Deep Molecular Characterization of Milder Spinal Muscular Atrophy Patients Carrying the c.859G>C Variant in SMN2

Spinal muscular atrophy (SMA) is a severe neuromuscular disorder caused by biallelic loss or pathogenic variants in the SMN1 gene. Copy number and modifier intragenic variants in SMN2, an almost identical paralog gene of SMN1, are known to influence the amount of complete SMN proteins. Therefore, SMN2 is considered the main phenotypic modifier of SMA, although genotype-phenotype correlation is not absolute. We present eleven unrelated SMA patients with milder phenotypes carrying the c.859G>C-positive modifier variant in SMN2. All were studied by a specific NGS method to allow a deep characterization of the entire SMN region. Analysis of two homozygous cases for the variant allowed us to identify a specific haplotype, Smn2-859C.1, in association with c.859G>C. Two other cases with the c.859G>C variant in their two SMN2 copies showed a second haplotype, Smn2-859C.2, in cis with Smn2-859C.1, assembling a more complex allele. We also identified a previously unreported variant in intron 2a exclusively linked to the Smn2-859C.1 haplotype (c.154-1141G>A), further suggesting that this region has been ancestrally conserved. The deep molecular characterization of SMN2 in our cohort highlights the importance of testing c.859G>C, as well as accurately assessing the SMN2 region in SMA patients to gain insight into the complex genotype-phenotype correlations and improve prognostic outcomes

A pathway-centered analysis of pig domestication and breeding in eurasia

Ascertaining the molecular and physiological basis of domestication and breeding is an active area of research. Due to the current wide distribution of its wild ancestor, the wild boar, the pig (Sus scrofa) is an excellent model to study these processes, which occurred independently in East Asia and Europe ca. 9,000 years ago. Analyzing genome variability patterns in terms of metabolic pathways is attractive since it considers the impact of interrelated functions of genes, in contrast to genome-wide scans that treat genes or genome-windows in isolation. To that end, we studied 40 wild boars and 123 domestic pig genomes from Asia and Europe when metabolic pathway was the unit of analysis. We computed statistical significance for differentiation (Fst) and linkage disequilibrium (nSL) statistics at the pathway level. In terms of Fst, we found 21 and 12 pathways significantly differentiated at a q-value < 0.05 in Asia and Europe, respectively; five were shared across continents. In Asia, we found six significant pathways related to behavior, which involved essential neurotransmitters like dopamine and serotonin. Several significant pathways were interrelated, and shared a variable percentage of genes. There were 12 genes present in more than 10 significant pathways (in terms of Fst), comprising genes involved in the transduction of a large number of signals, like phospholipase PCLB1, which is expressed in the brain, or ITPR3, which has an important role in taste transduction. In terms of nSL, significant pathways were mainly related to reproductive performance (ovarian steroidogenesis), an important target trait as well during domestication and modern animal breeding. Different levels of recombination cannot explain these results, since we found no correlation between Fst and recombination rate. However, we did find an increased ratio of deleterious mutations in domestic vs. wild populations, suggesting a relaxed functional constraint associated with the domestication and breeding processes. Purifying selection was, nevertheless, stronger in significantly differentiated pathways than in random pathways, mainly in Europe. We conclude that pathway analysis facilitates the biological interpretation of genome-wide studies. Notably in the case of pig, behavior played an important role, among other physiological and developmental processes

A pathway-centered analysis of pig domestication and breeding in Eurasia

Ascertaining the molecular and physiological basis of domestication and breeding is an active area of research. Due to the current wide distribution of its wild ancestor, the wild boar, the pig (Sus scrofa) is an excellent model to study these processes, which occurred independently in East Asia and Europe ca. 9000 yr ago. Analyzing genome variability patterns in terms of metabolic pathways is attractive since it considers the impact of interrelated functions of genes, in contrast to genome-wide scans that treat genes or genome windows in isolation. To that end, we studied 40 wild boars and 123 domestic pig genomes from Asia and Europe when metabolic pathway was the unit of analysis. We computed statistical significance for differentiation (Fst) and linkage disequilibrium (nSL) statistics at the pathway level. In terms of Fst, we found 21 and 12 pathways significantly differentiated at a q -value 10 significant pathways (in terms of Fst), comprising genes involved in the transduction of a large number of signals, like phospholipase PCLB1, which is expressed in the brain, or ITPR3, which has an important role in taste transduction. In terms of nSL, significant pathways were mainly related to reproductive performance (ovarian steroidogenesis), a similarly important target trait during domestication and modern animal breeding. Different levels of recombination cannot explain these results, since we found no correlation between Fst and recombination rate. However, we did find an increased ratio of deleterious mutations in domestic vs. wild populations, suggesting a relaxed functional constraint associated with the domestication and breeding processes. Purifying selection was, nevertheless, stronger in significantly differentiated pathways than in random pathways, mainly in Europe. We conclude that pathway analysis facilitates the biological interpretation of genome-wide studies. Notably, in the case of pig, behavior played an important role, among other physiological and developmental processes

Selection pressure in wild and domestic pigs

Resumen del póster presentado al SMBE satellite meeting ‘Towards an integrated concept of adaptation: uniting molecular population genetics and quantitative genetics’, celebrado en Viena (Austria) del 11 al 14 de febrero de 2019.Domestic animal histories are evolutionary experiments that have often lasted for millennia with the result of dramatic phenotypic changes to suit human needs. This history can be quite complex; many events remain unknown or poorly documented. They, therefore, offer a material of utmost interest to study the interplay of demography and accelerated adaptation. The pig (Sus scrofa) is a particularly interesting species and one in which there is abundant genetic tools and sequence data available. It originated in the Southeast Asian region ca. 4 MYA and migrated towards the west, colonizing all climates in Eurasia except the driest. Subsequently, the pig was domesticated out of local wild boars independently in both Asia and Europe ~9,000 years ago. The main purpose of this work is to detect the selective effect of the domestication. Domestication is an intense selection process that occurred in a short evolutive time and, as a result, it is expected that new mutations have been accumulated in a small proportion in relation to the mutations segregating at the whole genome. In all, a genome-wide appraisal of the relevance of protein coding changes associated with domestication is largely incomplete in animal species. To fill this gap, here we have investigated the patterns of selection genome-wide in domestic and wild pigs via the McDonald-Kreitman test (MKT), which exploits the fact that the ratio between non-synonymous and synonymous/silent mutations within a population is distorted under selection when compared to the same ratio in terms of divergence. Thus, we have analyzed the differential ratio of polymorphism-divergence of wild and domestic pigs at genomic, metabolic pathway and gene scale, in order to evaluate the effect of selection and of demographic patterns during the domestication process

The whole genome effect of selection in wild and domestic pigs

Trabajo presentado al VII Bienial Congress of the Spanish Society for Evolutionary Biology (SESBE), celebrado en Sevilla del 5 al 7 de febrero de 2020.Peer reviewe