MFSD2A frameshift variant in Kerry Hill sheep with microcephaly.

Microcephaly is a rare neurodevelopmental disorder characterized by reduced skull circumference and brain volume that occurs sporadically in farm animals. We investigated an early-onset neurodegenerative disorder observed in seven lambs of purebred Kerry Hill sheep. Clinical signs included inability to stand or severe ataxia, convulsions, and early death. Diagnostic imaging and brain necropsy confirmed microcephaly. The pedigree of the lambs suggested monogenic autosomal recessive inheritance. We sequenced the genome of one affected lamb, and comparison with 115 control genomes revealed a single private protein-changing variant. This frameshift variant, MFSD2A: c.285dupA, p.(Asp96fs*9), represents a 1-bp duplication predicted to truncate 80% of the open reading frame. MFSD2A is a transmembrane protein that is essential for maintaining blood-brain barrier homeostasis and plays a key role in regulating brain lipogenesis. Human MFSD2A pathogenic variants are associated with a neurodevelopmental disorder with progressive microcephaly, spasticity, and brain imaging abnormalities (NEDMISBA, OMIM 616486). Here we present evidence for the occurrence of a recessively inherited form of microcephaly in sheep due to a loss-of-function variant in MFSD2A (OMIA 002371-9940). To the best of our knowledge, this is the first report of a spontaneous MFSD2A variant in domestic animals.

Loss-of-function variant in the ovine TMCO6 gene in North Country Cheviot sheep with motor neuron disease.

In North Country Cheviot lambs with early-onset progressive ataxia and motor neuron degeneration, whole-genome sequencing identified a homozygous loss-of-function variant in the ovine transmembrane and coiled-coil domains (TMCO6) gene. The familial recessive form of motor neuron disease in sheep is due to a pathogenic 4 bp deletion leading to a 50% protein truncation that is assumed to result in the absence of a functional TMCO6. This uncharacterised protein is proposed to interact with ubiquilin 1 which is associated with Alzheimer's disease, whereas sporadic forms of amyotrophic lateral sclerosis are caused by variants in UBQLN2. Our findings provide a first spontaneous animal model for TMCO6, which could have implications in the studies of other comparative neurodegenerative diseases. In addition, these results will allow the design of a genetic test to prevent the occurrence of this fatal disease in the affected sheep population.

Increased heterozygosity in low-pass sequencing data allows identification of blood chimeras in cattle.

In about 90% of multiple pregnancies in cattle, shared blood circulation between fetuses leads to genetic chimerism in peripheral blood and can reduce reproductive performance in heterosexual co-twins. However, the early detection of heterosexual chimeras requires specialized tests. Here, we used low-pass sequencing data with a median coverage of 0.64× generated from blood samples of 322 F1 crosses between beef and dairy cattle and identified 20 putative blood chimeras through increased levels of genome-wide heterozygosity. In contrast, for 77 samples with routine SNP microarray data generated from hair bulbs of the same F1s, we found no evidence of chimerism, simultaneously observing high levels of genotype discordance with sequencing data. Fifteen out of 18 reported twins showed signs of blood chimerism, in line with previous reports, whereas the presence of five alleged singletons with strong signs of chimerism suggests that the in-utero death rate of co-twins is at the upper limit of former estimates. Together, our results show that low-pass sequencing data allow reliable screening for blood chimeras. They further affirm that blood is not recommended as a source of DNA for the detection of germline variants.

DYRK1B haploinsufficiency in a Holstein cattle with epilepsy.

In this study, epilepsy with focal seizures progressing to generalized seizures was diagnosed in a 6-month-old Holstein heifer. The seizures were characterized by a brief pre-ictal phase with depression and vocalization. During the ictal phase eyelid spasms, tongue contractions, nodding and abundant salivation were observed, rapidly followed by a convulsive phase with bilateral tonic, clonic or tonic-clonic activity and loss of consciousness. Finally, during the postictal phase the heifer was obtunded and disorientated, unable to perceive obstacles and hypermetric, and pressed its head against objects. In the inter-seizure phase, the heifer was clinically normal. Neuropathology revealed axonal degeneration in the brainstem and diffuse astrocytic hypertrophic gliosis. Whole genome sequencing of the affected heifer identified a private heterozygous splice-site variant in DYRK1B (NM_001081515.1: c.-101-1G>A), most likely resulting in haploinsufficiency owing to loss-of-function. This represents a report of a DYRK1B-associated disease in cattle and adds DYRK1B to the candidate genes for epilepsy.

