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Background: The Y-chromosome haplogroup Q has three major branches: Q1, Q2, and Q3. Q1 is found in both Asia and the Americas where it accounts for about 90% of indigenous Native American Y-chromosomes; Q2 is found in North and Central Asia; but little is known about the third branch, Q3, also named Q1b-L275. Here, we combined the efforts of population geneticists and genetic genealogists to use the potential of full Y-chromosome sequencing for reconstructing haplogroup Q3 phylogeography and suggest possible linkages to events in population history. Results: We analyzed 47 fully sequenced Y-chromosomes and reconstructed the haplogroup Q3 phylogenetic tree in detail. Haplogroup Q3-L275, derived from the oldest known split within Eurasian/American haplogroup Q, most likely occurred in West or Central Asia in the Upper Paleolithic period. During the Mesolithic and Neolithic epochs, Q3 remained a minor component of the West Asian Y-chromosome pool and gave rise to five branches (Q3a to Q3e), which spread across West, Central and parts of South Asia. Around 3-4 millennia ago (Bronze Age), the Q3a branch underwent a rapid expansion, splitting into seven branches, some of which entered Europe. One of these branches, Q3a1, was acquired by a population ancestral to Ashkenazi Jews and grew within this population during the 1st millennium AD, reaching up to 5% in present day Ashkenazi. Conclusions: This study dataset was generated by a massive Y-chromosome genotyping effort in the genetic genealogy community, and phylogeographic patterns were revealed by a collaboration of population geneticists and genetic genealogists. This positive experience of collaboration between academic and citizen science provides a model for further joint projects. Merging data and skills of academic and citizen science promises to combine, respectively, quality and quantity, generalization and specialization, and achieve a well-balanced and careful interpretation of the paternal-side history of human populations. [ABSTRACT FROM AUTHOR]

Background Patterns of genetic variation in a population carry information about the prehistory of the population, and for the human Y chromosome an especially informative phylogenetic tree has previously been constructed from fully-sequenced chromosomes. This revealed contrasting bifurcating and starlike phylogenies for the major lineages associated with the Neolithic expansions in sub-Saharan Africa and Western Europe, respectively. Results We used coalescent simulations to investigate the range of demographic models most likely to produce the phylogenetic structures observed in Africa and Europe, assessing the starting and ending genetic effective population sizes, duration of the expansion, and time when expansion ended. The best-fitting models in Africa and Europe are very different. In Africa, the expansion took about 12 thousand years, ending very recently; it started from approximately 40 men and numbers expanded approximately 50-fold. In Europe, the expansion was much more rapid, taking only a few generations and occurring as soon as the major R1b lineage entered Europe; it started from just one to three men, whose numbers expanded more than a thousandfold. Conclusions Although highly simplified, the demographic model we have used captures key elements of the differences between the male Neolithic expansions in Africa and Europe, and is consistent with archaeological findings. [ABSTRACT FROM AUTHOR]

This report is of a round-table discussion held in Cardiff in September 2009 for Cesagen, a research centre within the Genomics Network of the UK’s Economic and Social Research Council. The meeting was arranged to explore ideas as to the likely future course of human genomics. The achievements of genomics research were reviewed, and the likely constraints on the pace of future progress were explored. New knowledge is transforming biology and our understanding of evolution and human disease. The difficulties we face now concern the interpretation rather than the generation of new sequence data. Our understanding of gene-environment interaction is held back by our current primitive tools for measuring environmental factors, and in addition, there may be fundamental constraints on what can be known about these complex interactions. [ABSTRACT FROM AUTHOR]

