Current Role at Stanford

Basic Life Science Research Associate
Bustamante Lab, Genetics Department

Honors & Awards

  • George Rosenkranz Prize for Health Care Research in Developing Countries, Stanford University (2012)

Education & Certifications

  • PhD, Pompeu Fabra University (Spain), Genetics (2009)
  • Medical Doctor, University of Guadalajara (Mexico), Medicine (2002)

Personal Interests

I am a Medical Doctor by training and have a strong interest in understanding patterns of human genetic variation and its implications in health and disease, evolution, and population history reconstruction. After graduating from the University of Guadalajara School of Medicine in 2002, I moved from Mexico to Barcelona, Spain to pursue a PhD in Evolutionary Biology and Population Genetics, which I received from the Pompeu Fabra University in 2009.

I joined the Bustamante Lab at Stanford University in January 2010, where I got the opportunity to focus my research on population genomics in the Americas. My current work involves the use of genome-wide data sets to study fine-scale patterns of population structure in both Native Americans and Hispanic/Latino populations from throughout the Americas. One of the major goals is to better understand the evolutionary processes, including natural selection, that have shaped Native American genomes during the last ~10,000 years of independent evolution since the peopling of the Americas and before the European contact.

The other major goal is aimed at understanding the dynamics of the admixture process in present day Hispanic/Latino populations since the European contact. By applying methods of local ancestry estimation we are trying to trace back ancestry-specific segments of the genome to their potential source populations at the sub-continental level. Defining patterns of local variation and sub-continental ancestry in admixed populations and individual genomes is also allowing the field to move towards a more personalized view of medical genomics and to promote the study of diverse populations underrepresented in current catalogs of human variation.


Professional Interests

Human Population Genetics, Evolutionary Biology, Genomic Medicine

Work Experience

  • PhD Fellow, Universitat Pompeu Fabra (10/1/2003 - 4/30/2009)

    Thesis Title: Analysis of Human Genetic Variation in Candidate Genes under Positive Selection on the Human Lineage
    Thesis Director: Elena Bosch
    Institute of Evolutionary Biology, Bertranpetit Lab


    Barcelona, Spain

  • Visiting Grad Student, Max Planck Institute for Evolutionary Anthropology (10/1/2007 - 5/1/2008)

    Dept. of Evolutionary Genetics, Stoneking Lab


    Leipzig, Germany

  • Visiting Scholar, University College London (5/1/2009 - 9/15/2009)

    Dept. of Genetics and Evolution, Ruiz-Linares Lab


    London, UK

  • Postdoctoral Scholar, Cornell University (10/1/2009 - 12/31/2009)

    Dept. of Biological Statistics and Computational Biology, Bustamante Lab


    Ithaca, NY

  • Research Associate, Stanford University (3/1/2012 - Present)

    Dept. of Genetics, Bustamante Lab


    Stanford, CA


Journal Articles

  • HUMAN GENETICS The genetics of Mexico recapitulates Native American substructure and affects biomedical traits SCIENCE Moreno-Estrada, A., Gignoux, C. R., Carlos Fernandez-Lopez, J., Zakharia, F., Sikora, M., Contreras, A. V., Acuna-Alonzo, V., Sandoval, K., Eng, C., Romero-Hidalgo, S., Ortiz-Tello, P., Robles, V., Kenny, E. E., Nuno-Arana, I., Barquera-Lozano, R., Macin-Perez, G., Granados-Arriola, J., Huntsman, S., Galanter, J. M., Via, M., Ford, J. G., Chapela, R., Rodriguez-Cintron, W., Rodriguez-Santana, J. R., Romieu, I., Jose Sienra-Monge, J., del Rio Navarro, B., London, S. J., Ruiz-Linares, A., Garcia-Herrera, R., Estrada, K., Hidalgo-Miranda, A., Jimenez-Sanchez, G., Carnevale, A., Soberon, X., Canizales-Quinteros, S., Rangel-Villalobos, H., Silva-Zolezzi, I., Burchard, E. G., Bustamante, C. D. 2014; 344 (6189): 1280-1285


    Mexico harbors great cultural and ethnic diversity, yet fine-scale patterns of human genome-wide variation from this region remain largely uncharacterized. We studied genomic variation within Mexico from over 1000 individuals representing 20 indigenous and 11 mestizo populations. We found striking genetic stratification among indigenous populations within Mexico at varying degrees of geographic isolation. Some groups were as differentiated as Europeans are from East Asians. Pre-Columbian genetic substructure is recapitulated in the indigenous ancestry of admixed mestizo individuals across the country. Furthermore, two independently phenotyped cohorts of Mexicans and Mexican Americans showed a significant association between subcontinental ancestry and lung function. Thus, accounting for fine-scale ancestry patterns is critical for medical and population genetic studies within Mexico, in Mexican-descent populations, and likely in many other populations worldwide.

