BACKGROUND: Heritability partitioning approaches estimate the contribution of different functional classes, such as coding or regulatory variants, to the genetic variance. This information allows a better understanding of the genetic architecture of complex traits, including complex diseases, but can also help improve the accuracy of genomic selection in livestock species. However, methods have mainly been tested on human genomic data, whereas livestock populations have specific characteristics, such as high levels of relatedness, small effective population size or long-range levels of linkage disequilibrium.
RESULTS: Here, we used data from 14,762 cows, imputed at the whole-genome sequence level for 11,537,240 variants, to simulate traits in a typical livestock population and evaluate the accuracy of two state-of-the-art heritability partitioning methods, GREML and a Bayesian mixture model. In simulations where a single functional class had increased contribution to heritability, we observed that the estimators were unbiased but had low precision. When causal variants were enriched in variants with low (< 0.05) or high (> 0.20) minor allele frequency or low (below 1st quartile) or high (above 3rd quartile) linkage disequilibrium scores, it was necessary to partition the genetic variance into multiple classes defined on the basis of allele frequencies or LD scores to obtain unbiased results. When multiple functional classes had variable contributions to heritability, estimators showed higher levels of variation and confounding between certain categories was observed. In addition, estimators from small categories were particularly imprecise. However, the estimates and their ranking were still informative about the contribution of the classes. We also demonstrated that using methods that estimate the contribution of a single category at a time, a commonly used approach, results in an overestimation. Finally, we applied the methods to phenotypes for muscular development and height and estimated that, on average, variants in open chromatin regions had a higher contribution to the genetic variance (> 45%), while variants in coding regions had the strongest individual effects (> 25-fold enrichment on average). Conversely, variants in intergenic or intronic regions showed lower levels of enrichment (0.2 and 0.6-fold on average, respectively).
CONCLUSIONS: Heritability partitioning approaches should be used cautiously in livestock populations, in particular for small categories. Two-component approaches that fit only one functional category at a time lead to biased estimators and should not be used.

BACKGROUND: Alignment of reads to a reference genome sequence is one of the key steps in the analysis of human whole-genome sequencing data obtained through Next-generation sequencing (NGS) technologies. The quality of the subsequent steps of the analysis, such as the results of clinical interpretation of genetic variants or the results of a genome-wide association study, depends on the correct identification of the position of the read as a result of its alignment. The amount of human NGS whole-genome sequencing data is constantly growing. There are a number of human genome sequencing projects worldwide that have resulted in the creation of large-scale databases of genetic variants of sequenced human genomes. Such information about known genetic variants can be used to improve the quality of alignment at the read alignment stage when analysing sequencing data obtained for a new individual, for example, by creating a genomic graph. While existing methods for aligning reads to a linear reference genome have high alignment speed, methods for aligning reads to a genomic graph have greater accuracy in variable regions of the genome. The development of a read alignment method that takes into account known genetic variants in the linear reference sequence index allows combining the advantages of both sets of methods.
RESULTS: In this paper, we present the minimap2_index_modifier tool, which enables the construction of a modified index of a reference genome using known single nucleotide variants and insertions/deletions (indels) specific to a given human population. The use of the modified minimap2 index improves variant calling quality without modifying the bioinformatics pipeline and without significant additional computational overhead. Using the PrecisionFDA Truth Challenge V2 benchmark data (for HG002 short-read data aligned to the GRCh38 linear reference (GCA_000001405.15) with parameters k = 27 and w = 14) it was demonstrated that the number of false negative genetic variants decreased by more than 9500, and the number of false positives decreased by more than 7000 when modifying the index with genetic variants from the Human Pangenome Reference Consortium.

Populations in isolated and small fragments lose genetic variability very fast and are usually of conservation concern because they are at greater risk of local extinction. The largest native deer in South America, Blastocerus dichotomus (Illiger, 1815), is a Vulnerable species according to the IUCN categorization, which inhabits tropical and subtropical swampy areas. In Argentina, its presence has been restricted to four isolated fragments. Here we examine the genetic diversity and differentiation among three of them, including the three different patches that form the southernmost population, using 18 microsatellite markers genotyped by Amplicon Sequencing of DNA extracted from fecal samples. Genetic diversity was low (HE < 0.45) in all three populations studied. We found three genetic clusters compatible with the geographic location of the samples. We also found a metapopulation dynamics that involves the patches that make up the southernmost population, with evidence of a barrier to gene flow between two of them. Our results point to the creation of a corridor as a necessary and urgent management action. This is the first study, at the population level, employing microsatellite genotyping by Amplicon Sequencing with non-invasive samples in an endangered species.

