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In the last two decades, the molecular cause of six monogenic autosomal recessive disorders has been identified in native Italian beef cattle: two different ATP2A1 variants for the pseudomyotonia congenita, the first in Chianina and Romagnola (PMT1) and the second in Romagnola (PMT2); a KDM2B variant for the paunch calf syndrome (PCS) in Marchigiana and Romagnola; a NID1 variant for the congenital cataract (CC) in Romagnola; a LAMB1 variant for the hemifacial microsomia (HFM) in Romagnola; an ABCA12 variant for the ichthyosis fetalis (IF) in Chianina and a FA2H variant for the ichthyosis congenita (IC) in Chianina. The aim of this study was to evaluate the potential impact of these disorders in the affected Italian populations. For this purpose, 3331 Chianina, 2812 Marchigiana and 1680 Romagnola bulls born in the last 40 years were considered. The allelic frequency (AF) of the variant for PMT1 was 1.0% in Romagnola, 4.6% in Marchigiana and 5.9% in Chianina. The AF of the variant for PMT2 was 3.3% in Romagnola and 0% in the other two breeds. The AF of the variant for PCS was 11.7% in Romagnola, 2.0% in Marchigiana and 0% in Chianina. The AF of the variants for CC, HFM, IF and IC resulted below 3%, being the variants detected only in the breed populations in which they were previously reported. Considering a selected male population in the single breed, Chianina showed carrier prevalence of 11.9% for PMT1, 7.7% for IC and 6.4% for IF. Romagnola showed carrier prevalence of 23.4% for PCS, 6.7% for PMT2, 4.1% for HFM, 3.2% for CC and 2.0% for PMT1. Marchigiana showed carrier prevalence of 9.1% for PMT1 and 4.0% for PCS. With respect to the Romagnola cattle, the concerning presence of a total of five defect alleles in the population hampers a general approach based on the prevention of carriers from artificial insemination. However, identification of carriers may allow conscious mating to prevent the risk of homozygous descendants as well as the spread of heterozygous offspring. Therefore, systematic genotyping for all seven known harmful alleles is recommended to prevent risk mating between carriers, in particular to avoid the occurrence of affected offspring.

Variable selection via the LASSO regression analysis followed by a classification of phenotypes into two groups of cases and controls using SVM was performed to identify genomic regions associated with phenotypic traits of interest. This approach was successfully validated by identifying previously known genomic associations for two Mendelian traits and a complex polygenic trait in Swiss cattle populations. Furthermore, new associated regions for the trait multiple birth were found in Holstein. Therefore, this approach proved to be a valuable alternative to identify associated genomic regions for inherited traits in livestock.

By its paternal transmission, Y-chromosomal haplotypes are sensitive markers of population history and male-mediated introgression. We used whole-genome sequences (WGSs) of 386 domestic goats from 75 modern breeds and 7 wild goat species generated by the VarGoats goat genome project. Phylogenetic analyses indicated five domestic haplogroups Y1AA, Y1AB, Y1B, Y2A and Y2B. Haplogroup distributions for 180 domestic breeds indicate ancient paternal population bottlenecks during the migration into northern Europe, southern Asia and Africa. Sharing of haplogroups reveals male-mediated introgressions: from Asia into Madagascar and, more recently, into the South-African Boer goat; then from this breed into other southeastern African goats; and from Europe into native Korean and Ugandan goats. This study illustrates the power of the Y-chromosomal variation for the reconstructing the history of domestic species with a wide geographic range.

We scanned the genomic data of almost one thousand Evolèner cattle, representing the by far smallest local cattle population of Switzerland, whereof only pedigree records are available. A reverse genetic screen using 94k SNP markers in 585 trios mapped recessive deleterious loci using homozygous haplotype deficiency. We found two haplotypes, EH1 and EH2, with moderate allele frequencies of >0.10. Mining for candidate variants was carried out by linkage analysis of the predicted haplotype status and whole-genome sequencing variant catalogue of seven Evolèner bulls. This led to the detection of two perfectly linked missense variants affecting conserved residues: GBE1:p.Arg437Gln for EH1, and LRRC8A:p.Ala73Val for EH2. No homozygous animals were observed in >5,100 cattle of various breeds including Evolèner. The presented study showed that very limited data can lead to the identification of candidate variants and thereby help to improve reproduction success in an endangered indigenous breed of cattle.