    View details for DOI 10.1126/science.1251688

    View details for Web of Science ID 000337077500040

    View details for PubMedID 24926019

  • Reconstructing Native American Migrations from Whole-Genome and Whole-Exome Data PLOS GENETICS Gravel, S., Zakharia, F., Moreno-Estrada, A., Byrnes, J. K., Muzzio, M., Rodriguez-Flores, J. L., Kenny, E. E., Gignoux, C. R., Maples, B. K., Guiblet, W., Dutil, J., Via, M., Sandoval, K., Bedoya, G., Oleksyk, T. K., Ruiz-Linares, A., Burchard, E. G., Martinez-Cruzado, J. C., Bustamante, C. D. 2013; 9 (12)
  • Reconstructing the Population Genetic History of the Caribbean PLOS GENETICS Moreno-Estrada, A., Gravel, S., Zakharia, F., McCauley, J. L., Byrnes, J. K., Gignoux, C. R., Ortiz-Tello, P. A., Martinez, R. J., Hedges, D. J., Morris, R. W., Eng, C., Sandoval, K., Acevedo-Acevedo, S., Norman, P. J., Layrisse, Z., Parham, P., Martinez-Cruzado, J. C., Burchard, E. G., Cuccaro, M. L., Martin, E. R., Bustamante, C. D. 2013; 9 (11)
  • Y-chromosome diversity in Native Mexicans reveals continental transition of genetic structure in the Americas AMERICAN JOURNAL OF PHYSICAL ANTHROPOLOGY Sandoval, K., Moreno-Estrada, A., Mendizabal, I., Underhill, P. A., Lopez-Valenzuela, M., Penaloza-Espinosa, R., Lopez-Lopez, M., Buentello-Malo, L., Avelino, H., Calafell, F., Comas, D. 2012; 148 (3): 395-405


    The genetic characterization of Native Mexicans is important to understand multiethnic based features influencing the medical genetics of present Mexican populations, as well as to the reconstruct the peopling of the Americas. We describe the Y-chromosome genetic diversity of 197 Native Mexicans from 11 populations and 1,044 individuals from 44 Native American populations after combining with publicly available data. We found extensive heterogeneity among Native Mexican populations and ample segregation of Q-M242* (46%) and Q-M3 (54%) haplogroups within Mexico. The northernmost sampled populations falling outside Mesoamerica (Pima and Tarahumara) showed a clear differentiation with respect to the other populations, which is in agreement with previous results from mtDNA lineages. However, our results point toward a complex genetic makeup of Native Mexicans whose maternal and paternal lineages reveal different narratives of their population history, with sex-biased continental contributions and different admixture proportions. At a continental scale, we found that Arctic populations and the northernmost groups from North America cluster together, but we did not find a clear differentiation within Mesoamerica and the rest of the continent, which coupled with the fact that the majority of individuals from Central and South American samples are restricted to the Q-M3 branch, supports the notion that most Native Americans from Mesoamerica southwards are descendants from a single wave of migration. This observation is compatible with the idea that present day Mexico might have constituted an area of transition in the diversification of paternal lineages during the colonization of the Americas.

    View details for DOI 10.1002/ajpa.22062

    View details for Web of Science ID 000305327600010

    View details for PubMedID 22576278

  • Genome-wide patterns of population structure and admixture among Hispanic/Latino populations PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Bryc, K., Velez, C., Karafet, T., Moreno-Estrada, A., Reynolds, A., Auton, A., Hammer, M., Bustamante, C. D., Ostrer, H. 2010; 107: 8954-8961


    Hispanic/Latino populations possess a complex genetic structure that reflects recent admixture among and potentially ancient substructure within Native American, European, and West African source populations. Here, we quantify genome-wide patterns of SNP and haplotype variation among 100 individuals with ancestry from Ecuador, Colombia, Puerto Rico, and the Dominican Republic genotyped on the Illumina 610-Quad arrays and 112 Mexicans genotyped on Affymetrix 500K platform. Intersecting these data with previously collected high-density SNP data from 4,305 individuals, we use principal component analysis and clustering methods FRAPPE and STRUCTURE to investigate genome-wide patterns of African, European, and Native American population structure within and among Hispanic/Latino populations. Comparing autosomal, X and Y chromosome, and mtDNA variation, we find evidence of a significant sex bias in admixture proportions consistent with disproportionate contribution of European male and Native American female ancestry to present-day populations. We also find that patterns of linkage-disequilibria in admixed Hispanic/Latino populations are largely affected by the admixture dynamics of the populations, with faster decay of LD in populations of higher African ancestry. Finally, using the locus-specific ancestry inference method LAMP, we reconstruct fine-scale chromosomal patterns of admixture. We document moderate power to differentiate among potential subcontinental source populations within the Native American, European, and African segments of the admixed Hispanic/Latino genomes. Our results suggest future genome-wide association scans in Hispanic/Latino populations may require correction for local genomic ancestry at a subcontinental scale when associating differences in the genome with disease risk, progression, and drug efficacy, as well as for admixture mapping.

    View details for DOI 10.1073/pnas.0914618107

    View details for Web of Science ID 000277553800009

  • Genetic ancestry influences asthma susceptibility and lung function among Latinos. journal of allergy and clinical immunology Pino-Yanes, M., Thakur, N., Gignoux, C. R., Galanter, J. M., Roth, L. A., Eng, C., Nishimura, K. K., Oh, S. S., Vora, H., Huntsman, S., Nguyen, E. A., Hu, D., Drake, K. A., Conti, D. V., Moreno-Estrada, A., Sandoval, K., Winkler, C. A., Borrell, L. N., Lurmann, F., Islam, T. S., Davis, A., Farber, H. J., Meade, K., Avila, P. C., Serebrisky, D., Bibbins-Domingo, K., LeNoir, M. A., Ford, J. G., Brigino-Buenaventura, E., Rodriguez-Cintron, W., Thyne, S. M., Sen, S., Rodriguez-Santana, J. R., Bustamante, C. D., Williams, L. K., Gilliland, F. D., Gauderman, W. J., Kumar, R., Torgerson, D. G., Burchard, E. G. 2015; 135 (1): 228-235