Background: Ethnic minorities in Northern Thailand, often referred to as Hill Tribes, are considered an ideal model to study the different genetic impact of sex-specific migration rates expected in matrilocal (women remain in their natal villages after the marriage and men move to their wife's village) and patrilocal societies (the opposite is true). Previous studies identified such differences, but little is known about the possible interaction with another cultural factor that may potentially affect genetic diversity, i.e. linguistic differences. In addition, Hill Tribes started to migrate to Thailand in the last centuries from different Northern areas, but the history of these migrations, the level of genetic legacy with their places of origin, and the possible confounding effects related to this migration history in the patterns of genetic diversity, have not been analysed yet. Using both original and published data on the Hill Tribes and several other Asian populations, we focused on all these aspects. Results: Genetic variation within population at mtDNA is lower in matrilocal, compared to patrilocal, tribes. The opposite is true for Y-chromosome microsatellites within the Sino-Tibetan linguistic family, but Hmong-Mien speaking patrilocal groups have a genetic diversity very similar to the matrilocal samples. Population divergence ranges between 5% and 14% at mtDNA sequences, and between 5% and 36% at Y- chromosomes STRs, and follows the sex-specific differences expected in patrilocal and matrilocal tribes. On the average, about 2 men and 14 women, and 4 men and 4 women, are exchanged in patrilocal and matrilocal tribes every generation, respectively. Most of the Hill Tribes in Thailand seem to preserve a genetic legacy with their likely geographic origin, with children adoption probably affecting this pattern in one tribe. Conclusion: Overall, the sex specific genetic signature of different postmarital habits of residence in the Hill Tribes is robust. However, specific perturbations related to linguistic differences, population specific traits, and the complex migratory history of these groups, can be identified. Additional studies in different populations are needed, especially to obtain more precise estimates of the migration parameters. [ABSTRACT FROM AUTHOR]

Background: The Y-chromosome haplogroup Q has three major branches: Q1, Q2, and Q3. Q1 is found in both Asia and the Americas where it accounts for about 90% of indigenous Native American Y-chromosomes; Q2 is found in North and Central Asia; but little is known about the third branch, Q3, also named Q1b-L275. Here, we combined the efforts of population geneticists and genetic genealogists to use the potential of full Y-chromosome sequencing for reconstructing haplogroup Q3 phylogeography and suggest possible linkages to events in population history., Results: We analyzed 47 fully sequenced Y-chromosomes and reconstructed the haplogroup Q3 phylogenetic tree in detail. Haplogroup Q3-L275, derived from the oldest known split within Eurasian/American haplogroup Q, most likely occurred in West or Central Asia in the Upper Paleolithic period. During the Mesolithic and Neolithic epochs, Q3 remained a minor component of the West Asian Y-chromosome pool and gave rise to five branches (Q3a to Q3e), which spread across West, Central and parts of South Asia. Around 3-4 millennia ago (Bronze Age), the Q3a branch underwent a rapid expansion, splitting into seven branches, some of which entered Europe. One of these branches, Q3a1, was acquired by a population ancestral to Ashkenazi Jews and grew within this population during the 1st millennium AD, reaching up to 5% in present day Ashkenazi., Conclusions: This study dataset was generated by a massive Y-chromosome genotyping effort in the genetic genealogy community, and phylogeographic patterns were revealed by a collaboration of population geneticists and genetic genealogists. This positive experience of collaboration between academic and citizen science provides a model for further joint projects. Merging data and skills of academic and citizen science promises to combine, respectively, quality and quantity, generalization and specialization, and achieve a well-balanced and careful interpretation of the paternal-side history of human populations.

Background: Amplified gene families on sex chromosomes can harbour genes with important biological functions, especially relating to fertility. The Y-linked heat shock transcription factor (HSFY) family has become amplified on the Y chromosome of the domestic pig (Sus scrofa), in an apparently independent event to an HSFY expansion on the Y chromosome of cattle (Bos taurus). Although the biological functions of HSFY genes are poorly understood, they appear to be involved in gametogenesis in a number of mammalian species, and, in cattle, HSFY gene copy number may correlate with levels of fertility., Results: We have investigated the HSFY family in domestic pig, and other suid species including warthog, bushpig, babirusa and peccaries. The domestic pig contains at least two amplified variants of HSFY, distinguished predominantly by presence or absence of a SINE within the intron. Both these variants are expressed in testis, and both are present in approximately 50 copies each in a single cluster on the short arm of the Y. The longer form has multiple nonsense mutations rendering it likely non-functional, but many of the shorter forms still have coding potential. Other suid species also have these two variants of HSFY, and estimates of copy number suggest the HSFY family may have amplified independently twice during suid evolution., Conclusions: The HSFY genes have become amplified in multiple species lineages independently. HSFY is predominantly expressed in testis in domestic pig, a pattern conserved with cattle, in which HSFY may play a role in fertility. Further investigation of the potential associations of HSFY with fertility and testis development may be of agricultural interest.

