Variants modulating the expression of a chromosome domain encompassing PLAG1 influence bovine stature

We report mapping of a quantitative trait locus (QTL) with a major effect on bovine stature to a ∼780-kb interval using a Hidden Markov Model–based approach that simultaneously exploits linkage and linkage disequilibrium. We re-sequenced the interval in six sires with known QTL genotype and identified 13 clustered candidate quantitative trait nucleotides (QTNs) out of >9,572 discovered variants. We eliminated five candidate QTNs by studying the phenotypic effect of a recombinant haplotype identified in a breed diversity panel. We show that the QTL influences fetal expression of seven of the nine genes mapping to the ∼780-kb interval. We further show that two of the eight candidate QTNs, mapping to the PLAG1-CHCHD7 intergenic region, influence bidirectional promoter strength and affect binding of nuclear factors. By performing expression QTL analyses, we identified a splice site variant in CHCHD7 and exploited this naturally occurring null allele to exclude CHCHD7 as single causative gene.

[1]  Leif Andersson,et al.  Haplotype sharing refines the location of an imprinted quantitative trait locus with major effect on muscle mass to a 250-kb chromosome segment containing the porcine IGF2 gene. , 2003, Genetics.

[2]  Y. Sugimoto,et al.  Identification of a 1.1-Mb region for a carcass weight QTL onbovine Chromosome 14 , 2005, Mammalian Genome.

[3]  E. Schadt.  Molecular networks as sensors and drivers of common human diseases , 2009, Nature.

[4]  F. Speleman,et al.  Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes , 2002, Genome Biology.

[5]  N. Sagata.  What does mos do in oocytes and somatic cells? , 1997, BioEssays : news and reviews in molecular, cellular and developmental biology.

[6]  David L Stern,et al.  Is Genetic Evolution Predictable? , 2009, Science.

[7]  Thomas J Hudson,et al.  Survey of allelic expression using EST mining. , 2005, Genome research.

[8]  C. Gieger,et al.  Identification of ten loci associated with height highlights new biological pathways in human growth , 2008, Nature Genetics.

[9]  Andrew P Morris,et al.  Genetic dissection of a behavioral quantitative trait locus shows that Rgs2 modulates anxiety in mice , 2004, Nature Genetics.

[10]  A. McGregor,et al.  Morphological evolution through multiple cis-regulatory mutations at a single gene , 2007, Nature.

[11]  Y. Kamatani,et al.  A genome-wide association study in 19 633 Japanese subjects identified LHX3-QSOX2 and IGF1 as adult height loci. , 2010, Human Molecular Genetics.

[12]  Ayellet V. Segrè,et al.  Hundreds of variants clustered in genomic loci and biological pathways affect human height , 2010, Nature.

[13]  C. Kubota,et al.  Quantitative trait loci analysis for growth and carcass traits in a half-sib family of purebred Japanese Black (Wagyu) cattle. , 2004, Journal of animal science.

[14]  B. Han,et al.  Identification of 15 loci influencing height in a Korean population , 2010, Journal of Human Genetics.

[15]  F. Galton.  Regression Towards Mediocrity in Hereditary Stature. , 1886 .

[16]  M. Georges,et al.  A QTL with major effect on milk yield and composition maps to bovine Chromosome 14 , 1998, Mammalian Genome.

[17]  T. Nelsen,et al.  Heritabilities and genetic correlations of growth and reproductive measurements in Hereford bulls. , 1986, Journal of animal science.

[18]  W. V. D. Van de Ven,et al.  Targeted disruption of the murine Plag1 proto‐oncogene causes growth retardation and reduced fertility , 2004, Development, growth & differentiation.

[19]  Ignacy Misztal,et al.  BLUPF90 and related programs (BGF90) , 2002 .

[20]  W. Ewens.  Genetics and analysis of quantitative traits , 1999 .

[21]  R. Myers,et al.  An abundance of bidirectional promoters in the human genome. , 2003, Genome research.

[22]  U. Dräger,et al.  Retinoids in embryonal development. , 2000, Physiological reviews.

[23]  W. G. Hill,et al.  Genome partitioning of genetic variation for height from 11,214 sibling pairs. , 2007, American journal of human genetics.

[24]  Trudy F. C. Mackay,et al.  Quantitative trait loci in Drosophila , 2001, Nature Reviews Genetics.

[25]  Inês Barroso,et al.  Meta-Analysis of Genome-Wide Scans for Human Adult Stature Identifies Novel Loci and Associations with Measures of Skeletal Frame Size , 2009, PLoS genetics.

[26]  W. V. D. Van de Ven,et al.  PLAG1, the prototype of the PLAG gene family: versatility in tumour development (review). , 2007, International journal of oncology.

[27]  R. Doerge,et al.  Empirical threshold values for quantitative trait mapping. , 1994, Genetics.