    Childhood asthma prevalence and morbidity varies among Latinos in the United States, with Puerto Ricans having the highest and Mexicans the lowest.To determine whether genetic ancestry is associated with the odds of asthma among Latinos, and secondarily whether genetic ancestry is associated with lung function among Latino children.We analyzed 5493 Latinos with and without asthma from 3 independent studies. For each participant, we estimated the proportion of African, European, and Native American ancestry using genome-wide data. We tested whether genetic ancestry was associated with the presence of asthma and lung function among subjects with and without asthma. Odds ratios (OR) and effect sizes were assessed for every 20% increase in each ancestry.Native American ancestry was associated with lower odds of asthma (OR = 0.72, 95% CI: 0.66-0.78, P = 8.0 × 10(-15)), while African ancestry was associated with higher odds of asthma (OR = 1.40, 95% CI: 1.14-1.72, P = .001). These associations were robust to adjustment for covariates related to early life exposures, air pollution, and socioeconomic status. Among children with asthma, African ancestry was associated with lower lung function, including both pre- and post-bronchodilator measures of FEV1 (-77 ± 19 mL; P = 5.8 × 10(-5) and -83 ± 19 mL; P = 1.1 x 10(-5), respectively) and forced vital capacity (-100 ± 21 mL; P = 2.7 × 10(-6) and -107 ± 22 mL; P = 1.0 x 10(-6), respectively).Differences in the proportions of genetic ancestry can partially explain disparities in asthma susceptibility and lung function among Latinos.

    View details for DOI 10.1016/j.jaci.2014.07.053

    View details for PubMedID 25301036

  • Population Genomic Analysis of Ancient and Modern Genomes Yields New Insights into the Genetic Ancestry of the Tyrolean Iceman and the Genetic Structure of Europe PLOS GENETICS Sikora, M., Carpenter, M. L., Moreno-Estrada, A., Henn, B. M., Underhill, P. A., Sanchez-Quinto, F., Zara, I., Pitzalis, M., Sidore, C., Busonero, F., Maschio, A., Angius, A., Jones, C., Mendoza-Revilla, J., Nekhrizov, G., Dimitrova, D., Theodossiev, N., Harkins, T. T., Keller, A., Maixner, F., Zink, A., Abecasis, G., Sanna, S., Cucca, F., Bustamante, C. D. 2014; 10 (5)
  • A genome-wide association study of bronchodilator response in Latinos implicates rare variants. journal of allergy and clinical immunology Drake, K. A., Torgerson, D. G., Gignoux, C. R., Galanter, J. M., Roth, L. A., Huntsman, S., Eng, C., Oh, S. S., Yee, S. W., Lin, L., Bustamante, C. D., Moreno-Estrada, A., Sandoval, K., Davis, A., Borrell, L. N., Farber, H. J., Kumar, R., Avila, P. C., Brigino-Buenaventura, E., Chapela, R., Ford, J. G., LeNoir, M. A., Lurmann, F., Meade, K., Serebrisky, D., Thyne, S., Rodríguez-Cintrón, W., Sen, S., Rodríguez-Santana, J. R., Hernandez, R. D., Giacomini, K. M., Burchard, E. G. 2014; 133 (2): 370-378


    The primary rescue medication to treat acute asthma exacerbation is the short-acting β₂-adrenergic receptor agonist; however, there is variation in how well a patient responds to treatment. Although these differences might be due to environmental factors, there is mounting evidence for a genetic contribution to variability in bronchodilator response (BDR).To identify genetic variation associated with bronchodilator drug response in Latino children with asthma.We performed a genome-wide association study (GWAS) for BDR in 1782 Latino children with asthma using standard linear regression, adjusting for genetic ancestry and ethnicity, and performed replication studies in an additional 531 Latinos. We also performed admixture mapping across the genome by testing for an association between local European, African, and Native American ancestry and BDR, adjusting for genomic ancestry and ethnicity.We identified 7 genetic variants associated with BDR at a genome-wide significant threshold (P < 5 × 10(-8)), all of which had frequencies of less than 5%. Furthermore, we observed an excess of small P values driven by rare variants (frequency, <5%) and by variants in the proximity of solute carrier (SLC) genes. Admixture mapping identified 5 significant peaks; fine mapping within these peaks identified 2 rare variants in SLC22A15 as being associated with increased BDR in Mexicans. Quantitative PCR and immunohistochemistry identified SLC22A15 as being expressed in the lung and bronchial epithelial cells.Our results suggest that rare variation contributes to individual differences in response to albuterol in Latinos, notably in SLC genes that include membrane transport proteins involved in the transport of endogenous metabolites and xenobiotics. Resequencing in larger, multiethnic population samples and additional functional studies are required to further understand the role of rare variation in BDR.

    View details for DOI 10.1016/j.jaci.2013.06.043

    View details for PubMedID 23992748

  • 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
  • Factors associated with degree of atopy in Latino children in a nationwide pediatric sample: The Genes-environments and Admixture in Latino Asthmatics (GALA II) study JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Kumar, R., Nguyen, E. A., Roth, L. A., Oh, S. S., Gignoux, C. R., Huntsman, S., Eng, C., Moreno-Estrada, A., Sandoval, K., Penaloza-Espinosa, R. I., Lopez-Lopez, M., Avila, P. C., Farber, H. J., Tcheurekdjian, H., Rodriguez-Cintron, W., Rodriguez-Santana, J. R., Serebrisky, D., Thyne, S. M., Williams, L. K., Winkler, C., Bustamante, C. D., Perez-Stable, E. J., Borrell, L. N., Burchard, E. G. 2013; 132 (4): 896-?