Genomic regions underlying positive selection in local, Alpine cattle breeds.

We used genome-wide SNP data from 18 local cattle breeds from six countries of the Alpine region to characterize population structure and identify genomic regions underlying positive selection. The geographically close breeds Evolèner, Eringer, Valdostana Pezzata Nera, and Valdostana Castana were found to differ from all other Alpine breeds. In addition, three breeds, Simmental, and Original Braunvieh from Switzerland and Pinzgauer from Austria built three separate clusters. Of the 18 breeds studied, the intra-alpine Swiss breed Evolèner had the highest average inbreeding based on runs of homozygosity (FROH ) and the highest average genomic relationship within the breed. In contrast, Slovenian Cika cattle had the lowest average genomic inbreeding and the lowest average genomic relationship within the breed. We found selection signatures on chromosome 6 near known genes such as KIT and LCORL explaining variation in coat color and body size in cattle. The most prominent selection signatures were similar regardless of marker density and the breeds in the data set. In addition, using available high-density SNP data from 14 of the breeds we identified 47 genome regions as ROH islands. The proportion of homozygous animals was higher in all studied animals of local breeds than in Holstein and Brown Swiss cattle, the two most important commercial breeds in the Alpine region. We report ROH islands near genes related to thermoregulation, coat color, production, and stature. The results of this study serve as a basis for the search for causal variants underlying adaptation to the alpine environment and other specific characteristics selected during the evolution of local Alpine cattle breeds.

WNT10B: A locus increasing risk of brachygnathia inferior in Brown Swiss cattle.

Shortening of the mandible (brachygnathia inferior) is a congenital, often inherited and variably expressed craniofacial anomaly in domestic animals including cattle. Brachygnathia inferior can lead to poorer animal health and welfare and reduced growth, which ultimately affects productivity. Within the course of the systematic conformation scoring, cases with a frequency of about 0.1% were observed in the Brown Swiss cattle population of Switzerland. In contrast, this anomaly is almost unknown in the Original Braunvieh population, representing the breed of origin. Because none of the individually examined 46 living offspring of our study cohort of 145 affected cows showed the trait, we can most likely exclude a monogenic-dominant mode of inheritance. We hypothesized that either a monogenic recessive or a complex mode of inheritance was underlying. Through a genome-wide association study of 145 cases and 509 controls with imputed 624k SNP data, we identified a 4.5 Mb genomic region on bovine chromosome 5 significantly associated with this anomaly. This locus was fine-mapped using whole-genome sequencing data. A run of homozygosity analysis revealed a critical interval of 430 kb. A breed specific frameshift duplication in WNT10B (rs525007739; c.910dupC; p.Arg304ProfsTer14) located in this genomic region was found to be associated with a 21.5-fold increased risk of brachygnathia inferior in homozygous carriers. Consequently, we present for the first time a genetic locus associated with this well-known anomaly in cattle, which allows DNA-based selection of Brown Swiss animals at decreased risk for mandibular shortening. In addition, this study represents the first large animal model of a WNT10B-related inherited developmental disorder in a mammalian species.

Analysis of Polycerate Mutants Reveals the Evolutionary Co-option of HOXD1 for Horn Patterning in Bovidae.

