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Genomic regions showing copy number variations associate with resistance or susceptibility to gastrointestinal nematodes in Angus cattle

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Abstract

Genomic structural variation is an important and abundant source of genetic and phenotypic variation. We previously reported an initial analysis of copy number variations (CNVs) in Angus cattle selected for resistance or susceptibility to gastrointestinal nematodes. In this study, we performed a large-scale analysis of CNVs using SNP genotyping data from 472 animals of the same population. We detected 811 candidate CNV regions, which represent 141.8 Mb (~4.7%) of the genome. To investigate the functional impacts of CNVs, we created 2 groups of 100 individual animals with extremely low or high estimated breeding values of eggs per gram of feces and referred to these groups as parasite resistant (PR) or parasite susceptible (PS), respectively. We identified 297 (~51 Mb) and 282 (~48 Mb) CNV regions from PR and PS groups, respectively. Approximately 60% of the CNV regions were specific to the PS group or PR group of animals. Selected PR- or PS-specific CNVs were further experimentally validated by quantitative PCR. A total of 297 PR CNV regions overlapped with 437 Ensembl genes enriched in immunity and defense, like WC1 gene which uniquely expresses on gamma/delta T cells in cattle. Network analyses indicated that the PR-specific genes were predominantly involved in gastrointestinal disease, immunological disease, inflammatory response, cell-to-cell signaling and interaction, lymphoid tissue development, and cell death. By contrast, the 282 PS CNV regions contained 473 Ensembl genes which are overrepresented in environmental interactions. Network analyses indicated that the PS-specific genes were particularly enriched for inflammatory response, immune cell trafficking, metabolic disease, cell cycle, and cellular organization and movement.

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Abbreviations

aCGH:

Array comparative genomic hybridizations

CNV:

Copy number variation

CNVR:

CNV region

CT :

Cycle threshold

EPG:

Eggs per gram of feces

GI:

Gastrointestinal

MLN:

Mesenteric lymph node

OMIA:

Online Mendelian Inheritance in Animals

PR:

Parasite resistant

PS:

Parasite susceptible

qPCR:

Quantitative PCR

QTL:

Quantitative trait locus

SNP:

Single nucleotide polymorphism

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Acknowledgments

We thank D. Hebert, J. Shaffer, and R. Anderson for technical assistance. This work was supported in part by NRI grant no. 2007-35205-17869 from USDA CSREES (now NIFA).

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Correspondence to George E. Liu.

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Table S1

Btau_4.0 cattle CNV regions and their frequencies in the resource Angus population (472 animals). The description of CNV regions includes the coordinates (chromosome, start position, end position, length), CNV type (gain, loss, both), the start SNP name, the end SNP name, the number of SNPs in this region, the number of animals having CNV events in this region, as well as its frequency. The frequency was defined as “Unique” when the CNV region was unique only to one animal, “Multiple” when the CNV region was shared by two animals, or shown as the exact proportion of animals having CNV events in this region when the CNV region was shared by at least three animals (PDF 182 kb)

Table S2

Over/underrepresentation of PANTHER molecular function, biological process, and pathway terms in the resource Angus population (472 animals) (PDF 20 kb)

Table S3

Btau_4.0 cattle CNV regions and their frequencies in top 100 parasite resistant (PR100) Angus cattle. The description of CNV regions includes the coordinates (chromosome, start position, end position, length), CNV type (gain, loss, both), the start SNP name, the end SNP name, the number of SNPs in this region, the number of animals having CNV events in this region, as well as its frequency. The frequency was defined as “Unique” when the CNV region was unique only to one animal, “Multiple” when the CNV region was shared by two animals, or shown as the exact proportion of animals having CNV events in this region when the CNV region was shared by at least three animals (PDF 93.1 kb)

Table S4

Btau_4.0 cattle CNV regions and their frequencies in top 100 parasite susceptible (PS100) Angus cattle. The description of CNV regions includes the coordinates (chromosome, start position, end position, length), CNV type (gain, loss, both), the start SNP name, the end SNP name, the number of SNPs in this region, the number of animals having CNV events in this region, as well as its frequency. The frequency was defined as “Unique” when the CNV region was unique only to one animal, “Multiple” when the CNV region was shared by two animals, or shown as the exact proportion of animals having CNV events in this region when the CNV region was shared by at least three animals (PDF 90.2 kb)

Table S5

Over/underrepresentation of PANTHER molecular function, biological process, and pathway terms in two extreme groups (PR100 and PS100) (PDF 23 kb)

Table S6

Gene contents of CNV regions. See Table S6.xls (PDF 924 kb)

Table S7

qPCR summary (PDF 22 kb)

Fig. S1

Genomic landscape of cattle copy number variations and segmental duplications. CNV regions (811 events, 141 Mb, ~4.60% of the bovine genome) derived from all 472 SNP-genotyped Angus are shown above the chromosomes in green (gain), red (loss), and dark blue (both). Below the chromosomes are the CNV regions (682 events, 139 Mb, ~4.60% of the bovine genome) identified by the same method using the Bovine HapMap SNP genotyping data, including 539 animals of 21 modern cattle breeds and 6 outgroups (Hou et al. 2011). The bar height represents their frequencies: short (appeared in 1 sample), median (≥2 samples), and tall (≥5 samples). Segmental duplications (94.4 Mb, 3.1% of the bovine genome) predicted by two independent computational approaches (Liu et al. 2010) are illustrated on the chromosomes in red (WSSD), blue (WGAC), or purple (both). The patterns are depicted for all duplications for ≥5 kb in length and ≥90% sequence identity. The gaps in the assembly are represented on the chromosomes as white ticks (PDF 79.1 kb)

Fig. S2

Comparisons between identified 811 CNVRs in this study and the other existing cattle CNVR datasets in terms of count and length. A, compared to three CNVR datasets derived from SNP array (Bae et al. 2010; Seroussi et al. 2010; Hou et al. 2011); B, compared to two CNVR datasets derived from array CGH studies (Liu et al. 2010; Fadista et al. 2010); C, the summaries and legends of existing cattle CNVR datasets (PDF 168 kb)

Fig. S3

qPCR results for the TRMP7 locus. (Top) Representation of SNP CNV calls determined by PennCNV in two animals (IDs 1348 and 1461; blue and red, respectively) at the TRMP7 locus on Chr6. SNP marker coordinates are listed on the x-axis (spacing not to scale with actual distance) and the inferred copy number at the position is listed on the y-axis. One of the areas investigated using qPCR is highlighted with a black bar. (Bottom right) Whisker plot of qPCR determined copy number at the TRMP7 locus. Animal IDs are listed on the x-axis with animal 1348 represented in blue and animal 1461 represented in red. Plots were made from copy number estimates from triplicate qPCR reactions using the same conditions and primers (PDF 29.8 kb)

Fig. S4

The network for the PR100 group indentified by IPA is involved in the inflammatory response pathway. For meanings of shapes and lines, see legend in the figure (PDF 89.7 kb)

Fig. S5

The network for the PS100 group indentified by IPA is involved in the inflammatory response pathway. For meanings of shapes and lines, see legend in the figure (PDF 86.2 kb)

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Hou, Y., Liu, G.E., Bickhart, D.M. et al. Genomic regions showing copy number variations associate with resistance or susceptibility to gastrointestinal nematodes in Angus cattle. Funct Integr Genomics 12, 81–92 (2012). https://doi.org/10.1007/s10142-011-0252-1

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