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      The Genome Response to Artificial Selection: A Case Study in Dairy Cattle

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          Abstract

          Dairy cattle breeds have been subjected over the last fifty years to intense artificial selection towards improvement of milk production traits. In this study, we performed a whole genome scan for differentiation using 42,486 SNPs in the three major French dairy cattle breeds (Holstein, Normande and Montbéliarde) to identify the main physiological pathways and regions which were affected by this selection. After analyzing the population structure, we estimated F ST within and across the three breeds for each SNP under a pure drift model. We further considered two different strategies to evaluate the effect of selection at the genome level. First, smoothing F ST values over each chromosome with a local variable bandwidth kernel estimator allowed identifying 13 highly significant regions subjected to strong and/or recent positive selection. Some of them contained genes within which causal variants with strong effect on milk production traits (GHR) or coloration (MC1R) have already been reported. To go further in the interpretation of the observed signatures of selection we subsequently concentrated on the annotation of differentiated genes defined according to the F ST value of SNPs localized close or within them. To that end we performed a comprehensive network analysis which suggested a central role of somatotropic and gonadotropic axes in the response to selection. Altogether, these observations shed light on the antagonism, at the genome level, between milk production and reproduction traits in highly producing dairy cows.

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          A note on exact tests of Hardy-Weinberg equilibrium.

          Deviations from Hardy-Weinberg equilibrium (HWE) can indicate inbreeding, population stratification, and even problems in genotyping. In samples of affected individuals, these deviations can also provide evidence for association. Tests of HWE are commonly performed using a simple chi2 goodness-of-fit test. We show that this chi2 test can have inflated type I error rates, even in relatively large samples (e.g., samples of 1,000 individuals that include approximately 100 copies of the minor allele). On the basis of previous work, we describe exact tests of HWE together with efficient computational methods for their implementation. Our methods adequately control type I error in large and small samples and are computationally efficient. They have been implemented in freely available code that will be useful for quality assessment of genotype data and for the detection of genetic association or population stratification in very large data sets.
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            Development and Characterization of a High Density SNP Genotyping Assay for Cattle

            The success of genome-wide association (GWA) studies for the detection of sequence variation affecting complex traits in human has spurred interest in the use of large-scale high-density single nucleotide polymorphism (SNP) genotyping for the identification of quantitative trait loci (QTL) and for marker-assisted selection in model and agricultural species. A cost-effective and efficient approach for the development of a custom genotyping assay interrogating 54,001 SNP loci to support GWA applications in cattle is described. A novel algorithm for achieving a compressed inter-marker interval distribution proved remarkably successful, with median interval of 37 kb and maximum predicted gap of <350 kb. The assay was tested on a panel of 576 animals from 21 cattle breeds and six outgroup species and revealed that from 39,765 to 46,492 SNP are polymorphic within individual breeds (average minor allele frequency (MAF) ranging from 0.24 to 0.27). The assay also identified 79 putative copy number variants in cattle. Utility for GWA was demonstrated by localizing known variation for coat color and the presence/absence of horns to their correct genomic locations. The combination of SNP selection and the novel spacing algorithm allows an efficient approach for the development of high-density genotyping platforms in species having full or even moderate quality draft sequence. Aspects of the approach can be exploited in species which lack an available genome sequence. The BovineSNP50 assay described here is commercially available from Illumina and provides a robust platform for mapping disease genes and QTL in cattle.
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              Positional candidate cloning of a QTL in dairy cattle: identification of a missense mutation in the bovine DGAT1 gene with major effect on milk yield and composition.

              We recently mapped a quantitative trait locus (QTL) with a major effect on milk composition--particularly fat content--to the centromeric end of bovine chromosome 14. We subsequently exploited linkage disequilibrium to refine the map position of this QTL to a 3-cM chromosome interval bounded by microsatellite markers BULGE13 and BULGE09. We herein report the positional candidate cloning of this QTL, involving (1) the construction of a BAC contig spanning the corresponding marker interval, (2) the demonstration that a very strong candidate gene, acylCoA:diacylglycerol acyltransferase (DGAT1), maps to that contig, and (3) the identification of a nonconservative K232A substitution in the DGAT1 gene with a major effect on milk fat content and other milk characteristics.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2009
                12 August 2009
                : 4
                : 8
                : e6595
                Affiliations
                [1 ]INRA, UMR de Génétique Animale et Biologie Intégrative, Jouy-en-Josas, France
                [2 ]Union Nationale des Coopératives agricoles d'Elevage et d'Insémination Animale, Paris, France
                [3 ]Centre National de Genotypage, Institut de Génomique, Commissariat à l'Energie Atomique, Evry, France
                University of Utah, United States of America
                Author notes

                Conceived and designed the experiments: MG. Performed the experiments: MG. Analyzed the data: LF MG. Contributed reagents/materials/analysis tools: LF SF FJ MB IGG SH JLF MG. Wrote the paper: LF MG.

                Article
                09-PONE-RA-09639R1
                10.1371/journal.pone.0006595
                2722727
                19672461
                00b81994-e6af-4957-bb15-9936411fc437
                Flori et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 7 April 2009
                : 9 July 2009
                Page count
                Pages: 13
                Categories
                Research Article
                Genetics and Genomics/Animal Genetics
                Genetics and Genomics/Gene Function
                Genetics and Genomics/Population Genetics

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                Uncategorized

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