Background: The advancements in second-/third-generation sequencing technologies, alongside computational innovations, have significantly enhanced our understanding of the genomic structure of Y-chromosomes and their unique phylogenetic characteristics. These researches, despite the challenges posed by the lack of population-scale genomic databases, have the potential to revolutionize our approach to high-resolution, population-specific Y-chromosome panels and databases for anthropological and forensic applications. Objectives: This study aimed to develop the highest-resolution Y-targeted sequencing panel, utilizing time-stamped, core phylogenetic informative mutations identified from high-coverage sequences in the YanHuang cohort. This panel is intended to provide a new tool for forensic complex pedigree search and paternal biogeographical ancestry inference, as well as explore the general patterns of the fine-scale paternal evolutionary history of ethnolinguistically diverse Chinese populations. Results: The sequencing performance of the East Asian-specific Y-chromosomal panel, including 2999-core SNP variants, was found to be robust and reliable. The YHSeqY3000 panel was designed to capture the genetic diversity of Chinese paternal lineages from 3500 years ago, identifying 408 terminal lineages in 2097 individuals across 41 genetically and geographically distinct populations. We identified a fine-scale paternal substructure that was correlating with ancient population migrations and expansions. New evidence was provided for extensive gene flow events between minority ethnic groups and Han Chinese people, based on the integrative Chinese Paternal Genomic Diversity Database. Conclusions: This work successfully integrated Y-chromosome-related basic genomic science with forensic and anthropological translational applications, emphasizing the necessity of comprehensively characterizing Y-chromosome genomic diversity from genomically under-representative populations. This is particularly important in the second phase of our population-specific medical or anthropological genomic cohorts, where dense sampling strategies are employed. [ABSTRACT FROM AUTHOR]

Background: Fungal DNA is rarely reported in metagenomic studies of ancient samples. Although fungi are essential for their interactions with all kingdoms of life, limited information is available about ancient fungi. Here, we explore the possibility of the presence of ancient fungal species in the gut of Ötzi, the Iceman, a naturally mummified human found in the Tyrolean Alps (border between Italy and Austria). Methods: A robust bioinformatic pipeline has been developed to detect and authenticate fungal ancient DNA (aDNA) from muscle, stomach, small intestine, and large intestine samples. Results: We revealed the presence of ancient DNA associated with Pseudogymnoascus genus, with P. destructans and P. verrucosus as possible species, which were abundant in the stomach and small intestine and absent in the large intestine and muscle samples. Conclusion: We suggest that Ötzi may have consumed these fungi accidentally, likely in association with other elements of his diet, and they persisted in his gut after his death due to their adaptability to harsh and cold environments. This suggests the potential co-occurrence of ancient humans with opportunistic fungal species and proposes and validates a conservative bioinformatic approach for detecting and authenticating fungal aDNA in historical metagenomic samples. [ABSTRACT FROM AUTHOR]

Background: Powdery mildew, caused by Blumeria graminis f. sp. tritici (Bgt), is one of the most destructive wheat diseases worldwide. Durum wheat (Triticum turgidum L. var. durum Desf.) is a crucial gene donor for improving common wheat. Results: In this study, we investigated a durum wheat accession, DR88, which exhibits broad and high levels of resistance to powdery mildew. Using bulked segregant RNA-Seq (BSR-Seq), we identified a dominant gene, tentatively designated PmDR88, and localized it to 743–776 Mb interval on chromosome arm 2AL according to the reference genome of durum wheat cv. Svevo. Subsequently, PmDR88 was mapped in a genetic region of 3.9 cM flanked by the markers WGRE77410 and WGRC872 at genetic distances of 1.6 and 2.3 cM, respectively; it also co-segregated with JS717×JS718, the diagnostic marker for the Pm4 locus. Genotyping of a large population comprising 5,174 F2:3 families using JS717×JS718 confirmed that PmDR88 is located at the Pm4 locus on 2AL. Sequence alignment revealed that PmDR88 shares identical amino acid sequences with Pm4d, while qRT-PCR analysis suggested distinct expression patterns for PmDR88 compared with previously reported Pm4 alleles. Two complementary DNA markers, including the dominant co-segregating marker JS717×JS718 and a newly developed closely-linked co-dominant marker WGRE77410, were confirmed to be available for efficiently transferring PmDR88 into the tested wheat backgrounds by marker-assisted selection (MAS) strategy. Conclusions: PmDR88 was mapped in the Pm4 locus. Despite sharing identical amino acid sequences with Pm4d, PmDR88 exhibits distinct expression patterns. Moreover, DR88 shows broad and high levels of resistance to powdery mildew. Two complementary DNA markers were identified for MAS breeding. The molecular identification of PmDR88 will facilitate transfer of this Pm4 allele into susceptible cultivars for resistance improvement or into resistant cultivars for resistance-enhanced pyramiding breeding. [ABSTRACT FROM AUTHOR]

