Author: Marc Robinson-Rechavi

Motivation: Documenting the genomic variation of 17 inbred strains of mice. Describing the distribution of variants between strains and its relation to phenotypes and gene regulation. Exploring the evolutionary origins of the subspecies that gave rise to the laboratory mouse. –       Structure: The article is divided up in three main parts: i) description of genomic variants, ii) examination of functional consequences of allele-specific variation on transcript abundance, and iii) investigation of the molecular nature of functional variants and their position relative to genes. –       Experimental design: The 17 most widely used mouse strains (liver tissue) were selected for whole genome sequencing on the illumina GAIIx sequencing platform. To estimate error rates and evaluate the method a NOD/ShiLtJ BAC clone library was constructed. 107 BACs from seven loci on chromosomes 1, 6, 11 and 17 from this library were shotgun cloned and capillary sequenced. SNPs, structural variants (inversions, balanced translocations, CNVs), and transposable elements were identified based on a reference genome (the one that had already been sequenced before: C57BL/6J). Bayesian concordance analysis was used to construct gene trees across the genomes of M. m. musculus, M. m. domesticus and M. m. castaneus. M. spretus was used as the outgroup. Allele …

Background                                         Cryptic genetic variation (CGV) is defined as “standing genetic variation that does not contribute to the normal range of phenotypes observed in a population, but that is available to modify a phenotype that arises after environmental change or the introduction of novel alleles” [Gibson & Dworkin, 2004]. As such, CGV fills the gap between : 1.    expressed genetic variation, defined as genetic variation that contributes to the normal range of phenotypes actually present in a population ; 2.     neutral genetic variation, that does not contribute to phenotypes under any likely genetic or environmental conditions ; a typical example of neutral genetic variation would be synonymous substitutions in protein coding sequences. The necessity of the concept of CGV stems from the observation that environmental or genetic perturbations can reveal standing genetic variation that was silent or “cryptic” under standard conditions. CGV relative to a trait can thus be considered as genetic variation that conditionally affects that trait, the conditions or the trait itself being absent in the actual population and environment. A classic example of CGV concept is the scutellar bristle number in Drosophila. The number of bristles on the scutellum is 4 with low variation in wild type Drosophilae; when the …

Background                                         Cryptic genetic variation (CGV) is defined as “standing genetic variation that does not contribute to the normal range of phenotypes observed in a population, but that is available to modify a phenotype that arises after environmental change or the introduction of novel alleles” [Gibson & Dworkin, 2004]. As such, CGV fills the gap between : 1.    expressed genetic variation, defined as genetic variation that contributes to the normal range of phenotypes actually present in a population ; 2.     neutral genetic variation, that does not contribute to phenotypes under any likely genetic or environmental conditions ; a typical example of neutral genetic variation would be synonymous substitutions in protein coding sequences. The necessity of the concept of CGV stems from the observation that environmental or genetic perturbations can reveal standing genetic variation that was silent or “cryptic” under standard conditions. CGV relative to a trait can thus be considered as genetic variation that conditionally affects that trait, the conditions or the trait itself being absent in the actual population and environment. A classic example of CGV concept is the scutellar bristle number in Drosophila. The number of bristles on the scutellum is 4 with low variation in wild type Drosophilae; when the …

Reptiles had major evolutionary novelty: development of amniotic egg, which enabled breeding outside of the water. Until recently, only available genomes from the reptilian lineage were coming from the birds, therefore this paper and accompanying data provides a very valuable resource for further analysis of amniote evolution. The different aspects of lizard genome that were considered: transposable elements microchromosomes and synteny GC content sex determination system egg protein evolution adaptive radiation/ecology Around 30 percent of the lizard genome consists of transposable elements. It is fascinating that unlike in mammals and birds, there is much higher variety of active elements in the lizard genome, but also low rate of their accumulation. When the authors compared the mammalian conserved elements with the lizard genome, they found that several of these elements originate from transposable elements found in the lizard genome. The authors used the term exaptation to describe the process how certain mobile elements that were active in the amniote ancestor have putative function in mammals (most probably as regulatory elements). During the discussion we agreed that this term is not so appropriate since it would imply that the mobile elements had a function in the genome from the beginning (the time …

