Genetic Diversity and Selection (Aida Andrés)

Balancing selection maintains advantageous diversity in populations by a variety of mechanisms. In humans it is responsible, for example, for the extreme levels of genetic diversity of the MHC locus, and for the fascinating equilibrium that maintains sickle-cell anemia alleles in malaria-suffering populations due to heterozygotes advantage. In other species, balancing selection maintains diversity that is crucial for sex determination, self-incompatibility, defense against pathogens, or escape from predators. Our goal is to understand the influence of balancing selection in the genome (its prevalence, conservation among populations and species, its most common targets) and to unravel the biological factors behind its signatures (its specific targets, the functional consequences of selected variants, their contribution to phenotypic diversity in populations). For this, we combine genomic approaches with detailed population genetics, computational, and experimental studies, that allow us to go from the genome to the phenotype.

Representative publications

• de Filippo C, Key FM, Ghirotto S, Benazzo A, Meneu JR, Weihmann A; NISC Comparative Sequence Program, Parra G, Green ED, Andrés AM.
  Recent selection changes in human genes under long-term balancing selection.
  Molecular Biology and Evolution 33: 1435-1447 (2016) [Full text][PDF]
• Teixeira JC*, de Filippo C*, Weihmann A, Meneu JR, Racimo F, Dannemann M, Nickel B, Fischer A, Halbwax M, Andre C, Atencia R, Meyer M, Parra G, Paabo S, Andrés AM.
  Long-term balancing selection in LAD1 maintains a missense trans-species polymorphism in humans, chimpanzees and bonobos. 
  Molecular Biology and Evolution 32: 1186-1196 (2015) [Full text][PDF]
• Andrés AM*, Dennis MY* , Kretzschmar WW, Cannons JL, Lee-Lin SQ, Hurle B; NISC Comparative Sequencing Program, Schwartzberg PL, Williamson SH, Bustamante CD, Nielsen R, Clark AG, Green ED.
  Balancing Selection Maintains a Form of ERAP2 that Undergoes Nonsense-Mediated Decay and Affects Antigen Presentation.
  PLoS Genetics 6:e1001157 (2010). [PubMed] [Full text] [PDF] [Supplementary Material]
• [see also Cagan et al., MBE 2016 in Comparative Population Genomics section below]

Recent technological advances have enabled the production of high-quality genome sequences of several archaic Homo individuals. This provides an unprecedented opportunity to study extinct populations and the ancestors of present-day modern humans. We use these genomes to study ancestral and modern human populations, with particular emphasis on the effects of natural selection in their evolution.

Representative publications

• Kuhlwilm M, Gronau I, Hubisz MJ, de Filippo C, Prado-Martinez J, Kircher M, Fu Q, Burbano HA, Lalueza-Fox C, de la Rasilla M, Rosas A, Rudan P, Brajkovic D, Kucan Ž, Gušic I, Marques-Bonet T, Andrés AM, Viola B, Pääbo S, Meyer M, Siepel A, Castellano S.
  Ancient gene flow from early modern humans into Eastern Neanderthals.
  Nature 530: 29–433 (2016) [Full text][PDF]
• Dannemann D, Andrés AM, Kelso J.
  Introgression of Neandertal- and Denisovan-like Haplotypes Contributes to Adaptive Variation in Human Toll-like Receptors
  The American Journal of Human Genetics 98:22–33 (2016)
• Castellano S, Parra G, Sánchez-Quinto FA, Racimo F, Kuhlwilm M, Kircher M, Sawyer S, Fu Q, Heinze A, Nickel B, Dabney J, Siebauer M, White L, Burbano HA, Renaud G, Stenzel U, Lalueza-Fox C, de la Rasilla M, Rosas A, Rudan P, Brajković D, Kucan Ž, Gušic I, Shunkov MV, Derevianko AP, Viola B, Meyer M, Kelso J, Andrés AM, Pääbo S.
  Patterns of coding variation in the complete exomes of three Neandertals.
  PNAS 111:6666-71 (2014). [Full text][PDF]
• [See also Key et al., Nat Comm 2016 in Local adaptation above]

Through series of migration events, humans have colonizing virtually every habitable corner of the globe. Settling in such different environments was possible thanks to both cultural and biological adaptations. Although genetic differences among human groups are few and largely neutral, a few genetic differences are responsible for important phenotypic traits, including medically-related phenotypes. We are interested in measuring to what extent local selective pressures have influenced the genetic make up of humans, and which mechanisms mediated adaptation to each environment. We are particularly interested in complex genetic processes underlying local adaptation, such as changes in the strength or type of natural selection, and polygenic adaptation.

