Biology subjects

Mapel, X. M.

Publications and source records attributed to Mapel, X. M..

11 recordsLinked to original sources

bioRxiv2026

A large-effect locus on chromosome 4 underlies circadian feeding rhythmicity in pigs

Circadian feeding rhythmicity reflects the distribution of feed intake across the daily 24-hour cycle. Regular feeding-fasting cycles play an important role in regulating metabolism and maintaining health, but endogenous and environmental factors can disrupt the normal circadian pattern of feed intake. Here, we quantified hourly feed intake in 3,470 Swiss Landrace and 15,181 Swiss Large White pigs using 40.5 million records from automated feeding systems. We used the proportion of days exhibiting a significant feeding rhythm after wavelet analysis to investigate variation in circadian feeding organization. Circadian feeding rhythmicity was influenced by sex and age, with higher rhythmicity observed in females and older animals. Variance components analysis revealed a strong additive genetic contribution and a high heritability (0.53-0.57). Pigs with higher circadian feeding rhythmicity had reduced nocturnal intake, improved feed conversion ratio, and lower day-to-day variability in feed intake, suggesting improved feed efficiency and resilience. Genome-wide association testing of 15.7 and 23.1 million imputed sequence variants identified a QTL on chromosome 4 explaining 5.3% and 2.9% of the phenotypic variance of circadian feeding rhythmicity in Swiss Landrace and Swiss Large White pigs, respectively. The QTL overlaps OPRK1 and NPBWR1, two genes implicated in the regulation of feeding behavior, reward and energy homeostasis. Collectively, our findings establish circadian feeding behavior as a heritable trait in pigs and provide a basis to further investigate the genetic regulation of feeding rhythms in mammals and explore its use in animal breeding programs to improve feed efficiency and resilience.

genetics↗

bioRxiv2025

Structural variants are enriched for molecular QTL in a cattle long read cohort

Sequencing cohorts with long-read technology is crucial to understand the impact of structural variants (SVs) on complex traits. Here, we obtained 4.86 terabases of HiFi reads with an average read N50 of 16.3 Kb from 120 Bos taurus taurus bulls, yielding a mean coverage depth of 13.5-fold. We genotyped 23.8 M small variants (SNPs and short INDELs) and 79.3 k SVs to perform association testing with molecular phenotypes derived from a subset of 117 bulls with total RNA sequencing data from testis tissue. We identified 27.3 k molecular QTL (molQTL) including 316 for which SVs were the most significant variant. This corresponds to a 2.1- and 5.6-fold enrichment of SVs among expression and splicing QTL, respectively. When considering SVs in perfect LD with the lead small variant, the enrichment increased to 6.1- and 12-fold for expression and splicing QTL in testis, respectively. Imperfect genotyping for SVs limited our ability to detect all SV molQTL, suggesting that the true enrichment of SVs among molQTL may be even higher. These results demonstrate that SVs have a profound impact on gene expression and splicing variation but highlight the necessity of improved SV genotyping to fully leverage long-read sequencing cohorts for dissecting complex traits.

genetics↗

bioRxiv2024

RNA sequencing variants are enriched for eQTL in cattle tissues

Association testing between molecular phenotypes and genomic variants can help to understand how genotype affects phenotype. RNA sequencing provides access to molecular phenotypes such as gene expression and alternative splicing while DNA sequencing or microarray genotyping are the prevailing options to obtain genomic variants. Here we genotype variants for 74 male Braunvieh cattle from both DNA and deep total RNA sequencing from three tissues. We show that RNA sequencing calls approximately 40% of variants (7-10 million) called from DNA sequencing, with over 80% precision, rising to over 92% of variants called with nearly 98% precision in highly expressed coding regions. Allele-specific expression and putative post-transcriptional modifications negatively impact variant genotyping accuracy from RNA sequencing and contribute to RNA-DNA differences. Variants called from RNA sequencing detect roughly 75% of eGenes identified using variants called from DNA sequencing, demonstrating a nearly 2-fold enrichment of eQTL variants. We observe a moderate-to-strong correlation in nominal association p-values (Spearman {rho}2[~]0.6), although only 9% of eGenes have the same top associated variant. We also find several highly significant RNA variant-only eQTL, demonstrating that caution must be exercised beyond filtering for variant quality or imputation accuracy when analysing or imputing variants called from RNA sequencing.

