Influence of inbreeding on the morphobiological characteristics of meadow clover (Trifolium pratense L.)

The influence of inbreeding on the morphobiological characteristics of meadow clover was revealed. Self-pollination, repeated in the number of successive generations, leads to an increase in homozygosity and to inbred depression, which increases from I1 to I3 generation and stabilizes in the I4 generation. It was found that in the I1 generation, according to the main morphobiological characteristics, there is no inward depression, but the maximum release of recessive lethal mutations is manifested, which amounted to 6.2%, and the survival rate of seedlings decreases (91.7%). By the I4 generation, the number of chlorophyll-free seedlings decreases to 1.4%. All the main morpho-biological indicators that determine the productivity of plants decrease from generation I1 to generation I3 by 1.5-2 times and stabilize in generation I4. Obtaining hybrid F1 offspring by crossing a linear material with an I4 induction level leads to the restoration of plant productivity indicators. When creating a linear material, an increase in the number of highly self-compatible genotypes from I1 to I4 generation by 60% is clearly traced. The data obtained make it possible to take into account the survival rate of seedlings, the cleavage of lethal and semi-lethal mutations, the degree of inbred depression in the formation of sample volumes when creating a linear material of meadow clover.

Reliabilities of Genomic Prediction for Young Stock Survival Traits Using 54K SNP Chip Augmented With Additional Single-Nucleotide Polymorphisms Selected From Imputed Whole-Genome Sequencing Data

This study investigated effects of integrating single-nucleotide polymorphisms (SNPs) selected based on previous genome-wide association studies (GWASs), from imputed whole-genome sequencing (WGS) data, in the conventional 54K chip on genomic prediction reliability of young stock survival (YSS) traits in dairy cattle. The WGS SNPs included two groups of SNP sets that were selected based on GWAS in the Danish Holstein for YSS index (YSS_SNPs, n = 98) and SNPs chosen as peaks of quantitative trait loci for the traits of Nordic total merit index in Denmark–Finland–Sweden dairy cattle populations (DFS_SNPs, n = 1,541). Additionally, the study also investigated the possibility of improving genomic prediction reliability for survival traits by modeling the SNPs within recessive lethal haplotypes (LET_SNP, n = 130) detected from the 54K chip in the Nordic Holstein. De-regressed proofs (DRPs) were obtained from 6,558 Danish Holstein bulls genotyped with either 54K chip or customized LD chip that includes SNPs in the standard LD chip and some of the selected WGS SNPs. The chip data were subsequently imputed to 54K SNP together with the selected WGS SNPs. Genomic best linear unbiased prediction (GBLUP) models were implemented to predict breeding values through either pooling the 54K and selected WGS SNPs together as one genetic component (a one-component model) or considering 54K SNPs and selected WGS SNPs as two separate genetic components (a two-component model). Across all the traits, inclusion of each of the selected WGS SNP sets led to negligible improvements in prediction accuracies (0.17 percentage points on average) compared to prediction using only 54K. Similarly, marginal improvement in prediction reliability was obtained when all the selected WGS SNPs were included (0.22 percentage points). No further improvement in prediction reliability was observed when considering random regression on genotype code of recessive lethal alleles in the model including both groups of the WGS SNPs. Additionally, there was no difference in prediction reliability from integrating the selected WGS SNP sets through the two-component model compared to the one-component GBLUP.

Why Recessive Lethal Alleles Have Not Disappeared?

The article derives the probability for lethal recessive alleles in the case of recessive disadvantage or advantage. It is shown that recessive advantage of a lethal gene can be detected by the ratio of heterozygotes and homozygotes. This demonstrates that higher IQ of certain ethnic groups cannot be explained by recessive advantage of lethal genes. The article shows that lethal genes can survive in the population if some lineages of families have much more children than the average.

Why Recessive Lethal Alleles Have Not Disappeared?

The article derives the probability for lethal recessive alleles in the case of recessive disadvantage or advantage. It is shown that the recessive advantage of a lethal gene can be detected by the ratio of heterozygotes and homozygotes. This demonstrates that the higher IQ of certain ethnic groups cannot be explained by the recessive advantage of lethal genes. The article shows that lethal genes can survive in the population if some lineages of families have much more children than the average.

Identification of homozygous haplotypes carrying putative recessive lethal mutations that compromise fertility traits in French Lacaune dairy sheep

Background Homozygous recessive deleterious mutations can cause embryo/fetal or neonatal lethality, or genetic defects that affect female fertility and animal welfare. In livestock populations under selection, the frequency of such lethal mutations may increase due to inbreeding, genetic drift, and/or the positive pleiotropic effects of heterozygous carriers on selected traits. Results By scanning the genome of 19,102 Lacaune sheep using 50 k single nucleotide polymorphism (SNP) phased genotypes and pedigree data, we identified 11 Lacaune deficient homozygous haplotypes (LDHH1 to LDHH11) showing a highly significant deficit of homozygous animals ranging from 79 to 100%. These haplotypes located on chromosomes 3, 4, 13, 17 and 18, spanned regions from 1.2 to 3.0 Mb long with a frequency of heterozygous carriers between 3.7 and 12.1%. When we compared at-risk matings (between carrier rams and daughters of carrier rams) and safe matings, seven of the 11 haplotypes were associated with a significant alteration of two fertility traits, a reduced success of artificial insemination (LDHH1, 2, 8 and 9), and/or an increased stillbirth rate (LDHH3, 6, 8, 9, and 10). The 11 haplotypes were also tested for a putative selective advantage of heterozygous carrier rams based on their daughter yield deviation for six dairy traits (milk, fat and protein yields, fat and protein contents and lactation somatic cell score). LDHH1, 3, 4, 5, 7, 9 and 11 were associated with positive effects on at least one selected dairy trait, in particular milk yield. For each haplotype, the most probable candidate genes were identified based on their roles in lethality of mouse knock-out models and in mammalian genetic disorders. Conclusions Based on a reverse genetic strategy, we identified at least 11 haplotypes with homozygous deficiency segregating in French Lacaune dairy sheep. This strategy represents a first tool to limit at-risk matings in the Lacaune dairy selection scheme. We assume that most of the identified LDHH are in strong linkage disequilibrium with a recessive lethal mutation that affects embryonic or juvenile survival in sheep but is yet to be identified.