In the course of evolution, pecorans (i.e., higher ruminants) developed a remarkable diversity of osseous cranial appendages, collectively referred to as "headgear," which likely share the same origin and genetic basis. However, the nature and function of the genetic determinants underlying their number and position remain elusive. Jacob and other rare populations of sheep and goats are characterized by polyceraty, the presence of more than two horns. Here, we characterize distinct POLYCERATE alleles in each species, both associated with defective HOXD1 function. We show that haploinsufficiency at this locus results in the splitting of horn bud primordia, likely following the abnormal extension of an initial morphogenetic field. These results highlight the key role played by this gene in headgear patterning and illustrate the evolutionary co-option of a gene involved in the early development of bilateria to properly fix the position and number of these distinctive organs of Bovidae.

Runs of homozygosity in Swiss goats reveal genetic changes associated with domestication and modern selection.

BACKGROUND: The domestication of goat (Capra hircus) started 11,000 years ago in the fertile crescent. Breed formation in the nineteenth century, establishment of herd books, and selection for specific traits resulted in 10 modern goat breeds in Switzerland. We analyzed whole-genome sequencing (WGS) data from 217 modern goats and nine wild Bezoar goats (Capra aegagrus). After quality control, 27,728,288 biallelic single nucleotide variants (SNVs) were used for the identification of runs of homozygosity (ROH) and the detection of ROH islands. RESULTS: Across the 226 caprine genomes from 11 populations, we detected 344 ROH islands that harbor 1220 annotated genes. We compared the ROH islands between the modern breeds and the Bezoar goats. As a proof of principle, we confirmed a signature of selection, which contains the ASIP gene that controls several breed-specific coat color patterns. In two other ROH islands, we identified two missense variants, STC1:p.Lys139Arg and TSHR:p.Ala239Thr, which might represent causative functional variants for domestication signatures. CONCLUSIONS: We have shown that the information from ROH islands using WGS data is suitable for the analysis of signatures of selection and allowed the detection of protein coding variants that may have conferred beneficial phenotypes during goat domestication. We hypothesize that the TSHR:p.Ala239Thr variant may have played a role in changing the seasonality of reproduction in modern domesticated goats. The exact functional significance of the STC1:p.Lys139Arg variant remains unclear and requires further investigation. Nonetheless, STC1 might represent a new domestication gene affecting relevant traits such as body size and/or milk yield in goats.

DSP missense variant in a Scottish Highland calf with congenital ichthyosis, alopecia, acantholysis of the tongue and corneal defects.

BACKGROUND: Ichthyosis describes a localized or generalized hereditary cornification disorder caused by an impaired terminal keratinocyte differentiation resulting in excessive stratum corneum with the formation of more or less adherent scales. Ichthyosis affects humans and animals. Two rare bovine forms are reported, the severe harlequin ichthyosis and the less severe congenital ichthyosis, both characterized by a severe orthokeratotic lamellar hyperkeratosis. RESULTS: A 2-weeks-old purebred Scottish Highland calf was referred because of a syndrome resembling congenital ichthyosis. The clinical phenotype included diffuse alopecia and a markedly lichenified skin covered with large and excessive scales. Additionally, conjunctivitis and ulceration of the cornea were noted. Post-mortem examination revealed deep fissures in the diffusely thickened tongue and histopathological findings in the skin confirmed the clinical diagnosis. Whole-genome sequencing of the affected calf and comparison of the data with control genomes was performed. A search for private variants in known candidate genes for skin phenotypes including genes related with erosive and hyperkeratotic lesions revealed a single homozygous protein-changing variant, DSP: c.6893 C>A, or p.Ala2298Asp. The variant is predicted to change a highly conserved residue in the C-terminal plakin domain of the desmoplakin protein, which represents a main intracellular component of desmosomes, important intercellular adhesion molecules in various tissues including epidermis. Sanger sequencing confirmed the variant was homozygous in the affected calf and heterozygous in both parents. Further genotyping of 257 Scottish Highland animals from Switzerland revealed an estimated allele frequency of 1.2%. The mutant allele was absent in more than 4800 controls from various other cattle breeds. CONCLUSIONS: This study represents the first report of combined lesions compatible with congenital ichthyosis, alopecia, acantholysis of the tongue and corneal defects associated with a DSP missense variant as the most likely underlying cause. To the best of our knowledge, this study is also the first report of a DSP-related syndromic form of congenital ichthyosis in domestic animals. The results of our study enable genetic testing to avoid the unintentional occurrence of further affected cattle. The findings were added to the Online Mendelian Inheritance in Animals (OMIA) database (OMIA 002243-9913).

