An Intronic <i>MBTPS2</i> Variant Results in a Splicing Defect in Horses with Brindle Coat Texture

Background: X-chromosomal loci present different inheritance patterns compared to autosomal loci and must be modeled accordingly. Sexual chromosomes are not systematically considered in whole-genome relationship matrices although rules based on genealogical or marker information have been derived. Loci on the X-chromosome could have a significant contribution to the additive genetic variance, in particular for some traits such as those related to reproduction. Thus, accounting for the X-chromosome relationship matrix might be informative to better understand the architecture of complex traits (e.g., by estimating the variance associated to this chromosome) and to improve their genomic prediction. For such applications, previous studies have shown the benefits of combining information from genotyped and ungenotyped individuals. Results: In this paper, we start by presenting rules to compute a genomic relationship matrix (GRM) for the X-chromosome (G X) without making any assumption on dosage compensation, and based on coding of gene content with 0/1 for males and 0/1/2 for females. This coding adjusts naturally to previously derived pedigree-based relationships (S) for the X-chromosome. When needed, we propose to accommodate and estimate dosage compensation and genetic heterogeneity across sexes via multiple trait models. Using a Holstein dairy cattle dataset, including males and females, we then empirically illustrate that realized relationships (G X) matches expectations (S). However, G X presents high deviations from S. G X has also a lower dimensionality compared to the autosomal GRM. In particular, individuals are frequently identical along the entire chromosome. Finally, we confirm that the heritability of gene content for markers on the X-chromosome that are estimated by using S is 1, further demonstrating that S and G X can be combined. For the pseudo-autosomal region, we demonstrate that the expected relationships vary according to position because of the sex-gradient. We end by presenting the rules to construct the 'H matrix' by combining both relationship matrices. Conclusions: This work shows theoretically and empirically that a pedigree-based relationship matrix built with rules specifically developed for the X-chromosome (S) matches the realized GRM for the X-chromosome. Therefore, applications that combine expected relationships and genotypes for markers on the X-chromosome should use S and G X .

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“…Genotypes on the X-chromosome require also specific phasing, e.g. [ 46 , 47 ] or imputation strategies [ 47 – 49 ].…”

Section: Discussionmentioning

confidence: 99%

Theoretical and empirical comparisons of expected and realized relationships for the X-chromosome

Druet

Legarra

2020

Genet Sel Evol

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“…Sequencing and read mapping to the EquCab 2 reference assembly was performed as previously described (Murgiano et al . ). Data were deposited at the European Nucleotide Archive (study accession PRJEB14779, sample ERS1451611).…”

Section: New Variant In the Kit Genementioning

confidence: 97%

Whole genome sequencing reveals a novel deletion variant in the KIT gene in horses with white spotted coat colour phenotypes

et al. 2017

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White spotting phenotypes in horses can range in severity from the common white markings up to completely white horses. EDNRB, KIT, MITF, PAX3 and TRPM1 represent known candidate genes for such phenotypes in horses. For the present study, we re-investigated a large horse family segregating a variable white spotting phenotype, for which conventional Sanger sequencing of the candidate genes' individual exons had failed to reveal the causative variant. We obtained whole genome sequence data from an affected horse and specifically searched for structural variants in the known candidate genes. This analysis revealed a heterozygous ~1.9-kb deletion spanning exons 10-13 of the KIT gene (chr3:77,740,239_77,742,136del1898insTATAT). In continuity with previously named equine KIT variants we propose to designate the newly identified deletion variant W22. We had access to 21 horses carrying the W22 allele. Four of them were compound heterozygous W20/W22 and had a completely white phenotype. Our data suggest that W22 represents a true null allele of the KIT gene, whereas the previously identified W20 leads to a partial loss of function. These findings will enable more precise genetic testing for depigmentation phenotypes in horses.

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“…Skin lesions following Blaschko’s lines in heterozygous females are also known in animals with X-linked heritable phenotypes, for example, incontinentia pigmenti and brindle 1 in horses ( Towers et al 2013 ; Murgiano et al 2016 ), streaked hairlessness in cattle ( Murgiano et al 2015 ), or X-linked hypohidrotic ectodermal dysplasia in dogs ( Casal et al 1997 ).…”

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confidence: 99%

A Large Deletion in the NSDHL Gene in Labrador Retrievers with a Congenital Cornification Disorder

Bauer

Lucia

Jagannathan

et al. 2017

G3 Genes|Genomes|Genetics

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In heterozygous females affected by an X-linked skin disorder, lesions often appear in a characteristic pattern, the so-called Blaschko’s lines. We investigated a female Labrador Retriever and her crossbred daughter, which both showed similar clinical lesions that followed Blaschko’s lines. The two male littermates of the affected daughter had died at birth, suggesting a monogenic X-chromosomal semidominant mode of inheritance. Whole genome sequencing of the affected daughter, and subsequent automated variant filtering with respect to 188 nonaffected control dogs of different breeds, revealed 332 hetero-zygous variants on the X-chromosome private to the affected dog. None of these variants was protein-changing. By visual inspection of candidate genes located on the X-chromosome, we identified a large deletion in the NSDHL gene, encoding NAD(P) dependent steroid dehydrogenase-like, a 3β-hydroxysteroid dehydrogenase involved in cholesterol biosynthesis. The deletion spanned >14 kb, and included the last three exons of the NSDHL gene. By PCR and fragment length analysis, we confirmed the presence of the variant in both affected dogs, and its absence in 50 control Labrador Retrievers. Variants in the NSDHL gene cause CHILD syndrome in humans, and the bare patches (Bpa) and striated (Str) phenotypes in mice. Taken together, our genetic data and the known role of NSDHL in X-linked skin disorders strongly suggest that the identified structural variant in the NSDHL gene is causative for the phenotype in the two affected dogs.

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An Intronic MBTPS2 Variant Results in a Splicing Defect in Horses with Brindle Coat Texture

Cited by 9 publications

References 32 publications

Theoretical and empirical comparisons of expected and realized relationships for the X-chromosome

Theoretical and empirical comparisons of expected and realized relationships for the X-chromosome

Whole genome sequencing reveals a novel deletion variant in the KIT gene in horses with white spotted coat colour phenotypes

A Large Deletion in the NSDHL Gene in Labrador Retrievers with a Congenital Cornification Disorder

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