This comprehensive review provides insights and suggested strategies for the analysis of germline variants using second- and third-generation sequencing technologies (SGS and TGS). It addresses the critical stages of data processing, starting from alignment and preprocessing to quality control, variant calling, and the removal of artifacts. The document emphasized the importance of meticulous data handling, highlighting advanced methodologies for annotating variants and identifying structural variations and methylated DNA sites. Special attention is given to the inspection of problematic variants, a step that is crucial for ensuring the accuracy of the analysis, particularly in clinical settings where genetic diagnostics can inform patient care. Additionally, the document covers the use of various bioinformatics tools and software that enhance the precision and reliability of these analyses. It outlines best practices for the annotation of variants, including considerations for problematic genetic alterations such as those in the human leukocyte antigen region, runs of homozygosity, and mitochondrial DNA alterations. The document also explores the complexities associated with identifying structural variants and copy number variations, underscoring the challenges posed by these large-scale genomic alterations. The objective is to offer a comprehensive framework for researchers and clinicians, ensuring that genetic analyses conducted with SGS and TGS are both accurate and reproducible. By following these best practices, the document aims to increase the diagnostic accuracy for hereditary diseases, facilitating early diagnosis, prevention, and personalized treatment strategies. This review serves as a valuable resource for both novices and experts in the field, providing insights into the latest advancements and methodologies in genetic analysis. It also aims to encourage the adoption of these practices in diverse research and clinical contexts, promoting consistency and reliability across studies. [ABSTRACT FROM AUTHOR]

Background: Structural variations (SVs) are widespread across genome and have a great impact on evolution, disease, and phenotypic diversity. Despite the development of numerous bioinformatic tools, commonly referred to as SV callers, tailored for detecting SVs using whole genome sequence (WGS) data and employing diverse algorithms, their performance necessitates rigorous evaluation with real data and validated SVs. Moreover, a considerable proportion of these tools have been primarily designed and optimized using human genome data. Consequently, their applicability and performance in Avian species, characterized by smaller genomes and distinct genomic architectures, remain inadequately assessed. Results: We performed a comprehensive assessment of the performance of ten widely used SV callers using population-level real genomic data with the validated five common types of SVs. The performance of SV callers varies with the types and sizes of SVs. As compared with other tools, GRIDSS, Lumpy, Wham, and Manta present better detection accuracy. Pindel can detect more small SVs than others. CNVnator and CNVkit can detect more medium and large copy number variations. Given the poor consistency among different SV callers, the combination calling strategy is not recommended. All tools show poor ability in the detection of insertions (especially with size > 150 bp). At least 50× read depth is required to detect more than 80% of the SVs for most tools. Conclusions: This study highlights the importance and necessity of using real sequencing data, rather than simulated data only, with validated SVs for SV caller evaluation. Some practical guidance and suggestions are provided for SV detection in future researches. [ABSTRACT FROM AUTHOR]

Background: The development of sequence-specific precision treatments like CRISPR gene editing therapies for Duchenne muscular dystrophy (DMD) requires sequence humanized animal models to enable the direct clinical translation of tested strategies. The current available integrated transgenic mouse model containing the full-length human DMD gene, Tg(DMD)72Thoen/J (hDMDTg), has been found to have two copies of the transgene per locus in a tail-to-tail orientation, which does not accurately simulate the true (single) copy number of the DMD gene. This duplication also complicates analysis when testing CRISPR therapy editing outcomes, as large genetic alterations and rearrangements can occur between the cut sites on the two transgenes. Results: To address this, we performed long read nanopore sequencing on hDMDTg mice to better understand the structure of the duplicated transgenes. Following that, we performed a megabase-scale deletion of one of the transgenes by CRISPR zygotic microinjection to generate a single-copy, full-length, humanized DMD transgenic mouse model (hDMDTgSc). Functional, molecular, and histological characterisation shows that the single remaining human transgene retains its function and rescues the dystrophic phenotype caused by endogenous murine Dmd knockout. Conclusions: Our unique hDMDTgSc mouse model simulates the true copy number of the DMD gene, and can potentially be used for the further generation of DMD disease models that would be better suited for the pre-clinical assessment and development of sequence specific CRISPR therapies. [ABSTRACT FROM AUTHOR]

