3 research outputs found
Genomic and functional approaches to genetic adaptation
The genetic basis of phenotypes that have contributed to the adaptation of species and
organisms to new environments is a central question in evolutionary genetics. The
recent accumulation of genetic variability data has allowed a genome-wide search for
different signatures of positive selection which has led to the discovery of hundreds of
putative candidate genes that may have played a role in adaptation. However, such
hypothesis-free approaches do not reveal either causal variants or the actual biological
mechanisms that have made each adaptation possible. Furthermore, the detection of
molecular signatures is limited both by the complex architecture of the genome and
by the possible polygenic nature of the selected trait.
In this thesis, through different evolutionary and functional approaches, we have
disentangled the adaptive role of two non-synonymous variants in two different
candidate genes encoding for a lymphocyte receptor and a zinc transporter,
respectively. In past human adaptation, they were most likely selected as more
effective means to fight pathogens. We have also revealed differences in the action of
natural selection between different pathways and different coding and non-coding
genomic elements in the chimpanzee lineage by analyzing polymorphisms and
divergence data together. Thus, the results of this PhD thesis have contributed to
detect new instances of genetic adaptation and provide biological explanation to them.La base genética de los carácteres que han contribuido a la adaptación de los
organismos y las especies ha sido siempre una pregunta central en biología evolutiva.
Gracias a la acumulación masiva de datos de variabilidad genética, en los últimos
años se ha podido detectar en el genoma diferentes señales de selección positiva y
también localizar cientos de genes candidatos que han podido tener un papel en la
adaptación de las poblaciones a diferentes ambientes. Sin embargo en estos estudios,
donde no hay una hipótesis a priori, se desconoce qué variantes dentro de estos genes
fueron realmente las que proporcionaron una ventaja selectiva y por qué. Además, la
compleja arquitectura del genoma y la naturaleza poligénica de muchos carácteres
hace que sea difícil detectar casos más complejos de adaptación.
En esta tesis se intenta resolver algunos de estos problemas. En primer lugar,
mediante un enfoque evolutivo y funcional, hemos descifrado el rol adaptativo de dos
variantes genéticas, una en un receptor linfocitario y la otra en un transportador de
zinc, que probablemente fueron seleccionadas por conferir resistencia a patógenos. En
segundo lugar, mediante el análisis de datos de polimorfismo y divergencia
conjuntamente, también hemos detectado distintos mecanismos de acción de la
selección natural en distintos pathways y entre elementos codificantes y elementos no
codificantes reguladores en chimpancé
Extreme population differences in the human zinc transporter ZIP4 (SLC39A4) are explained by positive selection in Sub-Saharan Africa
Extreme differences in allele frequency between West Africans and Eurasians were observed for a leucine-to-valine substitution (Leu372Val) in the human intestinal zinc uptake transporter, ZIP4, yet no further evidence was found for a selective sweep around the ZIP4 gene (SLC39A4). By interrogating allele frequencies in more than 100 diverse human populations and resequencing Neanderthal DNA, we confirmed the ancestral state of this locus and found a strong geographical gradient for the derived allele (Val372), with near fixation in West Africa. In extensive coalescent simulations, we show that the extreme differences in allele frequency, yet absence of a classical sweep signature, can be explained by the effect of a local recombination hotspot, together with directional selection favoring the Val372 allele in Sub-Saharan Africans. The possible functional effect of the Leu372Val substitution, together with two pathological mutations at the same codon (Leu372Pro and Leu372Arg) that cause acrodermatitis enteropathica (a disease phenotype characterized by extreme zinc deficiency), was investigated by transient overexpression of human ZIP4 protein in HeLa cells. Both acrodermatitis mutations cause absence of the ZIP4 transporter cell surface expression and nearly absent zinc uptake, while the Val372 variant displayed significantly reduced surface protein expression, reduced basal levels of intracellular zinc, and reduced zinc uptake in comparison with the Leu372 variant. We speculate that reduced zinc uptake by the ZIP4-derived Val372 isoform may act by starving certain pathogens of zinc, and hence may have been advantageous in Sub-Saharan Africa. Moreover, these functional results may indicate differences in zinc homeostasis among modern human populations with possible relevance for disease risk.JE was supported through a Postdoc scholarship from the Volkswagenstiftung (Az: I/85 198). This work was partially funded by grants BFU2008-01046, SAF2011-29239, SAF2012-38140, CGL2012-36682 and SAF2010-16725 from the Spanish Ministry of Economy and Competitiveness, Fondo de Investigación Sanitaria (Red HERACLES RD12/0042/0014), and FEDER Funds as well as by grants 2009SGR-1101 and 2009SGR-1369 from Direcció General de Recerca, Generalitat de Catalunya. El Sidrón research was also supported by Consejería de Cultura del Principado de Asturias. MAV is the recipient of an ICREA Academia Award. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscrip
Analysis of ancestral and functionally relevant CD5 variants in systemic lupus erythematosus patients
Objective: CD5 plays a crucial role in autoimmunity and is a well-established genetic risk factor of developing RA. Recently, evidence of positive selection has been provided for the CD5 Pro224-Val471 haplotype in East Asian populations. The aim of the present work was to further analyze the functional relevance of non-synonymous CD5 polymorphisms conforming the ancestral and the newly derived haplotypes (Pro224-Ala471 and Pro224-Val471, respectively) as well as to investigate the potential role of CD5 on the development of SLE and/or SLE nephritis. Methods: The CD5 SNPs rs2241002 (C/T; Pro224Leu) and rs2229177 (C/T; Ala471Val) were genotyped using TaqMan allelic discrimination assays in a total of 1,324 controls and 681 SLE patients of Spanish origin. In vitro analysis of CD3-mediated T cell proliferative and cytokine response profiles of healthy volunteers homozygous for the above mentioned CD5 haplotypes were also analyzed. Results: T-cell proliferation and cytokine release were significantly increased showing a bias towards to a Th2 profile after CD3 cross-linking of peripheral mononuclear cells from healthy individuals homozygous for the ancestral Pro224-Ala471 (CC) haplotype, compared to the more recently derived Pro224-Val471 (CT). The same allelic combination was statistically associated with Lupus nephritis./nConclusion: The ancestral Ala471 CD5 allele confers lymphocyte hyper-responsiveness to TCR/CD3 cross-linking and is associated with nephritis in SLE patients.This work was supported by grants from the Spanish Ministerio de Economía y Competitividad [SAF2010-19717 to FL, SAF2009-11110 to JM, SAF2011-29239, and BFU2008-01046 to EB], Generalitat de Catalunya [2009SGR00252 to FL, and 2009SGR1101 to EB], Junta de Andalucía [CTS-4977], and Instituto de Salud Carlos III and Fondo Europeo de Desarrollo Regional/FEDER [RD12/0009/0004 to JM