Associated regions for multiple birth in Brown Swiss and Original Braunvieh cattle on chromosomes 15 and 11.

Twin and multiple births have negative effects on the performance and health of cows and calves. To decipher the genetic architecture of this trait in the two Swiss Brown Swiss cattle populations, we performed various association analyses based on de-regressed breeding values. Genome-wide association analyses were executed using ~600 K imputed SNPs for the maternal multiple birth trait in ~3500 Original Braunvieh and ~7800 Brown Swiss animals. Significantly associated QTL were observed on different chromosomes for both breeds. We have identified on chromosome 11 a QTL that explains ~6% of the total genetic variance of the maternal multiple birth trait in Original Braunvieh. For the Brown Swiss breed, we have discovered a QTL on chromosome 15 that accounts for ~4% of the total genetic variance. For Original Braunvieh, subsequent haplotype analysis revealed a 90-kb window on chromosome 11 at 88 Mb, where a likely regulatory region is located close to the ID2 gene. In Brown Swiss, a 130-kb window at 75 Mb on chromosome 15 was identified. Analysis of whole-genome sequence data using linkage-disequilibrium estimation revealed possible causal variants for the identified QTL. A presumably regulatory variant in the non-coding 5' region of the ID2 gene was strongly associated with the haplotype for Original Braunvieh. In Brown Swiss, an intron variant in PRDM11, one 3' UTR variant in SYT13 and three intergenic variants 5' upstream of SYT13 were identified as candidate variants for the trait multiple birth maternal. In this study, we report for the first time QTL for the trait of multiple births in Original Braunvieh and Brown Swiss cattle. Moreover, our findings are another step towards a better understanding of the complex genetic architecture of this polygenic trait.

A de novo variant in the bovine ADAMTSL4 gene in an Original Braunvieh calf with congenital cataract.

Inherited forms of cataract are a heterogeneous group of eye disorders known in livestock species. Clinicopathological analysis of a single case of impaired vision in a newborn Original Braunvieh calf revealed nuclear cataract. Whole-genome sequencing of the parent-offspring trio revealed a de novo mutation of ADAMTSL4 in this case. The heterozygous p.Arg776His missense variant affects a conserved residue of the ADAMTSL4 gene that encodes a secreted glycoprotein expressed in the lens throughout embryonic development. In humans, ADAMTSL4 genetic variants cause recessively inherited forms of subluxation of the lens. Given that ADAMTSL4 is a functional candidate gene for inherited disorders of the lens, we suggest that heterozygosity for the identified missense variant may have caused the congenital cataract in the affected calf. Cattle populations should be monitored for unexplained cataract cases, with subsequent DNA sequencing a hypothesized pathogenic effect of heterozygous ADAMTSL4 variants could be confirmed.

Identification of two new recessive MC1R alleles in red-coloured Evolèner cattle and other breeds.

Sequence variations in the melanocortin-1 receptor (MC1R) gene are associated with melanism in different animal species. Six functionally relevant alleles have been described in cattle to date. In a hypothesis-free approach we performed a genome-wide allelic association study with black, red and wild-coloured cattle of three Alpine cattle breeds (Eringer, Evolèner and Valdostana), revealing a single significant association signal close to the MC1R gene. We searched for candidate causative variants by sequencing the entire coding sequence and identified two novel protein-changing variants. We propose designating the mutant alleles at MC1R:c.424C>T as ev1 and at MC1R:c.263G>A as ev2 . Both affect conserved amino acid residues in functionally important transmembrane domains (p.Arg142Cys and p.Ser88Asn). Both alleles segregate predominantly in the Swiss Evolèner breed. They occur in other European cattle breeds such as Abondance and Rotes Höhenvieh as well. We observed almost perfect association between the MC1R genotypes and the coat colour phenotype in a cohort of 513 black, red and wild-coloured cattle. Animals carrying two copies of MC1R loss-of-function alleles or that were compound heterozygous for e, ev1 , or ev2 have a red to dark red (chestnut-like red) coat colour. These findings expand the spectrum of causal MC1R variants causing recessive red in cattle.

