Sònia Casillas

The Drosophila melanogaster Genetic Reference Panel

A major challenge of biology is understanding the relationship between molecular genetic variation and variation in quantitative traits, including fitness. This relationship determines our ability to predict phenotypes from genotypes and to understand how evolutionary forces shape variation within and between species. Previous efforts to dissect the genotype–phenotype map were based on incomplete genotypic information. Here, we describe the Drosophila melanogaster Genetic Reference Panel (DGRP), a community resource for analysis of population genomics and quantitative traits. The DGRP consists of fully sequenced inbred lines derived from a natural population. Population genomic analyses reveal reduced polymorphism in centromeric autosomal regions and the X chromosome, evidence for positive and negative selection, and rapid evolution of the X chromosome. Many variants in novel genes, most at low frequency, are associated with quantitative traits and explain a large fraction of the phenotypic variance. The DGRP facilitates genotype–phenotype mapping using the power of Drosophila genetics.

InvFEST, a database integrating information of polymorphic inversions in the human genome

The newest genomic advances have uncovered an unprecedented degree of structural variation throughout genomes, with great amounts of data accumulating rapidly. Here we introduce InvFEST (http://invfestdb.uab.cat), a database combining multiple sources of information to generate a complete catalogue of non-redundant human polymorphic inversions. Due to the complexity of this type of changes and the underlying high false-positive discovery rate, it is necessary to integrate all the available data to get a reliable estimate of the real number of inversions. InvFEST automatically merges predictions into different inversions, refines the breakpoint locations, and finds associations with genes and segmental duplications. In addition, it includes data on experimental validation, population frequency, functional effects and evolutionary history. All this information is readily accessible through a complete and user-friendly web report for each inversion. In its current version, InvFEST combines information from 34 different studies and contains 1092 candidate inversions, which are categorized based on internal scores and manual curation. Therefore, InvFEST aims to represent the most reliable set of human inversions and become a central repository to share information, guide future studies and contribute to the analysis of the functional and evolutionary impact of inversions on the human genome.

Genomics of Ecological Adaptation in Cactophilic Drosophila

Cactophilic Drosophila species provide a valuable model to study gene–environment interactions and ecological adaptation. Drosophila buzzatii and Drosophila mojavensis are two cactophilic species that belong to the repleta group, but have very different geographical distributions and primary host plants. To investigate the genomic basis of ecological adaptation, we sequenced the genome and developmental transcriptome of D. buzzatii and compared its gene content with that of D. mojavensis and two other noncactophilic Drosophila species in the same subgenus. The newly sequenced D. buzzatii genome (161.5 Mb) comprises 826 scaffolds (>3 kb) and contains 13,657 annotated protein-coding genes. Using RNA sequencing data of five life-stages we found expression of 15,026 genes, 80% protein-coding genes, and 20% noncoding RNA genes. In total, we detected 1,294 genes putatively under positive selection. Interestingly, among genes under positive selection in the D. mojavensis lineage, there is an excess of genes involved in metabolism of heterocyclic compounds that are abundant in Stenocereus cacti and toxic to nonresident Drosophila species. We found 117 orphan genes in the shared D. buzzatii–D. mojavensis lineage. In addition, gene duplication analysis identified lineage-specific expanded families with functional annotations associated with proteolysis, zinc ion binding, chitin binding, sensory perception, ethanol tolerance, immunity, physiology, and reproduction. In summary, we identified genetic signatures of adaptation in the shared D. buzzatii–D. mojavensis lineage, and in the two separate D. buzzatii and D. mojavensis lineages. Many of the novel lineage-specific genomic features are promising candidates for explaining the adaptation of these species to their distinct ecological niches.

The genome sequencing of an albino Western lowland gorilla reveals inbreeding in the wild

BackgroundThe only known albino gorilla, named Snowflake, was a male wild born individual from Equatorial Guinea who lived at the Barcelona Zoo for almost 40 years. He was diagnosed with non-syndromic oculocutaneous albinism, i.e. white hair, light eyes, pink skin, photophobia and reduced visual acuity. Despite previous efforts to explain the genetic cause, this is still unknown. Here, we study the genetic cause of his albinism and making use of whole genome sequencing data we find a higher inbreeding coefficient compared to other gorillas.ResultsWe successfully identified the causal genetic variant for Snowflake’s albinism, a non-synonymous single nucleotide variant located in a transmembrane region of SLC45A2. This transporter is known to be involved in oculocutaneous albinism type 4 (OCA4) in humans. We provide experimental evidence that shows that this amino acid replacement alters the membrane spanning capability of this transmembrane region. Finally, we provide a comprehensive study of genome-wide patterns of autozygogosity revealing that Snowflake’s parents were related, being this the first report of inbreeding in a wild born Western lowland gorilla.ConclusionsIn this study we demonstrate how the use of whole genome sequencing can be extended to link genotype and phenotype in non-model organisms and it can be a powerful tool in conservation genetics (e.g., inbreeding and genetic diversity) with the expected decrease in sequencing cost.