By its paternal transmission, Y-chromosomal haplotypes are sensitive markers of population history and male-mediated introgression. We used whole-genome sequences (WGSs) of 386 domestic goats from 75 modern breeds and 7 wild goat species generated by the VarGoats goat genome project. Phylogenetic analyses indicated five domestic haplogroups Y1AA, Y1AB, Y1B, Y2A and Y2B. Haplogroup distributions for 180 domestic breeds indicate ancient paternal population bottlenecks during the migration into northern Europe, southern Asia and Africa. Sharing of haplogroups reveals male-mediated introgressions: from Asia into Madagascar and, more recently, into the South-African Boer goat ; then from this breed into other southeastern African goats ; and from Europe into native Korean and Ugandan goats. This study illustrates the power of the Y-chromosomal variation for the reconstructing the history of domestic species with a wide geographic range.

In the last decade, five different genetic recessive disorders with known molecular causes were reported in Chianina, Marchigiana and Romagnola cattle. Targeted genotyping of the following pathogenic variants affecting five different genes became possible: the two forms of ATP2A1-related pseudomyotonia (PMT) in Chianina and Romagnola, KDM2B-related paunch calf syndrome (PCS) in Marchigiana and Romagnola, NID1-related congenital bilateral cataract (CC) in Romagnola, ABCA12-related ichthyosis fetalis (IF) and FA2H-related ichthyosis congenita (IC) in Chianina. This study aimed to characterize the frequency of the recessive alleles associated with PMT, PCS, CC, IF and IC and to investigate whether the causal variants are breed specific. Top sires used for artificial insemination and young bulls short-listed for the performance test, for a total of 7283 Chianina, 2696 Marchigiana and 1574 Romagnola animals were considered. Carriers rates (CR) considered on the base of the year of birth of the animals ranged as following: CR of PMT-ATP2A1 exon 6 from 8.1% to 22.3% in Chianina, 7.4% to 14.3% in Marchigiana and 0 to 8.1% in Romagnola; CR of PMT-ATP2A1 exon 8 in Romagnola from 3.9% to 13%; CR of CC-NID1 in Romagnola from 3.5% to 8.1%;CR of PCS-KDM2B from 0 to 14.3% in Marchigiana and from 9 to 55.6% in Romagnola; CR of IF-ABCA12 in Chianina from 1.8% to 6.3%; CR of IC-FA2H in Chianina from 3.8% to 31.8%. Considering only the top sires, the CR resulted as following: CR of PMT-ATP2A1 exon 6 was 3.5% in Chianina, and 9.7% in Marchigiana; CR of PMT-ATP2A1 exon 8 in Romagnola was 4%; CR of CC-NID1 in Romagnola was 6%; CR of PCS-KDM2B was 2.2% in Marchigiana and 27.8% in Romagnola; CR of IF-ABCA12 in Chianina was 1.7%; CR of IC-FA2H in Chianina was 15.2%. This study validates the concern regarding the impact of recessively inherited diseases on breeding programs. It also reports the first evidence of the segregation of PMT-ATP2A1 variant initially found in Chianina also in Marchigiana. Systematic genotyping of sires for these alleles is recommended to prevent risky matting.