genomics↗

bioRxiv2024

Wisent genome assembly uncovers extended runs of homozygosity and a large deletion that inactivates the thyroid hormone responsive gene

The wisent (Bison bonasus) is Europes largest land mammal. We produced a HiFi read-based wisent assembly with a contig N50 value of 91 Mb containing 99.7% of BUSCO genes which improves contiguity a thousand-fold over an existing assembly. Extended runs of homozygosity in the wisent genome compromised the separation of the HiFi reads into parental-specific read sets, which resulted in inferior haplotype assemblies. A bovine super-pangenome built with assemblies from wisent, bison, gaur, yak, taurine and indicine cattle identified a 1,580 bp deletion removing the protein-coding sequence of THRSP encoding thyroid hormone-responsive protein from the wisent and bison genomes. Analysis of 725 sequenced samples across the Bovinae subfamily showed that the deletion is fixed in both Bison species but absent in Bos and Bubalus. The THRSP transcript is abundant in adipose, fat, liver, muscle, and mammary gland tissue of Bos and Bubalus, but absent in bison indicating that the deletion inactivates THRSP possibly contributing to low bison milk and meat fat content. We show that super-pangenomes can reveal potentially trait-associated variation across phylogenies, but also demonstrate that haplotype assemblies from species that went through population bottlenecks warrant scrutiny, as they may have accumulated long runs of homozygosity that complicate phasing.

genomics↗

bioRxiv2024

Taurine pangenome uncovers a segmental duplication upstream of KIT associated with depigmentation in white-headed cattle

Cattle have been selectively bred for coat color, spotting, and depigmentation patterns. The assumed autosomal dominant inherited genetic variants underlying the characteristic white head of Fleckvieh, Simmental, and Hereford cattle have not been identified yet, although the contribution of structural variation upstream the KIT gene has been proposed. Here, we construct a graph pangenome from 24 haplotype assemblies representing seven taurine cattle breeds to identify and characterize the white head-associated locus for the first time based on long-read sequencing data and pangenome analyses. We introduce a pangenome-wide association mapping approach which examines assembly path similarities within the graph to reveal an association between two most likely serial alleles of a complex structural variant 66 kb upstream KIT and facial depigmentation. The complex structural variant contains a variable number of tandemly duplicated 14.3 kb repeats, consisting of LTRs, LINEs, and other repetitive elements, leading to misleading alignments of short and long reads when using a linear reference. We align 250 short-read sequencing samples spanning 15 cattle breeds to the pangenome graph, further validating that the alleles of the structural variant segregate with head depigmentation. We estimate an increased count of repeats in Hereford relative to Simmental and other white-headed cattle breeds from the graph alignment coverage, suggesting a large under-assembly in the current Hereford-based cattle reference genome which had fewer copies. We show that exploiting assembly path similarities within graph pangenomes can reveal trait-associated complex structural variants.

genomics↗

bioRxiv2023

Molecular quantitative trait loci in reproductive tissues impact male fertility in a large mammal

Breeding bulls are well suited to investigate inherited variation in male fertility because they are genotyped and their reproductive success is monitored through semen analyses and thousands of artificial inseminations. However, functional data from relevant tissues are lacking, which prevents fine-mapping fertility-associated genomic regions. Here, we characterize gene expression and splicing variation in testis, epididymis, and vas deferens transcriptomes of 118 mature bulls and conduct association tests between 417k molecular phenotypes and 21M genome-wide variants to identify 41k regulatory loci. We show broad consensus in tissue-specific and tissue-enriched gene expression between the three bovine tissues and their human and murine counterparts. Expression- and splicing-mediating variants are more than three times as frequent in testis than epididymis and vas deferens, highlighting the transcriptional complexity of testis. Finally, we identify genes (WDR19, SPATA16, KCTD19, ZDHHC1) and molecular phenotypes that are associated with quantitative variation in male fertility through transcriptome-wide association and colocalization analyses.

