cholesterol levels and shows evidence of positive selection in Native Americans HUMAN MOLECULAR GENETICS Acuna-Alonzo, V., Flores-Dorantes, T., Kruit, J. K., Villarreal-Molina, T., Arellano-Campos, O., Huenemeier, T., Moreno-Estrada, A., Guadalupe Ortiz-Lopez, M., Villamil-Ramirez, H., Leon-Mimila, P., Villalobos-Comparan, M., Jacobo-Albavera, L., Ramirez-Jimenez, S., Sikora, M., Zhang, L., Pape, T. D., de Angeles Granados-Silvestre, M., Montufar-Robles, I., Tito-Alvarez, A. M., Zurita-Salinas, C., Bustos-Arriaga, J., Cedillo-Barron, L., Gomez-Trejo, C., Barquera-Lozano, R., Vieira-Filho, J. P., Granados, J., Romero-Hidalgo, S., Huertas-Vazquez, A., Gonzalez-Martin, A., Gorostiza, A., Bonatto, S. L., Rodriguez-Cruz, M., Wang, L., Tusie-Luna, T., Aguilar-Salinas, C. A., Lisker, R., Moises, R. S., Menjivar, M., Salzano, F. M., Knowler, W. C., Catira Bortolini, M., Hayden, M. R., Baier, L. J., Canizales-Quinteros, S. 2010; 19 (14): 2877-2885


    It has been suggested that the higher susceptibility of Hispanics to metabolic disease is related to their Native American heritage. A frequent cholesterol transporter ABCA1 (ATP-binding cassette transporter A1) gene variant (R230C, rs9282541) apparently exclusive to Native American individuals was associated with low high-density lipoprotein cholesterol (HDL-C) levels, obesity and type 2 diabetes in Mexican Mestizos. We performed a more extensive analysis of this variant in 4405 Native Americans and 863 individuals from other ethnic groups to investigate genetic evidence of positive selection, to assess its functional effect in vitro and to explore associations with HDL-C levels and other metabolic traits. The C230 allele was found in 29 of 36 Native American groups, but not in European, Asian or African individuals. C230 was observed on a single haplotype, and C230-bearing chromosomes showed longer relative haplotype extension compared with other haplotypes in the Americas. Additionally, single-nucleotide polymorphism data from the Human Genome Diversity Panel Native American populations were enriched in significant integrated haplotype score values in the region upstream of the ABCA1 gene. Cells expressing the C230 allele showed a 27% cholesterol efflux reduction (P< 0.001), confirming this variant has a functional effect in vitro. Moreover, the C230 allele was associated with lower HDL-C levels (P = 1.77 x 10(-11)) and with higher body mass index (P = 0.0001) in the combined analysis of Native American populations. This is the first report of a common functional variant exclusive to Native American and descent populations, which is a major determinant of HDL-C levels and may have contributed to the adaptive evolution of Native American populations.

    View details for DOI 10.1093/hmg/ddq173

    View details for Web of Science ID 000279469100012

    View details for PubMedID 20418488

  • Sequence variation and genetic evolution at the human F12 locus: mapping quantitative trait nucleotides that influence FXII plasma levels HUMAN MOLECULAR GENETICS Calafell, F., Almasy, L., Sabater-Lleal, M., Buil, A., Mordillo, C., Ramirez-Soriano, A., Sikora, M., Carlos Souto, J., Blangero, J., Fontcuberta, J., Manuel Soria, J. 2010; 19 (3): 517-525