Vereinzelt treten in der Schweiz schwarz-weiss gescheckte Kälber auf, die im pigmentierten Bereich ein besonderes Fell aufweisen. Ansonsten sind diese Tiere normal entwickelt. Die weissen Haare sind normal, sie erscheinen jedoch verhältnismässig lang und glatt. Dagegen sind die pigmentierten Haare kraus und verkürzt. Zudem weisen die betroffenen Tiere eine variable Intensität der Fellfarbe im pigmentierten Bereich auf. Betroffene Kälber erscheinen bei Geburt eher schwarz, wobei mit zunehmendem Alter unterschiedlich aufgehellte Farben von rotbräunlich bis grau auftreten. Bei adulten Rindern erscheinen die farbigen Haare eher glatt, jedoch deutlich verkürzt. Damit verbunden ist eine sich während des Wachstums verstärkende, variable und auf den pigmentierten Bereich des Fells beschränkte Minderbehaarung. Dieses Phänomen der farbassoziierten Hypotrichose ist zuvor international in verschiedenen Fleischrinderpopulationen beschrieben worden. Diese Rinder sind oftmals einfarbig schwarz mit nur wenigen kleinen weissen Abzeichen. Auf Grund des Haarverlusts im pigmentierten Fell und insbesondere am pigmentierten Schwanz ist neben dem Begriff der kreuzungsbedingten kongenitalen Hypotrichose auch vom rat-tail syndrome gesprochen worden. Molekulargenetische Untersuchungen haben gezeigt, dass die betroffenen Tiere jeweils heterozygote Träger für zwei mit der Pigmentierung assoziierten Varianten in zwei verschiedenen Genen gewesen sind. Dieselbe Genotyp-Konstellation weisen auch die hier vorgestellten 33 ähnlich betroffenen Rinder aus der Schweiz auf. Einerseits tragen sie jeweils eine Kopie der MC1R Genvariante für die dominant vererbte schwarze Fellfarbe, sowie eine Kopie der rezessiv vererbten Rotfaktorvariante im MC1R Gen. Andererseits sind alle Fälle heterozygote Anlageträger für eine Variante im PMEL Gen, die mit einer semidominant vererbten Form der Farbverdünnung (falb) bei Simmental, Hereford und Highland Cattle assoziiert ist. Die seit Jahrzehnten praktizierte Einkreuzung der Rasse Holstein ins Original Simmental erklärt das gelegentliche Vorkommen dieses Phänomens in der Schweizer Rinderzucht., Occasionally black-and-white spotted calves appear in Switzerland, which show a special fur only in the pigmented area. Otherwise these animals are normally developed. The white hairs are normal, but they appear relatively long and smooth, because the pigmented hairs are curly and thus appear shortened. In addition, the affected animals show a variable intensity of coat colour in the pigmented area. At birth affected calves often appear black, whereas older cattle show bright colours from reddish brown to grey. This is associated with a variable hair loss that increases during growth and is limited to the pigmented area of the coat. In adult cattle the coloured hairs appear rather smooth, but they are considerably shorter. This phenomenon of pigmentation-associated hypotrichosis was previously described internationally in various beef cattle populations. The affected cattle are often solid black and show only small white spots. Therefore, the loss of hair at the pigmented fur and most visibly at the pigmented tail is called rat-tail syndrome. Another name used is also crossbreeding-related congenital hypotrichosis. Molecular genetic investigations showed that the affected animals are heterozygous carriers for two variants in two different genes associated with pigmentation. The same genotype constellation was found in the 33 similarly affected cattle from Switzerland presented here. On one hand, they each carry a copy of the MC1R gene gain-of-function variant causing dominant black, as well as a copy of the recessively inherited red factor loss-of-function variant in the MC1R gene. On the other hand, all cases are heterozygous carriers for a variant in the PMEL gene that is associated with a semi-dominantly inherited form of colour dilution (dun or silver) in Simmental, Hereford and Highland Cattle. The introgression of Holstein cattle into the Original Simmental breed, which has been practised for decades, explains the occasional occurrence of this phenomenon in Swiss cattle breeding., En Suisse, on peut parfois observer des veaux tachetés noirs et blancs présentant