Journal Articles
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Item Survey of functional Mendelian variants in New Zealand Huntaway and Heading dog breeds(John Wiley and Sons Ltd on behalf of Stichting International Foundation for Animal Genetics, 2025-10-01) Smith F; Lopdell T; Stephen M; Henry M; Dittmer K; Hunt H; Sneddon N; Williams L; Rolfe J; Garrick D; Littlejohn MDNew Zealand (NZ) Huntaway and Heading dogs are working breeds that play active roles on farms across NZ. While these breeds are common in NZ, they are not well-known elsewhere, and little is understood about their genetic make-up. Here, we used whole genome sequencing to provide a comprehensive genomic view of 249 working dogs. As first use of this resource, we report the allele frequencies of provisionally functional variants aggregated from the Online Mendelian Inheritance in Animals (OMIA) database. Of 435 “probably causal” variants, 27 segregated in our sample. Notable examples of disease variants potentially actionable for selection include those in the CUBN, CLN8, SGSH, SOD1, VWF, and VPS13B genes. These findings will enable genetic testing and selection opportunities to help improve the health and performance of future generations of these unique breeds.Item Fine mapping highlights ITGAL and MUS81 loss-of-function mutations modulating recessive impacts in dairy cattle(John Wiley and Sons Ltd on behalf of Stichting International Foundation for Animal Genetics, 2025-08-01) Duntsch L; Jivanji S; Lopdell T; Reynolds EGM; Williams L; Littlejohn MDWe recently described several major-effect recessive loci impacting anatomical and lactation traits in dairy cattle. Two of these loci in particular presented multiple candidate causative variants, comprising tightly linked coding variants that could not be easily differentiated on a statistical or functional basis. Here, we re-examine the candidacy of these variants by leveraging a dataset of 1 million genotyped animals. Assessing lactation and bodyweight effects in conjunction with rare, recombined genotypes for the IL4R, KIAA0556, ITGAL, DPF2, and MUS81 candidates, we highlight ITGAL and MUS81 as the most likely causative genes for the two QTL. Recombinant homozygotes for these genes present larger, more significant effects than other candidates at the same loci, with both representing premature stop mutations anticipated to inactivate ITGAL and MUS81. We further examined homozygotes for the ITGAL mutation to better understand the range of phenotypes impacted. While outwardly normal, ITGAL mutants showed significant differences in the number and composition of circulating leukocytes, consistent with the role of ITGAL as a key mediator of leukocyte signalling, adhesion, and migration. These results demonstrate how near-perfectly linked candidate mutations can be differentiated given population-scale data, and highlight the ITGAL and MUS81 mutations as diagnostic targets to help manage the frequency of these variants.Item An Increase in Male Recombination Rate With Age in Dairy Cattle Is Heritable and Polygenic(John Wiley and Sons Ltd, 2025-06-14) Jade E; Littlejohn MD; Eketone K; Spelman RJ; Stapley J; Santure AWMeiotic recombination is an essential process for shuffling genetic diversity in sexually reproducing organisms, can vary within and between individuals in response to intrinsic and extrinsic factors, and can be heritable. Interestingly, recombination rate has been found to vary with age in some species, but to date, there have been no assessments of the heritability and genetic architecture of this age effect. Here, we leverage a large pedigree of SNP chip-genotyped Aotearoa New Zealand Holstein-Friesian and Jersey dairy cattle to test for an effect of age on male recombination rate, the heritability of recombination rate and of any such age effect on recombination, and the genetic architecture underlying these two phenotypes. We found a significant, albeit small, increase in the average number of male autosomal recombinations with age. Consistent with previous studies, we found moderate heritability (h2 ≈ 0.15) of sire recombination rate and detected association with several regions on chromosome 10 encompassing genes such as