Selection signatures in goats reveal copy number variants underlying breed-defining coat color phenotypes.

Domestication and human selection have formed diverse goat breeds with characteristic phenotypes. This process correlated with the fixation of causative genetic variants controlling breed-specific traits within regions of reduced genetic diversity, so called selection signatures or selective sweeps. Using whole genome sequencing of DNA pools (pool-seq) from 20 genetically diverse modern goat breeds and bezoars, we identified 2,239 putative selection signatures. In two Pakistani goat breeds, Pak Angora and Barbari, we found selection signatures in a region harboring KIT, a gene involved in melanoblast development, migration, and survival. The search for candidate causative variants responsible for these selective sweeps revealed two different copy number variants (CNVs) downstream of KIT that were exclusively present in white Pak Angora and white-spotted Barbari goats. Several Swiss goat breeds selected for specific coat colors showed selection signatures at the ASIP locus encoding the agouti signaling protein. Analysis of these selective sweeps revealed four different CNVs associated with the white or tan (AWt), Swiss markings (Asm), badgerface (Ab), and the newly proposed peacock (Apc) allele. RNA-seq analyses on skin samples from goats with the different CNV alleles suggest that the identified structural variants lead to an altered expression of ASIP between eumelanistic and pheomelanistic body areas. Our study yields novel insights into the genetic control of pigmentation by identifying six functionally relevant CNVs. It illustrates how structural changes of the genome have contributed to phenotypic evolution in domestic goats.

Correction: Mutations in MITF and PAX3 Cause "Splashed White" and Other White Spotting Phenotypes in Horses.

[This corrects the article DOI: 10.1371/journal.pgen.1002653.].

The role of trust and risk perception in current German nuclear waste management.

One of the lessons learned in various countries that have to deal with spent nuclear fuel is that finding a proper place and siting a repository for high-level nuclear waste (HLW) cannot be achieved without public consent. After decades of obstruction, Germany recently launched a new, participatory, site-selection process for the disposal of HLW in deep geological formations. Nonetheless, significant opposition is assumed. Therefore, citizens' trust in the procedure and the agents involved may be paramount. We conducted an online survey (N ≈ 5000) in March/April 2020 to test a theoretical model on trust, perceived risks and benefits, and acceptance. We differentiated acceptance as a dependent variable according to distinct phases: the procedure, a possible decision on a disposal location, and the repository facility itself. The results show that trust is mainly important for explaining acceptance of the ongoing procedure and less so for the acceptance of the decision or the repository facility itself. Moreover, our investigation of the sample using a cluster analysis reveals characteristic patterns of trust, risk perception, and acceptance by three clusters: a cluster focusing on risk perception, an ambivalent cluster, and an indifferent cluster. Trust is lowest in the risk-focused cluster and highest in the ambivalent cluster.

Differential Analysis of Gly211Val and Gly286Val Mutations Affecting Sarco(endo)plasmic Reticulum Ca2+-ATPase (SERCA1) in Congenital Pseudomyotonia Romagnola Cattle.

