Genetic mechanisms underlying spermatic and testicular traits within and among cattle breeds: systematic review and prioritization of GWAS results

Abstract

Reduced bull fertility imposes economic losses in bovine herds. Specifically, testicular and spermatic traits are important indicators of reproductive efficiency. Several genome-wide association studies (GWAS) have identified genomic regions associated with these fertility traits. The aims of this study were as follows: 1) to perform a systematic review of GWAS results for spermatic and testicular traits in cattle and 2) to identify key functional candidate genes for these traits. The identification of functional candidate genes was performed using a systems biology approach, where genes shared between traits and studies were evaluated by a guilt by association gene prioritization (GUILDify and ToppGene software) in order to identify the best functional candidates. These candidate genes were integrated and analyzed in order to identify overlapping patterns among traits and breeds. Results showed that GWAS for testicular-related traits have been developed for beef breeds only, whereas the majority of GWAS for spermatic-related traits were conducted using dairy breeds. When comparing traits measured within the same study, the highest number of genes shared between different traits was observed, indicating a high impact of the population genetic structure and environmental effects. Several chromosomal regions were enriched for functional candidate genes associated with fertility traits. Moreover, multiple functional candidate genes were enriched for markers in a species-specific basis, taurine (Bos taurus) or indicine (Bos indicus). For the different candidate regions identified in the GWAS in the literature, functional candidate genes were detected as follows: B. Taurus chromosome X (BTX) (TEX11, IRAK, CDK16, ATP7A, ATRX, HDAC6, FMR1, L1CAM, MECP2, etc.), BTA17 (TRPV4 and DYNLL1), and BTA14 (MOS, FABP5, ZFPM2). These genes are responsible for regulating important metabolic pathways or biological processes associated with fertility, such as progression of spermatogenesis, control of ciliary activity, development of Sertoli cells, DNA integrity in spermatozoa, and homeostasis of testicular cells. This study represents the first systematic review on male fertility traits in cattle using a system biology approach to identify key candidate genes for these traits.

Figure 1.

Flow chart displaying the pipeline used to select articles based on specific criteria for the systematic review.

Figure 2.

Percentage of genes mapped around significant markers/windows shared between traits. The upper and lateral blue bars represent traits evaluated in dairy breeds, whereas the green bars represent traits evaluated in beef breeds. Within the matrix, darker shades of red represent high percentage of genes shared among traits. (a) Percentage of genes shared among traits evaluated in both dairy and beef breeds. (b) Percentage of genes shared among traits evaluated in dairy breeds. (c) Percentage of genes shared among traits evaluated in beef breeds. Ability to produce sperm (Sperm) at 18 mo; percentage of normal spermatozoa at 24 mo (PNS); semen volume (SV); total number of sperm (TNS); sperm concentration (SpermC); poor sperm motility (PSM); mitochondrial function (mitF); sperm plasma membrane integrity (SPMI); DNA status assessed both as DNA fragmentation index (DFI); membrane integrity (membINT); TUNEL assay (TUNEL); initial sperm motility (SMOT); number of motile sperm per ejaculate (NMSPE); number of sperm per ejaculate (NSPE); semen volume per ejaculate (SVPE); sperm concentration per ejaculate (SCPE); motility score (MOTscore); number of spermatozoa (Nsperm); scrotal circumference adjusted for 210 d of age (SC210d); scrotal circumference adjusted for 420 d of age (SC420d); scrotal circumference (SC); age at a scrotal circumference of 26 cm (AgeSC26); scrotal circumference at 6 mo (SC6m), scrotal circumference at 12 mo (SC12m), scrotal circumference at 18 mo (SC18m), scrotal circumference at 24 mo (SC24m); scrotal circumference at maturity (SCmat).

Figure 3.

Chord plot displaying the relationship between the genes in the top 100 ranked prioritized genes and the evaluated traits. The bars in the right-hand side represent the traits evaluated by each article and the bars in the left-hand side represent the genes found in one or more of these articles that are included in the top 100 ranked prioritized list. Poor sperm motility (PSM); percentage of normal spermatozoa at 24 mo (PNS); number of motile sperm per ejaculate (NMSPE); initial sperm motility (SMOT); scrotal circumference at 18 mo (SC18m); scrotal circumference at maturity (SCmat); scrotal circumference (SC); scrotal circumference adjusted for 420 d of age (SC420d); scrotal circumference at 12 mo (SC12m); membrane integrity (MembINT); scrotal circumference at 6 mo (SC6m); age at a scrotal circumference of 26 cm (AgeSC26); DNA fragmentation index (DFI); total number of sperm (TNS); scrotal circumference at 24 mo (SC24m)

Figure 4.

Number of genes, traits, and articles (that reported at least 1 significant signal) per chromosome. (a) All prioritized genes. (b) Top 100 ranked prioritized genes.