genomics↗

bioRxiv2023

Pangenome genotyped structural variation improves molecular phenotype mapping in cattle

Expression and splicing quantitative trait loci (e/sQTL) are large contributors to phenotypic variability. Achieving sufficient statistical power for e/sQTL mapping requires large cohorts with both genotypes and molecular phenotypes, and so the genomic variation is often called from short read alignments which are unable to comprehensively resolve structural variation. Here we build a pangenome from 16 HiFi haplotype-resolved assemblies to identify small and structural variation and genotype them with PanGenie in 307 short read samples. We find high (>90%) concordance of PanGenie-genotyped and DeepVariant-called small variation, and confidently genotype close to 21M small and 43k structural variants in the larger population. We validate 85% of these structural variants (with MAF>0.1) directly with a subset of 25 short read samples that also have medium coverage HiFi reads. We then conduct e/sQTL mapping with this comprehensive variant set in a subset of 117 cattle that have testis transcriptome data and find 92 structural variants as causal candidates for eQTL and 73 for sQTL. We find that roughly half of top associated structural variants affecting expression or splicing are transposable elements, such as SV-eQTLs for STN1 and MYH7 and SV-sQTLs for CEP89 and ASAH2. Extensive linkage disequilibrium between small and structural variation results in only 28 additional eQTL and 17 sQTL discovered when including SVs, although many top associated SVs are compelling candidates.

genomics↗

bioRxiv2023

Structural variants and short tandem repeats impact gene expression and splicing in bovine testis tissue

Structural variants (SVs) and short tandem repeats (STRs) are significant sources of genetic variation. However, the impacts of these variants on gene regulation have not been investigated in cattle. Here, we genotyped and characterized 19,408 SVs and 374,821 STRs in 183 bovine genomes and investigated their impact on molecular phenotypes derived from testis transcriptomes. We found that 71% STRs were multiallelic. The vast majority (95%) of STRs and SVs were in intergenic and intronic regions. Only 37% SVs and 40% STRs were in high LD (R2>0.8) with surrounding SNPs/Indels, indicating that SNP-based association testing and genomic prediction are blind to a non-negligible portion of genetic variation. We showed that both SVs and STRs were more than two-fold enriched among expression and splicing QTL (e/sQTL) relative to SNPs/Indels and were often associated with differential expression and splicing of multiple genes. Deletions and duplications had larger impacts on splicing and expression than any other type of structural variant. Exonic duplications predominantly increased gene expression either through alternative splicing or other mechanisms, whereas expression- and splicing-associated STRs primarily resided in intronic regions and exhibited bimodal effects on the molecular phenotypes investigated. Most e/sQTL resided within 100 kb of the affected genes or splicing junctions. We pinpoint candidate causal STRs and SVs associated with the expression of SLC13A4 and TTC7B, and alternative splicing of a lncRNA and CAPP1. We provide a catalogue of STRs and SVs for taurine cattle and show that these variants contribute substantially to gene expression and splicing variation.

genomics↗

bioRxiv2022

Graph construction method impacts variation representation and analyses in a bovine super-pangenome

Several models and algorithms have been proposed to build pangenomes from multiple input assemblies, but their impact on variant representation, and consequently downstream analyses, is largely unknown. We create multi-species "super-pangenomes" using pggb, cactus, and minigraph with the Bos taurus taurus reference sequence and eleven haplotype-resolved assemblies from taurine and indicine cattle, bison, yak, and gaur. We recover 221k nonredundant structural variations (SVs) from the pangenomes, of which 135k (61%) are common to all three. SVs derived from assembly-based calling show high agreement with the consensus calls from the pangenomes (96%), but validate only a small proportion of variations private to each graph. Pggb and cactus, which also incorporate base-level variation, have approximately 95% exact matches with assembly-derived small variant calls, which significantly improves the edit rate when realigning assemblies compared to minigraph. We use the three pangenomes to investigate 9,566 variable number tandem repeats (VNTRs), finding 63% have identical predicted repeat counts in the three graphs, while minigraph can over or underestimate the count given its approximate coordinate system. We examine a highly variable VNTR locus and show that repeat unit copy number impacts expression of proximal genes and non-coding RNA. Our findings indicate good consensus between the three pangenome methods but also show their individual strengths and weaknesses that need to be considered when analysing different types of variants from multiple input assemblies.