Papers that will be discuss between March and May 2012 : When and where? : On Fridays at 12:15, room 4311 of the Biophore Friday March 2ndThe genome of the green anole lizard and a comparative analysis with birds and mammals Afoldietal, Nature 2011 Friday March 9thBayesian inference of ancient human demography from individual genome sequences Gronau etal, Nature Genetics 2011 Friday March 16thCryptic genetic variation promotes rapid evolutionary adaptation in an RNA enzyme Hayden etal, Nature, 2011 Friday march 30thMouse genomic variation and its effect on phenotypes and gene regulation Kean etal, Nature 2011 Friday April 20thDistinct signatures of diversifying selection revealed by genome analysis of respiratory tract and invasive bacterial populationsShea etal, PNAS 2011 Friday April 27thAn Aboriginal Australian Genome Reveals Separate Human Dispersals into Asia Rasmussen etal, Science 2011 Friday May 11thRapid Evolution of Enormous, Multichromosomal Genomes in Flowering Plant Mitochondria with Exceptionally High Mutation RatesSloan etal, Plos Biol 2012 Friday June 1st May 25thThe Molecular Diversity of Adaptive ConvergenceTenaillon etal, Science 2012

Since we used the blog format to conduct this journal club, the whole world was able to enjoy the fruits of our work. So did they come? Well, yes, there were quite a few more readers than would have attended a classical journal club: And although most visitors were from Switzerland, many came from elsewhere: There is clearly a skewed distribution of the readership of the different posts. It is unclear what is the cause, but in part it seems to be the titles, and in part the speed with which it was picked up by researchblogging.org. Indeed, we were quite visible at researchblogging.org, which aggregates science blog posts. We totaled 1730 views on that website, and it is our main source of visitors. So overall, an enjoyable experience, which we will repeat this spring. Aiming for tens or thousands of visitors, of course. I thank all the students who played the game, and wrote excellent blog posts, adapting to this unusual requirement for a PhD student.

Plasmodium falciparum parasite spreads rapidly and widely, if it is out of control. The major prevention is antimalarial drugs. However, drug resistance in parasites has evolved and spread rapidly. In consequence, it’s necessary to launch genome-wide association studies of parasite traits. Previous studies show that mutations in MAL7P1.27 (also known as pfcrt, the gene encoding the P. falciparum CQ resistance transporter) and in the genes encoding P. falciparum dihydrofolate reductase (pfdhfr) and P. falciparum dihydrofolate reductase (pfdhps) have been shown to confer resistance to CQ and SP. Moreover, copy number and/or point mutations at pfmdr1 on chromosome 5 linked to the parasite response to MQ, QN, ART and other antimalarial drugs. Additionally, it has been shown that using 342 genome-wide microsatellite markers and 92 parasite isolates collected from different parts of the world is a more efficient and less-time-consuming way to identify the chromosome segment carrying the pfcrt locus. In the present study, with increase of the number of isolated parasites, it reports the first genome-wide P. falciparum using sensitive method and GWAS of resistance of multiple antimalarial drugs. In general, the authors isolated 189 culture-adapted P. falciparum parasites in vitro culture, from Asia, Africa, America and paua New Guina. …

The investigation of parallel evolution is a powerful paradigm to study mechanisms of adaptation.  This review and opinion paper stresses the fact that although remarkable examples have been studied, molecular bases of adaptation are still poorly understood in the vast majority of cases. In rare examples, a genetic variation has been linked to repeated and independent adaptation. In the examples of Mc1r , multiple mutations occurred in the same gene independently leading to different coat colours in mice.  In humans, lactose tolerance was acquired repeatedly due to mutations occurring independently in the same genes in different populations.  In the paper, authors describe mutations in Pitx1 which have occurred repeatedly in three spine stickleback fish leading to reduced pelvic armor plate which differentiates the sea water from the fresh water specie. These observations have been validated by transgenic animals demonstrating the fact that Pitx1 is the genetic basis of this recurrent phenotype and form of adaptation. As a reader naïve to the field, I found that this paper describes well the obstacles that researchers are facing in the investigation of the molecular basis of adaptation.  Genetic data is sparse and the vast majority of species have not been sequenced. For those …

Higher throughput, better accuracy, and lower costs of DNA sequencing technology revolutionized the field of genetics. Building upon these technological advances, 1000 genomes project marked the new era of human genetics. The ambitious goal of this international project is to build a detailed map of human genetic variation by sequencing 2500 individuals from five major population groups. The first insights into the project results got available upon completion of the pilot phase that covered some hundreds of individuals (The 1000 Genomes Project Consortium 2010). Whereas sequencing costs drop, data management costs are raising. The tremendous amounts of sequencing data from thousands of genomes over 3 billion DNA base pairs raise important challenges for storage and analysis. To tackle this, EBI developed a dedicated computer platform to manipulate and share large-scale data. Furthermore, although sequencing becomes cheaper, getting the sequences of 2500 genomes remains a burden. Pilot project assessed two cost-containment strategies: low-coverage (4x) sequencing of the whole genome and high coverage (50x) sequencing of exon-targeted regions (8140 exons were included). According to pilot study, low-coverage whole genome sequencing approach performs reasonably well. Targeting multiple individuals increases the power to detect different frequency variants in the population. The number and accuracy …