Mono- and bi-allelic effects of coding variants on disease in 176,899 Finns

Identifying Mendelian diseases with recessive inheritance is challenging as the majority of cases are caused by compound heterozygous genotypes which require sequencing data in families to definitively identify. Bottleneck events, such as in the Finnish population, enrich specific homozygous variants to higher frequencies and thus facilitate identification of disease associations through easily recognized homozygous genotypes. Here, we study homozygous and heterozygous effects of 82,516 coding variants on 2,444 disease endpoints using nationwide electronic health record (EHR) data of 176,899 Finns. We find known and novel associations to homozygous genotypes across a broad spectrum of phenotypes such as retinal dystrophy, adult-onset cataract and female infertility (13/20 of which would have been missed by the traditional additive GWAS model). With these results, and supporting simulations, we demonstrate the added benefit of homozygous scans in GWAS. We further use these results to explore inheritance patterns of known Mendelian variants. We find many Mendelian variants whose inheritance cannot be adequately described with the traditional definition of dominant or recessive. In particular, we find disease risk in heterozygous carriers of variants known to cause disease with recessive inheritance, as well as for variants labeled benign in ClinVar. Our results demonstrate how biobank efforts, particularly in founder populations, can broaden our understanding of the impact of genetic variants.

Genome-wide selection signatures reveal widespread synergistic effects of culture conditions and temperature stress in Drosophila melanogaster

Experimental evolution combined with whole-genome sequencing is a powerful approach to study the adaptive architecture of selected traits, in particular when replicated experimental populations evolving in opposite selective conditions (e.g. hot vs. cold temperature) are compared. Nevertheless, such comparisons could be affected by environmental effects shared between selective regimes (e.g. laboratory adaptation), which complicate the interpretation of selection signatures. Here, we used an experimental design, which takes advantage of the simplicity of selection signatures from founder populations with reduced variation, to study the fitness consequences of the laboratory environment (culture conditions) at two temperature regimes. After 20 generations of adaptation at 18°C and 29°C, strong genome-wide selection signatures were observed. About one third of the selection signatures can be either attributed to temperature effects, laboratory adaptation or the joint effects of both. The fitness consequences reflecting the combined effects of temperature and laboratory adaptation were more extreme in the hot environment for 83% of the affected genomic regions, fitting the pattern of larger expression differences between founders at 29°C. We propose that evolve and resequence (E&R) with reduced genetic variation allows to study genome-wide fitness consequences driven by the interaction of multiple environmental factors.

Genetic and genomic architecture in eight strains of the laboratory opossum Monodelphis domestica

The gray short-tailed opossum (Monodelphis domestica) is an established laboratory-bred marsupial model for biomedical research. It is a critical species for comparative genomics research, providing the pivotal phylogenetic outgroup for studies of derived vs. ancestral states of genomic/epigenomic characteristics for eutherian mammal lineages. To characterize the current genetic profile of this laboratory marsupial, we examined 79 individuals from eight established laboratory strains. Double digest restriction-site associated DNA sequencing (ddRAD-seq) and whole-genome resequencing experiments were performed to investigate the genetic architecture in these strains. A total of 66,640 high-quality single nucleotide polymorphisms (SNPs) were identified. We analyzed SNP density, average heterozygosity, nucleotide diversity, and population differentiation parameter Fst within and between the eight strains. Principal component and population structure analysis clearly resolve the strains at the level of their ancestral founder populations, and the genetic architecture of these strains correctly reflects their breeding history. We confirmed the successful establishment of the first inbred laboratory opossum strain LSD (inbreeding coefficient F > 0.99) and a nearly inbred strain FD2M1 (0.98 < F < 0.99), each derived from a different ancestral background. These strains are suitable for various experimental protocols requiring controlled genetic backgrounds and for intercrosses and backcrosses that can generate offspring with informative SNPs for studying a variety of genetic and epigenetic processes. Together with recent advances in reproductive manipulation and CRISPR/Cas9 techniques for M. domestica, the existence of distinctive inbred strains will enable genome editing on different genetic backgrounds, greatly expanding the utility of this marsupial model for biomedical research.

