Sabrina Rodriguez

Bio: Sabrina Rodriguez is an academic researcher from Institut national de la recherche agronomique. The author has contributed to research in topics: Genome-wide association study & Genetic association. The author has an hindex of 5, co-authored 5 publications receiving 849 citations. Previous affiliations of Sabrina Rodriguez include Agro ParisTech.

Whole-genome sequencing of 234 bulls facilitates mapping of monogenic and complex traits in cattle

Abstract: The 1000 bull genomes project supports the goal of accelerating the rates of genetic gain in domestic cattle while at the same time considering animal health and welfare by providing the annotated sequence variants and genotypes of key ancestor bulls. In the first phase of the 1000 bull genomes project, we sequenced the whole genomes of 234 cattle to an average of 8.3-fold coverage. This sequencing includes data for 129 individuals from the global Holstein-Friesian population, 43 individuals from the Fleckvieh breed and 15 individuals from the Jersey breed. We identified a total of 28.3 million variants, with an average of 1.44 heterozygous sites per kilobase for each individual. We demonstrate the use of this database in identifying a recessive mutation underlying embryonic death and a dominant mutation underlying lethal chrondrodysplasia. We also performed genome-wide association studies for milk production and curly coat, using imputed sequence variants, and identified variants associated with these traits in cattle.

Detection of haplotypes associated with prenatal death in dairy cattle and identification of deleterious mutations in GART, SHBG and SLC37A2.

Abstract: The regular decrease of female fertility over time is a major concern in modern dairy cattle industry. Only half of this decrease is explained by indirect response to selection on milk production, suggesting the existence of other factors such as embryonic lethal genetic defects. Genomic regions harboring recessive deleterious mutations were detected in three dairy cattle breeds by identifying frequent haplotypes (>1%) showing a deficit in homozygotes among Illumina Bovine 50k Beadchip haplotyping data from the French genomic selection database (47,878 Holstein, 16,833 Montbeliarde, and 11,466 Normande animals). Thirty-four candidate haplotypes (p<10−4) including previously reported regions associated with Brachyspina, CVM, HH1, and HH3 in Holstein breed were identified. Haplotype length varied from 1 to 4.8 Mb and frequencies from 1.7 up to 9%. A significant negative effect on calving rate, consistent in heifers and in lactating cows, was observed for 9 of these haplotypes in matings between carrier bulls and daughters of carrier sires, confirming their association with embryonic lethal mutations. Eight regions were further investigated using whole genome sequencing data from heterozygous bull carriers and control animals (45 animals in total). Six strong candidate causative mutations including polymorphisms previously reported in FANCI (Brachyspina), SLC35A3 (CVM), APAF1 (HH1) and three novel mutations with very damaging effect on the protein structure, according to SIFT and Polyphen-2, were detected in GART, SHBG and SLC37A2 genes. In conclusion, this study reveals a yet hidden consequence of the important inbreeding rate observed in intensively selected and specialized cattle breeds. Counter-selection of these mutations and management of matings will have positive consequences on female fertility in dairy cattle.

Attenuated sensing of SHH by Ptch1 underlies evolution of bovine limbs

Abstract: The large spectrum of limb morphologies reflects the wide evolutionary diversification of the basic pentadactyl pattern in tetrapods. In even-toed ungulates (artiodactyls, including cattle), limbs are adapted for running as a consequence of progressive reduction of their distal skeleton to symmetrical and elongated middle digits with hoofed phalanges. Here we analyse bovine embryos to establish that polarized gene expression is progressively lost during limb development in comparison to the mouse. Notably, the transcriptional upregulation of the Ptch1 gene, which encodes a Sonic hedgehog (SHH) receptor, is disrupted specifically in the bovine limb bud mesenchyme. This is due to evolutionary alteration of a Ptch1 cis-regulatory module, which no longer responds to graded SHH signalling during bovine handplate development. Our study provides a molecular explanation for the loss of digit asymmetry in bovine limb buds and suggests that modifications affecting the Ptch1 cis-regulatory landscape have contributed to evolutionary diversification of artiodactyl limbs.

C-Nap1 mutation affects centriole cohesion and is associated with a Seckel-like syndrome in cattle

Abstract: Caprine-like Generalized Hypoplasia Syndrome (SHGC) is an autosomal-recessive disorder in Montbeliarde cattle. Affected animals present a wide range of clinical features that include the following: delayed development with low birth weight, hind limb muscular hypoplasia, caprine-like thin head and partial coat depigmentation. Here we show that SHGC is caused by a truncating mutation in the CEP250 gene that encodes the centrosomal protein C-Nap1. This mutation results in centrosome splitting, which neither affects centriole ultrastructure and duplication in dividing cells nor centriole function in cilium assembly and mitotic spindle organization. Loss of C-Nap1-mediated centriole cohesion leads to an altered cell migration phenotype. This discovery extends the range of loci that constitute the spectrum of autosomal primary recessive microcephaly (MCPH) and Seckel-like syndromes.