REC8, REC114, RNF212B and NEK9. Further, we found novel evidence of some heritability (h2 ≈ 0.05) in the rate of change in recombination with age in sires. Variation in the rate of change with age is likely also polygenic, but there is a region on chromosome 1 that is weakly associated with the rate of change. It is unclear whether the heritability of age-related recombination rate change is widespread across species, and we encourage studies in other taxa to assess its prevalence and evolutionary significance.Item An integrative approach to prioritize candidate causal genes for complex traits in cattle(PLOS, 2025-05-30) Ghoreishifar M; Macleod IM; Chamberlain AJ; Liu Z; Lopdell TJ; Littlejohn MD; Xiang R; Pryce JE; Goddard ME; Groenen MGenome-wide association studies (GWAS) have identified many quantitative trait loci (QTL) associated with complex traits, predominantly in non-coding regions, posing challenges in pinpointing the causal variants and their target genes. Three types of evidence can help identify the gene through which QTL acts: (1) proximity to the most significant GWAS variant, (2) correlation of gene expression with the trait, and (3) the gene’s physiological role in the trait. However, there is still uncertainty about the success of these methods in identifying the correct genes. Here, we test the ability of these methods in a comparatively simple series of traits associated with the concentration of polar lipids in milk. We conducted single-trait GWAS for ~14 million imputed variants and 56 individual milk polar lipid (PL) phenotypes in 336 cows. A multi-trait meta-analysis of GWAS identified 10,063 significant SNPs at FDR≤10% (P≤7.15E-5). Transcriptome data from blood (~12.5K genes, 143 cows) and mammary tissue (~12.2K genes, 169 cows) were analyzed using the genetic score omics regression (GSOR) method. This method links observed gene expression to genetically predicted phenotypes and was used to find associations between gene expression and 56 PL phenotypes. GSOR identified 2,186 genes in blood and 1,404 in mammary tissue associated with at least one PL phenotype (FDR≤1%). We partitioned the genome into non-overlapping windows of 100 Kb to test for overlap between GSOR-identified genes and GWAS signals. We found a significant overlap between these two datasets, indicating that GSOR-significant genes were more likely to be located within 100 Kb windows that include GWAS signals than those that do not (P=0.01; odds ratio=1.47). These windows included 70 significant genes expressed in mammary tissue and 95 in blood. Compared to all expressed genes in each tissue, these genes were enriched for lipid metabolism gene ontology (GO). That is, seven of the 70 significant mammary transcriptome genes (P<0.01; odds ratio=3.98) and five of the 95 significant blood genes (P<0.10; odds ratio=2.24) were involved in lipid metabolism GO. The candidate causal genes include DGAT1, ACSM5, SERINC5, ABHD3, CYP2U1, PIGL, ARV1, SMPD5, and NPC2, with some overlap between the two tissues. The overlap between GWAS, GSOR, and GO analyses suggests that together, these methods are more likely to identify genes mediating QTL, though their power remains limited, as reflected by modest odds ratios. Larger sample sizes would enhance the power of these analyses, but issues like linkage disequilibrium would remain.Item A new mechanism for a familiar mutation – bovine DGAT/K232A modulates gene expression through multi-junction exon splice enhancement(2020-02-05) Fink T; Lopdell TJ; Tiplady K; Handley R; Johnson TJJ; Spelman RJ; Davis SR; Snell RG; Littlejohn MDItem Comparison of genomic prediction accuracies in dairy cattle lactation traits using five classes of functional variants versus generic SNP(BioMed Central Ltd, 2025-12) Alemu SW; Lopdell TJ; Trevarton AJ; Snell RG; Littlejohn MD; Garrick DJBackground: Genomic selection, typically employing genetic markers from SNP chips, is routine in modern dairy cattle breeding. This study assessed the impact of functional sequence variants on genomic prediction accuracy relative to 50 k SNP chip markers for fat percent, protein percent, milk volume, fat yield, and protein yield in lactating dairy cattle. The functional variants were identified