Remapping of the belted phenotype in cattle on BTA3 identifies a multiplication event as the candidate causal mutation

A quantitative trait locus (QTL) affecting milk fat percentage has been mapped to the centromeric end of the bovine chromosome 14 (BTA14). This genomic area includes the DGAT1 gene, which encodes acyl-CoA:diacylglycerol acyltransferase 1, the key enzyme of triglyceride biosynthesis. Genetic and biochemical studies led to the identification of the nonconservative DGAT1-K232A polymorphism as a causal mutation for the QTL. In addition to this, another polymorphism in the 5′-regulatory region of this gene, the DGAT1 variable number of tandem repeat (VNTR), also showed a strong association with milk fat percentage. This promoter VNTR polymorphism affects the number of potential Sp1 binding sites and therefore might have an impact on DGAT1 expression and also milk fat content. Hence, the DGAT1 VNTR polymorphism might be another causal mutation for the BTA14 QTL. However, evidence for Sp1 binding to this polymorphic site and for the capability of DGAT1 VNTR alleles to stimulate gene expression was lacking. In the current work Sp1-VNTR interactions were analyzed by EMSA. In addition, effects of DGAT1 VNTR alleles on gene expression were measured with reporter gene analyses. Conclusions from the results are that 1) the DGAT1 VNTR sequence is indeed a target for Sp1 binding; 2) DGAT1 VNTR alleles can stimulate gene expression in vitro and probably in vivo as well; and 3) although the stimulating effects of the different DGAT1 VNTR alleles did not show significant differences in vitro, their effects on transcription might be different in the chromatin context existing in vivo.

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Molecular study of congenital erythrocytosis in 70 unrelated patients revealed a potential causal mutation in less than half of the cases (Where is/are the missing gene(s)?)

European Journal Of Haematology ◽

10.1111/ejh.12170 ◽

2013 ◽

pp. n/a-n/a ◽

Cited By ~ 6

Author(s):

Celeste Bento ◽

Helena Almeida ◽

Tabita M. Maia ◽

Luís Relvas ◽

Ana C. Oliveira ◽

...

Keyword(s):

Molecular Study ◽

Missing Gene ◽

Causal Mutation

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Identification of a doublet missense substitution in the bovine LRP4 gene as a candidate causal mutation for syndactyly in Holstein cattle

Genomics ◽

10.1016/j.ygeno.2006.05.007 ◽

2006 ◽

Vol 88 (5) ◽

pp. 610-621 ◽

Cited By ~ 36

Author(s):

A. Duchesne ◽

M. Gautier ◽

S. Chadi ◽

C. Grohs ◽

S. Floriot ◽

...

Keyword(s):

Holstein Cattle ◽

Causal Mutation ◽

Lrp4 Gene ◽

Missense Substitution

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Long QT syndrome: beyond the causal mutation

The Journal of Physiology ◽

10.1113/jphysiol.2013.254920 ◽

2013 ◽

Vol 591 (17) ◽

pp. 4125-4139 ◽

Cited By ~ 41

Author(s):

Ahmad S. Amin ◽

Yigal M. Pinto ◽

Arthur A. M. Wilde

Keyword(s):

Long Qt Syndrome ◽

Long Qt ◽

Qt Syndrome ◽

Causal Mutation

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Identification and validation of a regulatory mutation upstream of the BMP2 gene associated with carcass length in pigs

Genetics Selection Evolution ◽

10.1186/s12711-021-00689-0 ◽

2021 ◽

Vol 53 (1) ◽

Author(s):

Jing Li ◽

Song Peng ◽

Liepeng Zhong ◽

Lisheng Zhou ◽

Guorong Yan ◽

...