Concordance analysis for QTL detection in dairy cattle: a case study of leg morphology

Abstract: Background: The present availability of sequence data gives new opportunities to narrow down from QTL (quantitative trait locus) regions to causative mutations. Our objective was to decrease the number of candidate causative mutations in a QTL region. For this, a concordance analysis was applied for a leg conformation trait in dairy cattle. Several QTL were detected for which the QTL status (homozygous or heterozygous for the QTL) was inferred for each individual. Subsequently, the inferred QTL status was used in a concordance analysis to reduce the number of candidate mutations. Methods: Twenty QTL for rear leg set side view were mapped using Bayes C. Marker effects estimated during QTL mapping were used to infer the QTL status for each individual. Subsequently, polymorphisms present in the QTL regions were extracted from the whole-genome sequences of 71 Holstein bulls. Only polymorphisms for which the status was concordant with the QTL status were kept as candidate causative mutations. Results: QTL status could be inferred for 15 of the 20 QTL. The number of concordant polymorphisms differed between QTL and depended on the number of QTL statuses that could be inferred and the linkage disequilibrium in the QTL region. For some QTL, the concordance analysis was efficient and narrowed down to a limited number of candidate mutations located in one or two genes, while for other QTL a large number of genes contained concordant polymorphisms. Conclusions: For regions for which the concordance analysis could be performed, we were able to reduce the number of candidate mutations. For part of the QTL, the concordant analyses narrowed QTL regions down to a limited number of genes, of which some are known for their role in limb or skeletal development in humans and mice. Mutations in these genes are good candidates for QTN (quantitative trait nucleotides) influencing rear leg set side view.

The Ensembl Variant Effect Predictor.

Abstract: The Ensembl Variant Effect Predictor is a powerful toolset for the analysis, annotation, and prioritization of genomic variants in coding and non-coding regions. It provides access to an extensive collection of genomic annotation, with a variety of interfaces to suit different requirements, and simple options for configuring and extending analysis. It is open source, free to use, and supports full reproducibility of results. The Ensembl Variant Effect Predictor can simplify and accelerate variant interpretation in a wide range of study designs.

Sequencing pools of individuals — mining genome-wide polymorphism data without big funding

Abstract: The analysis of polymorphism data is becoming increasingly important as a complementary tool to classical genetic analyses. Nevertheless, despite plunging sequencing costs, genomic sequencing of individuals at the population scale is still restricted to a few model species. Whole-genome sequencing of pools of individuals (Pool-seq) provides a cost-effective alternative to sequencing individuals separately. With the availability of custom-tailored software tools, Pool-seq is being increasingly used for population genomic research on both model and non-model organisms. In this Review, we not only demonstrate the breadth of questions that are being addressed by Pool-seq but also discuss its limitations and provide guidelines for users.

Genomic selection: A paradigm shift in animal breeding

Abstract: • Traditional marker-assisted selection (MAS) did not result in a widespread use of DNA information in animal breeding. The main reason was that the traits of interest in livestock production were much more complex than expected: they were determined by thousands of genes with small effects on phenotype. These effects were usually too small to be statistically significant and so were ignored. • Genomic selection (GS) assumes that all markers might be linked to a gene affecting the trait and concentrates on estimating their effect rather than testing its significance. Three technological breakthroughs resulted in the current wide-spread use of DNA information in animal breeding: the development of the genomic selection technology, the discovery of massive numbers of genetic markers (single nucleotide polymorphisms; SNPs), and high-throughput technology to genotype animals for (hundreds of) thousands of SNPs in a cost-effective manner. • Here we review current methods for GS, including how they deal with practical data, where genotypes are missing on a large scale. The use of whole-genome sequence data is anticipated, and its advantages and disadvantages are depicted. Current and predicted future impacts of GS on dairy and beef cattle, pigs, and poultry breeding are described. Finally, future directions for GS are discussed. • It is anticipated that future GS applications will either be: within breed (wbGS), where accuracy is obtained by maintaining huge withinbreed reference populations; or across breed (abGS) where accuracy is obtained from across-breed reference populations and high-density GS methods that focus on causative genomic regions. We argue that future GS applications will increasingly turn toward abGS.

Coordinated international action to accelerate genome-to-phenome with FAANG, the Functional Annotation of Animal Genomes project

Abstract: We describe the organization of a nascent international effort, the Functional Annotation of Animal Genomes (FAANG) project, whose aim is to produce comprehensive maps of functional elements in the genomes of domesticated animal species.

Genetics and genomics of reproductive performance in dairy and beef cattle.

Abstract: Excellent reproductive performance in both males and females is fundamental to profitable dairy and beef production systems. In this review we undertook a meta-analysis of genetic parameters for female reproductive performance across 55 dairy studies or populations and 12 beef studies or populations as well as across 28 different studies or populations for male reproductive performance. A plethora of reproductive phenotypes exist in dairy and beef cattle and a meta-analysis of the literature suggests that most of the female reproductive traits in dairy and beef cattle tend to be lowly heritable (0.02 to 0.04). Reproductive-related phenotypes in male animals (e.g. semen quality) tend to be more heritable than female reproductive phenotypes with mean heritability estimates of between 0.05 and 0.22 for semen-related traits with the exception of scrotal circumference (0.42) and field non-return rate (0.001). The low heritability of reproductive traits, in females in particular, does not however imply that genetic selection cannot alter phenotypic performance as evidenced by the decline until recently in dairy cow reproductive performance attributable in part to aggressive selection for increased milk production. Moreover, the antagonistic genetic correlations among reproductive traits and both milk (dairy cattle) and meat (beef cattle) yield is not unity thereby implying that simultaneous genetic selection for both increased (milk and meat) yield and reproductive performance is indeed possible. The required emphasis on reproductive traits within a breeding goal to halt deterioration will vary based on the underlying assumptions and is discussed using examples for Ireland, the United Kingdom and Australia as well as quantifying the impact on genetic gain for milk production. Advancements in genomic technologies can aid in increasing the accuracy of selection for especially reproductive traits and thus genetic gain. Elucidation of the underlying genomic mechanisms for reproduction could also aid in resolving genetic antagonisms. Past breeding programmes have contributed to the deterioration in reproductive performance of dairy and beef cattle. The tools now exist, however, to reverse the genetic trends in reproductive performance underlying the observed phenotypic trends.