Putative bovine topological association domains and CTCF binding motifs can reduce the search space for causative regulatory variants of complex traits

Wang, Min; Hancock, Tim; Chamberlain, Amanda J.; Jagt, Christy J. Vander; Pryce, J.E.; Cocks, Benjamin G.; Goddard, Michael E.; Hayes, Ben J.

doi:10.1186/s12864-018-4800-0

Cited by 22 publications

(32 citation statements)

References 56 publications

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“…E i = expected frequency of genes (i) from the overall clusters ( i = Nu MP, Non- NuMP gene) the effect of TAD in co-expression of Nu MP genes in Nu MP- Mt MP cluster considering TAD as one of the several factors potentially influencing the co-expression of small group of genes. Briefly, we mapped the co-expressed bovine genes across the clusters (3643) to the putative bovine TADs derived from the IMR90hg18 [ 78 ] and 3022 genes mapped to 1286 TADs. Similarly, within the Nu MP- Mt MP cluster, 651 of 813 co-expressed genes mapped to 484 TADs.…”

Section: Methodsmentioning

confidence: 99%

Expression of mitochondrial protein genes encoded by nuclear and mitochondrial genomes correlate with energy metabolism in dairy cattle

et al. 2020

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Background Mutations in the mitochondrial genome have been implicated in mitochondrial disease, often characterized by impaired cellular energy metabolism. Cellular energy metabolism in mitochondria involves mitochondrial proteins (MP) from both the nuclear (NuMP) and mitochondrial (MtMP) genomes. The expression of MP genes in tissues may be tissue specific to meet varying specific energy demands across the tissues. Currently, the characteristics of MP gene expression in tissues of dairy cattle are not well understood. In this study, we profile the expression of MP genes in 29 adult and six foetal tissues in dairy cattle using RNA sequencing and gene expression analyses: particularly differential gene expression and co-expression network analyses. Results MP genes were differentially expressed (DE; over-expressed or under-expressed) across tissues in cattle. All 29 tissues showed DE NuMP genes in varying proportions of over-expression and under-expression. On the other hand, DE of MtMP genes was observed in < 50% of tissues and notably MtMP genes within a tissue was either all over-expressed or all under-expressed. A high proportion of NuMP (up to 60%) and MtMP (up to 100%) genes were over-expressed in tissues with expected high metabolic demand; heart, skeletal muscles and tongue, and under-expressed (up to 45% of NuMP, 77% of MtMP genes) in tissues with expected low metabolic rates; leukocytes, thymus, and lymph nodes. These tissues also invariably had the expression of all MtMP genes in the direction of dominant NuMP genes expression. The NuMP and MtMP genes were highly co-expressed across tissues and co-expression of genes in a cluster were non-random and functionally enriched for energy generation pathway. The differential gene expression and co-expression patterns were validated in independent cow and sheep datasets. Conclusions The results of this study support the concept that there are biological interaction of MP genes from the mitochondrial and nuclear genomes given their over-expression in tissues with high energy demand and co-expression in tissues. This highlights the importance of considering MP genes from both genomes in future studies related to mitochondrial functions and traits related to energy metabolism.

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Section: Methodsmentioning

confidence: 99%

Expression of mitochondrial protein genes encoded by nuclear and mitochondrial genomes correlate with energy metabolism in dairy cattle

et al. 2020

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“…) (Wang et al . ). TADs are regions of a genome where there are more interactions between loci within a domain than between loci located in different domains (Dixon et al ; Szalaj & Plewczynski ).…”

Section: Candidate Genesmentioning

confidence: 97%

“…The POLLED variants are located within one predicted topologically associating domain (TAD) (1 226 028-2 201 452 bp) containing 23 protein coding genes and non-coding RNAs (Fig. 3) (Wang et al 2018). TADs are regions of a genome where there are more interactions between loci within a domain than between loci located in different domains (Dixon et al 2012;Szalaj & Plewczynski 2018).…”

