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Variants in SNAP25 are targets of natural selection and influence verbal performances in women

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Abstract

Descriptions of genes that are adaptively evolving in humans and that carry polymorphisms with an effect on cognitive performances have been virtually absent. SNAP25 encodes a presynaptic protein with a role in regulation of neurotransmitter release. We analysed the intra-specific diversity along SNAP25 and identified a region in intron 1 that shows signatures of balancing selection in humans. The estimated TMRCA (time to the most recent common ancestor) of the SNAP25 haplotype phylogeny amounted to 2.08 million years. The balancing selection signature is not secondary to demographic events or to biased gene conversion, and encompasses rs363039. This SNP has previously been associated to cognitive performances with contrasting results in different populations. We analysed this variant in two Italian cohorts in different age ranges and observed a significant genotype effect for rs363039 on verbal performances in females alone. Post hoc analysis revealed that the effect is driven by differences between heterozygotes and both homozygous genotypes. Thus, heterozygote females for rs363039 display higher verbal performances compared to both homozygotes. This finding was replicated in a cohort of Italian subjects suffering from neuromuscular diseases that do not affect cognition. Heterozygote advantage is one of the possible reasons underlying the maintenance of genetic diversity in natural populations. The observation that heterozygotes for rs363039 display higher verbal abilities compared to homozygotes perfectly fits the underlying balancing selection model. Although caution should be used in inferring selective pressures from observed signatures, SNAP25 might represent the first description of an adaptively evolving gene with a role in cognition.

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Abbreviations

SNP:

Single nucleotide polymorphism

EAS:

East Asians

CEU:

Europeans

YRI:

Yoruba

TMRCA:

Time to the most recent common ancestor

ASF:

Allele frequency spectrum

MLHKA:

Maximum-likelihood HKA

BGC:

Biased gene conversion

IQ:

Intelligence quotient

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Acknowledgments

We are grateful to Drs A. Frigerio and F.R. Guerini for useful comments about the manuscript. We also wish to thank Dr Andreina Bordoni for technical support. M. Clerici is supported by grants from Istituto Superiore di Sanita’ “Programma Nazionale di Ricerca sull’ AIDS”, the nGIN EC WP7 Project, Ricerca Finalizzata [Italian Ministry of Health], 2008 Ricerca Corrente [Italian Ministry of Health], Progetto FIRB RETI: Rete Italiana Chimica Farmaceutica CHEM-PROFARMA-NET [RBPR05NWWC], and Fondazione CARIPLO.

Conflict of interest

The authors have no conflict of interest to declare.

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Authors and Affiliations

  1. Bioinformatic Lab, Scientific Institute IRCCS E. Medea, Via don L. Monza 20, 23842, Bosisio Parini, LC, Italy

    Rachele Cagliani, Stefania Riva, Cecilia Marino, Matteo Fumagalli, Maria Grazia D’Angelo, Uberto Pozzoli, Diego Forni, Nereo Bresolin & Manuela Sironi

  2. The Academic Centre for the Study of Behavioural Plasticity, Vita-Salute San Raffaele University, Milan, Italy

    Valentina Riva

  3. Department of Neurological Sciences, Dino Ferrari Centre, University of Milan, Fondazione Ca’ Granda IRCCS Ospedale Maggiore Policlinico, 20122, Milan, Italy

    Giacomo P. Comi & Nereo Bresolin

  4. Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, 08193, Bellaterra, Spain

    Mario Cáceres

  5. Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010, Barcelona, Spain

    Mario Cáceres

  6. Chair of Immunology, Department of Biomedical Sciences and Technologies LITA Segrate, University of Milan, 20090, Milano, Italy

    Mario Clerici

  7. Fondazione Don C. Gnocchi, IRCCS, 20148, Milano, Italy

    Mario Clerici

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  1. Rachele Cagliani
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  2. Stefania Riva
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  3. Cecilia Marino
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  4. Matteo Fumagalli
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  5. Maria Grazia D’Angelo
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  6. Valentina Riva
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  7. Giacomo P. Comi
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  8. Uberto Pozzoli
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  9. Diego Forni
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  10. Mario Cáceres
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  11. Nereo Bresolin
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  12. Mario Clerici
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  13. Manuela Sironi
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Correspondence to Manuela Sironi.

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Cagliani, R., Riva, S., Marino, C. et al. Variants in SNAP25 are targets of natural selection and influence verbal performances in women. Cell. Mol. Life Sci. 69, 1705–1715 (2012). https://doi.org/10.1007/s00018-011-0896-y

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  • DOI: https://doi.org/10.1007/s00018-011-0896-y

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