Molecular Population Genetics

Molecular population genetics aims to explain genetic variation and molecular evolution from population genetics principles. The field was born 50 years ago with the first measures of genetic variation in allozyme loci, continued with the nucleotide sequencing era, and is currently in the era of population genomics. During this period, molecular population genetics has been revolutionized by progress in data acquisition and theoretical developments. The conceptual elegance of the neutral theory of molecular evolution or the footprint carved by natural selection on the patterns of genetic variation are two examples of the vast number of inspiring findings of population genetics research. Since the inception of the field, Drosophila has been the prominent model species: molecular variation in populations was first described in Drosophila and most of the population genetics hypotheses were tested in Drosophila species. In this review, we describe the main concepts, methods, and landmarks of molecular population genetics, using the Drosophila model as a reference. We describe the different genetic data sets made available by advances in molecular technologies, and the theoretical developments fostered by these data. Finally, we review the results and new insights provided by the population genomics approach, and conclude by enumerating challenges and new lines of inquiry posed by increasingly large population scale sequence data.

Human inversions and their functional consequences

Polymorphic inversions are a type of structural variants that are difficult to analyze owing to their balanced nature and the location of breakpoints within complex repeated regions. So far, only a handful of inversions have been studied in detail in humans and current knowledge about their possible functional effects is still limited. However, inversions have been related to phenotypic changes and adaptation in multiple species. In this review, we summarize the evidences of the functional impact of inversions in the human genome. First, given that inversions have been shown to inhibit recombination in heterokaryotes, chromosomes displaying different orientation are expected to evolve independently and this may lead to distinct gene-expression patterns. Second, inversions have a role as disease-causing mutations both by directly affecting gene structure or regulation in different ways, and by predisposing to other secondary arrangements in the offspring of inversion carriers. Finally, several inversions show signals of being selected during human evolution. These findings illustrate the potential of inversions to have phenotypic consequences also in humans and emphasize the importance of their inclusion in genome-wide association studies.

Fast sequence evolution of Hox and Hox -derived genes in the genus Drosophila

BackgroundIt is expected that genes that are expressed early in development and have a complex expression pattern are under strong purifying selection and thus evolve slowly. Hox genes fulfill these criteria and thus, should have a low evolutionary rate. However, some observations point to a completely different scenario. Hox genes are usually highly conserved inside the homeobox, but very variable outside it.ResultsWe have measured the rates of nucleotide divergence and indel fixation of three Hox genes, labial (lab), proboscipedia (pb) and abdominal-A (abd-A), and compared them with those of three genes derived by duplication from Hox3, bicoid (bcd), zerknüllt (zen) and zerknüllt-related (zen2), and 15 non-Hox genes in sets of orthologous sequences of three species of the genus Drosophila. These rates were compared to test the hypothesis that Hox genes evolve slowly. Our results show that the evolutionary rate of Hox genes is higher than that of non-Hox genes when both amino acid differences and indels are taken into account: 43.39% of the amino acid sequence is altered in Hox genes, versus 30.97% in non-Hox genes and 64.73% in Hox-derived genes. Microsatellites scattered along the coding sequence of Hox genes explain partially, but not fully, their fast sequence evolution.ConclusionThese results show that Hox genes have a higher evolutionary dynamics than other developmental genes, and emphasize the need to take into account indels in addition to nucleotide substitutions in order to accurately estimate evolutionary rates.

Protein Polymorphism Is Negatively Correlated with Conservation of Intronic Sequences and Complexity of Expression Patterns in Drosophila melanogaster

We report a significant negative correlation between nonsynonymous polymorphism and intron length in Drosophila melanogaster. This correlation is similar to that between protein divergence and intron length previously reported in Drosophila. We show that the relationship can be explained by the content of conserved noncoding sequences (CNS) within introns. In addition, genes with a high regulatory complexity and many genetic interactions also exhibit larger amounts of CNS within their introns and lower values of nonsynonymous polymorphism. The present study provides relevant evidence on the importance of intron content and expression patterns on the levels of coding polymorphism.

PDA v.2: improving the exploration and estimation of nucleotide polymorphism in large datasets of heterogeneous DNA

Pipeline Diversity Analysis (PDA) is an open-source, web-based tool that allows the exploration of polymorphism in large datasets of heterogeneous DNA sequences, and can be used to create secondary polymorphism databases for different taxonomic groups, such as the Drosophila Polymorphism Database (DPDB). A new version of the pipeline presented here, PDA v.2, incorporates substantial improvements, including new methods for data mining and grouping sequences, new criteria for data quality assessment and a better user interface. PDA is a powerful tool to obtain and synthesize existing empirical evidence on genetic diversity in any species or species group. PDA v.2 is available on the web at .

MamPol: a database of nucleotide polymorphism in the Mammalia class

Multi-locus and multi-species nucleotide diversity studies would benefit enormously from a public database encompassing high-quality haplotypic sequences with their associated genetic diversity measures. MamPol, ‘Mammalia Polymorphism Database’, is a website containing all the well-annotated polymorphic sequences available in GenBank for the Mammalia class grouped by name of organism and gene. Diversity measures of single nucleotide polymorphisms are provided for each set of haplotypic homologous sequences, including polymorphism at synonymous and non-synonymous sites, linkage disequilibrium and codon bias. Data gathering, calculation of diversity measures and daily updates are automatically performed using PDA software. The MamPol website includes several interfaces for browsing the contents of the database and making customizable comparative searches of different species or taxonomic groups. It also contains a set of tools for simple re-analysis of the available data and a statistics section that is updated daily and summarizes the contents of the database. MamPol is available at and can be downloaded via FTP.