    BACKGROUND: Atopy varies by ethnicity, even within Latino groups. This variation might be due to environmental, sociocultural, or genetic factors. OBJECTIVE: We sought to examine risk factors for atopy within a nationwide study of US Latino children with and without asthma. METHODS: Aeroallergen skin test responses were analyzed in 1830 US Latino subjects. Key determinants of atopy included country/region of origin, generation in the United States, acculturation, genetic ancestry, and site to which subjects migrated. Serial multivariate zero-inflated negative binomial regressions stratified by asthma status examined the association of each key determinant variable with the number of positive skin test responses. In addition, the independent effect of each key variable was determined by including all key variables in the final models. RESULTS: In baseline analyses African ancestry was associated with 3 times (95% CI, 1.62-5.57) as many positive skin test responses in asthmatic participants and 3.26 times (95% CI, 1.02-10.39) as many positive skin test responses in control participants. Generation and recruitment site were also associated with atopy in crude models. In final models adjusted for key variables, asthmatic patients of Puerto Rican (exp[β] [95% CI], 1.31 [1.02-1.69]) and mixed (exp[β] [95% CI], 1.27 [1.03-1.56]) ethnicity had a greater probability of positive skin test responses compared with Mexican asthmatic patients. Ancestry associations were abrogated by recruitment site but not region of origin. CONCLUSIONS: Puerto Rican ethnicity and mixed origin were associated with degree of atopy within US Latino children with asthma. African ancestry was not associated with degree of atopy after adjusting for recruitment site. Local environment variation, represented by site, was associated with degree of sensitization.