Keyword(s):

Gene Expression ◽

Body Size ◽

Bone Growth ◽

Chromosome 17 ◽

Meat Production ◽

Whole Genome ◽

Functional Assays ◽

A Genome ◽

Improvement Programs ◽

Causal Mutation

Abstract Background Carcass length is very important for body size and meat production for swine, thus understanding the genetic mechanisms that underly this trait is of great significance in genetic improvement programs for pigs. Although many quantitative trait loci (QTL) have been detected in pigs, very few have been fine-mapped to the level of the causal mutations. The aim of this study was to identify potential causal single nucleotide polymorphisms (SNPs) for carcass length by integrating a genome-wide association study (GWAS) and functional assays. Results Here, we present a GWAS in a commercial Duroc × (Landrace × Yorkshire) (DLY) population that reveals a prominent association signal (P = 4.49E−07) on pig chromosome 17 for carcass length, which was further validated in two other DLY populations. Within the detected 1 Mb region, the BMP2 gene stood out as the most likely causal candidate because of its functions in bone growth and development. Whole-genome gene expression studies showed that the BMP2 gene was differentially expressed in the cartilage tissues of pigs with extreme carcass length. Then, we genotyped an additional 267 SNPs in 500 selected DLY pigs, followed by further whole-genome SNP imputation, combined with deep genome resequencing data on multiple pig breeds. Reassociation analyses using genotyped and imputed SNP data revealed that the rs320706814 SNP, located approximately 123 kb upstream of the BMP2 gene, was the strongest candidate causal mutation, with a large association with carcass length, with a ~ 4.2 cm difference in length across all three DLY populations (N = 1501; P = 3.66E−29). This SNP segregated in all parental lines of the DLY (Duroc, Large White and Landrace) and was also associated with a significant effect on body length in 299 pure Yorkshire pigs (P = 9.2E−4), which indicates that it has a major value for commercial breeding. Functional assays showed that this SNP is likely located within an enhancer and may affect the binding affinity of transcription factors, thereby regulating BMP2 gene expression. Conclusions Taken together, these results suggest that the rs320706814 SNP on pig chromosome 17 is a putative causal mutation for carcass length in the widely used DLY pigs and has great value in breeding for body size in pigs.

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IDENTIFICATION OF GENOMIC REGIONS CARRYING A CAUSAL MUTATION IN UNORDERED GENOMES

10.1101/026856 ◽

2015 ◽

Author(s):

Pilar Corredor-Moreno ◽

Ed Chalstrey ◽

Carlos A Lugo ◽

Dan MacLean

Keyword(s):

High Throughput Sequencing ◽

Chromosome 1 ◽

Causative Mutation ◽

Genetic Screens ◽

Distribution Method ◽

Forward Genetic Screens ◽

Causal Mutation ◽

Genomic Regions ◽

User Friendly ◽

Mapping By Sequencing

Whole genome sequencing using high-throughput sequencing (HTS) technologies offers powerful opportunities to study genetic variation. Mapping the mutations responsible for different phenotypes is generally an involved and time-consuming process so researchers have developed user-friendly tools for mapping-by-sequencing, yet they are not applica- ble to organisms with non-sequenced genomes. We introduce SDM (SNP Distribution Method), a reference independent method for rapid discovery of mutagen-induced muta- tions in typical forward genetic screens. SDM aims to order a disordered collection of HTS reads or contigs such that the fragment carrying the causative mutation can be identified. SDM uses typical distributions of homozygous SNPs that are linked to a phenotype-altering SNP in a non-recombinant region as a model to order the fragments. To implement and test SDM, we created model genomes with an idealised SNP density based on Arabidop- sis thaliana chromosome 1 and analysed fragments with size distribution similar to reads or contigs assembled from HTS sequencing experiments. SDM groups the contigs by their normalised SNP density and arranges them to maximise the fit to the expected SNP distribution. We tested the procedure in existing datasets by examining SNP distributions in recent out-cross and back-cross experiments in Arabidopsis thaliana backgrounds. In all the examples we analysed, homozygous SNPs were normally distributed around the causal mutation. We used the real SNP densities obtained from these experiments to prove the efficiency and accuracy of SDM. The algorithm was able to successfully identify small sized (10-100 kb) genomic regions containing the causative mutation.

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