un pelage spécial uniquement dans la zone pigmentée des poils. Ces animaux sont normalement développés; les poils blancs sont normaux mais semblent relativement longs et lisses, alors que les poils pigmentés sont bouclés et raccourcis. En outre, les animaux atteints présentent une intensité variable de la couleur du pelage dans la zone pigmentée. À la naissance, ces veaux apparaissent souvent noirs, alors qu’en grandissant ils présentent une couleur plus claire allant du brun rougeâtre au gris. Chez les bovins adultes, les poils colorés semblent plutôt lisses mais sont nettement raccourcis. Ceci est associé à une diminution de la pilosité variable augmentant pendant la croissance et se limitant à la zone pigmentée du pelage. Ce phénomène d’hypotrichose associée à la pigmentation a déjà été décrit au niveau international dans diverses races à viande bovines. Ces bovins sont souvent d’un noir uniforme et ne présentent que de petites taches blanches. En raison de la perte de poils dans le pelage pigmenté et plus visiblement au niveau de la queue pigmentée, on appelle ce syndrome syndrome de la queue de rat (rat-tail syndrom), également appelé hypotrichose congénitale liée au croisement. Les études de génétique moléculaire ont montré que les animaux affectés sont porteurs hétérozygotes de deux variantes de deux gènes différents associés à la pigmentation. La même constellation génotypique a été retrouvée chez les 33 bovins suisses présentés ici. D’une part, ces derniers portent chacun une copie de la variante du gène dominant MC1R causant le noir, ainsi qu’une copie de la variante récessive du facteur rouge dans le gène MC1R. D’autre part, tous les cas sont porteurs hétérozygotes d’une variante du gène PMEL associée à une forme de dilution de couleur semi-dominante héréditaire (dun ou argent) chez les races Simmental, Hereford et Highland Cattle. Le croisement des bovins Holstein avec la race Simmental originale, pratiquée depuis des décennies, explique la présence occasionnelle de ce phénomène dans l’élevage bovin suisse., Di tanto in tanto, in Svizzera nascono vitelli maculati di bianco e nero, che hanno un pelo particolare solo nella zona pigmentata. Altrimenti questi animali hanno uno sviluppo normale. I peli bianchi sono normali, ma appaiono relativamente lunghi e lisci mentre i peli pigmentati sono ricci e corti. Inoltre, gli animali in questione mostrano un’intensità variabile del colore del mantello nella zona pigmentata. I vitelli coinvolti tendono ad apparire neri alla nascita, ma con l’età cambiano con vari gradi di schiarimento dal bruno rossastro al grigio. Nei bovini adulti, i peli colorati appaiono piuttosto lisci, ma notevolmente accorciati. Questo viene associato durante la crescita a un incremento della pelosità ridotta che è variabile e limitata alla zona pigmentata del mantello. Questo fenomeno di ipotricosi associata ai colori è stato già precedentemente descritto a livello internazionale in varie popolazioni di bovini da carne. Questi bovini sono spesso di colore nero monocromatico con solo poche e piccole macchie bianche. A causa della perdita dei peli del mantello pigmentato e soprattutto sulla coda pigmentata, è stato usato il termine rat-tail syndrome in aggiunta al termine ipotricosi congenita causata dall’incrocio. Studi di genetica molecolare hanno dimostrato che gli animali colpiti erano portatori eterozigoti per due varianti associate alla pigmentazione in due geni diversi. La stessa costellazione di genotipi si è rilevata anche nei 33 bovini qui presentati provenienti dalla Svizzera, che sono stati colpiti in modo molto simile. Da un lato, ognuno di essi porta una copia della variante del gene MC1R per il colore del mantello nero ereditato dominante, così come una copia della variante del fattore rosso ereditato recessivamente nel gene MC1R. D’altra parte, tutti i casi sono portatori eterozigoti per una variante del gene PMEL associata a una forma semidominante di dispersione del colore (giallo pallido) nelle razze Simmental, Hereford e ­Highland Cattle. L’incrocio della razza Holstein con la razza Original Simmental, praticato da decenni, spiega il verificarsi occasionale di questo fenomeno nell’allevamento bovino svizzero.