Representative publications

• Key FM, Fu Q, Romagné F, Lachmann M, Andrés AM.
  Human adaptation and population differentiation in the light of ancient genomes.
  Nature Communications 7:10775 (2016) [Full text][PDF]
• Key FM, Peter B, Dennis MY, Huerta-Sánchez E, Tang W, Prokunina-Olsson L, Nielsen R, Andrés AM.
  Selection on a Variant Associated with Improved Viral Clearance Drives Local, Adaptive Pseudogenization of Interferon Lambda 4 (IFNL4).
  PLoS Genetics 10:e1004681 (2014). [Full text][PDF]
• White L, Romagné F, Müller E, Erlebach E, Weihmann A, Parra G, Andrés AM, Castellano S.
  Genetic adaptation to levels of dietary selenium in recent human history.
  Molecular Biology and Evolution 32: 1507-1518 (2015) [Full text][PDF]
• [See also de Filippo et al., MBE 2016 in Balancing selection above]
• [See also Dannemann et al., AJHG 2016 in Ancient DNA below]

Considerable knowledge has accumulated on the influence of natural selection in specific human populations. Still, little is known about the conservation of such selective pressures, both among human populations and across different species. Loci under similar selective pressures are likely affected by common environmental factors and are behind shared phenotypes; loci under species- or population-specific selection are likely affected by local selective forces and are responsible for differential traits. Through a number of genomic approaches we aim at helping establish the level of conservation of different types of natural selection, and at identifying loci that are responsible for species- and population-specific traits.

Representative publications

• Cagan A*, Theunert C*, Laayouni H*, Santpere G*, Pybus M, Casals F, Prüfer K, Navarro A, Marques-Bonet T, Bertranpetit J#, Andrés AM#.
  Natural selection in the great apes.
  Molecular Biology and Evolution, 33:3268-3283 (2016) [Full text][PDF]
• Manuel M*, Kuhlwilm M*, Frandsen P*, Sousa V, Desai T, Prado-Martinez J, Hernandez-Rodriguez J, Dupanloup I, Lao O, Hallast P, Schmidt JM, Heredia-Genestar JM, Benazzo A, Barbujani G, Peter B, Kuderna LFK, Casals F, Angedakin S, Arandjelovic M, Boesch C, Kühl H, Vigilant L, Langergraber K, Novembre J, Gut M, Gut I, Navarro A, Carlsen F, Andrés AM, Siegismund HR, Scally A, Excoffier L, Tyler-Smith C, Castellano S, Xue Y, Hvilsom C, Marques-Bonet T
  Chimpanzee genomic diversity reveals ancient admixture with bonobos. 
  Science 354:477-481 )2016). [Full text][PDF]
• Prado-Martinez J, Sudmant PH, Kidd JM, Li H, Kelley JL, Lorente-Galdos B, Veeramah KR, Woerner AE, O'Connor TD, Santpere G, Cagan A, Theunert C, ..., Andrés AM, Wall JD, Bustamante CD, Hammer MF, Eichler EE, Marques-Bonet T.
  Great ape genetic diversity and population history.
  Nature 499:471-5 (2013). [PubMed] [Full text][PDF]
• [See also Teixeira et al., MBE 2015 in Balancing selection above]

• Aida Andrés (Group leader)
• Muslih Abdul-Aziz
• Àngel Belmonte Aguirre
• Bárbara Bitarello
• Katalina Bobowik
• Cesare de Filippo
• Felix-M. Key
• Philip Kleinert
• Romain Laurent
• Juan Ramón Meneu
• Homa Papoli
• Genís Parra
• David Reher
• Joshua Schmidt
• João Teixeira