Combining modelling, field data and genetic variation to understand the post-reintroduction population genetics of the Marsh Fritillary butterfly (Euphydryas aurinia)

The Marsh Fritillary butterfly (Euphydryas aurinia) is a Eurasian species which has suffered significant reductions in occurrence and abundance over the past century, particularly across the western side of its range, due to agricultural intensification and habitat loss. This loss has been particularly severe in the UK with extensive localised extinctions. Following sympathetic management, reintroduction was undertaken at four Cumbria (northern UK) sites in 2007 with stock from a captive admixture population descended from Cumbrian and Scottish founders. Annual population monitoring of the reintroductions was undertaken. Nine years post-reintroduction, the level of population genetic variation was assessed using microsatellites. Variation in historical Cumbrian samples was determined using museum samples and Scottish samples from current populations were assayed to characterise natural population variation. Half of the Scottish sites also served as indicators of the alleles present in the founder populations. The genetic contribution of the founder populations allied to population size data allowed patterns of genetic variation to be modelled. Alleles from Cumbrian and Scottish founders are present in the reintroduced populations. The four sites have levels of variation akin to natural populations and exhibit differentiation as predicted by statistical modelling and comparable with natural populations. This suggests that reintroduction following captive breeding can produce self-sustaining populations with natural levels of genetic diversity. These populations appear to be undergoing the same evolutionary dynamics with bottlenecks and drift as natural populations. Implications for insect conservation Reintroduction of captive bred individuals is a viable strategy for producing populations with natural levels of genetic diversity and evolutionary dynamics. Hybridisation of populations on the brink of extinction with those thriving can preserve some of the genetic distinctiveness of the declining population.

Current Developments in Detection of Identity-by-Descent Methods and Applications

Identity-by-descent (IBD), the detection of shared segments inherited from a common ancestor, is a fundamental concept in genomics with broad applications in the characterization and analysis of genomes. While historically the concept of IBD was extensively utilized through linkage analyses and in studies of founder populations, applications of IBD-based methods subsided during the genome-wide association study era. This was primarily due to the computational expense of IBD detection, which becomes increasingly relevant as the field moves toward the analysis of biobank-scale datasets that encompass individuals from highly diverse backgrounds. To address these computational barriers, the past several years have seen new methodological advances enabling IBD detection for datasets in the hundreds of thousands to millions of individuals, enabling novel analyses at an unprecedented scale. Here, we describe the latest innovations in IBD detection and describe opportunities for the application of IBD-based methods across a broad range of questions in the field of genomics.

Ancestral polymorphisms shape the adaptive radiation of Metrosideros across the Hawaiian Islands

Some of the most spectacular adaptive radiations begin with founder populations on remote islands. How genetically limited founder populations give rise to the striking phenotypic and ecological diversity characteristic of adaptive radiations is a paradox of evolutionary biology. We conducted an evolutionary genomics analysis of genus Metrosideros, a landscape-dominant, incipient adaptive radiation of woody plants that spans a striking range of phenotypes and environments across the Hawaiian Islands. Using nanopore-sequencing, we created a chromosome-level genome assembly for Metrosideros polymorpha var. incana and analyzed whole-genome sequences of 131 individuals from 11 taxa sampled across the islands. Demographic modeling and population genomics analyses suggested that Hawaiian Metrosideros originated from a single colonization event and subsequently spread across the archipelago following the formation of new islands. The evolutionary history of Hawaiian Metrosideros shows evidence of extensive reticulation associated with significant sharing of ancestral variation between taxa and secondarily with admixture. Taking advantage of the highly contiguous genome assembly, we investigated the genomic architecture underlying the adaptive radiation and discovered that divergent selection drove the formation of differentiation outliers in paired taxa representing early stages of speciation/divergence. Analysis of the evolutionary origins of the outlier single nucleotide polymorphisms (SNPs) showed enrichment for ancestral variations under divergent selection. Our findings suggest that Hawaiian Metrosideros possesses an unexpectedly rich pool of ancestral genetic variation, and the reassortment of these variations has fueled the island adaptive radiation.

Genetic and genomic architecture in eight strains of the laboratory opossum Monodelphis domestica

The gray short-tailed opossum is an established laboratory-bred marsupial model for biomedical research. It serves as a critical species for comparative genomics research, providing the pivotal phylogenetic outgroup for studies of derived vs. ancestral states of genomic/epigenomic characteristics for all eutherian mammal lineages. To characterize the current genetic profile of this laboratory marsupial, we examined 79 individuals from eight established laboratory strains. Double digest restriction-site associated DNA sequencing (ddRAD-seq) and whole-genome resequencing experiments were performed to investigate the genetic architecture in these strains. A total of 66,640 high-quality single nucleotide polymorphisms (SNPs) were identified. We analyzed SNP density, average heterozygosity, nucleotide diversity, and population differentiation parameter Fst within and between the eight strains. Principal component and population structure analysis clearly resolve the strains at the level of their ancestral founder populations, and the genetic architecture of these strains correctly reflects their breeding history. We confirmed the successful establishment of the first inbred laboratory opossum strain LSD (inbreeding coefficient F > 0.99) and a nearly inbred strain FD2M1 (0.98 < F < 0.99), each derived from a different ancestral background. These strains are suitable for various experimental protocols requiring controlled genetic backgrounds and for intercrosses and backcrosses that can generate offspring with informative SNPs for studying a variety of genetic and epigenetic processes. Together with recent advances in reproductive manipulation and CRISPR/Cas9 techniques for M. domestica, the existence of distinctive inbred strains will enable genome editing on different genetic backgrounds, greatly expanding the utility of this marsupial model for biomedical research.

