Selection in action: dissecting the molecular underpinnings of the increasing muscle mass of Belgian Blue Cattle.

BACKGROUND: Belgian Blue cattle are famous for their exceptional muscular development or "double-muscling". This defining feature emerged following the fixation of a loss-of-function variant in the myostatin gene in the eighties. Since then, sustained selection has further increased muscle mass of Belgian Blue animals to a comparable extent. In the present paper, we study the genetic determinants of this second wave of muscle growth. RESULTS: A scan for selective sweeps did not reveal the recent fixation of another allele with major effect on muscularity. However, a genome-wide association study identified two genome-wide significant and three suggestive quantitative trait loci (QTL) affecting specific muscle groups and jointly explaining 8-21% of the heritability. The top two QTL are caused by presumably recent mutations on unique haplotypes that have rapidly risen in frequency in the population. While one appears on its way to fixation, the ascent of the other is compromised as the likely underlying MRC2 mutation causes crooked tail syndrome in homozygotes. Genomic prediction models indicate that the residual additive variance is largely polygenic. CONCLUSIONS: Contrary to complex traits in humans which have a near-exclusive polygenic architecture, muscle mass in beef cattle (as other production traits under directional selection), appears to be controlled by (i) a handful of recent mutations with large effect that rapidly sweep through the population, and (ii) a large number of presumably older variants with very small effects that rise slowly in the population (polygenic adaptation)

Intrahost evolution leading to distinct lineages in the upper and lower respiratory tracts during SARS-CoV-2 prolonged infection

Accumulating evidence points to persistent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in immunocompromised individuals as a source of genetically divergent, novel lineages, generally characterised by increased transmissibility and immune escape. While intrahost evolutionary dynamics of the virus in chronically infected patients have been previously reported, existing knowledge is primarily based on samples obtained from the nasopharyngeal compartment. In this study, we investigate the intrahost evolution and genetic diversity that accumulated during a prolonged SARS-CoV-2 infection with the Omicron sublineage BF.7, estimated to have persisted for over one year in an immunosuppressed patient. Based on the sequencing of eight viral genomes collected from the patient at six time points, we identified 86 intrahost single-nucleotide variants (iSNVs), two indels, and a 362 bp deletion. Our analysis revealed distinct viral genotypes in the nasopharyngeal (NP), endotracheal aspirate (ETA), and bronchoalveolar (BAL) samples. Notably, while significant divergence was observed between NP and BAL samples, most of the iSNVs found in ETA samples were also detected in NP or BAL samples. This suggests that NP samples may not offer a comprehensive representation of the overall intrahost viral diversity. Nonsynonymous mutations were most frequent in the spike and envelope genes, along with loss-of-function mutations in ORF8, generated by a frameshift mutation and a large deletion detected in the BAL and NP samples, respectively. Using long-range PCR on SARS-CoV-2 samples sequenced as part of routine surveillance, we validated that similar deletions causing ORF8 loss of function can be carried by SARS-CoV-2 during acute infection. Our findings not only demonstrate that the Omicron sublineage BF.7 can further diverge from its already exceptionally mutated state but also highlight that patients chronically infected with SARS-CoV-2 can develop genetically specific viral populations across distinct anatomical compartments. This provides novel insights into the intricate nature of viral diversity and evolution dynamics in persistent infections

Scan for selective sweeps associated with muscular devolpment in Belgian Blue beef cattle