Background: Sheep breeds native to the United Kingdom exhibit a striking diversity of different traits. Some of these traits are highly sustainable, such as seasonal wool shedding in the Wiltshire Horn, and are likely to become more important as pressures on sheep production increase in coming decades. Despite their clear importance to the future of sheep farming, the genetic diversity of native UK sheep breeds is poorly characterised. This increases the risk of losing the ability to select for breed-specific traits from native breeds that might be important to the UK sheep sector in the future. Here, we use 50 K genotyping to perform preliminary analysis of breed relationships and genetic diversity within native UK sheep breeds, as a first step towards a comprehensive characterisation. This study generates novel data for thirteen native UK breeds, including six on the UK Breeds at Risk (BAR) list, and utilises existing data from the publicly available Sheep HapMap dataset to investigate population structure, heterozygosity and admixture. Results: In this study the commercial breeds exhibited high levels of admixture, weaker population structure and had higher heterozygosity compared to the other native breeds, which generally tend to be more distinct, less admixed, and have lower genetic diversity and higher kinship coefficients. Some breeds including the Wiltshire Horn, Lincoln Longwool and Ryeland showed very little admixture at all, indicating a high level of breed integrity but potentially low genetic diversity. Population structure and admixture were strongly influenced by sample size and sample provenance – highlighting the need for equal sample sizes, sufficient numbers of individuals per breed, and sampling across multiple flocks. The genetic profiles both within and between breeds were highly complex for UK sheep, reflecting the complexity in the demographic history of these breeds. Conclusion: Our results highlight the utility of genotyping data for investigating breed diversity and genetic structure. They also suggest that routine generation of genotyping data would be very useful in informing conservation strategies for rare and declining breeds with small population sizes. We conclude that generating genetic resources for the sheep breeds that are native to the UK will help preserve the considerable genetic diversity represented by these breeds, and safe-guard this diversity as a valuable resource for the UK sheep sector to utilise in the face of future challenges. [ABSTRACT FROM AUTHOR]

Background: The objective of this study was to introduce a genome-wide association study (GWAS) in conjunction with segregation analysis on monogenic categorical traits. Genotype probabilities calculated from phenotypes, mode of inheritance and pedigree information, are expressed as the expected allele count (EAC) (range 0 to 2), and are inherited additively, by definition, unlike the original phenotypes, which are non-additive and could be of incomplete penetrance. The EAC are regressed on the single nucleotide polymorphism (SNP) genotypes, similar to an additive GWAS. In this study, horn phenotypes in Merino sheep are used to illustrate the advantages of using the segregation GWAS, a trait believed to be monogenic, affected by dominance, sex-dependent expression and likely affected by incomplete penetrance. We also used simulation to investigate whether incomplete penetrance can cause prediction errors in Merino sheep for horn status. Results: Estimated penetrance values differed between the sexes, where males showed almost complete penetrance, especially for horned and polled phenotypes, while females had low penetrance values for the horned status. This suggests that females homozygous for the 'horned allele' have a horned phenotype in only 22% of the cases while 78% will be knobbed or have scurs. The GWAS using EAC on 4001 animals and 510,174 SNP genotypes from the Illumina Ovine high-density (600k) chip gave a stronger association compared to using actual phenotypes. The correlation between the EAC and the allele count of the SNP with the highest –log10(p-value) was 0.73 in males and 0.67 in females. Simulations using penetrance values found by the segregation analyses resulted in higher correlations between the EAC and the causative mutation (0.95 for males and 0.89 for females, respectively), suggesting that the most predictive SNP is not in full LD with the causative mutation. Conclusions: Our results show clear differences in penetrance values between males and female Merino sheep for horn status. Segregation analysis for a trait with mutually exclusive phenotypes, non-additive inheritance, and/or incomplete penetrance can lead to considerably more power in a GWAS because the linearized genotype probabilities are additive and can accommodate incomplete penetrance. This method can be extended to any monogenic controlled categorical trait of which the phenotypes are mutually exclusive. [ABSTRACT FROM AUTHOR]