    View details for DOI 10.1016/j.jaci.2013.02.046

    View details for Web of Science ID 000325096500017

    View details for PubMedID 23684070

  • An integrated map of genetic variation from 1,092 human genomes NATURE Altshuler, D. M., Durbin, R. M., Abecasis, G. R., Bentley, D. R., Chakravarti, A., Clark, A. G., Donnelly, P., Eichler, E. E., Flicek, P., Gabriel, S. B., Gibbs, R. A., Green, E. D., Hurles, M. E., Knoppers, B. M., Korbel, J. O., Lander, E. S., Lee, C., Lehrach, H., Mardis, E. R., Marth, G. T., McVean, G. A., Nickerson, D. A., Schmidt, J. P., Sherry, S. T., Wang, J., Wilson, R. K., Gibbs, R. A., Dinh, H., Kovar, C., Lee, S., Lewis, L., Muzny, D., Reid, J., Wang, M., Wang, J., Fang, X., Guo, X., Jian, M., Jiang, H., Jin, X., Li, G., Li, J., Li, Y., Li, Z., Liu, X., Lu, Y., Ma, X., Su, Z., Tai, S., Tang, M., Wang, B., Wang, G., Wu, H., Wu, R., Yin, Y., Zhang, W., Zhao, J., Zhao, M., Zheng, X., Zhou, Y., Lander, E. S., Altshuler, D. M., Gabriel, S. B., Gupta, N., Flicek, P., Clarke, L., Leinonen, R., Smith, R. E., Zheng-Bradley, X., Bentley, D. R., Grocock, R., Humphray, S., James, T., Kingsbury, Z., Lehrach, H., Sudbrak, R., Albrecht, M. W., Amstislavskiy, V. S., Borodina, T. A., Lienhard, M., Mertes, F., Sultan, M., Timmermann, B., Yaspo, M., Sherry, S. T., McVean, G. A., Mardis, E. R., Wilson, R. K., Fulton, L., Fulton, R., Weinstock, G. M., Durbin, R. M., Balasubramaniam, S., Burton, J., Danecek, P., Keane, T. M., Kolb-Kokocinski, A., McCarthy, S., Stalker, J., Quail, M., Schmidt, J. P., Davies, C. J., Gollub, J., Webster, T., Wong, B., Zhan, Y., Auton, A., Gibbs, R. A., Yu, F., Bainbridge, M., Challis, D., Evani, U. S., Lu, J., Muzny, D., Nagaswamy, U., Reid, J., Sabo, A., Wang, Y., Yu, J., Wang, J., Coin, L. J., Fang, L., Guo, X., Jin, X., Li, G., Li, Q., Li, Y., Li, Z., Lin, H., Liu, B., Luo, R., Qin, N., Shao, H., Wang, B., Xie, Y., Ye, C., Yu, C., Zhang, F., Zheng, H., Zhu, H., Marth, G. T., Garrison, E. P., Kural, D., Lee, W., Leong, W. F., Ward, A. N., Wu, J., Zhang, M., Lee, C., Griffin, L., Hsieh, C., Mills, R. E., Shi, X., von Grotthuss, M., Zhang, C., Daly, M. J., DePristo, M. A., Altshuler, D. M., Banks, E., Bhatia, G., Carneiro, M. O., del Angel, G., Gabriel, S. B., Genovese, G., Gupta, N., Handsaker, R. E., Hartl, C., Lander, E. S., McCarroll, S. A., Nemesh, J. C., Poplin, R. E., Schaffner, S. F., Shakir, K., Yoon, S. C., Lihm, J., Makarov, V., Jin, H., Kim, W., Kim, K. C., Korbel, J. O., Rausch, T., Flicek, P., Beal, K., Clarke, L., Cunningham, F., Herrero, J., McLaren, W. M., Ritchie, G. R., Smith, R. E., Zheng-Bradley, X., Clark, A. G., Gottipati, S., Keinan, A., Rodriguez-Flores, J. L., Sabeti, P. C., Grossman, S. R., Tabrizi, S., Tariyal, R., Cooper, D. N., Ball, E. V., Stenson, P. D., Bentley, D. R., Barnes, B., Bauer, M., Cheetham, R. K., Cox, T., Eberle, M., Humphray, S., Kahn, S., Murray, L., Peden, J., Shaw, R., Ye, K., Batzer, M. A., Konkel, M. K., Walker, J. A., MacArthur, D. G., Lek, M., Sudbrak, R., Amstislavskiy, V. S., Herwig, R., Shriver, M. D., Bustamante, C. D., Byrnes, J. K., De La Vega, F. M., Gravel, S., Kenny, E. E., Kidd, J. M., Lacroute, P., Maples, B. K., Moreno-Estrada, A., Zakharia, F., Halperin, E., Baran, Y., Craig, D. W., Christoforides, A., Homer, N., Izatt, T., Kurdoglu, A. A., Sinari, S. A., Squire, K., Sherry, S. T., Xiao, C., Sebat, J., Bafna, V., Ye, K., Burchard, E. G., Hernandez, R. D., Gignoux, C. R., Haussler, D., Katzman, S. J., Kent, W. J., Howie, B., Ruiz-Linares, A., Dermitzakis, E. T., Lappalainen, T., Devine, S. E., Liu, X., Maroo, A., Tallon, L. J., Rosenfeld, J. A., Michelson, L. P., Abecasis, G. R., Kang, H. M., Anderson, P., Angius, A., Bigham, A., Blackwell, T., Busonero, F., Cucca, F., Fuchsberger, C., Jones, C., Jun, G., Li, Y., Lyons, R., Maschio, A., Porcu, E., Reinier, F., Sanna, S., Schlessinger, D., Sidore, C., Tan, A., Trost, M. K., Awadalla, P., Hodgkinson, A., Lunter, G., McVean, G. A., Marchini, J. L., Myers, S., Churchhouse, C., Delaneau, O., Gupta-Hinch, A., Iqbal, Z., Mathieson, I., Rimmer, A., Xifara, D. K., Oleksyk, T. K., Fu, Y., Liu, X., Xiong, M., Jorde, L., Witherspoon, D., Xing, J., Eichler, E. E., Browning, B. L., Alkan, C., Hajirasouliha, I., Hormozdiari, F., Ko, A., Sudmant, P. H., Mardis, E. R., Chen, K., Chinwalla, A., Ding, L., Dooling, D., Koboldt, D. C., McLellan, M. D., Wallis, J. W., Wendl, M. C., Zhang, Q., Durbin, R. M., Hurles, M. E., Tyler-Smith, C., Albers, C. A., Ayub, Q., Balasubramaniam, S., Chen, Y., Coffey, A. J., Colonna, V., Danecek, P., Huang, N., Jostins, L., Keane, T. M., Li, H., McCarthy, S., Scally, A., Stalker, J., Walter, K., Xue, Y., Zhang, Y., Gerstein, M. B., Abyzov, A., Balasubramanian, S., Chen, J., Clarke, D., Fu, Y., Habegger, L., Harmanci, A. O., Jin, M., Khurana, E., Mu, X. J., Sisu, C., Li, Y., Luo, R., Zhu, H., Lee, C., Griffin, L., Hsieh, C., Mills, R. E., Shi, X., von Grotthuss, M., Zhang, C., Marth, G. T., Garrison, E. P., Kural, D., Lee, W., Ward, A. N., Wu, J., Zhang, M., McCarroll, S. A., Altshuler, D. M., Banks, E., del Angel, G., Genovese, G., Handsaker, R. E., Hartl, C., Nemesh, J. C., Shakir, K., Yoon, S. C., Lihm, J., Makarov, V., Degenhardt, J., Flicek, P., Clarke, L., Smith, R. E., Zheng-Bradley, X., Korbel, J. O., Rausch, T., Stuetz, A. M., Bentley, D. R., Barnes, B., Cheetham, R. K., Eberle, M., Humphray, S., Kahn, S., Murray, L., Shaw, R., Ye, K., Batzer, M. A., Konkel, M. K., Walker, J. A., Lacroute, P., Craig, D. W., Homer, N., Church, D., Xiao, C., Sebat, J., Bafna, V., Michaelson, J. J., Ye, K., Devine, S. E., Liu, X., Maroo, A., Tallon, L. J., Lunter, G., McVean, G. A., Iqbal, Z., Witherspoon, D., Xing, J., Eichler, E. E., Alkan, C., Hajirasouliha, I., Hormozdiari, F., Ko, A., Sudmant, P. H., Chen, K., Chinwalla, A., Ding, L., McLellan, M. D., Wallis, J. W., Hurles, M. E., Ben Blackburne, Li, H., Lindsay, S. J., Ning, Z., Scally, A., Walter, K., Zhang, Y., Gerstein, M. B., Abyzov, A., Chen, J., Clarke, D., Khurana, E., Mu, X. J., Sisu, C., Gibbs, R. A., Yu, F., Bainbridge, M., Challis, D., Evani, U. S., Kovar, C., Lewis, L., Lu, J., Muzny, D., Nagaswamy, U., Reid, J., Sabo, A., Yu, J., Guo, X., Li, Y., Wu, R., Marth, G. T., Garrison, E. P., Leong, W. F., Ward, A. N., del Angel, G., DePristo, M. A., Gabriel, S. B., Gupta, N., Hartl, C., Poplin, R. E., Clark, A. G., Rodriguez-Flores, J. L., Flicek, P., Clarke, L., Smith, R. E., Zheng-Bradley, X., MacArthur, D. G., Bustamante, C. D., Gravel, S., Craig, D. W., Christoforides, A., Homer, N., Izatt, T., Sherry, S. T., Xiao, C., Dermitzakis, E. T., Abecasis, G. R., Kang, H. M., McVean, G. A., Mardis, E. R., Dooling, D., Fulton, L., Fulton, R., Koboldt, D. C., Durbin, R. M., Balasubramaniam, S., Keane, T. M., McCarthy, S., Stalker, J., Gerstein, M. B., Balasubramanian, S., Habegger, L., Garrison, E. P., Gibbs, R. A., Bainbridge, M., Muzny, D., Yu, F., Yu, J., del Angel, G., Handsaker, R. E., Makarov, V., Rodriguez-Flores, J. L., Jin, H., Kim, W., Kim, K. C., Flicek, P., Beal, K., Clarke, L., Cunningham, F., Herrero, J., McLaren, W. M., Ritchie, G. R., Zheng-Bradley, X., Tabrizi, S., MacArthur, D. G., Lek, M., Bustamante, C. D., De La Vega, F. M., Craig, D. W., Kurdoglu, A. A., Lappalainen, T., Rosenfeld, J. A., Michelson, L. P., Awadalla, P., Hodgkinson, A., McVean, G. A., Chen, K., Tyler-Smith, C., Chen, Y., Colonna, V., Frankish, A., Harrow, J., Xue, Y., Gerstein, M. B., Abyzov, A., Balasubramanian, S., Chen, J., Clarke, D., Fu, Y., Harmanci, A. O., Jin, M., Khurana, E., Mu, X. J., Sisu, C., Gibbs, R. A., Fowler, G., Hale, W., Kalra, D., Kovar, C., Muzny, D., Reid, J., Wang, J., Guo, X., Li, G., Li, Y., Zheng, X., Altshuler, D. M., Flicek, P., Clarke, L., Barker, J., Kelman, G., Kulesha, E., Leinonen, R., McLaren, W. M., Radhakrishnan, R., Roa, A., Smirnov, D., Smith, R. E., Streeter, I., Toneva, I., Vaughan, B., Zheng-Bradley, X., Bentley, D. R., Cox, T., Humphray, S., Kahn, S., Sudbrak, R., Albrecht, M. W., Lienhard, M., Craig, D. W., Izatt, T., Kurdoglu, A. A., Sherry, S. T., Ananiev, V., Belaia, Z., Beloslyudtsev, D., Bouk, N., Chen, C., Church, D., Cohen, R., Cook, C., Garner, J., Hefferon, T., Kimelman, M., Liu, C., Lopez, J., Meric, P., O'Sullivan, C., Ostapchuk, Y., Phan, L., Ponomarov, S., Schneider, V., Shekhtman, E., Sirotkin, K., Slotta, D., Xiao, C., Zhang, H., Haussler, D., Abecasis, G. R., McVean, G. A., Alkan, C., Ko, A., Dooling, D., Durbin, R. M., Balasubramaniam, S., Keane, T. M., McCarthy, S., Stalker, J., Chakravarti, A., Knoppers, B. M., Abecasis, G. R., Barnes, K. C., Beiswanger, C., Burchard, E. G., Bustamante, C. D., Cai, H., Cao, H., Durbin, R. M., Gharani, N., Gibbs, R. A., Gignoux, C. R., Gravel, S., Henn, B., Jones, D., Jorde, L., Kaye, J. S., Keinan, A., Kent, A., Kerasidou, A., Li, Y., Mathias, R., McVean, G. A., Moreno-Estrada, A., Ossorio, P. N., Parker, M., Reich, D., Rotimi, C. N., Royal, C. D., Sandoval, K., Su, Y., Sudbrak, R., Tian, Z., Timmermann, B., Tishkoff, S., Toji, L. H., Tyler-Smith, C., Via, M., Wang, Y., Yang, H., Yang, L., Zhu, J., Bodmer, W., Bedoya, G., Ruiz-Linares, A., Ming, C. Z., Yang, G., You, C. J., Peltonen, L., Garcia-Montero, A., Orfao, A., Dutil, J., Martinez-Cruzado, J. C., Oleksyk, T. K., Brooks, L. D., Felsenfeld, A. L., McEwen, J. E., Clemm, N. C., Duncanson, A., Dunn, M., Green, E. D., Guyer, M. S., Peterson, J. L., Abecasis, G. R., Auton, A., Brooks, L. D., DePristo, M. A., Durbin, R. M., Handsaker, R. E., Kang, H. M., Marth, G. T., McVean, G. A. 2012; 491 (7422): 56-65