[28]  B. Moor,et al.  Microarray screening for target genes of the proto-oncogene PLAG1 , 2004, Oncogene.

[29]  M Georges,et al.  A rank-based nonparametric method for mapping quantitative trait loci in outbred half-sib pedigrees: application to milk production in a granddaughter design. , 1998, Genetics.

[30]  A. Long,et al.  Genetic interactions between naturally occurring alleles at quantitative trait loci and mutant alleles at candidate loci affecting bristle number in Drosophila melanogaster. , 1996, Genetics.

[31]  D. Altshuler,et al.  A map of human genome variation from population-scale sequencing , 2010, Nature.

[32]  P M Visscher,et al.  Confidence intervals in QTL mapping by bootstrapping. , 1996, Genetics.

[33]  How good are quantitative complementation tests? , 2004, Science of aging knowledge environment : SAGE KE.

[34]  King Khama, Emperor Joe and the Great White Queen: Victorian Britain through African Eyes , 1999 .

[35]  Taesung Park,et al.  A large-scale genome-wide association study of Asian populations uncovers genetic factors influencing eight quantitative traits , 2009, Nature Genetics.

[36]  R. Bartusiak,et al.  Primary genome scan to identify putative quantitative trait loci for feedlot growth rate, feed intake, and feed efficiency of beef cattle. , 2007, Journal of animal science.

[37]  Jeremiah D. Degenhardt,et al.  A Simple Genetic Architecture Underlies Morphological Variation in Dogs , 2010, PLoS biology.

[38]  Leif Andersson,et al.  A regulatory mutation in IGF2 causes a major QTL effect on muscle growth in the pig , 2003, Nature.

[39]  M. Georges.  Mapping, fine mapping, and molecular dissection of quantitative trait Loci in domestic animals. , 2007, Annual review of genomics and human genetics.

[40]  L. Penrose,et al.  THE CORRELATION BETWEEN RELATIVES ON THE SUPPOSITION OF MENDELIAN INHERITANCE , 2022 .

[41]  C. Bustamante,et al.  A Single IGF1 Allele Is a Major Determinant of Small Size in Dogs , 2007, Science.

[42]  C. Gaveriaux-Ruff,et al.  Exploring the opioid system by gene knockout , 2002, Progress in Neurobiology.

[43]  S. Moore,et al.  Identification and fine mapping of quantitative trait loci for growth traits on bovine chromosomes 2, 6, 14, 19, 21, and 23 within one commercial line of Bos taurus. , 2004, Journal of animal science.

[44]  N. Kobayashi,et al.  Identification of bovine QTL for growth and carcass traits in Japanese Black cattle by replication and identical-by-descent mapping , 2007, Mammalian Genome.

[45]  Judy H. Cho,et al.  Finding the missing heritability of complex diseases , 2009, Nature.

[46]  T. Frayling,et al.  Reaching new heights: insights into the genetics of human stature. , 2008, Trends in Genetics.

[47]  W. Bodmer,et al.  Common and rare variants in multifactorial susceptibility to common diseases , 2008, Nature Genetics.

[48]  Daniel R. Richards,et al.  Dissecting the architecture of a quantitative trait locus in yeast , 2002, Nature.

[49]  Timothy P. L. Smith,et al.  Development and Characterization of a High Density SNP Genotyping Assay for Cattle , 2009, PloS one.

[50]  Bjarni V. Halldórsson,et al.  Many sequence variants affecting diversity of adult human height , 2008, Nature Genetics.

[51]  C. Haley,et al.  Mapping quantitative trait loci in crosses between outbred lines using least squares. , 1994, Genetics.

[52]  Christopher Y. Park,et al.  Ribosomal mutations cause p53-mediated dark skin and pleiotropic effects , 2008, Nature Genetics.

[53]  R. Schnabel,et al.  A genome scan for quantitative trait loci influencing carcass, post-natal growth and reproductive traits in commercial Angus cattle. , 2010, Animal genetics.

[54]  P. Yu,et al.  Single nucleotide polymorphisms in the corticotrophin-releasing hormone and pro-opiomelancortin genes are associated with growth and carcass yield in beef cattle. , 2005, Animal genetics.

[55]  R. Spelman,et al.  A high density linkage map of the bovine genome , 2009, BMC Genetics.

[56]  P. Visscher,et al.  Common SNPs explain a large proportion of heritability for human height , 2011 .

[57]  Tom Druet,et al.  A Hidden Markov Model Combining Linkage and Linkage Disequilibrium Information for Haplotype Reconstruction and Quantitative Trait Locus Fine Mapping , 2010, Genetics.

[58]  S. Northcutt,et al.  Genetic parameter estimates and expected progeny differences for mature size in Angus cattle. , 1993, Journal of animal science.

[59]  R. Fisher.  XV.—The Correlation between Relatives on the Supposition of Mendelian Inheritance. , 1919, Transactions of the Royal Society of Edinburgh.