Deviations from Mendelian Inheritance on Bovine X-Chromosome Revealing Recombination, Sex-of-Offspring Effects and Fertility-Related Candidate Genes

Abstract

Transmission ratio distortion (TRD), or significant deviations from Mendelian inheritance, is a well-studied phenomenon on autosomal chromosomes, but has not yet received attention on sex chromosomes. TRD was analyzed on 3832 heterosomal single nucleotide polymorphisms (SNPs) and 400 pseudoautosomal SNPs spanning the length of the X-chromosome using 436,651 genotyped Holstein cattle. On the pseudoautosomal region, an opposite sire-TRD pattern between male and female offspring was identified for 149 SNPs. This finding revealed unique SNPs linked to a specific-sex (Y- or X-) chromosome and describes the accumulation of recombination events across the pseudoautosomal region. On the heterosomal region, 13 SNPs and 69 haplotype windows were identified with dam-TRD. Functional analyses for TRD regions highlighted relevant biological functions responsible to regulate spermatogenesis, development of Sertoli cells, homeostasis of endometrium tissue and embryonic development. This study uncovered the prevalence of different TRD patterns across both heterosomal and pseudoautosomal regions of the X-chromosome and revealed functional candidate genes for bovine reproduction.

Keywords: bovine; chromosome X; recombination; transmission ratio distortion.

Figure 1

Mendelian inconsistencies across bovine X-chromosome based on the pseudoautosomal inheritance model (positive value and black color) and the heterosomal inheritance model (negative values and grey color).

Figure 2

Schematic representation of the long arm of X-chromosome (Xq) and short arm of Y-chromosome (Yp) and sire-TRD patterns. (A) Magnitude of sire-TRD with opposite sign between male- (blue color) and female-offspring (red color) on pseudoautosomal SNPs. (B) Schematic representation of X and Y peudoautosomal regions (PARX and PARY) and peudoautosomal boundaires (PABX and PABY). (C) Density of SNP available for analyses (pseudoautosomal with red color and heterosomal with blue color). The pink and blue circles represent the first two markers with α = 0.5 (BTX:143,865,210 and BTX:143,870,595), respectively. The red circle represents the last marker with an opposite sire-TRD effect between male and female offspring (BTX:148,789,832). The orange and green rectangles correspond to the markers with opposite sire-TRD effects between male and female offspring and dam-TRD for male (orange) and female (green) offspring. The blue diamonds represent the region with highest homology between the X- and Y-chromosomes (BTX:144,251,086–144,399,458). It is important to highlight that this is a schematic image and some genes where suppressed.

Figure 3

Distribution of male and female offspring for informative mattings for the SNP with highest BF with opposite sire-TRD between sex offspring.

Figure 4

Overlapping between opposite sire-TRD (right y-axis) and sum of the probability of recombination (left y-axis) in the main pseudoautosomal part of the bovine X-chromosome (143,865,210–148,816,634 bp). The x-axis shows the genomic coordinated in Mega bases (Mb). The red and blue dots correspond to the sire-TRD magnitude in the male and female offspring, respectively.

Figure 5

Interaction network between the positional candidate genes around TRD regions on bovine X-chromosome and biological functions and diseases identified. For the most relevant biological functions, the edges between the genes and the processes were colored in order to highlight the connection. These biological functions were: cell viability (green), angiogenesis (pink), development of cardiovascular tissue (red), migration of endothelial cells (blue), growth of connective tissue (cyan), abnormal morphology of body cavity (orange) and neuritogenesis (purple). The positional candidate genes were colored in function of the predominant (highest |α|) TRD observed for the associated marker, where: pink represents dam-TRD among in heterosomal regions (RNF128, PIGA, PLP1, BMX, KDM6A, CSNK1A1, VEGFD, DRP2 and bta-mir-221); yellow represents male- and female-dam-TRD in heterosomal regions (FLNA, FGF13 and MECP2); blue represents recessive TRD pattern in heterosomal regions (TNMD, SLITRK4 and BTK). The gene TSC22D3 was colored in red because two different TRD patterns were observed for the markers mapped in the interval used to annotate the gene. These TRD patterns were dam-TRD and recessive-TRD, both in heterosomal regions.