    By characterizing the geographic and functional spectrum of human genetic variation, the 1000 Genomes Project aims to build a resource to help to understand the genetic contribution to disease. Here we describe the genomes of 1,092 individuals from 14 populations, constructed using a combination of low-coverage whole-genome and exome sequencing. By developing methods to integrate information across several algorithms and diverse data sources, we provide a validated haplotype map of 38?million single nucleotide polymorphisms, 1.4?million short insertions and deletions, and more than 14,000 larger deletions. We show that individuals from different populations carry different profiles of rare and common variants, and that low-frequency variants show substantial geographic differentiation, which is further increased by the action of purifying selection. We show that evolutionary conservation and coding consequence are key determinants of the strength of purifying selection, that rare-variant load varies substantially across biological pathways, and that each individual contains hundreds of rare non-coding variants at conserved sites, such as motif-disrupting changes in transcription-factor-binding sites. This resource, which captures up to 98% of accessible single nucleotide polymorphisms at a frequency of 1% in related populations, enables analysis of common and low-frequency variants in individuals from diverse, including admixed, populations.

    View details for DOI 10.1038/nature11632

    View details for Web of Science ID 000310434500030

    View details for PubMedID 23128226

  • Population Genetic Inference from Personal Genome Data: Impact of Ancestry and Admixture on Human Genomic Variation AMERICAN JOURNAL OF HUMAN GENETICS Kidd, J. M., Gravel, S., Byrnes, J., Moreno-Estrada, A., Musharoff, S., Bryc, K., Degenhardt, J. D., Brisbin, A., Sheth, V., Chen, R., McLaughlin, S. F., Peckham, H. E., Omberg, L., Chung, C. A., Stanley, S., Pearlstein, K., Levandowsky, E., Acevedo-Acevedo, S., Auton, A., Keinan, A., Acuna-Alonzo, V., Barquera-Lozano, R., Canizales-Quinteros, S., Eng, C., Burchard, E. G., Russell, A., Reynolds, A., Clark, A. G., Reese, M. G., Lincoln, S. E., Butte, A. T., De La Vega, F. M., Bustamante, C. D. 2012; 91 (4): 660-671


