Genomic Estimated Breeding Valueof Milk Performance and Fertility Traits in the Russian Black-and-White Cattle Population

A breakthrough in cattle breeding was achieved with the incorporation of animal genomic data into breeding programs. The introduction of genomic selection has a major impact on traditional genetic assessment systems and animal genetic improvement programs. Since 2010, genomic selection has been officially introduced in the evaluation of the breeding and genetic potential of cattle in Europe, the U.S., Canada, and many other developed countries. The purpose of this study is to develop a system for a genomic evaluation of the breeding value of the domestic livestock of Black-and-White and Russian Holstein cattle based on 3 milk performance traits: daily milk yield (kg), daily milk fat (%), and daily milk protein content (%) and 6 fertility traits: age at first calving (AFC), calving interval (CI), calving to first insemination interval (CFI), interval between first and last insemination (IFL), days open (DO), and number of services (NS). We built a unified database of breeding animals from 523 breeding farms in the Russian Federation. The database included pedigree information on 2,551,529 cows and 69,131 bulls of the Russian Holstein and Black-and-White cattle breeds, as well as information on the milk performance of 1,597,426 cows with 4,771,366 completed lactations. The date of birth of the animals included in the database was between 1975 and 2017. Genotyping was performed in 672 animals using a BovineSNP50 v3 DNA Analysis BeadChip microarray (Illumina, USA). The genomic estimated breeding value (GEBV) was evaluated only for 644 animals (427 bulls and 217 cows) using the single-step genomic best linear unbiased prediction animal model (ssGBLUP-AM). The mean genetic potential was +0.88 and +1.03 kg for the daily milk yield, -0.002% for the milk fat content, and 0.003 and 0.001% for the milk protein content in the cows and bulls, respectively. There was negative genetic progress in the fertility traits in the studied population between 1975 and 2017. The reliability of the estimated breeding value (EBV) for genotyped bulls ranged from 89 to 93% for the milk performance traits and 85 to 90% for the fertility traits, whereas the reliability of the genomic estimated breeding value (GEBV) varied 54 to 64% for the milk traits and 23 to 60% for the fertility traits. This result shows that it is possible to use the genomic estimated breeding value with rather high reliability to evaluate the domestic livestock of Russian Holstein and Black-and-White cattle breeds for fertility and milk performance traits. This system of genomic evaluation may help bring domestic breeding in line with modern competitive practices and estimate the breeding value of cattle at birth based on information on the animals genome.</jats:p

DNA Methylation: Genomewide Distribution, Regulatory Mechanism and Therapy Target

DNA methylation is the most important epigenetic modification involved in the regulation of transcription, imprinting, establishment of X-inactivation, and the formation of a chromatin structure. DNA methylation in the genome is often associated with transcriptional repression and the formation of closed heterochromatin. However, the results of genome-wide studies of the DNA methylation pattern and transcriptional activity of genes have nudged us toward reconsidering this paradigm, since the promoters of many genes remain active despite their methylation. The differences in the DNA methylation distribution in normal and pathological conditions allow us to consider methylation as a diagnostic marker or a therapy target. In this regard, the need to investigate the factors affecting DNA methylation and those involved in its interpretation becomes pressing. Recently, a large number of protein factors have been uncovered, whose ability to bind to DNA depends on their methylation. Many of these proteins act not only as transcriptional activators or repressors, but also affect the level of DNA methylation. These factors are considered potential therapeutic targets for the treatment of diseases resulting from either a change in DNA methylation or a change in the interpretation of its methylation level. In addition to protein factors, a secondary DNA structure can also affect its methylation and can be considered as a therapy target. In this review, the latest research into the DNA methylation landscape in the genome has been summarized to discuss why some DNA regions avoid methylation and what factors can affect its level or interpretation and, therefore, can be considered a therapy target.</jats:p

VHL inactivation without hypoxia is sufficient to achieve genome hypermethylation

AbstractVHL inactivation is a key oncogenic event for renal carcinomas. In normoxia, VHL suppresses HIF1a-mediated response to hypoxia. It has previously been shown that hypoxic conditions inhibit TET-dependent hydroxymethylation of cytosines and cause DNA hypermethylation at gene promoters. In this work, we performed VHL inactivation by CRISPR/Cas9 and studied its effects on gene expression and DNA methylation. We showed that even without hypoxia, VHL inactivation leads to hypermethylation of the genome which mainly occurred in AP-1 and TRIM28 binding sites. We also observed promoter hypermethylation of several transcription regulators associated with decreased gene expression.</jats:p

Report on noninvasive prenatal testing: classical and alternative approaches [version 1; referees: 2 approved]

Concerns of traditional prenatal aneuploidy testing methods, such as low accuracy of noninvasive and health risks associated with invasive procedures, were overcome with the introduction of novel noninvasive methods based on genetics (NIPT). These were rapidly adopted into clinical practice in many countries after a series of successful trials of various independent submethods. Here we present results of own NIPT trial carried out in Moscow, Russia. 1012 samples were subjected to the method aimed at measuring chromosome coverage by massive parallel sequencing. Two alternative approaches are ascertained: one based on maternal/fetal differential methylation and another based on allelic difference. While the former failed to provide stable results, the latter was found to be promising and worthy of conducting a large-scale trial. One critical point in any NIPT approach is the determination of fetal cell-free DNA fraction, which dictates the reliability of obtained results for a given sample. We show that two different chromosome Y representation measures—by real-time PCR and by whole-genome massive parallel sequencing—are practically interchangeable (r=0.94). We also propose a novel method based on maternal/fetal allelic difference which is applicable in pregnancies with fetuses of either sex. Even in its pilot form it correlates well with chromosome Y coverage estimates (r=0.74) and can be further improved by increasing the number of polymorphisms

Comparison of the 3D organization of sperm and fibroblast genomes using the Hi-C approach

The 3D organization of the genome is tightly connected to its biological function. The Hi-C approach was recently introduced as a method that can be used to identify higher-order chromatin interactions genome-wide. The aim of this study was to determine genome-wide chromatin interaction frequencies using the Hi-C approach in mouse sperm cells and embryonic fibroblasts. The obtained results demonstrated that the 3D genome organizations of sperm and fibroblast cells show a high degree of similarity both with each other and with the previously described mouse embryonic stem (ES) cells. Both A- and B-compartments and topologically associated domains (TADs) are present in spermatozoa and fibroblasts. Nevertheless, sperm cells and fibroblasts exhibited statistically significant differences between each other in the contact probabilities of defined loci. Tight packaging of the sperm genome resulted in an enrichment of long-range contacts compared with the fibroblasts. However, only 30% of the differences in the number of contacts are based on differences in the densities of their genome packages; the main source of the differences is the gain or loss of contacts that are specific for defined genome regions. An analysis of interchromosomal contacts in both cell types demonstrated that the large chromosomes showed a tendency to interact with each other more than with the small chromosomes and vice versa. We found that the dependence of the contact probability P(s) on genomic distance for sperm is in a good agreement with the fractal globular folding of chromatin. The similarity of the spatial DNA organization in sperm and somatic cell genomes suggests the stability of the 3D structure of genomes through generations.</jats:p