Congenital pseudomyotonia in cattle (PMT) is a rare skeletal muscle disorder, clinically characterized by stiffness and by delayed muscle relaxation after exercise. Muscle relaxation impairment is due to defective content of the Sarco(endo)plasmic Reticulum Ca2+ ATPase isoform 1 (SERCA1) protein, caused by missense mutations in the ATP2A1 gene. PMT represents the only mammalian model of human Brody myopathy. In the Romagnola breed, two missense variants occurring in the same allele were described, leading to Gly211Val and Gly286Val (G211V/G286V) substitutions. In this study, we analyzed the consequences of G211V and G286V mutations. Results support that the reduced amount of SERCA1 is a consequence of the G211V mutation, the G286V mutation almost being benign and the ubiquitin-proteasome system (UPS) being involved. After blocking the proteasome using a proteasome inhibitor, we found that the G211V mutant accumulates in cells at levels comparable to those of WT SERCA1. Our conclusion is that G211/286V mutations presumably originate in a folding-defective SERCA1 protein, recognized and diverted to degradation by UPS, although still catalytically functional, and that the main role is played by G211V mutation. Rescue of mutated SERCA1 to the sarcoplasmic reticulum membrane can re-establish resting cytosolic Ca2+ concentration and prevent the appearance of pathological signs, paving the way for a possible therapeutic approach against Brody disease.

Compound heterozygous PLA2G6 loss-of-function variants in Swaledale sheep with neuroaxonal dystrophy.

Sporadic occurrences of neurodegenerative disorders including neuroaxonal dystrophy (NAD) have been previously reported in sheep. However, so far no causative genetic variant has been found for ovine NAD. The aim of this study was to characterize the phenotype and the genetic aetiology of an early-onset neurodegenerative disorder observed in several lambs of purebred Swaledale sheep, a native English breed. Affected lambs showed progressive ataxia and stiff gait and subsequent histopathological analysis revealed the widespread presence of axonal spheroid indicating neuronal degeneration. Thus, the observed clinical phenotype could be explained by a novel form of NAD. After SNP genotyping and subsequent linkage mapping within a paternal half-sib pedigree with a total of five NAD-affected lambs, we identified two loss-of-function variants by whole-genome sequencing in the ovine PLA2G6 gene situated in a NAD-linked genome region on chromosome 3. All cases were carriers of a compound heterozygous splice site variant in intron 2 and a nonsense variant in exon 8. Herein we present evidence for the occurrence of a familial novel form of recessively inherited NAD in sheep due to allelic heterogeneity at PLA2G6. This study reports two pathogenic variants in PLA2G6 causing a novel form of NAD in Swaledale sheep which enables selection against this fatal disorder.

A frameshift insertion in FA2H causes a recessively inherited form of ichthyosis congenita in Chianina cattle.

The aim of this study was to characterize the phenotype and to identify the genetic etiology of a syndromic form of ichthyosis congenita (IC) observed in Italian Chianina cattle and to estimate the prevalence of the deleterious allele in the population. Sporadic occurrence of different forms of ichthyosis including IC have been previously reported in cattle. However, so far, no causative genetic variant has been found for bovine IC. Nine affected cattle presenting congenital xerosis, hyperkeratosis and scaling of the skin as well as urolithiasis and cystitis associated with retarded growth were examined. Skin histopathology revealed a severe, diffuse orthokeratotic hyperkeratosis with mild to moderate epidermal hyperplasia. The pedigree records indicated a monogenic recessive trait. Homozygosity mapping and whole-genome sequencing allowed the identification of a homozygous frameshift 1 bp insertion in the FA2H gene (c.9dupC; p.Ala4ArgfsTer142) located in a 1.92 Mb shared identical-by-descent region on chromosome 18 present in all cases, while the parents were heterozygous as expected for obligate carriers. These findings enable the selection against this sub-lethal allele showing an estimated frequency of ~ 7.5% in Chianina top sires. A sporadic incidence of mild clinical signs in the skin of heterozygous carriers was observed. So far, pathogenic variants affecting the encoded fatty acid 2-hydroxylase catalyzing the synthesis of 2-hydroxysphingolipids have been associated with myelin disorders. In conclusion, this study represents the first report of an FA2H-related autosomal recessive inherited skin disorder in a mammalian species and adds FA2H to the list of candidate genes for ichthyosis in humans and animals. Furthermore, this study provides a DNA-based diagnostic test that enables selection against the identified pathogenic variant in the Chianina cattle population. However, functional studies are needed to better understand the expression of FA2H in IC-affected Chianina cattle.