Section: Candidate Genesmentioning

confidence: 99%

Understanding the effects of the bovine POLLED variants

Aldersey

Sonstegard²,

Williams

et al. 2020

Animal Genetics

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Summary Horns are paired appendages on the head of bovine species, comprising an inner bony core and outer keratin sheath. The horn bud forms during early fetal development but ossification of the developing horn does not occur until approximately 1 month after birth. Little is known about the genetic pathways that lead to horn growth. Hornless, or polled, animals are found in all domestic bovids. Histological studies of bovine fetuses have shown that the horn bud does not form in polled individuals. There are currently four known genetic variants for polledness in cattle on BTA1. All of the variants are intergenic, but probably affect regulation of nearby genes or long non‐coding RNAs. Transcriptomic studies suggest that the expression of two nearby long non‐coding RNAs are affected by the Celtic POLLED variant, but further studies are required to confirm these data. Candidate genes located elsewhere in the genome are involved in regulating bone formation and epithelial‐to‐mesenchymal transition. Expression of one of these candidate genes, RXFP2, appears to be reduced in the fetal horn bud of polled animals carrying the Celtic variant compared with horned individuals. Investigating horn ontogenesis and the genetic pathway by which the POLLED variants prevent horn development has implications for cattle breeding. If the genetic basis of horn bud formation and polledness is better understood, then new targets may be identified for precision genome editing to create polled individuals.

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“…including HELB and HMGA2-CNVR, was in linkage disequilibrium or segregated independently, since independent segregation would explain the contribution of individual genomic elements in the region to multiple production traits in cattle. Towards this aim, we mapped bovine predicted topologically domains (TAD) in this region [92]. TAD are indicative of regions that physically interact more frequently with each other than with other sequences outside of the TAD [93].…”

Section: Mutations In the Helb Gene And The Hmga2-cnvr Segregate Indementioning

confidence: 99%

Selection signatures in tropical cattle are enriched for promoter and coding regions and reveal missense mutations in the damage response gene HELB

et al. 2020

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Background: Distinct domestication events, adaptation to different climatic zones, and divergent selection in productive traits have shaped the genomic differences between taurine and indicine cattle. In this study, we assessed the impact of artificial selection and environmental adaptation by comparing whole-genome sequences from European taurine and Asian indicine breeds and from African cattle. Next, we studied the impact of divergent selection by exploiting predicted and experimental functional annotation of the bovine genome. Results: We identified selective sweeps in beef cattle taurine and indicine populations, including a 430-kb selective sweep on indicine cattle chromosome 5 that is located between 47,670,001 and 48,100,000 bp and spans five genes, i.e. HELB, IRAK3, ENSBTAG00000026993, GRIP1 and part of HMGA2. Regions under selection in indicine cattle display significant enrichment for promoters and coding genes. At the nucleotide level, sites that show a strong divergence in allele frequency between European taurine and Asian indicine are enriched for the same functional categories. We identified nine single nucleotide polymorphisms (SNPs) in coding regions that are fixed for different alleles between subspecies, eight of which were located within the DNA helicase B (HELB) gene. By mining information from the 1000 Bull Genomes Project, we found that HELB carries mutations that are specific to indicine cattle but also found in taurine cattle, which are known to have been subject to indicine introgression from breeds, such as N'Dama, Anatolian Red, Marchigiana, Chianina, and Piedmontese. Based on in-house genome sequences, we proved that mutations in HELB segregate independently of the copy number variation HMGA2-CNV, which is located in the same region. Conclusions: Major genomic sequence differences between Bos taurus and Bos indicus are enriched for promoter and coding regions. We identified a 430-kb selective sweep in Asian indicine cattle located on chromosome 5, which carries SNPs that are fixed in indicine populations and located in the coding sequences of the HELB gene. HELB is involved in the response to DNA damage including exposure to ultraviolet light and is associated with reproductive traits and yearling weight in tropical cattle. Thus, HELB likely contributed to the adaptation of tropical cattle to their harsh environment.

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Putative bovine topological association domains and CTCF binding motifs can reduce the search space for causative regulatory variants of complex traits

Cited by 22 publications

References 56 publications

Expression of mitochondrial protein genes encoded by nuclear and mitochondrial genomes correlate with energy metabolism in dairy cattle

Expression of mitochondrial protein genes encoded by nuclear and mitochondrial genomes correlate with energy metabolism in dairy cattle

Understanding the effects of the bovine POLLED variants

Selection signatures in tropical cattle are enriched for promoter and coding regions and reveal missense mutations in the damage response gene HELB

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