The Belgian Blue beef cattle is well known for its double muscling phenotype resulting from fixation of a deletion in the myostatin gene. Since this fixation, further intensive selection for muscular development has been particularly succesful. This response to selection might be due to fixation of more genetic variants increasing muscular development. In the present study, we search for selective sweeps in the Belgian Blue genome which might result from the fixation of such variants. To that end we used data from 593 sires genotyped with the BovineHD SNP array. In addition, we used the Belgian Blue dual purpose and the Holstein breeds as controls. We first performed scans for regions of complete homozygosity resulting from fixation. Large fixed regions were found around major genes known to be fixed in the Belgian Blue cattle breed (MSTN, PLAG1 and MC1R) but no other regions of the same magnitude was found. Among the smaller identified regions, only few of them were unique to the Belgian Blue breed. Statistical tests based on long range haplotype information were also implemented, revealing large regions in the genome of reduced haplotype homozygosity specific to the Belgian Blue breed. Some of these regions corresponded to known major genes (MSTN, roan locus, PLAG1 or MC1R) while other regions were new. To determine whether these regions might be the result of selection for muscular development, we performed association studies for muscular development. None of the identified QTL matched with the regions of reduced haplotype homozygosity and the largest QTLs did not presented evidence of strong selective sweeps. These results suggest that the response to selection for muscular development in Belgian Blue beef cattle is probably the result of polygenic selection

On the use of the transmission disequilibrium test to detect pseudo-autosomal variants affecting traits with sex-limited expression

We herein describe the realization of a genome-wide association study for scrotal hernia and cryptorchidism in Norwegian and Belgian commercial pig populations. We have used the transmission disequilibrium test to avoid spurious associations due to population stratification. By doing so, we obtained genome-wide significant signals for both diseases with SNPs located in the pseudo-autosomal region in the vicinity of the pseudo-autosomal boundary. By further analyzing these signals, we demonstrate that the observed transmission disequilibria are artifactual. We determine that transmission bias at pseudo-autosomal markers will occur (i) when analyzing traits with sex-limited expression and (ii) when the allelic frequencies at the marker locus differ between X and Y chromosomes. We show that the bias is due to the fact that (i) sires will preferentially transmit the allele enriched on the Y (respectively X) chromosome to affected sons (respectively daughters) and (ii) dams will appear to preferentially transmit the allele enriched on the Y (respectively X) to affected sons (respectively daughters), as offspring inheriting the other allele are more likely to be non-informative. We define the conditions to mitigate these issues, namely by (i) extracting information from maternal meiosis only and (ii) ignoring trios for which sire and dam have the same heterozygous genotype. We show that by applying these rules to scrotal hernia and cryptorchidism, the pseudo-autosomal signals disappear, confirming their spurious nature.status: publishe

Adapting the TDT for the pseudoautosomal region

We herein describe the realization of a genome-wide association study for scrotal hernia and cryptorchidism in Norwegian and Belgian commercial pig populations. We have used the transmission disequilibrium test to avoid spurious associations due to population stratification. By doing so, we obtained genome-wide significant signals for both diseases with SNPs located in the pseudo-autosomal region in the vicinity of the pseudo-autosomal boundary. By further analyzing these signals, we demonstrate that the observed transmission disequilibria are artifactual. We determine that transmission bias at pseudo-autosomal markers will occur (i) when analyzing traits with sex-limited expression and (ii) when the allelic frequencies at the marker locus differ between X and Y chromosomes. We show that the bias is due to the fact that (i) sires will preferentially transmit the allele enriched on the Y (respectively X) chromosome to affected sons (respectively daughters) and (ii) dams will appear to preferentially transmit the allele enriched on the Y (respectively X) to affected sons (respectively daughters), as offspring inheriting the other allele are more likely to be non-informative. We define the conditions to mitigate these issues, namely by (i) extracting information from maternal meiosis only and (ii) ignoring trios for which sire and dam have the same heterozygous genotype. We show that by applying these rules to scrotal hernia and cryptorchidism, the pseudo-autosomal signals disappear, confirming their spurious nature.PIGENDE

Selection in action: dissecting the molecular underpinnings of the increasing muscle mass of Belgian Blue Cattle.