A pathogenic HEXA missense variant in wild boars with Tay-Sachs disease.

Gangliosidoses are inherited lysosomal storage disorders caused by reduced or absent activity of either a lysosomal enzyme involved in ganglioside catabolism, or an activator protein required for the proper activity of a ganglioside hydrolase, which results in the intra-lysosomal accumulation of undegraded metabolites. We hereby describe morphological, ultrastructural, biochemical and genetic features of GM2 gangliosidosis in three captive bred wild boar littermates. The piglets were kept in a partially-free range farm and presented progressive neurological signs, starting at 6 months of age. Animals were euthanized at approximately one year of age due to their poor conditions. Neuropathogens were excluded as a possible cause of the signs. Gross examination showed a reduction of cerebral and cerebellar consistency. Central (CNS) and peripheral (PNS) nervous system neurons were enlarged and foamy, with severe and diffuse cytoplasmic vacuolization. Transmission electron microscopy (TEM) of CNS neurons demonstrated numerous lysosomes, filled by parallel or concentric layers of membranous electron-dense material, defined as membranous cytoplasmic bodies (MCB). Biochemical composition of gangliosides analysis from CNS revealed accumulation of GM2 ganglioside; furthermore, Hex A enzyme activity was less than 1% compared to control animals. These data confirmed the diagnosis of GM2 gangliosidosis. Genetic analysis identified, at a homozygous level, the presence of a missense nucleotide variant c.1495C > T (p Arg499Cys) in the hexosaminidase subunit alpha gene (HEXA), located within the GH20 hexosaminidase superfamily domain of the encoded protein. This specific HEXA variant is known to be pathogenic and associated with Tay-Sachs disease in humans, but has never been identified in other animal species. This is the first report of a HEXA gene associated Tay-Sachs disease in wild boars and provides a comprehensive description of a novel spontaneous animal model for this lysosomal storage disease.

Mining massive genomic data of two Swiss Braunvieh cattle populations reveals six novel candidate variants that impair reproductive success.

BACKGROUND: This study was carried out on the two Braunvieh populations reared in Switzerland, the dairy Brown Swiss (BS) and the dual-purpose Original Braunvieh (OB). We performed a genome-wide analysis of array data of trios (sire, dam, and offspring) from the routine genomic selection to identify candidate regions showing missing homozygosity and phenotypic associations with five fertility, ten birth, and nine growth-related traits. In addition, genome-wide single SNP regression studies based on 114,890 single nucleotide polymorphisms (SNPs) for each of the two populations were performed. Furthermore, whole-genome sequencing data of 430 cattle including 70 putative haplotype carriers were mined to identify potential candidate variants that were validated by genotyping the current population using a custom array. RESULTS: Using a trio-based approach, we identified 38 haplotype regions for BS and five for OB that segregated at low to moderate frequencies. For the BS population, we confirmed two known haplotypes, BH1 and BH2. Twenty-four variants that potentially explained the missing homozygosity and associated traits were detected, in addition to the previously reported TUBD1:p.His210Arg variant associated with BH2. For example, for BS we identified a stop-gain variant (p.Arg57*) in the MRPL55 gene in the haplotype region on chromosome 7. This region is associated with the 'interval between first and last insemination' trait in our data, and the MRPL55 gene is known to be associated with early pregnancy loss in mice. In addition, we discuss candidate missense variants in the CPT1C, MARS2, and ACSL5 genes for haplotypes mapped in BS. In OB, we highlight a haplotype region on chromosome 19, which is potentially caused by a frameshift variant (p.Lys828fs) in the LIG3 gene, which is reported to be associated with early embryonic lethality in mice. Furthermore, we propose another potential causal missense variant in the TUBGCP5 gene for a haplotype mapped in OB. CONCLUSIONS: We describe, for the first time, several haplotype regions that segregate at low to moderate frequencies and provide evidence of causality by trait associations in the two populations of Swiss Braunvieh. We propose a list of six protein-changing variants as potentially causing missing homozygosity. These variants need to be functionally validated and incorporated in the breeding program.