Background: The human lineage has undergone a postcranial skeleton gracilization (i.e. lower bone mass and strength relative to body size) compared to other primates and archaic populations such as the Neanderthals. This gracilization has been traditionally explained by differences in the mechanical load that our ancestors exercised. However, there is growing evidence that gracilization could also be genetically influenced. Results: We have analyzed the LRP5 gene, which is known to be associated with high bone mineral density conditions, from an evolutionary and functional point of view. Taking advantage of the published genomes of archaic Homo populations, our results suggest that this gene has a complex evolutionary history both between archaic and living humans and within living human populations. In particular, we identified the presence of different selective pressures in archaics and extant modern humans, as well as evidence of positive selection in the African and South East Asian populations from the 1000 Genomes Project. Furthermore, we observed a very limited evidence of archaic introgression in this gene (only at three haplotypes of East Asian ancestry out of the 1000 Genomes), compatible with a general erasing of the fingerprint of archaic introgression due to functional differences in archaics compared to extant modern humans. In agreement with this hypothesis, we observed private mutations in the archaic genomes that we experimentally validated as putatively increasing bone mineral density. In particular, four of five archaic missense mutations affecting the first β-propeller of LRP5 displayed enhanced Wnt pathway activation, of which two also displayed reduced negative regulation. Conclusions: In summary, these data suggest a genetic component contributing to the understanding of skeletal differences between extant modern humans and archaic Homo populations. [ABSTRACT FROM AUTHOR]

Background: The advancement of sequencing technologies results in the rapid release of hundreds of new genome assemblies a year providing unprecedented resources for the study of genome evolution. Within this context, the significance of in-depth analyses of repetitive elements, transposable elements (TEs) in particular, is increasingly recognized in understanding genome evolution. Despite the plethora of available bioinformatic tools for identifying and annotating TEs, the phylogenetic distance of the target species from a curated and classified database of repetitive element sequences constrains any automated annotation effort. Moreover, manual curation of raw repeat libraries is deemed essential due to the frequent incompleteness of automatically generated consensus sequences. Results: Here, we present an example of a crowd-sourcing effort aimed at curating and annotating TE libraries of two non-model species built around a collaborative, peer-reviewed teaching process. Manual curation and classification are time-consuming processes that offer limited short-term academic rewards and are typically confined to a few research groups where methods are taught through hands-on experience. Crowd-sourcing efforts could therefore offer a significant opportunity to bridge the gap between learning the methods of curation effectively and empowering the scientific community with high-quality, reusable repeat libraries. Conclusions: The collaborative manual curation of TEs from two tardigrade species, for which there were no TE libraries available, resulted in the successful characterization of hundreds of new and diverse TEs in a reasonable time frame. Our crowd-sourcing setting can be used as a teaching reference guide for similar projects: A hidden treasure awaits discovery within non-model organisms. [ABSTRACT FROM AUTHOR]

Background: Although many studies have been done to reveal artificial selection signatures in commercial and indigenous chickens, a limited number of genes have been linked to specific traits. To identify more trait-related artificial selection signatures and genes, we re-sequenced a total of 85 individuals of five indigenous chicken breeds with distinct traits from Yunnan Province, China. Results: We found 30 million non-redundant single nucleotide variants and small indels (< 50 bp) in the indigenous chickens, of which 10 million were not seen in 60 broilers, 56 layers and 35 red jungle fowls (RJFs) that we compared with. The variants in each breed are enriched in non-coding regions, while those in coding regions are largely tolerant, suggesting that most variants might affect cis-regulatory sequences. Based on 27 million bi-allelic single nucleotide polymorphisms identified in the chickens, we found numerous selective sweeps and affected genes in each indigenous chicken breed and substantially larger numbers of selective sweeps and affected genes in the broilers and layers than previously reported using a rigorous statistical model. Consistent with the locations of the variants, the vast majority (~ 98.3%) of the identified selective sweeps overlap known quantitative trait loci (QTLs). Meanwhile, 74.2% known QTLs overlap our identified selective sweeps. We confirmed most of previously identified trait-related genes and identified many novel ones, some of which might be related to body size and high egg production traits. Using RT-qPCR, we validated differential expression of eight genes (GHR, GHRHR, IGF2BP1, OVALX, ELF2, MGARP, NOCT, SLC25A15) that might be related to body size and high egg production traits in relevant tissues of relevant breeds. Conclusion: We identify 30 million single nucleotide variants and small indels in the five indigenous chicken breeds, 10 million of which are novel. We predict substantially more selective sweeps and affected genes than previously reported in both indigenous and commercial breeds. These variants and affected genes are good candidates for further experimental investigations of genotype-phenotype relationships and practical applications in chicken breeding programs. [ABSTRACT FROM AUTHOR]