BACKGROUND: Belgian Blue cattle are famous for their exceptional muscular development or "double-muscling". This defining feature emerged following the fixation of a loss-of-function variant in the myostatin gene in the eighties. Since then, sustained selection has further increased muscle mass of Belgian Blue animals to a comparable extent. In the present paper, we study the genetic determinants of this second wave of muscle growth. RESULTS: A scan for selective sweeps did not reveal the recent fixation of another allele with major effect on muscularity. However, a genome-wide association study identified two genome-wide significant and three suggestive quantitative trait loci (QTL) affecting specific muscle groups and jointly explaining 8-21% of the heritability. The top two QTL are caused by presumably recent mutations on unique haplotypes that have rapidly risen in frequency in the population. While one appears on its way to fixation, the ascent of the other is compromised as the likely underlying MRC2 mutation causes crooked tail syndrome in homozygotes. Genomic prediction models indicate that the residual additive variance is largely polygenic. CONCLUSIONS: Contrary to complex traits in humans which have a near-exclusive polygenic architecture, muscle mass in beef cattle (as other production traits under directional selection), appears to be controlled by (i) a handful of recent mutations with large effect that rapidly sweep through the population, and (ii) a large number of presumably older variants with very small effects that rise slowly in the population (polygenic adaptation)

Haplotype sharing score across the genome.

<p>The limits between the 22 autosomes are indicated by the black horizontal bars (<i>right Y-axis</i>). The scores (<i>left Y-axis</i>) obtained when imposing haplotype sharing for the nine/nine cases plus the obligate carrier are given by the red circles. The scores obtained when imposing haplotype sharing for eight/nine cases plus the obligate carrier are given by the blue circles. The six identified chromosome segments are marked by the black arrows.</p

Multigenerational pedigree with convergent strabismus.

<p>Individuals for which DNA samples could be collected are represented in blue when unaffected and in black when affected. Assuming that all cases in the pedigree share an identical-by-descent (IBD) autosomal dominant mutation (i) one of the two grand-grand parents (individuals I.2 or I.3) has to be at least germ-line carrier as indicated by the black dotted lining, and (ii) grand-father II.5 is obligate carrier as indicated by the black lining. Under the same hypothesis, the parental origin of the mutation can be determined for all cases of generation III or IV as indicated by the red (maternal origin) or blue lining (paternal origin). The numbers within the symbols indicate the number of IBD risk haplotypes carried by the corresponding individual for the six putative loci, which are described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0083574#pone-0083574-t001" target="_blank">Table 1</a>. The numbers outside the symbols are the individual identifiers within generation (roman numbers).</p

Features of the six identified candidate loci.

<p>NB: Non-affected individuals only provide linkage information and are hence considered if their parent is heterozygous for the studied haplotype, explain why their numbers vary depending on the considered locus.</p

High resolution mapping of cross-over events in cattle using NGS data

peer reviewedHigh resolution mapping of cross-over events in cattle using NGS data Keywords: recombination, cattle, NGS Homologous recombination plays an important role in proper segregation of homologues in the first meiotic division. Failure in proper segregation results in aneuploidy, which is a leading cause for pregnancy loss in humans. Recently, global recombination rate has been studied in large cattle populations genotyped with SNP arrays ( 50K). However, the fine-scale resolution of these studies remained limited as a result of the relatively low marker density. Here we report high-resolution mapping of cross-over (CO) events in a cattle pedigree using whole genome sequence data. We carry out an extensive cleaning of our sequence data to remove errors (errors in the genome build, sequencing errors and presence of CNVs) that dramatically inflate CO counts. Using 5 million high quality sequence variants we identify 3,880 CO events in 155 male gametes and 3,088 CO events in 124 female gametes. The median resolution of the identified COs was 34 kb with about 70% of the events mapped to an interval less than 100 kb. The male and female map lengths were estimated at 27.5 M and 23.8 M respectively. Consistent with previous studies in cattle, we find higher recombination rate in males and higher frequency of COs at chromosome ends. Interestingly, compared to the map lengths estimated from SNP chip we find an increase of 3.7 and 2.7 M in male and female maps respectively. Despite the cleaning efforts, we cannot determine at this time whether the increased in map lengths correspond to CO missed with genotyping arrays, to spurious CO identified with NGS data (due to unidentified sources of errors) or both