    Full sequencing of individual human genomes has greatly expanded our understanding of human genetic variation and population history. Here, we present a systematic analysis of 50 human genomes from 11 diverse global populations sequenced at high coverage. Our sample includes 12 individuals who have admixed ancestry and who have varying degrees of recent (within the last 500 years) African, Native American, and European ancestry. We found over 21 million single-nucleotide variants that contribute to a 1.75-fold range in nucleotide heterozygosity across diverse human genomes. This heterozygosity ranged from a high of one heterozygous site per kilobase in west African genomes to a low of 0.57 heterozygous sites per kilobase in segments inferred to have diploid Native American ancestry from the genomes of Mexican and Puerto Rican individuals. We show evidence of all three continental ancestries in the genomes of Mexican, Puerto Rican, and African American populations, and the genome-wide statistics are highly consistent across individuals from a population once ancestry proportions have been accounted for. Using a generalized linear model, we identified subtle variations across populations in the proportion of neutral versus deleterious variation and found that genome-wide statistics vary in admixed populations even once ancestry proportions have been factored in. We further infer that multiple periods of gene flow shaped the diversity of admixed populations in the Americas-70% of the European ancestry in today's African Americans dates back to European gene flow happening only 7-8 generations ago.

    View details for DOI 10.1016/j.ajhg.2012.08.025

    View details for Web of Science ID 000309568500008

    View details for PubMedID 23040495

  • EVOLUTION AND MEDICINE IN UNDERGRADUATE EDUCATION: A PRESCRIPTION FOR ALL BIOLOGY STUDENTS EVOLUTION Antolin, M. F., Jenkins, K. P., Bergstrom, C. T., Crespi, B. J., De, S., Hancock, A., Hanley, K. A., Meagher, T. R., Moreno-Estrada, A., Nesse, R. M., Omenn, G. S., Stearns, S. C. 2012; 66 (6): 1991-2006


    The interface between evolutionary biology and the biomedical sciences promises to advance understanding of the origins of genetic and infectious diseases in humans, potentially leading to improved medical diagnostics, therapies, and public health practices. The biomedical sciences also provide unparalleled examples for evolutionary biologists to explore. However, gaps persist between evolution and medicine, for historical reasons and because they are often perceived as having disparate goals. Evolutionary biologists have a role in building a bridge between the disciplines by presenting evolutionary biology in the context of human health and medical practice to undergraduates, including premedical and preprofessional students. We suggest that students will find medical examples of evolution engaging. By making the connections between evolution and medicine clear at the undergraduate level, the stage is set for future health providers and biomedical scientists to work productively in this synthetic area. Here, we frame key evolutionary concepts in terms of human health, so that biomedical examples may be more easily incorporated into evolution courses or more specialized courses on evolutionary medicine. Our goal is to aid in building the scientific foundation in evolutionary biology for all students, and to encourage evolutionary biologists to join in the integration of evolution and medicine.

    View details for DOI 10.1111/j.1558-5646.2011.01552.x

    View details for Web of Science ID 000304757200026

    View details for PubMedID 22671563

  • 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

  • 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

  • Genomic Ancestry of North Africans Supports Back-to-Africa Migrations PLOS GENETICS Henn, B. M., Botigue, L. R., Gravel, S., Wang, W., Brisbin, A., Byrnes, J. K., Fadhlaoui-Zid, K., Zalloua, P. A., Moreno-Estrada, A., Bertranpetit, J., Bustamante, C. D., Comas, D. 2012; 8 (1)


    North African populations are distinct from sub-Saharan Africans based on cultural, linguistic, and phenotypic attributes; however, the time and the extent of genetic divergence between populations north and south of the Sahara remain poorly understood. Here, we interrogate the multilayered history of North Africa by characterizing the effect of hypothesized migrations from the Near East, Europe, and sub-Saharan Africa on current genetic diversity. We present dense, genome-wide SNP genotyping array data (730,000 sites) from seven North African populations, spanning from Egypt to Morocco, and one Spanish population. We identify a gradient of likely autochthonous Maghrebi ancestry that increases from east to west across northern Africa; this ancestry is likely derived from "back-to-Africa" gene flow more than 12,000 years ago (ya), prior to the Holocene. The indigenous North African ancestry is more frequent in populations with historical Berber ethnicity. In most North African populations we also see substantial shared ancestry with the Near East, and to a lesser extent sub-Saharan Africa and Europe. To estimate the time of migration from sub-Saharan populations into North Africa, we implement a maximum likelihood dating method based on the distribution of migrant tracts. In order to first identify migrant tracts, we assign local ancestry to haplotypes using a novel, principal component-based analysis of three ancestral populations. We estimate that a migration of western African origin into Morocco began about 40 generations ago (approximately 1,200 ya); a migration of individuals with Nilotic ancestry into Egypt occurred about 25 generations ago (approximately 750 ya). Our genomic data reveal an extraordinarily complex history of migrations, involving at least five ancestral populations, into North Africa.