    The level of Factor XII (FXII) is an important phenotype that exhibits a high genetic component and is associated with thrombotic disease. In a genome-wide linkage scan, we demonstrated that the F12 gene represents a quantitative trait locus (QTL) that influences FXII levels. The current study investigated the genetic architecture of the F12 gene to locate polymorphism(s) responsible for the variation of FXII levels. Re-sequencing of the F12 gene in 40 unrelated individuals (selected from the tails of normal distribution of FXII levels) identified 26 polymorphisms which were genotyped in 398 individuals belonging to 21 families from the GAIT Project. By a measured genotype association analysis, eight of 26 SNPs showed significant P-values less than 10(-5) (after multiple test correction) with FXII levels. In addition, the Bayesian Quantitative Trait Nucleotide method, which infers those polymorphisms most likely to have a direct influence on the trait under study, provided evidence that only rs1801020 variation accounted for the variance attributed to this QTL. Moreover, we have analyzed the evolutionary processes that produced the variation in F12 gene and concluded that is evolutionarily neutral and that the T allele of the rs1801020 appeared approximately 100 000 years ago and spread to most human populations rising to high frequencies by genetic drift. Our study provides a template for future genetic studies of human quantitative traits, as we move beyond QTL localization to the polymorphisms responsible for the variation of important biomedical phenotypes.

    View details for DOI 10.1093/hmg/ddp517

    View details for Web of Science ID 000273227200011

    View details for PubMedID 19933701

  • Interrogating 11 Fast-Evolving Genes for Signatures of Recent Positive Selection in Worldwide Human Populations MOLECULAR BIOLOGY AND EVOLUTION Moreno-Estrada, A., Tang, K., Sikora, M., Marques-Bonet, T., Casals, F., Navarro, A., Calafell, F., Bertranpetit, J., Stoneking, M., Bosch, E. 2009; 26 (10): 2285-2297


    Different signatures of natural selection persist over varying time scales in our genome, revealing possible episodes of adaptative evolution during human history. Here, we identify genes showing signatures of ancestral positive selection in the human lineage and investigate whether some of those genes have been evolving adaptatively in extant human populations. Specifically, we compared more than 11,000 human genes with their orthologs in chimpanzee, mouse, rat, and dog and applied a branch-site likelihood method to test for positive selection on the human lineage. Among the significant cases, a robust set of 11 genes was then further explored for signatures of recent positive selection using single nucleotide polymorphism (SNP) data. We genotyped 223 SNPs in 39 worldwide populations from the HGDP-CEPH diversity panel and supplemented this information with available genotypes for up to 4,814 SNPs distributed along 2 Mb centered on each gene. After exploring the allele frequency spectrum, population differentiation and the maintenance of long unbroken haplotypes, we found signals of recent adaptative phenomena in only one of the 11 candidate gene regions. However, the signal of recent selection in this region may come from a different, neighboring gene (CD5) rather than from the candidate gene itself (VPS37C). For this set of positively selected genes in the human lineage, we find no indication that these genes maintained their rapid evolutionary pace among human populations. Based on these data, it therefore appears that adaptation for human-specific and for population-specific traits may have involved different genes.

    View details for DOI 10.1093/molbev/msp134

    View details for Web of Science ID 000270268900013

    View details for PubMedID 19578157

  • A Natural History of FUT2 Polymorphism in Humans MOLECULAR BIOLOGY AND EVOLUTION Ferrer-Admetlla, A., Sikora, M., Laayouni, H., Esteve, A., Roubinet, F., Blancher, A., Calafell, F., Bertranpetit, J., Casals, F. 2009; 26 (9): 1993-2003


    Because pathogens are powerful selective agents, host-cell surface molecules used by pathogens as identification signals can reveal the signature of selection. Most of them are oligosaccharides, synthesized by glycosyltransferases. One known example is balancing selection shaping ABO evolution as a consequence of both, A and B antigens being recognized as receptors by some pathogens, and anti-A and/or anti-B natural antibodies produced by hosts conferring protection against the numerous infectious agents expressing A and B motifs. These antigens can also be found in tissues other than blood if there is activity of another enzyme, FUT2, a fucosyltransferase responsible for ABO biosynthesis in body fluids. Homozygotes for null variants at this locus present the nonsecretor phenotype (se), because they cannot express ABO antigens in secretions. Multiple independent mutations have been shown to be responsible for the nonsecretor phenotype, which is coexisting with the secretor phenotype in most populations. In this study, we have resequenced the coding region of FUT2 in 732 individuals from 39 worldwide human populations. We report a complex pattern of natural selection acting on the gene. Although frequencies of secretor and nonsecretor phenotypes are similar in different populations, the point mutations at the base of the phenotypes are different, with some variants showing a long history of balancing selection among Eurasian and African populations, and one recent variant showing a fast spread in East Asia, likely due to positive selection. Thus, a convergent phenotype composition has been achieved through different mutations with different evolutionary histories.