Background: Accurate identification of genetic variants, such as point mutations and insertions/deletions (indels), is crucial for various genetic studies into epidemic tracking, population genetics, and disease diagnosis. Genetic studies into microbiomes often require processing numerous sequencing datasets, necessitating variant identifiers with high speed, accuracy, and robustness. Results: We present QuickVariants, a bioinformatics tool that effectively summarizes variant information from read alignments and identifies variants. When tested on diverse bacterial sequencing data, QuickVariants demonstrates a ninefold higher median speed than bcftools, a widely used variant identifier, with higher accuracy in identifying both point mutations and indels. This accuracy extends to variant identification in virus samples, including SARS-CoV-2, particularly with significantly fewer false negative indels than bcftools. The high accuracy of QuickVariants is further demonstrated by its detection of a greater number of Omicron-specific indels (5 versus 0) and point mutations (61 versus 48–54) than bcftools in sewage metagenomes predominated by Omicron variants. Much of the reduced accuracy of bcftools was attributable to its misinterpretation of indels, often producing false negative indels and false positive point mutations at the same locations. Conclusions: We introduce QuickVariants, a fast, accurate, and robust bioinformatics tool designed for identifying genetic variants for microbial studies. QuickVariants is available at https://github.com/caozhichongchong/QuickVariants. [ABSTRACT FROM AUTHOR]

Background: The commercial determinants of health is a rapidly expanding field of research; however Indigenous perspectives remain notably underrepresented. For Indigenous peoples the intersection of globalisation, colonialism and capitalism may amplify commercially-driven health inequities. This study aimed to explore the perspectives of Aboriginal leaders regarding the influence of commercial activities on Aboriginal health and wellbeing in Victoria, Australia. Methods: Semi-structured interviews with 23 Aboriginal leaders from across five sectors (n = 15 urban, n = 8 rural/regional) were analysed through reflexive thematic analysis. Results: Three overarching themes were identified encompassing (i) harmful commercial practices and processes, (ii) improving corporate engagement and (iii) opportunities for self-determination through business. Participants expressed concern over aggressive marketing by the gambling industry, commercial exploitation of Aboriginal culture, the privatisation of public services, and lack of oversignt of corporate social responsibility strategies. Simultaneously, Aboriginal-led businesses were viewed as opportunities for cultural connection, and financial empowerment and self-determination. Conclusion: Numerous commercial entities and activities are perceived to influence Aboriginal health and wellbeing. This study highlights the need for stronger policy and regulation to mitigate harmful industry practices while incentivising the potential positive impacts of the commercial activities on Aboriginal health and wellbeing. [ABSTRACT FROM AUTHOR]

Background: Gene flow is crucial for enhancing economic traits of livestock. In China, breeders have used hybridization strategies for decades to improve livestock performance. Here, we performed whole-genome sequencing of a native Chinese Lijiang pig (LJP) breed. By integrating previously published data, we explored the genetic structure and introgression of genetic components from commercial European pigs (EP) into the LJP, and examined the impact of this introgression on phenotypic traits. Results: Our analysis revealed significant introgression of EP breeds into the LJP and other domestic pig breeds in China. Using a haplotype-based approach, we quantified introgression levels and compared EP to LJP and other Chinese domestic pigs. The results show that EP introgression is widely prevalent in Chinese domestic pigs, although there are significant differences between breeds. We propose that LJP could potentially act as a mediator for the transmission of EP haplotypes. We also examined the correlation between EP introgression and the number of thoracic vertebrae in LJP and identified VRTN and STUM as candidate genes for this trait. Conclusions: Our study provides evidence of introgressed European haplotypes in the LJP breed and describes the potential role of EP introgression on phenotypic changes of this indigenous breed. [ABSTRACT FROM AUTHOR]

