De novo variants in the RNU4-2 snRNA cause a frequent neurodevelopmental syndrome

Around 60% of individuals with neurodevelopmental disorders (NDD) remain undiagnosed after comprehensive genetic testing, primarily of protein-coding genes1. Large genome-sequenced cohorts are improving our ability to discover new diagnoses in the non-coding genome. Here, we identify the non-coding RNA RNU4-2 as a syndromic NDD gene. RNU4-2 encodes the U4 small nuclear RNA (snRNA), which is a critical component of the U4/U6.U5 tri-snRNP complex of the major spliceosome2. We identify an 18 bp region of RNU4-2 mapping to two structural elements in the U4/U6 snRNA duplex (the T-loop and Stem III) that is severely depleted of variation in the general population, but in which we identify heterozygous variants in 115 individuals with NDD. Most individuals (77.4%) have the same highly recurrent single base insertion (n.64_65insT). In 54 individuals where it could be determined, the de novo variants were all on the maternal allele. We demonstrate that RNU4-2 is highly expressed in the developing human brain, in contrast to RNU4-1 and other U4 homologs. Using RNA-sequencing, we show how 5’ splice site usage is systematically disrupted in individuals with RNU4-2 variants, consistent with the known role of this region during spliceosome activation. Finally, we estimate that variants in this 18 bp region explain 0.4% of individuals with NDD. This work underscores the importance of non-coding genes in rare disorders and will provide a diagnosis to thousands of individuals with NDD worldwide

The origin of plastids

It is generally accepted that plastids first arose by acquisition of photosynthetic prokaryotic endosymbionts by non-photosynthetic eukaryotic hosts. It is also accepted that photosynthetic eukaryotes were acquired on several occasions as endosymbionts by non-photosynthetic eukaryote hosts to form secondary plastids. In some lineages, secondary plastids were lost and new symbionts were acquired, to form tertiary plastids. Most recent work has been interpreted to indicate that primary plastids arose only once, referred to as a ‘monophyletic’ origin. We critically assess the evidence for this. We argue that the combination of Ockham's razor and poor taxon sampling will bias studies in favour of monophyly. We discuss possible concerns in phylogenetic reconstruction from sequence data. We argue that improved understanding of lineage-specific substitution processes is needed to assess the reliability of sequence-based trees. Improved understanding of the timing of the radiation of present-day cyanobacteria is also needed. We suggest that acquisition of plastids is better described as the result of a process rather than something occurring at a discrete time, and describe the ‘shopping bag’ model of plastid origin. We argue that dinoflagellates and other lineages provide evidence in support of this

Genetic diversity of Calpain 1 gene in Bolivian Creole, Nellore and Brahman bovine breeds in Bolivia

In Bolivia, beef production is mainly based on two genotypes, Bos taurus (Creole cattle) and B. indicus (zebu), being weight gain the main selection criteria used by farmers. However, meat quality and especially tenderness must be incorporated in the selection process. Meat tenderness is partly determined by the calpain (CAPN1)/calpastatin (CAST) protein system. Thus, the objective of the present work was to determine and compare the genetic variability of the CAPN1 gene in Creole (CreBo), Brahman (BraBo) and Nellore (NelBo) breeds in Bolivia. DNA was extracted from blood samples from 147 CreBo, 59 BraBo and 93 NelBo, and three polymorphisms were genotyped using ARMS-PCR (CAPN1-316 and CAPN1-4751) and PCR-RFLP (CAPN1-530). Furthermore, CAPN1-316 and CAPN1-4751 were analyzed with Axiom™ Bos 1 Genotyping Array r3. Allele frequencies associated with higher tenderness in CreBo, BraBo and NelBo were 0.22, 0 and 0.09 (CAPN1-316 C), 0.76, 0.16 and 0.08 (CAPN1-4751 C), and 0.77, 0.92 and 0.94 (CAPN1-530 G). Linkage disequilibrium (LD) analysis revealed the presence of two LD blocks. Our results evidence that CreBo has a higher frequency of alleles associated with higher meat tenderness than the analyzed zebu breeds. These markers could be used in breeding programs to improve Bolivian cattle herd meat quality either by selection within Creole breeds or crosses with zebu cattle.En Bolivia, la producción de carne se basa principalmente en la cría de dos genotipos, Bos taurus (ganado Criollo) y B. indicus (cebú), siendo la ganancia de peso el principal criterio de selección utilizado por los criadores. Sin embargo, la calidad y especialmente la terneza de la carne deben ser incorporadas al proceso de selección. La terneza en parte está determinada por el sistema proteico calpaína (CAPN1)/calpastatina (CAST). Por lo tanto, el objetivo del presente trabajo fue determinar y comparar la variabilidad genética del gen CAPN1 en las razas Criolla (CreBo), Brahman (BraBo) y Nelore (NelBo) de Bolivia. El ADN se extrajo de muestras de sangre de 147 CreBo, 59 BraBo y 93 NelBo, y tres polimorfismos se genotipificaron por ARMS-PCR (CAPN1-316 y CAPN1-4751) y PCR-RFLP (CAPN1-530). Adicionalmente, CAPN1-316 y CAPN1-4751 fueron analizados con el microarray Axiom™ Bos 1 Genotyping Array r3. Las frecuencias de los alelos asociados con una mayor terneza en CreBo, BraBo y NelBo fueron 0,22, 0 y 0,09 (CAPN1-316 C), 0,76, 0,16 y 0,08 (CAPN1-4751 C), y 0,77, 0,92 y 0,94 (CAPN1-530 G). El análisis del desequilibrio de ligamiento reveló la presencia de dos bloques. Estos resultados muestran que CreBo presenta una mayor frecuencia de alelos asociados a mayor terneza en la carne que las razas cebuinas analizadas. Estos marcadores podrían ser utilizados en los programas de cría para mejorar la calidad de la carne del ganado boliviano, tanto por selección dentro del ganado Criollo como por cruzamiento con ganado cebú