Unraveling the relationship between genetic variation and phenotypic traits remains a fundamental challenge in biology. Mapping variants underlying complex traits while controlling for confounding environmental factors is often problematic. To address this, we have established a vertebrate genetic resource specifically to allow for robust genotype-to-phenotype investigations. The teleost medaka (Oryzias latipes) is an established genetic model system with a long history of genetic research and a high tolerance to inbreeding from the wild. Here we present the Medaka Inbred Kiyosu-Karlsruhe (MIKK) panel: the first near-isogenic panel of 80 inbred lines in a vertebrate model derived from a wild founder population. Inbred lines provide fixed genomes that are a prerequisite for the replication of studies, studies which vary both the genetics and environment in a controlled manner and functional testing. The MIKK panel will therefore enable phenotype-to-genotype association studies of complex genetic traits while allowing for careful control of interacting factors, with numerous applications in genetic research, human health, and drug development and fundamental biology. Here we present a detailed characterisation of the genetic variation across the MIKK panel, which provides a rich and unique genetic resource to the community by enabling large-scale experiments for mapping complex traits.

/pdf/the-medaka-inbred-kiyosu-karlsruhe-mikk-panel-c7nuqgk2yi.pdf

The Medaka Inbred Kiyosu-Karlsruhe (MIKK) Panel

One of the big challenges in the study of animal behavior is to combine the molecular-level questions of functional genetics, typically performed in the lab, with meaningful combinations of environmental stimuli. Light and temperature are important external cues, influencing the behaviors of organisms. Thus, understanding the combined effect of light and temperature changes on wildtype versus genetically modified animals is a first step to understand the role of individual genes in the ability of animals to cope with changing environments. Many behavioral traits can be extrapolated from behavioral tests performed from automated motion tracking combined with machine learning. The acquired datasets, typically complex and large, can be challenging for subsequent quantitative analyses. Here we investigate medaka behavior of tmt-opsin2 mutants versus corresponding wildtypes under different light and temperature conditions using automated tracking combined with a convolutional neuronal network and a Hidden Markov model-based approach. The temperatures in this study can occur in summer versus late spring/early autumn in the natural habitat of medakafish. Under summer-like temperature, tmt-opsin2 mutants did not exhibit changes in overall locomotion, consistent with previous observations. However, detailed analyses of fish position revealed that tmt-opsin2 mutants spent more time in central locations of the dish, possibly due to decreased anxiety. Furthermore, a clear difference in location and overall movement was obvious between mutant and wildtypes under colder conditions. These data indicate a role of tmt-opsin2 in behavioral adjustment, at least in part depending on the season.

/pdf/characterization-of-tmt-opsin2-in-medaka-fish-provides-opl0zwvf42.pdf

Characterization of tmt-opsin2 in Medaka Fish Provides Insight Into the Interplay of Light and Temperature for Behavioral Regulation.

High-quality sequence assembly is the ultimate representation of complete genetic information of an individual. Several ongoing pangenome projects are producing collections of high-quality assemblies of various species. Here, we show how to represent the sequenced genomes in 2–3 orders of magnitude smaller space, allowing easy and fast extraction of any contig or its part.

AGC: Compact representation of assembled genomes

Background
Epigenomic experiments can be used to survey the chromatin state of the human genome and find functionally relevant sequences in given cells. However, the reference genome that is typically used to interpret these data does not account for SNPs, indels, and other structural variants present in the individual being profiled. Fortunately, population studies and whole genome sequencing can assemble tens of thousands of sequences that are not in the reference, including mobile element insertions (MEIs), which are known to influence the epigenome. We hypothesized that the use of a genome graph, which can capture this genetic diversity, could help identify more peaks and reveal notable regulatory sequences hidden by the use of a biased reference.

Results
Given the contributions of MEIs to the evolution of human innate immunity, we wanted to test this hypothesis in macrophages derived from 35 individuals of African and European ancestry before and after in-vitro Influenza infection. We used local assembly to resolve non-reference MEIs based on linked reads obtained from these individuals and reconstructed over five thousand Alu, over three hundred L1, and tens of SVA and ERV insertions. Next, we built a genome graph representing SNPs, indels and MEIs in these genomes and demonstrated improved read mapping sensitivity and specificity. Aligning H3K27ac and H3K4me1 ChIP-seq and ATAC-seq data on this genome graph revealed between 2 to 6 thousand novel peaks per sample. Notably, we observed hundreds of polymorphic MEIs that were marked by active histone modifications or accessible chromatin, of which 12 were associated with differential gene expression. Lastly, we found a MEI polymorphism in an active epigenomic state that is associated with the expression of TRIM25, a gene that restricts influenza RNA synthesis.

