The Genomic Basis of Life History Adaptation
Description: Life history traits are central to our understanding of adaptation because they represent direct targets of selection. However, while much progress has been made in uncovering the molecular mechanisms underlying fitness-related traits, mainly by studying large-effect mutants in model organisms, little is known about naturally occurring genetic variants that affect these traits. The central aim of my current SNSF Professorship grant is to identify naturally occurring polymorphisms that underlie evolutionary changes in life history, using Drosophila melanogaster as a model. Over the last 33 months, we have used two complementary approaches to tackle this problem: to generate 'catalogs' of candidate variants we have applied whole-genome Pool-sequencing to (1) North American populations clinally differentiated for life history and (2) a >30-year-long artificial selection experiment for longevity. Both approaches are 'designed' to maximize among-population life-history differentiation and thus to increase our ability to map life-history variants via sequencing. In a second step, we have begun to perform experiments to examine the life-history effects of some of these candidate mechanisms. Based on our genomic analyses, we have prioritized three candidate mechanisms for experiments: (1) for the cline, we have identified clinal SNP polymorphisms in several genes involved in insulin signaling, a pathway known from molecular studies to regulate life-history physiology, including a clinal 2-SNP polymorphism in the transcription factor gene foxo; (2) a clinal chromosomal inversion polymorphism, In(3R)Payne, to which 79% of the most strongly clinal SNPs in the genome map; and (3), in the selection experiment, we have found strong enrichment of immunity genes among our top candidates. To date, our experiments show that (1) the foxo polymorphism has major pleiotropic on egg-to-adult survival, body size and starvation resistance, in assays based on synthetic recombinant inbred lines; (2) the In(3R)Payne polymorphism is maintained by clinal selection, independent of neutrality and admixture, and affects body size, a strongly clinal trait; and (3) the long-lived selection lines survive pathogenic infections much better than the controls. In this application for a 2-year extension of my grant, we propose to follow up on these promising leads. First, to better understand how the foxo polymorphism affects life history, we will use homologous replacement of the 2 SNPs (and their allelic combinations) into a common background via CRISPR/Cas9, in collaboration with Alistair McGregor (Oxford); we will measure additive and epistatic effects of these constructs on life history and FOXO activity. Second, to identify targets of selection within In(3R)Payne, we will phase-sequence isochromosomal lines and apply ABC-based coalescent models to the data, in collaboration with Mark Kirkpatrick (Austin). In addition, we will perform RNA-seq of standard vs. inverted lines to uncover transcriptional differences between inversion karyotypes. Finally, to begin to uncover the regulatory details of the intriguing but poorly understood connection between lifespan and immunity in the longevity selection lines, we will assay transcriptional responses to infection in selection versus control lines, both in young and old flies, and – secondly – test whether silencing immune genes via transgenic RNAi affects lifespan, as hypothesized. Together, this integrative approach – spanning population genomics, functional genetics, and physiology – will significantly advance our understanding of the molecular basis of adaptive changes in life history and aging, a fundamental but largely unresolved problem in evolutionary biology.
Amount: CHF 743,500
Funding type: fellowship
Funder scheme: SNSF Professorships
Start date: 2016-12-01
End date: 2019-05-31
Investigator: Flatt, Thomas
Institution: University of Fribourg – FR
Subfield: Aging
Domain: Life Sciences
Funded outputs count: 21
Funder award ID: 165836
OpenAlex ID: G8919737172