    View details for DOI 10.1093/molbev/msp108

    View details for Web of Science ID 000269001500006

    View details for PubMedID 19487333

  • Human pseudogenes of the ABO family show a complex evolutionary dynamics and loss of function GLYCOBIOLOGY Casals, F., Ferrer-Admetlla, A., Sikora, M., Ramirez-Soriano, A., Marques-Bonet, T., Despiau, S., Roubinet, F., Calafell, F., Bertranpetit, J., Blancher, A. 2009; 19 (6): 583-591


    The GT6 glycosyltransferases gene family, that includes the ABO blood group, shows a complex evolution pattern, with multiple events of gain and loss in different mammal species. In humans the ABO gene is considered the sole functional member although the O allele is null and is fixed in certain populations. Here, we analyze the human GT6 pseudogene sequences (Forssman, IGB3, GGTA1, GT6m5, GT6m6, and GT6m7) from an evolutionary perspective, by the study of (i) their diversity levels in populations through the resequencing analysis of European and African individuals; (ii) the interpopulation differentiation, with genotyping data from a survey of populations covering most of human genetic diversity; and (iii) the interespecific divergence, by the comparison of the human and some other primate species sequences. Since pseudogenes are expected to evolve under neutrality, they should show an evolutionary pattern different to that of functional sequences, with higher levels of diversity as well as a ratio of nonsynonymous to synonymous changes close to 1. We describe some departures from these expectations, including selection for inactivation in IGB3, GGTA1, and the interesting case of FS (Forssman) with a probable shift of its initial function in the primate lineage, which put it apart from a pure neutral pseudogene. These results suggest that some of these GT6 human pseudogenes may still be functional and retain some valuable unknown function in humans, in some case even at the protein level. The evolutionary analysis of all members of the GT6 family in humans allows an insight into their functional history, a process likely due to the interaction of the host glycans that they synthesize with pathogens; the past process that can be unraveled through the footprints left by natural selection in the extant genome variation.

    View details for DOI 10.1093/glycob/cwp017

    View details for Web of Science ID 000266117300005

    View details for PubMedID 19218399

  • Balancing selection is the main force shaping the evolution of innate immunity genes JOURNAL OF IMMUNOLOGY Ferrer-Admetlla, A., Bosch, E., Sikora, M., Marques-Bonet, T., Ramirez-Soriano, A., Muntasell, A., Navarro, A., Lazarus, R., Calafell, F., Bertranpetit, J., Casals, F. 2008; 181 (2): 1315-1322


    The evolutionarily recent geographic expansion of humans, and the even more recent development of large, relatively dense human settlements, has exposed our species to new pathogenic environments. Potentially lethal pathogens are likely to have exerted important selective pressures on our genome, so immunity genes can be expected to show molecular signatures of the adaptation of human populations to these recent conditions. While genes related to the acquired immunity system have indeed been reported to show traces of local adaptation, little is known about the response of the innate immunity system. In this study, we analyze the variability patterns in different human populations of fifteen genes related to innate immunity. We have used both single nucleotide polymorphism and sequence data, and through the analysis of interpopulation differentiation, the linkage disequilibrium pattern, and intrapopulation diversity, we have discovered some signatures of positive and especially balancing selection in these genes, thus confirming the importance of the immune system genetic plasticity in the evolutionary adaptive process. Interestingly, the strongest evidence is found in three TLR genes and CD14. These innate immunity genes play a pivotal role, being involved in the primary recognition of pathogens. In general, more evidences of selection appear in the European populations, in some case possibly related to severe population specific pressures. However, we also describe evidence from African populations, which may reflect parallel or long-term selective forces acting in different geographic areas.

    View details for Web of Science ID 000257958800053

    View details for PubMedID 18606686

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