Conclusion
Our results demonstrate that the use of graph genomes capturing genetic variability can reveal notable regulatory regions that would have been missed by standard analytical approaches.

/pdf/genome-graphs-detect-human-polymorphisms-in-active-25ulhtwq6j.pdf

Genome graphs detect human polymorphisms in active epigenomic states during influenza infection

Development and function of the heart are crucially controlled by individual genetic factors determining the continuum from health to disease. A prime example of a quantitative pathological phenotype is left ventricular hypoplasia, affecting the left ventricle (LV) and its associated inflow and outflow structures and reducing its size to varying degrees1. Current models suggest polygenic contributions on heart development and disease, but we are just beginning to understand the impact of naturally occurring sequence variations. Here we show how natural genetic variants exert cumulative, environment-sensitive effects on both embryonic heart development as well as adult heart function. We addressed this in embryos of five inbred strains of the Japanese rice fish medaka (Oryzias latipes2 and Oryzias sakaizumii3), analyzing heart rates as a functional proxy to capture combined characteristics of the conduction system and structural morphology. We identified one strain, HO52, with embryonic hypoplastic ventricles, fast heart rates, and significantly impaired cardiac function and overall fitness in adults. We created an interpopulation cross of the divergent HO5 strain to HdrR, which exhibits a morphologically normal heart and comparably slow heart rates, to leverage segregation variance in the second filial generation (F2) for genetic mapping. The correlation of 1192 individually phenotyped F2 embryos (heart rate) with the corresponding whole-genome sequences established a single nucleotide polymorphism-based linkage map. Integrated analysis of parental cardiac transcriptomes highlighted 59 loci containing genes prominently linked to human cardiovascular phenotypes. In vivo knockout models of the top 12 candidate genes demonstrated a causal and differential impact on heart development, ventricular size, and heart rate, evidencing the polygenic nature of heart phenotypes and establishing new loci for genetic diagnostics of human congenital heart disease. The controllable and scalable genetics and experimental validation in inbred vertebrate models complement and expand human association studies to provide novel and unique insights into the role of natural genetic variation in the mechanism of cardiac disease and allow to identify genetic susceptibility in individual human subjects.

Natural genetic variation quantitatively regulates heart-rate and -dimension

The teleost medaka (Oryzias latipes) is a well-established vertebrate model system, with a long history of genetic research, and multiple high-quality reference genomes available for several inbred strains (HdrR, HNI and HSOK). Medaka has a high tolerance to inbreeding from the wild, thus allowing one to establish inbred lines from wild founder individuals. We have exploited this feature to create an inbred panel resource: the Medaka Inbred Kiyosu-Karlsruhe (MIKK) panel. This panel of 80 near-isogenic inbred lines contains a large amount of genetic variation inherited from the original wild population. We used Oxford Nanopore Technologies (ONT) long read data to further investigate the genomic and epigenomic landscapes of a subset of the MIKK panel. Nanopore sequencing allowed us to identify a much greater variety of high-quality structural variants compared with Illumina sequencing. We also present results and methods using a pan-genome graph representation of 12 individual medaka lines from the MIKK panel. This graph-based reference MIKK panel genome revealed novel differences between the MIKK panel lines compared to standard linear reference genomes. We found additional MIKK panel-specific genomic content that would be missing from linear reference alignment approaches. We were also able to identify and quantify the presence of repeat elements in each of the lines. Finally, we investigated line-specific CpG methylation and performed differential DNA methylation analysis across the 12 lines. We thus present a detailed analysis of the MIKK panel genomes using long and short read sequence technologies, creating a MIKK panel specific pan genome reference dataset allowing for the investigation of novel variation types that would be elusive using standard approaches.

/pdf/genomic-variations-and-epigenomic-landscape-of-the-medaka-4lucxlu77s.pdf

Genomic variations and epigenomic landscape of the Medaka Inbred Kiyosu-Karlsruhe (MIKK) panel

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Genomic variations and epigenomic landscape of the Medaka Inbred Kiyosu-Karlsruhe (MIKK) panel