In domestic goats, the polled intersex syndrome (PIS) refers to XX female-to-male sex reversal associated with the absence of horn growth (polled). The causal variant was previously reported as a 11.7 kb deletion at approximately 129 Mb on chromosome 1 that affects the transcription of both FOXL2 and several long non-coding RNAs. In the meantime the presence of different versions of the PIS deletion was postulated and trials to establish genetic testing with the existing molecular genetic information failed. Therefore, we revisited this variant by long-read whole-genome sequencing of two genetically female (XX) goats, a PIS-affected and a horned control. This revealed the presence of a more complex structural variant consisting of a deletion with a total length of 10 159 bp and an inversely inserted approximately 480 kb-sized duplicated segment of a region located approximately 21 Mb further downstream on chromosome 1 containing two genes, KCNJ15 and ERG. Publicly available short-read whole-genome sequencing data, Sanger sequencing of the breakpoints and FISH using BAC clones corresponding to both involved genome regions confirmed this structural variant. A diagnostic PCR was developed for simultaneous genotyping of carriers for this variant and determination of their genetic sex. We showed that the variant allele was present in all 334 genotyped polled goats of diverse breeds and that all analyzed 15 PIS-affected XX goats were homozygous. Our findings enable for the first time a precise genetic diagnosis for polledness and PIS in goats and add a further genomic feature to the complexity of the PIS phenomenon.

White-spotting coat colour phenotypes in cattle are either fixed characteristics of specific cattle breeds or occur sporadically owing to germline genetic variation of solid-coloured parents. A Brown Swiss cow showing a piebald pattern resembling colour-sidedness was referred for genetic evaluation. Both parents were normal solid-brown-coloured cattle. The cow was tested negative for the three known DNA variants in KIT, MITF and TWIST2 associated with different depigmentation phenotypes in Brown Swiss cattle. Whole-genome sequencing of the cow was performed and a heterozygous variant affecting the coding sequence of the bovine KIT gene was identified on chromosome 6. The variant is a 40 bp deletion in exon 9, NM_001166484.1:c.1390_1429del, and leads to a frameshift that is predicted to produce a novel 50 amino acid-long C-terminus replacing almost 50% of the wt KIT protein, including the functionally important intracellular tyrosine kinase domain (NP_001159956.1:p.(Asn464AlafsTer50)). Interestingly, among three available offspring, two solid-coloured daughters were genotyped as homozygous wt whereas a single son showing a slightly milder but still obvious depigmentation phenotype inherited a copy of the novel variant allele. The genetic findings provide strong evidence that the identified loss-of-function KIT variant most likely represents a de novo germline mutation that is causative owing to haploinsufficiency.

Die Entwicklung moderner Technologien erlaubt es heute, mittels einer DNA-Genotypisierung den Zustand an Tausenden von Stellen im Erbgut eines Tieres aufzudecken. Diese Information kann verwendet werden, um die genomische Inzucht herzuleiten. Dies ist wertvoll für Populationen, die keine oder nur unvollständige Pedigree-Information haben. Weiter können Unterschiede in der Inzucht von Vollgeschwistern aufgezeigt werden und es kann sichtbar gemacht werden, wo im Erbgut Inzucht gewirkt hat. Dadurch liefert sie Anhaltspunkte zur genetischen Vielfalt innerhalb einer Rasse. In dieser Studie wurde für 1120 Schafe von elf Rassen und für 332 Ziegen von zehn Rassen die genomische Inzucht hergeleitet. Für die untersuchten Tiere der Ziegenrassen Saanenziege (SA), Toggenburgerziege (TO), Bündner Strahlenziege (BS), Walliser Ziegen (WZ), Appenzellerziege (AP) und Stiefelgeiss (ST), sowie der Schafrassen Walliser Schwarznasenschaf (SN), Spiegelschaf (SPS), Walliser Landschaf (WLS) und Ouessant Schaf (OUE) wurde eine durchschnittliche genomische Inzucht > 6,25 % berechnet. Generell erlaubt der Miteinbezug von genomischen Daten ein besseres Verständnis der Verwandtschafts- und Inzuchtverhältnisse