Andrés AM, Hubisz MJ, Indap A, Torgerson DG, Degenhardt JD, Boyko AR, Gutenkunst RN, White TJ, Green ED, Bustamante CD, Clark AG, Nielsen R. (2009). Targets of balancing selection in the human genome. Molecular Biology and Evolution, 26:2755-64.
PubMed   Full text   PDF   Supplementary Material

Castellano S*, Andrés AM*, Bosch E, Bayes M, Guigó R, Clark AG. (2009). Low exchangeability of selenocysteine, the 21st amino acid, in vertebrate proteins. Molecular Biology and Evolution, 26:2031-40.
PubMed   Full Text   PDF   Supplementary Material
* Denotes equal contribution.

Nielsen R, Hubisz MJ, Hellmann I, Torgerson D, Andrés AM, Albrechtsen A, Gutenkunst R, Adams MD, Cargill M, Boyko A, Indap A, Bustamante CD, and Clark AG. (2009). Darwinian and demographic forces affecting human protein coding genes. Genome Research, 19:838-49.
PubMed   Full Text   PDF   Supplementary Material

Andrés AM, Clark AG, Shimmin L, Boerwinkle E, Sing CF and Hixson JE. (2007). Understanding the accuracy of statistical haplotype inference with sequence data of known phase. Genetic Epidemiology, 31:659-71.
PubMed   PDF

Andrés AM, de Hemptinne C and Bertranpetit J. (2007). Heterogenetous rate of protein evolution in serotonin genes. Molecular Biology and Evolution, 24:2707-15.
PubMed   Full text   PDF   Supplementary Material

Soldevila M, Andrés AM, Helgason A, Ramírez-Soriano A, Marquès-Bonet T, Sigurdadóttir S, Calafell F, Navarro A, Stefánsson K and Bertranpetit J. (2006). The prion protein gene in humans revisited: lessons from a worldwide resequencing study. Genome Research, 16:231-9.
PubMed   Full text   PDF

Andrés AM, Soldevila M, Navarro A, Kidd KK, Oliva B and Bertranpetit J. (2004). Positive selection in MAOA gene is human exclusive: determination of the putative amino acid change selected in the human lineage. Human Genetics 115:377-86.
PubMed   Full text   PDF

Andrés AM, Soldevila M, Lao O, Volpini V, Saitou N, Jacobs HT, Hayasaka I, Calafell F and Bertranpetit J. (2004). Comparative genetics of functional trinucleotide tandem repeats in humans and apes. Journal of Molecular Evolution 59:329-39.
PubMed   Full text   PDF

Clarimón J, Andrés AM, Bertranpetit J and Comas D. (2004). Comparative analysis of Alu insertion sequences in the APP 5’flanking region in humans and other primates. Journal of Molecular Evolution 58:722-731 (2004).
PubMed   Full text   PDF

Soldevila M, Andrés AM, Blancher A, Calafell F, Ordoñez M, Pumarola M, Oliva B, Aramburu J and Bertranpetit J. (2004). Variation of the prion gene in chimpanzees and its implication for prion diseases. Neuroscience Letters 355:157-60.
PubMed   Full text   PDF

Andrés AM, Soldevila M, Saitou N, Volpini V, Calafell F and Bertranpetit J. (2003). Understanding the dynamics of Spinocerebellar Ataxia 8 (SCA8) locus through a comparative genetic approach in humans and apes. Neuroscience Letters 336:143-146.
PubMed   Full text   PDF

Andrés AM, Lao O, Soldevila M, Calafell F and Bertranpetit J. (2003). Dynamics of CAG repeat loci revealed by the analysis of their variability. Human Mutation 21:61-70.
PubMed   PDF

Martínez-Arias R, Calafell R, Mateu E, Comas D, Andrés A and Bertranpetit J. (2002). Sequence variability of a human pseudogene. Genome Research 11:1071-1085.
PubMed   Full text   PDF