Biology subjects

Ville Mustonen

Publications and source records attributed to Ville Mustonen.

3 recordsLinked to original sources

bioRxiv2016

Quantitative Seq-LGS: Genome-Wide Identification of Genetic Drivers of Multiple Phenotypes in Malaria Parasites

Identifying the genetic determinants of phenotypes that impact on disease severity is of fundamental importance for the design of new interventions against malaria. Traditionally, such discovery has relied on labor-intensive approaches that require significant investments of time and resources. By combining Linkage Group Selection (LGS), quantitative whole genome population sequencing and a novel mathematical modeling approach (qSeq-LGS), we simultaneously identified multiple genes underlying two distinct phenotypes, identifying novel alleles for growth rate and strain specific immunity (SSI), while removing the need for traditionally required steps such as cloning, individual progeny phenotyping and marker generation. The detection of novel variants, verified by experimental phenotyping methods, demonstrates the remarkable potential of this approach for the identification of genes controlling selectable phenotypes in malaria and other apicomplexan parasites for which experimental genetic crosses are amenable.\n\nSignificance StatementThis paper describes a powerful and rapid approach to the discovery of genes underlying medically important phenotypes in malaria parasites. This is crucial for the design of new drug and vaccine interventions. The approach bypasses the most time-consuming steps required by traditional genetic linkage studies and combines Mendelian genetics, quantitative deep sequencing technologies, genome analysis and mathematical modeling. We demonstrate that the approach can simultaneously identify multigenic drivers of multiple phenotypes, thus allowing complex genotyping studies to be conducted concomitantly. This methodology will be particularly useful for discovering the genetic basis of medically important phenotypes such as drug resistance and virulence in malaria and other apicomplexan parasites, as well as potentially in any organism undergoing sexual recombination.

Genomics↗

bioRxiv2016

Background-dependent effects of selection on subclonal heterogeneity

In BriefVazquez-Garcia et al. examine the role of clonal heterogeneity in the acquisition of antimicrobial resistance. They report that pre-existing and de novo genetic variation jointly contribute to clonal evolution. By building a library of adaptive mutations in multiple genetic backgrounds, they resolve the fitness effects of mutations in a clonal lineage.\n\nHighlightsO_LIClonal heterogeneity influences the acquisition of antimicrobial resistance\nC_LIO_LIJoint role of pre-existing and de novo genetic variation in clonal evolution\nC_LIO_LIClonal dynamics are shaped by background-dependent fitness effects of mutations\nC_LIO_LILoss of clonal heterogeneity is balanced by genomic instability and diversification\nC_LI\n\nSummaryThe joint contribution of pre-existing and de novo genetic variation to clonal adaptation is poorly understood, but essential to design successful antimicrobial or cancer therapies. To address this, we evolve genetically diverse populations of budding yeast, S. cerevisiae, consisting of diploid cells with unique haplotype combinations. We study the asexual evolution of these populations under selective inhibition with chemotherapeutic drugs by time-resolved whole-genome sequencing and phenotyping. All populations undergo clonal expansions driven by de novo mutations, but remain genetically and phenotypically diverse. The clones exhibit widespread genomic instability, rendering recessive de novo mutations homozygous and refining pre-existing variation. Finally, we decompose the fitness contributions of pre-existing and de novo mutations by creating a large recombinant library of adaptive mutations in an ensemble of genetic backgrounds. Both pre-existing and de novo mutations substantially contribute to fitness, and the relative fitness of pre-existing variants sets a selective threshold for new adaptive mutations.

Genetics↗

bioRxiv2014

Rate and cost of adaptation in the Drosophila genome

Recent studies have consistently inferred high rates of adaptive molecular evolution between Drosophila species. At the same time, the Drosophila genome evolves under different rates of recombination, which results in partial genetic linkage between alleles at neighboring genomic loci. Here we analyze how linkage correlations affect adaptive evolution. We develop a new inference method for adaptation that takes into account the effect on an allele at a focal site caused by neighboring deleterious alleles (background selection) and by neighboring adaptive substitutions (hitchhiking). Using complete genome sequence data and fine-scale recombination maps, we infer a highly heterogeneous scenario of adaptation in Drosophila. In high-recombining regions, about 50% of all amino acid substitutions are adaptive, together with about 20% of all substitutions in proximal intergenic regions. In low-recombining regions, only a small fraction of the amino acid substitutions are adaptive, while hitchhiking accounts for the majority of these changes. Hitchhiking of deleterious alleles generates a substantial collateral cost of adaptation, leading to a fitness decline of about 30/2N per gene and per million years in the lowest-recombining regions. Our results show how recombination shapes rate and efficacy of the adaptive dynamics in eukaryotic genomes.

Evolutionary Biology↗