in Schweizer Rassen. Dadurch sind differenziertere Entscheide für die Zucht und allfällige Erhaltungsaktivitäten möglich., Lo sviluppo delle moderne tecnologie permette oggigiorno, tramite la genotipizzazione del DNA, di individuare migliaia marcatori genetici nel patrimonio genetico di un animale. Questa informazione può essere utilizzata per derivare la consanguineità genomica, che è molto utile per le popolazioni il cui pedigree è assente o incompleto. Inoltre, possono essere evidenziate differenze nella consanguineità tra fratelli pieni e può essere accertato dove la consanguineità abbia influenzato il patrimonio genetico. La consanguineità fornisce in tal modo indicazioni sulla diversità genetica all’interno di una razza. Nel presente studio è stata ricavata la consanguineità genomica di 1120 pecore appartenenti a undici razze e di 332 capre di dieci razze. Per gli animali esaminati appartenenti alle razze caprine Saanen (SA), Toggenburgo (TO), Striata grigionese (BS), Capre vallesane (WZ), Appenzello (AP) e Sangallese dagli stivali (ST), così come per le razze ovine Naso nero del Vallese (SN), Pecora dagli specchi (SPS), Roux du Valais (WLS) e Nana d’Ouessant (OUE) è risultata una consanguineità genomica media superiore al 6,25 %. In generale, la presa in considerazione dei dati genomici permette una migliore comprensione dei gradi di parentela e delle relazioni di consanguineità nelle razze svizzere e in tal modo rende possibili scelte più consapevoli nell’allevamento e in eventuali attività di conservazione delle razze., The development of modern technologies now allows thousands of genetic markers in an animal’s genome to be revealed by means of DNA genotyping. This information can be used to deduce genomic inbreeding. This is valuable for populations that have no, or only incomplete, pedigree information. Furthermore, differences in the inbreeding of full siblings can be demonstrated and it is possible to identify where in the genome the inbreeding has had an effect. In this way it provides clues to genetic diversity within a breed. In this study, genomic inbreeding was investigated for 1,120 sheep from eleven breeds and for 332 goats from ten breeds. An average genomic inbreeding > 6.25 % between individual animals was observed in the goat breeds Saanen (SA), Toggen-burg (TO), Grisons Striped (BS), Valais goat (WZ), Appenzell (AP) and Stiefelgeiss (ST), as well as for the sheep breeds Valais Blacknose (SN), Spiegel (SPS), Roux du Valais (WLS) and Ouessant (OUE). In general, the consideration of genomic data allows a better understanding of kinship and inbreeding conditions in Swiss breeds and therefore enables better decision-making in relation to breeding and possible conservation activities.

A specific white spotting phenotype, termed finching or line-backed spotting, is known for all Pinzgauer cattle and occurs occasionally in Tux-Zillertaler cattle, two Austrian breeds. The so-called Pinzgauer spotting is inherited as an autosomal incompletely dominant trait. A genome-wide association study using 27 white spotted and 16 solid-coloured Tux-Zillertaler cattle, based on 777k SNP data, revealed a strong signal on chromosome 6 at the KIT locus. Haplotype analyses defined a critical interval of 122 kb downstream of the KIT coding region. Whole-genome sequencing of a Pinzgauer cattle and comparison to 338 control genomes revealed a complex structural variant consisting of a 9.4-kb deletion and an inversely inserted duplication of 1.5 kb fused to a 310-kb duplicated segment from chromosome 4. A diagnostic PCR was developed for straightforward genotyping of carriers for this structural variant (KIT ) and confirmed that the variant allele was present in all Pinzgauer and most of the white spotted Tux-Zillertaler cattle. In addition, we detected the variant in all Slovenian Cika, British Gloucester and Spanish Berrenda en negro cattle with similar spotting patterns. Interestingly, the KIT variant occurs in some white spotted animals of the Swiss breeds Evolèner and Eringer. The introgression of the KIT variant confirms admixture and the reported historical relationship of these short-headed breeds with Austrian Tux-Zillertaler and suggests a mutation event, occurring before breed formation.