A confinable home and rescue gene drive for population modification

Homing based gene drives, engineered using CRISPR/Cas9, have been proposed to spread desirable genes throughout populations. However, invasion of such drives can be hindered by the accumulation of resistant alleles. To limit this obstacle, we engineer a confinable population modification Home-and-Rescue (HomeR) drive in Drosophila targeting an essential gene. In our experiments, resistant alleles that disrupt the target gene function were recessive lethal, and therefore disadvantaged. We demonstrate that HomeR can achieve an increase in frequency in population cage experiments, but that fitness costs due to the Cas9 insertion limit drive efficacy. Finally, we conduct mathematical modeling comparing HomeR to contemporary gene drive architectures for population modification over wide ranges of fitness costs, transmission rates, and release regimens. HomeR could potentially be adapted to other species, as a means for safe, confinable, modification of wild populations.

352 Awardee Talk: Identification of novel haplotypes with recessive and allelic inheritance patterns affecting embryonic development processes, gestation losses and post-natal lethality in cattle

Genomic data allows the screening of homozygous haplotypes and recessive lethal alleles, which could affect reproductive performance in cattle and other species. Here, we propose an approach based on tracing the inheritance of alleles from heterozygous parents to offspring to identify significant departure from the expected Mendelian inheritance (Transmission Ratio Distortion – TRD). TRDscan software was used to identify genomic regions with TRD using 436,651 trios (sire-dam-offspring) of genotypes from Holstein dairy cattle. SNP-by-SNP analysis was performed using 132,990 SNPs. TRD haplotypes were identified using sliding windows of 2-,4-,7-,10- and 20-SNPs. In total, 109 SNPs and 495 haplotypes were identified with significant TRD (Bayes factor≥100). Interestingly, some of the identified TRD regions overlap with previously known regions with recessive lethal alleles (e.g., HH0, HH1, HH3, HH5). Novel genomic regions with significant TRD were also identified with annotated genes functionally clustered into specific phenotypes related to male and female infertility and postnatal lethality. Approximately 18% of previously identified quantitative trait loci mapped around the TRD regions were related with fertility traits (calving ease, scrotal circumference, fertility index, and non-return rate). Validation of the results was performed using ~13,000 of Holstein embryo genotypes, in trios. The results will be integrated with the TRD regions identified to fine mapping the contribution of the TRD for each embryonic stage and they may be helpful to precisely target genomic regions associated with fertility, embryonic development processes, gestation losses and post-natal lethality in cattle.

A genome-wide scan for candidate lethal variants in Thoroughbred horses

Recessive lethal variants often segregate at low frequencies in animal populations, such that two randomly selected individuals are unlikely to carry the same mutation. However, the likelihood of an individual inheriting two copies of a recessive lethal mutation is dramatically increased by inbreeding events. Such occurrences are particularly common in domestic animal populations, which are often characterised by high rates of inbreeding and low effective population sizes. To date there have been no published investigations into the presence of specific variants at high frequencies in domestic horse populations. This study aimed to identify potential recessive lethal haplotypes in the Thoroughbred horse breed, a closed population that has been selectively bred for racing performance.In this study, we scanned genotype data from Thoroughbred horses (n = 526) for adjacent single nucleotide polymorphisms (SNPs) at high heterozygote frequencies, but with a complete absence of homozygotes. Two SNPs that matched these criteria were mapped to an intronic region in the LY49B gene, indicating that a closely linked mutation may cause lethality in homozygous state. Despite a complete absence of homozygotes, almost 35% of Thoroughbreds included in these analyses were heterozygous for both SNPs. A similar loss or absence of homozygotes was observed in genotype data from other domestic horse breeds (n = 2030). Variant analysis of whole-genome sequence data (n = 90) identified two SNPs in the 3’UTR region of the LY49B gene that may result in loss of function. Analysis of transcriptomic data from equine embryonic tissue revealed that LY49B is expressed in the trophoblast during placentation stage of development.In this study, a region in the LY49B gene was identified as a strong candidate for harbouring a variant causing lethality in homozygous state. These findings suggest that LY49B may have an essential, but as yet unknown function in the implantation stage of equine development. Further investigation of this region may allow for the development of a genetic test to improve fertility rates in horse populations. Identification of other lethal variants could assist in improving natural levels of fertility in horse populations.Author SummaryRecessive lethal mutations may reach high frequencies in livestock populations due to selective breeding practices, resulting in reduced fertility rates. In this study, we characterise recessive lethal mutations at high frequencies in the Thoroughbred horse population, a breed with high rates of inbreeding and low genetic diversity. We identified a haplotype in the LY49B gene that shows strong evidence of being homozygous lethal, despite having high frequencies of heterozygotes in Thoroughbreds and other domestic horse breeds. Two 3’UTR variants were identified as most likely to cause loss of function in the LY49B gene, resulting in lethality. This finding provides novel insights into the potential importance of LY49B in equine development. Additionally, this study may assist with breeding strategies to improve fertility rates in the Thoroughbred and other domestic horse breeds.