    View details for DOI 10.1371/journal.pgen.1002397

    View details for Web of Science ID 000300223400001

    View details for PubMedID 22253600

  • Fine-scale population structure and the era of next-generation sequencing HUMAN MOLECULAR GENETICS Henn, B. M., Gravel, S., Moreno-Estrada, A., Acevedo-Acevedo, S., Bustamante, C. D. 2010; 19: R221-R226


    Fine-scale population structure characterizes most continents and is especially pronounced in non-cosmopolitan populations. Roughly half of the world's population remains non-cosmopolitan and even populations within cities often assort along ethnic and linguistic categories. Barriers to random mating can be ecologically extreme, such as the Sahara Desert, or cultural, such as the Indian caste system. In either case, subpopulations accumulate genetic differences if the barrier is maintained over multiple generations. Genome-wide polymorphism data, initially with only a few hundred autosomal microsatellites, have clearly established differences in allele frequency not only among continental regions, but also within continents and within countries. We review recent evidence from the analysis of genome-wide polymorphism data for genetic boundaries delineating human population structure and the main demographic and genomic processes shaping variation, and discuss the implications of population structure for the distribution and discovery of disease-causing genetic variants, in the light of the imminent availability of sequencing data for a multitude of diverse human genomes.

    View details for DOI 10.1093/hmg/ddq403

    View details for Web of Science ID 000284456100014

    View details for PubMedID 20876616

  • 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

  • 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

  • Decay of linkage disequilibrium within genes across HGDP-CEPH human samples: most population isolates do not show increased LD BMC GENOMICS Bosch, E., Laayouni, H., Morcillo-Suarez, C., Casals, F., Moreno-Estrada, A., Ferrer-Admetlla, A., Gardner, M., Rosa, A., Navarro, A., Comas, D., Graffelman, J., Calafell, F., Bertranpetit, J. 2009; 10


    It is well known that the pattern of linkage disequilibrium varies between human populations, with remarkable geographical stratification. Indirect association studies routinely exploit linkage disequilibrium around genes, particularly in isolated populations where it is assumed to be higher. Here, we explore both the amount and the decay of linkage disequilibrium with physical distance along 211 gene regions, most of them related to complex diseases, across 39 HGDP-CEPH population samples, focusing particularly on the populations defined as isolates. Within each gene region and population we use r2 between all possible single nucleotide polymorphism (SNP) pairs as a measure of linkage disequilibrium and focus on the proportion of SNP pairs with r2 greater than 0.8.Although the average r2 was found to be significantly different both between and within continental regions, a much higher proportion of r2 variance could be attributed to differences between continental regions (2.8% vs. 0.5%, respectively). Similarly, while the proportion of SNP pairs with r2 > 0.8 was significantly different across continents for all distance classes, it was generally much more homogenous within continents, except in the case of Africa and the Americas. The only isolated populations with consistently higher LD in all distance classes with respect to their continent are the Kalash (Central South Asia) and the Surui (America). Moreover, isolated populations showed only slightly higher proportions of SNP pairs with r2 > 0.8 per gene region than non-isolated populations in the same continent. Thus, the number of SNPs in isolated populations that need to be genotyped may be only slightly less than in non-isolates.The "isolated population" label by itself does not guarantee a greater genotyping efficiency in association studies, and properties other than increased linkage disequilibrium may make these populations interesting in genetic epidemiology.

    View details for DOI 10.1186/1471-2164-10-338

    View details for Web of Science ID 000269509000001

    View details for PubMedID 19638193

  • SNP analysis to results (SNPator): a web-based environment oriented to statistical genomics analyses upon SNP data BIOINFORMATICS Morcillo-Suarez, C., Alegre, J., Sangros, R., Gazave, E., de Cid, R., Milne, R., Amigo, J., Ferrer-Admetlla, A., Moreno-Estrada, A., Gardner, M., Casals, F., Perez-Lezaun, A., Comas, D., Bosch, E., Calafell, F., Bertranpetit, J., Navarro, A. 2008; 24 (14): 1643-1644


    Single nucleotide polymorphisms (SNPs) are the most widely used marker in studies to assess associations between genetic variants and complex traits or diseases. They are also becoming increasingly important in the study of the evolution and history of humans and other species. The analysis and processing of SNPs obtained thanks to high-throughput technologies imply the time consuming and costly use of different, complex and usually format-incompatible software. SNPator is a user-friendly web-based SNP data analysis suite that integrates, among many other algorithms, the most common steps of a SNP association study. It frees the user from the need to have large computer facilities and an in depth knowledge of genetic software installation and management. Genotype data is directly read from the output files of the usual genotyping platforms. Phenotypic data on the samples can also be easily uploaded. Many different quality control and analysis procedures can be performed either by using built-in SNPator algorithms or by calling standard genetic software.Access is granted from the SNPator webpage

    View details for DOI 10.1093/bioinformatics/btn241

    View details for Web of Science ID 000257576000014

    View details for PubMedID 18515823

  • Signatures of selection in the human olfactory receptor OR5I1 gene MOLECULAR BIOLOGY AND EVOLUTION Moreno-Estrada, A., Casals, F., Ramirez-Soriano, A., Oliva, B., Calafell, F., Bertranpetit, J., Bosch, E. 2008; 25 (1): 144-154


    The human olfactory receptor (OR) repertoire is reduced in comparison to other mammals and to other nonhuman primates. Nonetheless, this olfactory decline opens an opportunity for evolutionary innovation and improvement. In the present study, we focus on an OR gene, OR5I1, which had previously been shown to present an excess of amino acid replacement substitutions between humans and chimpanzees. We analyze the genetic variation in OR5I1 in a large worldwide human panel and find an excess of derived alleles segregating at relatively high frequencies in all populations. Additional evidence for selection includes departures from neutrality in allele frequency spectra tests but no unusually extended haplotype structure. Moreover, molecular structural inference suggests that one of the nonsynonymous polymorphisms defining the presumably adaptive protein form of OR5I1 may alter the functional binding properties of the OR. These results are compatible with positive selection having modeled the pattern of variation found in the OR5I1 gene and with a relatively ancient, mild selective sweep predating the "Out of Africa" expansion of modern humans.

    View details for DOI 10.1093/molbev/msm240

    View details for Web of Science ID 000253375900015

    View details for PubMedID 17981927

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