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Title: Genomic Variation and Its Impact on Gene Expression in Drosophila melanogaster}
Article:
Abstract:
Understanding the relationship between genetic and phenotypic variation is one of the great outstanding challenges in biology. To meet this challenge, comprehensive genomic variation maps of human as well as of model organism populations are required. Here, we present a nucleotide resolution catalog of single-nucleotide, multi-nucleotide, and structural variants in 39 Drosophila melanogaster Genetic Reference Panel inbred lines. Using an integrative, local assembly-based approach for variant discovery, we identify more than 3. 6 million distinct variants, among which were more than 800, 000 unique insertions, deletions( indels), and complex variants( 1 to 6, 000 bp). While the SNP density is higher near other variants, we find that variants themselves are not mutagenic, nor are regions with high variant density particularly mutation-prone. Rather, our data suggest that the elevated SNP density around variants is mainly due to population-level processes. We also provide insights into the regulatory architecture of gene expression variation in adult flies by mapping cis-expression quantitative trait loci( cis-eQTLs) for more than 2, 000 genes. Indels comprise around 10% of all cis-eQTLs and show larger effects than SNP cis-eQTLs. In addition, we identified two-fold more gene associations in males as compared to females and found that most cis-eQTLs are sex-specific, revealing a partial decoupling of the genomic architecture between the sexes as well as the importance of genetic factors in mediating sex-biased gene expression. Finally, we performed RNA-seq-based allelic expression imbalance analyses in the offspring of crosses between sequenced lines, which revealed that the majority of strong cis-eQTLs can be validated in heterozygous individuals.
Introduction:
An important challenge in biology is to elucidate the relationship between genetic and phenotypic variation[1]. The increasing availability of comprehensive genome sequences of both human[2],[3] and model organism populations[4],[5] constitutes an important step towards meeting this challenge. The Drosophila Genetic Reference Panel( DGRP) is an example of such a recently emerging population resource, consisting of 192 sequenced wild-derived inbred Drosophila melanogaster lines[6],[7]. Drosophila is a premier model organism to understand genome function given the availability of powerful and cost-effective genetic tools and resources[8]–[10]. In addition, its genome is small, but highly polymorphic[7],[11]–[15], which has already proven helpful in studying the molecular basis of morphological evolution[16],[17]. Moreover, linkage disequilibrium( LD) decays quickly across the genome[7],[18], which is favorable to elucidating the relationship between genotypic and phenotypic variation at high resolution. This requires that we genotype all classes of segregating variants( i. e., insertions, deletions, and structural variants) and not only the commonly studied single nucleotide polymorphisms( SNPs) to investigate their effect on phenotypes. Here, we use an integrative approach to derive and characterize a genome-wide, nucleotide-resolution catalog of variants including SNPs, insertions, deletions, complex substitutions, and structural variants in 39 DGRP lines. We then investigate the impact of naturally occurring genetic variation on adult gene expression, revealing novel insights into the regulatory architecture of gene expression variation in Drosophila.
Discussion:
We present a comprehensive, genome-wide list of variants of all major types( i. e., single-, multi-nucleotide-, and structural variation) for a Drosophila wild-derived population, significantly expanding the catalog of variants that has been compiled to date for this model organism( e. g.,[7],[13]–[15],[20]). Our analyses reveal extensive non-SNP variation among lines, with a high indel frequency( roughly every 150 bp) and indels in 80% of the protein-coding genes. The majority of indels do not alter the reading frame, but nevertheless reveal surprising tolerance for indels in coding regions. Our data are relevant to the inference of underlying mechanisms of varying mutation rates across genomes[32]. We show elevated SNP density around other SNPs as well as indels; that neighboring variants have similar allele frequencies; and that regions with indels are not particularly mutation-prone. These data suggest that this phenomenon reflects the existence of small haploblocks. While these may arise because of segregating mutational hotspots, a more likely explanation invokes the demographic history of the population. For example, admixture may generate such a haplotype structure to an extent largely dictated by the local genomic recombination environment[54] – potentially consistent with our observed correlation between recombination rate and variant density. Thus, while our data suggest that these population level processes may lead to incorrect inference regarding the mutagenic nature of indels, this will be a topic of further investigation in future studies during which alternative explanations( e. g., duplication hotspots) will also be explored. The presented variant collection constitutes a useful resource for several scientific disciplines, including phylogenetics and population genetics, which are beyond the scope of this study. Here, we applied this resource to study the impact of natural polymorphisms on gene expression, identifying cis-eQTLs for >2, 000 genes( 10% FDR). Although further work is necessary to identify the causal variants underlying cis-eQTLs, the combined results provide general insights into the complexity and evolution of the cis-regulatory architecture of gene expression in Drosophila. More specifically, the data suggest that gene expression variation is governed by multiple cis-eQTLs of different variant types, that the most significant cis-eQTLs are tightly clustered around the TSS and immediately upstream of the TES, but that many cis-eQTLs are also located in regions currently devoid of regulatory annotations. These regions likely play an important role in gene regulation as their alteration has an expression impact that can be observed in whole adult fly expression profiles. In addition, the data suggest that the regulatory architecture is partly decoupled between males and females, at least within the tested settings, as underlying changes predominantly affect gene expression in males. However, cis-eQTLs common to both sexes typically have larger effects. This supports the hypothesis that intersexual ontogenetic conflict in D. melanogaster may stem from many sexually antagonistic alleles with low effect sizes[55]. Finally, the detection of many sex-specific cis-eQTLs indicates that genetic factors play an important role in sex-biased gene expression as changes in cis-regulatory sequences appear to significantly contribute to this phenomenon. While the relative significance of these changes and cis-regulatory variation in general in governing morphological evolution remains an important topic of debate[56],[57], we believe that the presented catalog of cis-regulatory changes constitutes a valuable resource to further illuminate this discussion.
One of the principal challenges in current biology is to understand the relationship between genetic and phenotypic variation . The increasing availability of genomic variation maps of human as well as of model organism populations ( mouse and Arabidopsis ) constitutes an important step towards meeting this challenge . However , despite its excellent track record as a premier model to understand genome function , no genome-wide variation data beyond single-nucleotide variants and microsatellites are currently available for D . melanogaster . Here , we present a comprehensive , nucleotide-resolution catalogue of variants of various types ( single-nucleotide , multi-nucleotide , and structural variants ) for 39 wild-derived inbred D . melanogaster lines based on high-throughput sequencing . This catalogue confirms that non–SNP variants account for more than half of genomic variation , allowing us to provide new insights into the non-random distribution of variants in the Drosophila genome . We further present genome-wide cis-associations with gene expression based on whole adult fly microarray data , revealing significant associations for about 2 , 000 genes . Most associations are sex-specific , providing evidence for a decoupling of the genomic , regulatory architecture between males and females .