Long-read sequencing technology has enabled variant detection in difficult-to-map regions of the genome and enabled rapid genetic diagnosis in clinical settings. Rapidly evolving third-generation sequencing platforms like Pacific Biosciences (PacBio) and Oxford Nanopore Technologies (ONT) are introducing newer platforms and data types. It has been demonstrated that variant calling methods based on deep neural networks can use local haplotyping information with long-reads to improve the genotyping accuracy. However, using local haplotype information creates an overhead as variant calling needs to be performed multiple times which ultimately makes it difficult to extend to new data types and platforms as they get introduced. In this work, we have developed a local haplotype approximate method that enables state-of-the-art variant calling performance with multiple sequencing platforms including PacBio Revio system, ONT R10.4 simplex and duplex data. This addition of local haplotype approximation simplifies long-read variant calling with DeepVariant.

Alzheimer\'s disease (AD) and Frontotemporal lobar degeneration (FTLD) represent the most common forms of neurodegenerative dementias with a highly phenotypic variability. Herein, we investigated the role of genetic variants related to the immune system and inflammation as genetic modulators in AD and related dementias. In patients with sporadic AD/FTLD (n = 300) and GRN/C9orf72 mutation carriers (n = 80), we performed a targeted sequencing of 50 genes belonging to the immune system and inflammation, selected based on their high expression in brain regions and low tolerance to genetic variation. The linear regression analyses revealed two genetic variants: (i) the rs1049296 in the transferrin (TF) gene, shown to be significantly associated with age at onset in the sporadic AD group, anticipating the disease onset of 4 years for each SNP allele with respect to the wild-type allele, and (ii) the rs7550295 in the calsyntenin-1 (CLSTN1) gene, which was significantly associated with age at onset in the C9orf72 group, delaying the disease onset of 17 years in patients carrying the SNP allele. In conclusion, our data support the role of genetic variants in iron metabolism (TF) and in the modulation of the calcium signalling/axonal anterograde transport of vesicles (CLSTN1) as genetic modulators in AD and FTLD due to C9orf72 expansions.

BACKGROUND: Canine circovirus (CanineCV) is a single-stranded circular DNA virus that infects domestic and wild canids in many countries. CanineCV is associated with gastroenteritis and diarrhea, respiratory disease, and generalized vasculitis leading to a fatal event. The Capsid protein (Cap) is a structural protein of the virus which has high genetic variability and plays a role in the canine immune response. In this study, we cloned the full-length CanineCV Capsid gene (Cap). In-silico analyses were used to explore the genomic and amino acid variability and natural selection acting on the Cap gene. The immune relevance for T-cell and B-cell epitopes was predicted by the immunoinformatic approach.
RESULTS: According to the Cap gene, our results showed that CanineCV was separated into five phylogenetic groups. The obtained CanineCV strain from this study was grouped with the previously discovered Thai strain (MG737385), as supported by a haplotype network. Entropy analyses revealed high nucleotide and amino acid variability of the Capsid region. Selection pressure analysis revealed four codons at positions 24, 50, 103, and 111 in the Cap protein evolved under diversifying selection. Prediction of B-cell epitopes exhibited four consensus sequences based on physiochemical properties, and eleven peptide sequences were predicted as T-cell epitopes. In addition, the positive selection sites were located within T-cell and B-cell epitopes, suggesting the role of the host immune system as a driving force in virus evolution.
CONCLUSIONS: Our study provides knowledge of CanineCV genetic diversity, virus evolution, and potential epitopes for host cell immune response.

The basis for criteria of the taxonomic classification of DNA and RNA viruses based on data of the genomic sequencing are viewed in this review. The genomic sequences of viruses, which have genome represented by double-stranded DNA (orthopoxviruses as example), positive-sense single-stranded RNA (alphaviruses and flaviviruses as example), non-segmented negative-sense single-stranded RNA (filoviruses as example), segmented negative-sense single-stranded RNA (arenaviruses and phleboviruses as example) are analyzed. The levels of genetic variability that determine the assignment of compared viruses to taxa of various orders are established for each group of viruses.
В обзоре рассмотрено обоснование критериев идентификации таксономической принадлежности некоторых групп патогенных ДНК- и РНК-содержащих вирусов на основе результатов секвенирования генома. Проанализированы данные секвенирования геномной нуклеиновой кислоты вирусов, геном которых представлен двухцепочечной ДНК (на примере ортопоксвирусов), одноцепочечной «плюс» РНК (на примере альфавирусов и флавивирусов), одноцепочечной несегментированной «минус» РНК (на примере филовирусов), одноцепочечной сегментированной «минус» РНК (на примере аренавирусов и флебовирусов). Для каждой группы вирусов установлены уровни генетической изменчивости, определяющие отнесение сравниваемых вирусов к таксонам разных порядков.

