Multistep Ion Channel Remodeling and Lethal Arrhythmia Precede Heart Failure in a Mouse Model of Inherited Dilated Cardiomyopathy

Background: Patients with inherited dilated cardiomyopathy (DCM) frequently die with severe heart failure (HF) or die suddenly with arrhythmias, although these symptoms are not always observed at birth. It remains unclear how and when HF and arrhythmogenic changes develop in these DCM mutation carriers. In order to address this issue, properties of the myocardium and underlying gene expressions were studied using a knock-in mouse model of human inherited DCM caused by a deletion mutation DK210 in cardiac troponinT. Methodology/Principal Findings: By 1 month, DCM mice had already enlarged hearts, but showed no symptoms of HF and a much lower mortality than at 2 months or later. At around 2 months, some would die suddenly with no clear symptoms of HF, whereas at 3 months, many of the survivors showed evident symptoms of HF. In isolated left ventricular myocardium (LV) from 2 month-mice, spontaneous activity frequently occurred and action potential duration (APD) was prolonged. Transient outward (Ito) and ultrarapid delayed rectifier K + (IKur) currents were significantly reduced in DCM myocytes. Correspondingly, down-regulation of Kv4.2, Kv1.5 and KChIP2 was evident in mRNA and protein levels. In LVs at 3-months, more frequent spontaneous activity, greater prolongation of APD and further down-regulation in above K + channels were observed. At 1 month, in contrast, infrequent spontaneous activity and down-regulation of Kv4.2, but not Kv1.5 or KChIP2, were observed

Massive haplotypes underlie ecotypic differentiation in sunflowers

Species often include multiple ecotypes that are adapted to different environments 1. However, it is unclear how ecotypes arise and how their distinctive combinations of adaptive alleles are maintained despite hybridization with non-adapted populations 2-4. Here, by resequencing 1,506 wild sunflowers from 3 species (Helianthus annuus, Helianthus petiolaris and Helianthus argophyllus), we identify 37 large (1-100 Mbp in size), non-recombining haplotype blocks that are associated with numerous ecologically relevant traits, as well as soil and climate characteristics. Limited recombination in these haplotype blocks keeps adaptive alleles together, and these regions differentiate sunflower ecotypes. For example, haplotype blocks control a 77-day difference in flowering between ecotypes of the silverleaf sunflower H. argophyllus (probably through deletion of a homologue of FLOWERING LOCUS T (FT)), and are associated with seed size, flowering time and soil fertility in dune-adapted sunflowers. These haplotypes are highly divergent, frequently associated with structural variants and often appear to represent introgressions from other-possibly now-extinct-congeners. These results highlight a pervasive role of structural variation in ecotypic adaptation. Local adaptation is common in species that experience different environments across their range, often resulting in the formation of ecotypes-ecological races with distinct morphological and/or physiological characteristics that provide an environment-specific fitness advantage. Despite the prevalence of ecotypic differentiation, much remains to be understood about the genetic basis and evolutionary mechanisms that underlie its establishment and maintenance. In particular , a longstanding evolutionary question-dating to criticisms of Darwin's theories by his contemporaries 4-concerns how such ecological divergence can occur when challenged by hybridization with non-adapted populations 2. Local adaptation typically requires alleles at multiple loci that contribute to increased fitness in the same environment ; however, different ecotypes are often geographically close and interfertile, and hybridization between them should break up adaptive allelic combinations 3. To better understand the genetic basis of local adaptation and ecotypic differentiation, we conducted an in-depth study of genetic, phenotypic and environmental variation in three annual sunflower species, each of which includes multiple reproductively compatible ecotypes. Two species (H. annuus and H. petiolaris) have broad, overlapping distributions across North America. Helianthus annuus, the common sunflower, is generally found on mesic soils, but can grow in a variety of disturbed or extreme habitats, including semi-desert or frequently flooded areas. An especially well-characterized ecotype (formally known as H. annuus subsp. texanus) is adapted to the higher temperatures and herbivore pressures in Texas (USA) 5. Helianthus petiolaris, the prairie sunflower, prefers sandier soils; ecotypes of this species are adapted to sand sheets and dunes 6. The third species-H. argophyllus, the silverleaf sunflower-is endemic to southern Texas and includes both an early-flowering, coastal-island ecotype and a late-flowering inland ecotype 7. Population structure of wild sunflowers In a common garden experiment, we grew 10 plants from each of 151 populations of the 3 species, selected from across their native range (Fig. 1a); for each of these populations, we collected corresponding soil samples. We generated extensive records of developmental and morphological traits, and resequenced the genomes of 1,401 individual plants. We resequenced an additional 105 H. annuus plants to fill gaps in geographical coverage, as well as 12 outgroup taxa (Supplementary Table 1). Sunflower genomes are relatively large (H. annuus, 3.5 Gbp; https://doi