Balancing selection at a premature stop mutation in the myostatin gene underlies a recessive leg weakness syndrome in pigs

Balancing selection provides a plausible explanation for the maintenance of deleterious alleles at moderate frequency in livestock, including lethal recessives exhibiting heterozygous advantage in carriers. In the current study, a leg weakness syndrome causing mortality of piglets in a commercial line showed monogenic recessive inheritance, and a region on chromosome 15 associated with the syndrome was identified by homozygosity mapping. Whole genome resequencing of cases and controls identified a mutation causing a premature stop codon within exon 3 of the porcine Myostatin (MSTN) gene, similar to those causing a double-muscling phenotype observed in several mammalian species. The MSTN mutation was in Hardy-Weinberg equilibrium in the population at birth, but significantly distorted amongst animals still in the herd at 110 kg, due to an absence of homozygous mutant genotypes. In heterozygous form, the MSTN mutation was associated with a major increase in muscle depth and decrease in fat depth, suggesting that the deleterious allele was maintained at moderate frequency due to heterozygous advantage (allele frequency, q = 0.22). Knockout of the porcine MSTN by gene editing has previously been linked to problems of low piglet survival and lameness. This MSTN mutation is an example of putative balancing selection in livestock, providing a plausible explanation for the lack of disrupting MSTN mutations in pigs despite many generations of selection for lean growth

Traits associated with innate and adaptive immunity in pigs: heritability and associations with performance under different health status conditions

There is a need for genetic markers or biomarkers that can predict resistance towards a wide range of infectious diseases, especially within a health environment typical of commercial farms. Such markers also need to be heritable under these conditions and ideally correlate with commercial performance traits. In this study, we estimated the heritabilities of a wide range of immune traits, as potential biomarkers, and measured their relationship with performance within both specific pathogen-free (SPF) and non-SPF environments. Immune traits were measured in 674 SPF pigs and 606 non-SPF pigs, which were subsets of the populations for which we had performance measurements (average daily gain), viz. 1549 SPF pigs and 1093 non-SPF pigs. Immune traits measured included total and differential white blood cell counts, peripheral blood mononuclear leucocyte (PBML) subsets (CD4+ cells, total CD8α+ cells, classical CD8αβ+ cells, CD11R1+ cells (CD8α+ and CD8α-), B cells, monocytes and CD16+ cells) and acute phase proteins (alpha-1 acid glycoprotein (AGP), haptoglobin, C-reactive protein (CRP) and transthyretin). Nearly all traits tested were heritable regardless of health status, although the heritability estimate for average daily gain was lower under non-SPF conditions. There were also negative genetic correlations between performance and the following immune traits: CD11R1+ cells, monocytes and the acute phase protein AGP. The strength of the association between performance and AGP was not affected by health status. However, negative genetic correlations were only apparent between performance and monocytes under SPF conditions and between performance and CD11R1+ cells under non-SPF conditions. Although we cannot infer causality in these relationships, these results suggest a role for using some immune traits, particularly CD11R1+ cells or AGP concentrations, as predictors of pig performance under the lower health status conditions associated with commercial farms

Autoantibodies neutralizing type I IFNs are present in ~4% of uninfected individuals over 70 years old and account for ~20% of COVID-19 deaths

Publisher Copyright: © 2021 The Authors, some rights reserved.Circulating autoantibodies (auto-Abs) neutralizing high concentrations (10 ng/ml; in plasma diluted 1:10) of IFN-alpha and/or IFN-omega are found in about 10% of patients with critical COVID-19 (coronavirus disease 2019) pneumonia but not in individuals with asymptomatic infections. We detect auto-Abs neutralizing 100-fold lower, more physiological, concentrations of IFN-alpha and/or IFN-omega (100 pg/ml; in 1:10 dilutions of plasma) in 13.6% of 3595 patients with critical COVID-19, including 21% of 374 patients >80 years, and 6.5% of 522 patients with severe COVID-19. These antibodies are also detected in 18% of the 1124 deceased patients (aged 20 days to 99 years; mean: 70 years). Moreover, another 1.3% of patients with critical COVID-19 and 0.9% of the deceased patients have auto-Abs neutralizing high concentrations of IFN-beta. We also show, in a sample of 34,159 uninfected individuals from the general population, that auto-Abs neutralizing high concentrations of IFN-alpha and/or IFN-omega are present in 0.18% of individuals between 18 and 69 years, 1.1% between 70 and 79 years, and 3.4% >80 years. Moreover, the proportion of individuals carrying auto-Abs neutralizing lower concentrations is greater in a subsample of 10,778 uninfected individuals: 1% of individuals 80 years. By contrast, auto-Abs neutralizing IFN-beta do not become more frequent with age. Auto-Abs neutralizing type I IFNs predate SARS-CoV-2 infection and sharply increase in prevalence after the age of 70 years. They account for about 20% of both critical COVID-19 cases in the over 80s and total fatal COVID-19 cases.Peer reviewe