through GWAS, RNA-seq, Histone modification ChIP-seq, ATAC-seq, or were coding variants. The genomic prediction accuracy obtained using each class of functional variants was compared with matched numbers of SNPs randomly selected from the Illumina 50 k SNP chip. Results: The investigation revealed that variants identified by GWAS or RNA-seq, significantly improved the prediction accuracy across all five traits. Contributions from ChIP-seq, ATAC-seq, and coding variants varied. Some variants identified using ChIP-seq showed marked improvements, while others reduced accuracy in protein yield predictions. Relative to a matched number of 32,595 SNPs from the SNP chip, pooling all the functional variants demonstrated prediction accuracy increases of 1.76% for fat percent, 2.97% for protein percent, 0.51% for milk volume, and 0.26% for fat yield, but with a slight decrease of 0.43% in protein yield. Conclusion: The study demonstrates that functional variants can improve prediction accuracy relative to equivalent numbers of variants from a generic SNP panel, with percent traits showing more significant gains than yield traits. The main advantage of using functional variants for genomic prediction was achievement of comparable accuracy using a smaller, more selective set of loci. This is particularly evident in trait-specific scenarios. Our findings indicate that specific combinations of functional variants comprising 16 k variants can achieve genomic prediction accuracy comparable to employing a standard panel of twice the size (32.6 k), especially for percent traits. This highlights the potential for the development of more efficient, trait-focused SNP panels utilizing functional variants.Item Holstein Friesian dairy cattle edited for diluted coat color as adaptation to climate change(2020-09-17) Laible G; Cole S-A; Brophy B; Wei J; Leath S; Jivanji S; Littlejohn MD; Wells DNItem A common regulatory haplotype doubles lactoferrin concentration in milk.(BioMed Central Ltd, 2024-03-28) Lopdell TJ; Trevarton AJ; Moody J; Prowse-Wilkins C; Knowles S; Tiplady K; Chamberlain AJ; Goddard ME; Spelman RJ; Lehnert K; Snell RG; Davis SR; Littlejohn MDBACKGROUND: Bovine lactoferrin (Lf) is an iron absorbing whey protein with antibacterial, antiviral, and antifungal activity. Lactoferrin is economically valuable and has an extremely variable concentration in milk, partly driven by environmental influences such as milking frequency, involution, or mastitis. A significant genetic influence has also been previously observed to regulate lactoferrin content in milk. Here, we conducted genetic mapping of lactoferrin protein concentration in conjunction with RNA-seq, ChIP-seq, and ATAC-seq data to pinpoint candidate causative variants that regulate lactoferrin concentrations in milk. RESULTS: We identified a highly-significant lactoferrin protein quantitative trait locus (pQTL), as well as a cis lactotransferrin (LTF) expression QTL (cis-eQTL) mapping to the LTF locus. Using ChIP-seq and ATAC-seq datasets representing lactating mammary tissue samples, we also report a number of regions where the openness of chromatin is under genetic influence. Several of these also show highly significant QTL with genetic signatures similar to those highlighted through pQTL and eQTL analysis. By performing correlation analysis between these QTL, we revealed an ATAC-seq peak in the putative promotor region of LTF, that highlights a set of 115 high-frequency variants that are potentially responsible for these effects. One of the 115 variants (rs110000337), which maps within the ATAC-seq peak, was predicted to alter binding sites of transcription factors known to be involved in lactation-related pathways. CONCLUSIONS: Here, we report a regulatory haplotype of 115 variants with conspicuously large impacts on milk lactoferrin concentration. These findings could enable the selection of animals for high-producing specialist herds.Item Screening for phenotypic outliers identifies an unusually low concentration of a β-lactoglobulin B protein isoform in bovine milk caused by a synonymous SNP.