The Medaka Inbred Kiyosu-Karlsruhe (MIKK) Panel

Abstract

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.

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

“…The MIKK panel lines were established from a wild Medaka ( Oryzias latipes ) population as detailed in our back to back companion paper [4]. Liver and brain samples dissection procedures are also described in detail in the companion paper.…”

“…Additional information on the Structural variant calling analysis can be found at: https://birneylab.github.io/MIKK_genome_companion_paper/Nanopore_SV_analysis/. To polish the calls with Illumina reads, we used the Illumina reads and VCF described in [4] with SViper v2.0.0 (https://github.com/smehringer/SViper) to produce a “polished” set of structural variants for 9 of the 12 MIKK panel samples. We used bcftools v1.9 and Picard v2.25.0 [43,44] to further process the data, then R version 4.0.4 and a suite of R packages [45–55] to carry out the analysis set out in full at: https://brettellebi.github.io/mikk_genome/20210409_sv_notebook.html.…”

“…We aligned the DNA-Seq nanopore reads for each of our 12 MIKK samples to the pangenome graph using minigraph2 v0.10 [11] (−x lr mode) and obtained alignment files in GAF format. We also aligned the 50 Illumina RNA-Seq datasets obtained from MIKK lines liver samples described in [4] to the graph. However since pair-end mapping is not supported by minigraph, we first merged overlapping pairs together using Flash v1.2.11 [62], then aligned the merged reads to the graph with minigraph2 v0.10 [11] (−x sr mode).…”

“…We took advantage of its unusually high tolerance to inbreeding to establish the Medaka Inbred Kiyosu-Karlsruhe (MIKK) panel: the largest collection of near-isogenic vertebrate lines derived from a single wild population [3]. In the companion article published with this one, we provide a detailed genetic characterisation of the 80 individual MIKK panel lines [4], based on the alignment of Illumina short reads to the closest, fully-assembled reference genome – the southern Japanese medaka inbred strain, HdrR . Although this allowed us to discover much of the genetic variation in the MIKK panel relative to HdrR , the approach inevitably kept certain variants hidden, including larger and more complex structural variation – “dark variation” – that is likely to have functional consequences for each of the lines.…”

Private and sub-family specific mutations of founder haplotypes in the BXD family reveal phenotypic consequences relevant to health and disease

“…Recombinant inbred (RI) strainsinbred strains produced from crosses of two or more inbred parentshave been generated and used for a wide variety of applications in many species that tolerate inbreeding, including yeast 1 , many plants [2][3][4][5] , flies 6,7 , nematodes 8 , fish 9 , rats and other rodents 10 . The BXD family is the largest and one of the oldest families of RI strains, started in the early 1970s by crossing female C57BL/6J (B6 or B) and male DBA/2J (D2 or D) inbred mice 11 .…”