Balancing selection at a premature stop mutation in the <i>myostatin</i> gene underlies a recessive leg weakness syndrome in pigs - Fig 2

A: Position of the premature stop causing mutation within the porcine myostatin locus; B: Conservation of the amino acid sequence surrounding the mutation, with the consequences of the premature stop mutation highlighted in red.</p

Estimates and statistical significance of the effect of the <i>MSTN</i> c.820G>T locus on the growth and carcass traits of pigs obtained from a commercial performance test.

Estimates are shown in absolute units and standardised by phenotypic standard deviations (σP). Standard errors are in parentheses. The traits are categorised into: live weights and live weight gain; muscle and fat depths measured by ultrasound at the end of the test either conditional on age or on live weight; and periods to achieve growth targets.</p

Number of animals in pedigree and records used for variance components analyses.

Number of animals in pedigree and records used for variance components analyses.</p

Balancing selection at a premature stop mutation in the <i>myostatin</i> gene underlies a recessive leg weakness syndrome in pigs - Fig 1

A: Homozygosity mapping of the leg weakness syndrome assuming a single underlying recessive mutation on Chromosome 15 (SSC15). Vertical blocks in red and yellow represent homozygous genotypes, and blue the heterozygote genotype. The ten cases (above) and ten controls (below) are shown (one per line). A summary of homozygosity mapping is provided cases vs control at the bottom of Fig 1A in which if all the animals within a group (i.e. case or control) are homozygous for the same allele, then the relevant colour (red or yellow) is shown and if any animal within a group (i.e. case or control) is heterozygous then the SNP is coloured blue B: This is an extract from Fig 1A, showing the longest shared haplotype segment (55 SNPs) in the cases on SSC15 ranging from ALGA0110636 (rs81338938) to H3GA0044732 (rs80936849) and corresponds to position 86,745,668–95,062,143 in the new pig reference genome assembly Sscrofa11.1 GCA_000003025.6). The first ten lines are the cases; the second ten lines are the controls with genotypes shown only for the region of homozygosity shared across the controls. Genotypes shown for controls are shown only if they are different to cases (blank genotype in controls within the targeted segment means that they share the same genotype as cases). Finally, the bottom two lines are summary lines shown on the same basis as the summary lines in Fig 1A.</p

Genetic parameter estimates and standard errors (in parentheses) for the trait of leg weakness on the liability scale using the logit transformation showing the outcomes of fitting sire or dam models with or without maternal environment (σ2w).

All models have litter variance (σ2v) fitted.</p

Inborn errors of type I IFN immunity in patients with life-threatening COVID-19

The genetics underlying severe COVID-19 The immune system is complex and involves many genes, including those that encode cytokines known as interferons (IFNs). Individuals that lack specific IFNs can be more susceptible to infectious diseases. Furthermore, the autoantibody system dampens IFN response to prevent damage from pathogen-induced inflammation. Two studies now examine the likelihood that genetics affects the risk of severe coronavirus disease 2019 (COVID-19) through components of this system (see the Perspective by Beck and Aksentijevich). Q. Zhang et al. used a candidate gene approach and identified patients with severe COVID-19 who have mutations in genes involved in the regulation of type I and III IFN immunity. They found enrichment of these genes in patients and conclude that genetics may determine the clinical course of the infection. Bastard et al. identified individuals with high titers of neutralizing autoantibodies against type I IFN-α2 and IFN-ω in about 10% of patients with severe COVID-19 pneumonia. These autoantibodies were not found either in infected people who were asymptomatic or had milder phenotype or in healthy individuals. Together, these studies identify a means by which individuals at highest risk of life-threatening COVID-19 can be identified. Science , this issue p. eabd4570 , p. eabd4585 ; see also p. 404 </jats:p