Genetic Diversity and Identification of Homozygosity-Rich Genomic Regions in Seven Italian Heritage Turkey (Meleagris gallopavo) Breeds

Italian autochthonous turkey breeds are an important reservoir of genetic biodiversity that should be maintained with an in vivo approach. The aim of this study, part of the TuBAvI national project on biodiversity, was to use run of homozygosity (ROH), together with others statistical approaches (e.g., Wright’s F-statistics, principal component analysis, ADMIXTURE analysis), to investigate the genomic diversity in several heritage turkey breeds. We performed a genome-wide characterization of ROH-rich regions in seven autochthonous turkey breeds, i.e., Brianzolo (Brzl), Bronzato Comune Italiano (BrCI), Bronzato dei Colli Euganei (CoEu), Parma e Piacenza (PrPc), Nero d’Italia (NeIt), Ermellinato di Rovigo (ErRo) and Romagnolo (Roma). ROHs were detected based on a 650K SNP genotyping. ROH_islands were identified as homozygous ROH regions shared by at least 75% of birds (within breed). Annotation of genes was performed with DAVID. The admixture analyses revealed that six breeds are unique populations while the Roma breed consists in an admixture of founder populations. Effective population size estimated on genomic data shows a numeric contraction. ROH_islands harbour genes that may be interesting for target selection in commercial populations also. Among them the PTGS2 and PLA2G4A genes on chr10 were related to reproduction efficiency. This is the first study mapping genetic variation in autochthonous turkey populations. Breeds were genetically different among them, with the Roma breed proving to be a mixture of the other breeds. The ROH_islands identified harboured genes peculiar to the selection that occurred in heritage breeds. Finally, this study releases previously undisclosed information on existing genetic variation in the turkey species.

Evidence of long-term purging of mutation load in killer whale genomes

Genomes of high latitude killer whales harbour signatures of post-glacial founding and expansion. Here, we investigate whether reduced efficacy of selection increased mutation load in founder populations, or whether recessive deleterious mutations exposed to selection in homozygous genotypes were purged. Comparing the accumulation of synonymous and non-synonymous mutations across pairs of globally sampled genomes reveals that the most significant outliers are high latitude North Atlantic genomes, which have accumulated significantly fewer non-synonymous mutations than all other populations. Comparisons with the genome of a 7.5-Kyr-old North Atlantic killer whale, inferred to be closely related to the population directly ancestral to present-day Icelandic and Norwegian populations, calibrates the timing of the action of selection on non-synonymous mutations predominantly to the mid-late Holocene. Non-synonymous mutations purged in modern Norwegian killer whale genomes are found as globally shared standing variation in heterozygote genotypes more often than expected, suggesting overdominance. Taken together, our findings are consistent with purging of recessive non-synonymous mutations exposed to selection in founder-associated homozygous genotypes.

The genetic architecture of temperature adaptation is shaped by population ancestry and not by selection regime

Background Understanding the genetic architecture of temperature adaptation is key for characterizing and predicting the effect of climate change on natural populations. One particularly promising approach is Evolve and Resequence, which combines advantages of experimental evolution such as time series, replicate populations, and controlled environmental conditions, with whole genome sequencing. Recent analysis of replicate populations from two different Drosophila simulans founder populations, which were adapting to the same novel hot environment, uncovered very different architectures—either many selection targets with large heterogeneity among replicates or fewer selection targets with a consistent response among replicates. Results Here, we expose the founder population from Portugal to a cold temperature regime. Although almost no selection targets are shared between the hot and cold selection regime, the adaptive architecture was similar. We identify a moderate number of targets under strong selection (19 selection targets, mean selection coefficient = 0.072) and parallel responses in the cold evolved replicates. This similarity across different environments indicates that the adaptive architecture depends more on the ancestry of the founder population than the specific selection regime. Conclusions These observations will have broad implications for the correct interpretation of the genomic responses to a changing climate in natural populations.