Mithun (Bos frontalis), a domestically raised herbivore, holds significant economic importance for the farming community of Northeast India. This study aimed to elucidate the genetic parameters governing Mithun body weight traits across different ages using data from the sole organized semi-intensive Mithun farm in India. Information was gathered from 110 Mithuns born over a period spanning from 2011 to 2022. Body weight taken at week 1 (W1), 1-month (M1), 3-months (M3), 6-months (M6), 9-months (M9), 12-months (M12), 30-months (M30) and 45-months (M45) were considered for the study. The genetic parameters estimation employed the BLUPF90 suite of programs, incorporating univariate Gibbs sampler animal model with fixed effects; season and period of birth, and sex of the animal. Variance and covariance components, including direct additive genetic effects, were estimated. Heritability estimates for the eight body weight traits ranged from 0.47 ± 0.0050 to 0.50 ± 0.0043, indicating varying genetic influence across growth stages. Results revealed that Mithun herd has a substantial genetic variability for growth traits and therefore there is ample scope to select for a better growth rate. Here, we conclude that Month 12 (M12) and Month 9 (M9) body weights exhibit higher heritability, indicating potential for genetic improvement through selective breeding.

The high proportion of AIDS cases and mortality rates in Guangxi underscores the urgency to investigate the influence of HIV-1 genetic diversity on disease progression in this region. Newly diagnosed HIV-1 patients were enrolled from January 2016 to December 2021, and the follow-up work and detection of CD4+T lymphocytes were carried out every six months until December 2022. Multivariate logistic regression was used to analyze the factors affecting pre-treatment CD4+T lymphocyte counts, while local weighted regression models (LOESS) and generalized estimating equation models (GEE) were conducted to assess factors influencing CD4+T Lymphocyte Recovery. Cox regression analysis was utilized to examine the impact of subtypes on survival risk. Additionally, HIV-1 env sequences were utilized for predicting CXCR4 and CCR5 receptors. The study encompassed 1867 individuals with pol sequences and 281 with env sequences. Our findings indicate that age over 30, divorced/widowed, peasant, heterosexual infection, CRF01_AE, long-term infection, and Pre-treatment Viral load >10000 copies/ml were factors associated with higher risk for pre-treatment CD4+T lymphocyte decline. Specifically, male gender, age over 30, heterosexual infection (HETs), long-term infection, CRF01_AE, and Pre-treatment CD4 T cell counts below 350/µL were identified as risk factors impeding CD4+T lymphocyte recovery. Pre-treatment CD4+T lymphocyte counts and recovery in individuals infected with CRF01_AE were lower compared to CRF07_BC and CRF55_01B. Additionally, CRF01_AE and CRF08_BC subtypes exhibited higher mortality rates than CRF07_BC, CRF55_01B, and other subtypes. Notably, CRF01_AE demonstrated the highest percentage of CXCR4 affinity ratios. This research unveils the intricate influence of HIV-1 gene diversity on CD4+T lymphocyte dynamics and clinical outcomes. It highlights the multifaceted nature of HIV infection in Guangxi, providing novel insights into subtype-specific disease progression among HIV-infected individuals in this region.

Zinc (Zn) is an essential micronutrient but can be cytotoxic when present in excess. Plants have evolved mechanisms to tolerate Zn toxicity. To identify genetic loci responsible for natural variation of plant tolerance to Zn toxicity, we conduct genome-wide association studies for root growth responses to high Zn and identify 21 significant associated loci. Among these loci, we identify Trichome Birefringence (TBR) allelic variation determining root growth variation in high Zn conditions. Natural alleles of TBR determine TBR transcript and protein levels which affect pectin methylesterification in root cell walls. Together with previously published data showing that pectin methylesterification increase goes along with decreased Zn binding to cell walls in TBR mutants, our findings lead to a model in which TBR allelic variation enables Zn tolerance through modulating root cell wall pectin methylesterification. The role of TBR in Zn tolerance is conserved across dicot and monocot plant species.