genomics↗

bioRxiv2021

A 1-bp deletion in bovine QRICH2 causes low sperm count and immotile sperm with multiple morphological abnormalities

BackgroundSemen quality and male fertility are monitored in artificial insemination bulls to ensure high insemination success rates. Only ejaculates that fulfill minimum quality requirements are processed and eventually used for artificial inseminations. We examined 70,990 ejaculates from 1343 Brown Swiss bulls to identify bulls from which all ejaculates were rejected due to low semen quality. This procedure identified a bull that produced twelve ejaculates with an aberrantly low number of sperm (0.2{+/-}0.2 x 109 sperm per ml) which were mostly immotile due to multiple morphological abnormalities. ResultsThe genome of the bull was sequenced at 12-fold coverage to investigate a suspected genetic cause. Comparing the sequence variant genotypes of the bull with those from 397 fertile bulls revealed a 1-bp deletion in the coding sequence of QRICH2 encoding glutamine rich 2 as a compelling candidate causal variant. The 1-bp deletion causes a frameshift in translation and induces a premature termination codon (ENSBTAP00000018337.1:p.Cys1644AlafsTer52). The analysis of testis transcriptomes from 76 bulls showed that the transcript with the premature termination codon is subjected to nonsense-mediated mRNA decay. The 1-bp deletion resides on a 675 kb haplotype spanning 181 SNPs from the Illumina BovineHD Bead chip. The haplotype segregates at a frequency of 5% in the Brown Swiss cattle population. This analysis also identified another bull that carried the 1-bp deletion in the homozygous state. Semen analyses from the second bull confirmed low sperm concentration and immotile sperm with multiple morphological abnormalities primarily affecting the sperm flagellum and, to a lesser extent, the sperm head. ConclusionsA recessive loss-of-function allele of bovine QRICH2 likely causes low sperm concentration and immotile sperm with multiple morphological abnormalities. Routine sperm analyses unambiguously identify homozygous bulls. A direct gene test can be implemented to monitor the frequency of the undesired allele in cattle populations.

genetics↗

bioRxiv2020

Detecting turnover among complex communities using null models: A case study with sky-island haemosporidian parasites

Turnover in species composition between sites, or beta diversity, is a critical component of species diversity that is typically influenced by geography, environment, and biotic interactions. Quantifying turnover is particularly challenging, however, in multi-host, multi-parasite assemblages where undersampling is unavoidable, resulting in inflated estimates of turnover and uncertainty about its spatial scale. We developed and implemented a framework using null models to test for community turnover in avian haemosporidian communities of three sky islands in the southwestern United States. We screened 776 birds for haemosporidian parasites from three genera (Parahaemoproteus, Plasmodium, and Leucocytozoon) by amplifying and sequencing a mitochondrial DNA barcode. We detected infections in 280 birds (36.1%), sequenced 357 infections, and found a total of 99 parasite haplotypes. When compared to communities simulated from a regional pool, we observed more unique, single-mountain haplotypes and fewer haplotypes shared among three mountain ranges than expected, indicating that haemosporidian communities differ to some degree among adjacent mountain ranges. These results were robust even after pruning datasets to include only identical sets of host species, and they were consistent for two of the three haemosporidian genera. The two more distant mountain ranges were more similar to each other than the one located centrally, suggesting that the differences we detected were due to stochastic colonization-extirpation dynamics. These results demonstrate that avian haemosporidian communities of temperate-zone forests differ on relatively fine spatial scales associated with adjacent sky-islands. Null models are essential tools for detecting turnover in complex, undersampled, and poorly known systems.

ecology↗