Aurélien Capitan

Bio: Aurélien Capitan is an academic researcher from Université Paris-Saclay. The author has contributed to research in topics: Population & Locus (genetics). The author has an hindex of 16, co-authored 40 publications receiving 1529 citations. Previous affiliations of Aurélien Capitan include Institut national de la recherche agronomique & 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.

Meta-analysis of genome-wide association studies for cattle stature identifies common genes that regulate body size in mammals.

Abstract: Stature is affected by many polymorphisms of small effect in humans 1 . In contrast, variation in dogs, even within breeds, has been suggested to be largely due to variants in a small number of genes2,3. Here we use data from cattle to compare the genetic architecture of stature to those in humans and dogs. We conducted a meta-analysis for stature using 58,265 cattle from 17 populations with 25.4 million imputed whole-genome sequence variants. Results showed that the genetic architecture of stature in cattle is similar to that in humans, as the lead variants in 163 significantly associated genomic regions (P < 5 × 10-8) explained at most 13.8% of the phenotypic variance. Most of these variants were noncoding, including variants that were also expression quantitative trait loci (eQTLs) and in ChIP-seq peaks. There was significant overlap in loci for stature with humans and dogs, suggesting that a set of common genes regulates body size in mammals.

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.

Whole-genome analysis of introgressive hybridization and characterization of the bovine legacy of Mongolian yaks.

Abstract: The yak is remarkable for its adaptation to high altitude and occupies a central place in the economies of the mountainous regions of Asia. At lower elevations, it is common to hybridize yaks with cattle to combine the yak's hardiness with the productivity of cattle. Hybrid males are sterile, however, preventing the establishment of stable hybrid populations, but not a limited introgression after backcrossing several generations of female hybrids to male yaks. Here we inferred bovine haplotypes in the genomes of 76 Mongolian yaks using high-density SNP genotyping and whole-genome sequencing. These yaks inherited ∼1.3% of their genome from bovine ancestors after nearly continuous admixture over at least the last 1,500 years. The introgressed regions are enriched in genes involved in nervous system development and function, and particularly in glutamate metabolism and neurotransmission. We also identified a novel mutation associated with a polled (hornless) phenotype originating from Mongolian Turano cattle. Our results suggest that introgressive hybridization contributed to the improvement of yak management and breeding.

Novel Insights into the Bovine Polled Phenotype and Horn Ontogenesis in Bovidae

Abstract: Despite massive research efforts, the molecular etiology of bovine polledness and the developmental pathways involved in horn ontogenesis are still poorly understood. In a recent article, we provided evidence for the existence of at least two different alleles at the Polled locus and identified candidate mutations for each of them. None of these mutations was located in known coding or regulatory regions, thus adding to the complexity of understanding the molecular basis of polledness. We confirm previous results here and exhaustively identify the causative mutation for the Celtic allele (PC) and four candidate mutations for the Friesian allele (PF). We describe a previously unreported eyelash-and-eyelid phenotype associated with regular polledness, and present unique histological and gene expression data on bovine horn bud differentiation in fetuses affected by three different horn defect syndromes, as well as in wild-type controls. We propose the ectopic expression of a lincRNA in PC/p horn buds as a probable cause of horn bud agenesis. In addition, we provide evidence for an involvement of OLIG2, FOXL2 and RXFP2 in horn bud differentiation, and draw a first link between bovine, ovine and caprine Polled loci. Our results represent a first and important step in understanding the genetic pathways and key process involved in horn bud differentiation in Bovidae.

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.

Integrative Genomics Viewer

Abstract: Rapid improvements in sequencing and array-based platforms are resulting in a flood of diverse genome-wide data, including data from exome and whole-genome sequencing, epigenetic surveys, expression profiling of coding and noncoding RNAs, single nucleotide polymorphism (SNP) and copy number profiling, and functional assays. Analysis of these large, diverse data sets holds the promise of a more comprehensive understanding of the genome and its relation to human disease. Experienced and knowledgeable human review is an essential component of this process, complementing computational approaches. This calls for efficient and intuitive visualization tools able to scale to very large data sets and to flexibly integrate multiple data types, including clinical data. However, the sheer volume and scope of data pose a significant challenge to the development of such tools.

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.