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. 2023 Jan 3:101:skad063.
doi: 10.1093/jas/skad063.

gBLUP-GWAS identifies candidate genes, signaling pathways, and putative functional polymorphisms for age at puberty in gilts

Hiruni R Wijesena  1 , Dan J Nonneman  2 , Warren M Snelling  2 , Gary A Rohrer  2 , Brittney N Keel  2 , Clay A Lents  1
Affiliations

gBLUP-GWAS identifies candidate genes, signaling pathways, and putative functional polymorphisms for age at puberty in gilts

Hiruni R Wijesena et al. J Anim Sci. .

Abstract

Successful development of replacement gilts determines their reproductive longevity and lifetime productivity. Selection for reproductive longevity is challenging due to low heritability and expression late in life. In pigs, age at puberty is the earliest known indicator for reproductive longevity and gilts that reach puberty earlier have a greater probability of producing more lifetime litters. Failure of gilts to reach puberty and display a pubertal estrus is a major reason for early removal of replacement gilts. To identify genomic sources of variation in age at puberty for improving genetic selection for early age at puberty and related traits, gilts (n = 4,986) from a multigeneration population representing commercially available maternal genetic lines were used for a genomic best linear unbiased prediction-based genome-wide association. Twenty-one genome-wide significant single nucleotide polymorphisms (SNP) located on Sus scrofa chromosomes (SSC) 1, 2, 9, and 14 were identified with additive effects ranging from -1.61 to 1.92 d (P < 0.0001 to 0.0671). Novel candidate genes and signaling pathways were identified for age at puberty. The locus on SSC9 (83.7 to 86.7 Mb) was characterized by long range linkage disequilibrium and harbors the AHR transcription factor gene. A second candidate gene on SSC2 (82.7 Mb), ANKRA2, is a corepressor for AHR, suggesting a possible involvement of AHR signaling in regulating pubertal onset in pigs. Putative functional SNP associated with age at puberty in the AHR and ANKRA2 genes were identified. Combined analysis of these SNP showed that an increase in the number of favorable alleles reduced pubertal age by 5.84 ± 1.65 d (P < 0.001). Candidate genes for age at puberty showed pleiotropic effects with other fertility functions such as gonadotropin secretion (FOXD1), follicular development (BMP4), pregnancy (LIF), and litter size (MEF2C). Several candidate genes and signaling pathways identified in this study play a physiological role in the hypothalamic-pituitary-gonadal axis and mechanisms permitting puberty onset. Variants located in or near these genes require further characterization to identify their impact on pubertal onset in gilts. Because age at puberty is an indicator of future reproductive success, these SNP are expected to improve genomic predictions for component traits of sow fertility and lifetime productivity expressed later in life.

Keywords: aryl hydrocarbon receptor; candidate gene; genome-wide association; genomic best linear unbiased prediction; puberty; swine.

Plain language summary

Selecting for replacement gilts is challenging because sow reproductive traits are lowly heritable and expressed late in life. Age at puberty is the earliest indicator of future reproductive success of gilts. Genetic selection for early onset of puberty could be feasible with the availability of molecular genetic predictors for age at puberty. To identify genomic sources associated with variation in age at puberty in gilts, a large-scale genome-wide association study was conducted at the U.S Meat Animal Research Center, Clay Center, Nebraska. Novel genomic associations for age at puberty were identified. Several candidate genes identified for age at puberty are involved in signaling pathways that regulate ovarian functions and pubertal onset. Potential causative genetic variants for age at puberty were identified within the candidate genes. These novel SNP are important new markers for use in genomic selection of replacement gilts with early puberty and provide critical new insight into biological mechanisms important for pubertal development in gilts.

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Figures

Figure 1.
Figure 1.
Genome-wide association analysis for age at puberty using 4,986 gilts and 71,634 imputed SNP genotypes. The autosomes from SSC1 to SSC18, followed by chromosome X are represented by different colors. Each dot represents a SNP. A Bonferroni adjusted −log10P value of 6.16 was used to identify genome-wide significant SNP.
Figure 2.
Figure 2.
Linkage disequilibrium plot of markers in the SSC9 QTL region. The 12 genome-wide significant SNP in the region are highlighted. The SNP ASGA0094390 is an intronic variant located in the AHR gene. The average LD of 12 significant SNP with ASGA0094390 was r2 = 0.79.
Figure 3.
Figure 3.
Proposed model for reduced activation of the AHR pathway that contributes to ovarian changes for onset of puberty in pigs. AHR and ANKRA2 (asterisks) are candidates for age at puberty located within SSC9 (86.5 Mb) and SSC2 (82.7 Mb) QTL, respectively. Activated AHR forms heterodimers with ARNT and other coactivators, which in turn bind to xenobiotic responsive elements (XRE) in the promoter region of _target genes. CYP1A1 and CYP1A2 limit production of estrogen by catalyzing the conversion of 17β-estradiol to 2-OH-estradiol and increase the oxidative state, which promotes follicular atresia through apoptosis of granulosa cells; thereby limiting follicular development. Nonsynonymous SNP and deletions in the porcine AHR gene could lead to increased or decreased (dashed line) transcriptional activation by AHR (Nonneman et al., 2021). The transcriptional activity of AHR can be further suppressed by two separate AHRR pathways, one of which is dependent on ANKRA2 corepressor. AHRR-ARNT heterodimer binds to XRE regions of the AHR _targeted genes to inhibit transcription. The porcine ANKRA2 gene has putative functional polymorphisms but their effect on this inhibitory process is presently unknown. The increased reduction in AHR-induced transcription leads to increased estrogen production and normalized redox homeostasis.
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