RESUMEN
Balkan endemic nephropathy (BEN) is a familial chronic tubulointerstitial disease with insidious onset and slow progression leading to terminal renal failure. The results of molecular biological investigations propose that BEN is a multifactorial disease with genetic predisposition to environmental risk agents. Exome sequencing of 22 000 genes with Illumina Nextera Exome Enrichment Kit was performed on 22 DNA samples (11 Bulgarian patients and 11 Serbian patients). Software analysis was performed via NextGene, Provean, and PolyPhen. The frequency of all annotated genetic variants with deleterious/damaging effect was compared with those of European populations. Then we focused on nonannotated variants (with no data available about them and not found in healthy Bulgarian controls). There is no statistically significant difference between annotated variants in BEN patients and European populations. From nonannotated variants with more than 40% frequency in both patients' groups, we nominated 3 genes with possible deleterious/damaging variants--CELA1, HSPG2, and KCNK5. Mutant genes (CELA1, HSPG2, and KCNK5) in BEN patients encode proteins involved in basement membrane/extracellular matrix and vascular tone, tightly connected to process of angiogenesis. We suggest that an abnormal process of angiogenesis plays a key role in the molecular pathogenesis of BEN.
Asunto(s)
Nefropatía de los Balcanes/genética , Proteoglicanos de Heparán Sulfato/genética , Fallo Renal Crónico/genética , Elastasa Pancreática/genética , Canales de Potasio de Dominio Poro en Tándem/genética , Nefropatía de los Balcanes/patología , Exoma/genética , Predisposición Genética a la Enfermedad , Genotipo , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Fallo Renal Crónico/patologíaRESUMEN
Adaptability depends on the presence of additive genetic variance for important traits. Yet few estimates of additive genetic variance and heritability are available for wild populations, particularly so for fishes. Here, we estimate heritability of length-at-age for wild-living brown trout (Salmo trutta), based on long-term mark-recapture data and pedigree reconstruction based on large-scale genotyping at 15 microsatellite loci. We also tested for the presence of maternal and paternal effects using a Bayesian version of the Animal model. Heritability varied between 0.16 and 0.31, with reasonable narrow confidence bands, and the total phenotypic variance increased with age. When introducing dam as an additional random effect (accounting for c. 7% of total phenotypic variance), the level of additive genetic variance and heritability decreased (0.12-0.21). Parental size (both for sires and for dams) positively influenced length-at-age for juvenile trout--either through direct parental effects or through genotype-environment correlations. Length-at-age is a complex trait reflecting the effects of a number of physiological, behavioural and ecological processes. Our data show that fitness-related traits such as length-at-age can retain high levels of additive genetic variance even when total phenotypic variance is high.