(BioMed Central Ltd, 2022-03-16) Davis SR; Ward HE; Kelly V; Palmer D; Ankersmit-Udy AE; Lopdell TJ; Berry SD; Littlejohn MD; Tiplady K; Adams LF; Carnie K; Burrett A; Thomas N; Snell RG; Spelman RJ; Lehnert KBackground Milk samples from 10,641 dairy cattle were screened by a mass spectrometry method for extreme concentrations of the A or B isoforms of the whey protein, β-lactoglobulin (BLG), to identify causative genetic variation driving changes in BLG concentration. Results A cohort of cows, from a single sire family, was identified that produced milk containing a low concentration of the BLG B protein isoform. A genome-wide association study (GWAS) of BLG B protein isoform concentration in milk from AB heterozygous cows, detected a group of highly significant single nucleotide polymorphisms (SNPs) within or close to the BLG gene. Among these was a synonymous G/A variation at position + 78 bp in exon 1 of the BLG gene (chr11:103256256G > A). The effect of the A allele of this SNP (which we named B’) on BLG expression was evaluated in a luciferase reporter assay in transfected CHO-K1 and MCF-7 cells. In both cell types, the presence of the B’ allele in a plasmid containing the bovine BLG gene from -922 to + 898 bp (relative to the transcription initiation site) resulted in a 60% relative reduction in mRNA expression, compared to the plasmid containing the wild-type B sequence allele. Examination of a mammary RNAseq dataset (n = 391) identified 14 heterozygous carriers of the B’ allele which were homozygous for the BLG B protein isoform (BB’). The level of expression of the BLG B’ allele was 41.9 ± 1.0% of that of the wild-type BLG B allele. Milk samples from three cows, homozygous for the A allele at chr11:103,256,256 (B’B’), were analysed (HPLC) and showed BLG concentrations of 1.04, 1.26 and 1.83 g/L relative to a mean of 4.84 g/L in milk from 16 herd contemporaries of mixed (A and B) BLG genotypes. The mechanism by which B’ downregulates milk BLG concentration remains to be determined. Conclusions High-throughput screening and identification of outliers, enabled the discovery of a synonymous G > A mutation in exon 1 of the B allele of the BLG gene (B’), which reduced the milk concentration of β-lactoglobulin B protein isoform, by more than 50%. Milk from cows carrying the B’ allele is expected to have improved processing characteristics, particularly for cheese-making.Item Multiple QTL underlie milk phenotypes at the CSF2RB locus.(BioMed Central Ltd, 2019-01-24) Lopdell TJ; Tiplady K; Couldrey C; Johnson TJJ; Keehan M; Davis SR; Harris BL; Spelman RJ; Snell RG; Littlejohn MDBackground Over many years, artificial selection has substantially improved milk production by cows. However, the genes that underlie milk production quantitative trait loci (QTL) remain relatively poorly characterised. Here, we investigate a previously reported QTL located at the CSF2RB locus on chromosome 5, for several milk production phenotypes, to better understand its underlying genetic and molecular causes. Results Using a population of 29,350 taurine dairy cows, we conducted association analyses for milk yield and composition traits, and identified highly significant QTL for milk yield, milk fat concentration, and milk protein concentration. Strikingly, protein concentration and milk yield appear to show co-located yet genetically distinct QTL. To attempt to understand the molecular mechanisms that might be mediating these effects, gene expression data were used to investigate eQTL for 11 genes in the broader interval. This analysis highlighted genetic impacts on CSF2RB and NCF4 expression that share similar association signatures to those observed for lactation QTL, strongly implicating one or both of these genes as responsible for these effects. Using the same gene expression dataset representing 357 lactating cows, we also identified 38 novel RNA editing sites in the 3′ UTR of CSF2RB transcripts. The extent to which two of these sites were edited also appears to be genetically co-regulated with lactation QTL, highlighting a further layer of regulatory complexity that involves the CSF2RB gene. Conclusions This locus presents a diversity of molecular and lactation QTL, likely representing multiple overlapping effects that, at a minimum, highlight the CSF2RB gene as having a causal role in these processes.