Climate change is a threat to sustainable livestock production and livelihoods in the tropics. It has adverse impacts on feed and water availability, disease prevalence, production, environmental temperature, and biodiversity. Unravelling the drivers of local adaptation and understanding the underlying genetic variation in random mating indigenous livestock populations informs the design of genetic improvement programmes that aim to increase productivity and resilience. In the present study, we combined environmental, genomic, and phenotypic information of Ethiopian indigenous chickens to investigate their environmental adaptability. Through a hybrid sampling strategy, we captured wide biological and ecological variabilities across the country. Our environmental dataset comprised mean values of 34 climatic, vegetation and soil variables collected over a thirty-year period for 260 geolocations. Our biological dataset included whole genome sequences and quantitative measurements (on eight traits) from 513 individuals, representing 26 chicken populations spread along 4 elevational gradients (6–7 populations per gradient). We performed signatures of selection analyses ( and XP-EHH) to detect footprints of natural selection, and redundancy analyses (RDA) to determine genotype-environment and genotype-phenotype-associations. RDA identified 1909 outlier SNPs linked with six environmental predictors, which have the highest contributions as ecological drivers of adaptive phenotypic variation. The same method detected 2430 outlier SNPs that are associated with five traits. A large overlap has been observed between signatures of selection identified by and XP-EHH showing that both methods target similar selective sweep regions. Average genetic differences measured by are low between gradients, but XP-EHH signals are the strongest between agroecologies. Genes in the calcium signalling pathway, those associated with the hypoxia-inducible factor (HIF) transcription factors, and sports performance (GALNTL6) are under selection in high-altitude populations. Our study underscores the relevance of landscape genomics as a powerful interdisciplinary approach to dissect adaptive phenotypic and genetic variation in random mating indigenous livestock populations. [ABSTRACT FROM AUTHOR]

Background: Invasive breast cancer (IBC) is a leading cause of cancer-related death among women in Israel, regardless of ethnicity. This study compared IBC epidemiological, clinical, and pathological characteristics in Bedouin and Jewish patients in southern Israel. Methods: Medical records of 1514 Jewish and 191 Bedouin women with IBC treated at Soroka University Medical Center between 2014 and 2021 were analyzed retrospectively. Baseline measures and tumor characteristics were compared between groups. Overall survival (OS) and disease-free survival (DFS) were analyzed using log-rank test. Multivariate analysis was performed using the Cox proportional hazard model. Results: Bedouin patients exhibited a significantly younger age at diagnosis (median 48 vs. 62 years, p < 0.001), larger tumor size (median 2.5 vs. 2.13 cm, p < 0.001), and higher metastasis rate (18.8% vs. 12.7%, p = 0.03) compared to Jewish patients. In early-stage (non-metastatic) disease, Jewish and Bedouin patients had comparable overall survival (OS) rates (127 vs. 126 months, p = 0.2), consistent across stages 1 to 3. However, among patients with metastatic disease, Bedouins exhibited significantly longer OS (76.6 vs. 37.8 months, p = 0.006). Disease-free survival (DFS) showed no ethnic differences (not reached vs. 122 months, p = 0.31). There were no significant differences in OS between Bedouin and Jewish patients undergoing various treatment modalities for early-stage disease: surgery, adjuvant radiotherapy, chemotherapy, and systemic neoadjuvant therapy. Conclusion: Breast cancer among Bedouin women in southern Israel manifests at a younger age, with larger tumors and more advanced stages than in Jewish women. However, recent data indicate no differences in OS and DFS between the ethnic groups despite past disparities in prognosis. [ABSTRACT FROM AUTHOR]

Background: Cattle populations harbor generally high inbreeding levels that can lead to inbreeding depression (ID). Here, we study ID with different estimators of the inbreeding coefficient F, evaluate their sensitivity to used allele frequencies (founder versus sample allele frequencies), and compare effects from recent and ancient inbreeding. Methods: We used data from 14,205 Belgian Blue beef cattle genotyped cows that were phenotyped for 11 linear classification traits. We computed estimators of F based on the pedigree information (FPED), on the correlation between uniting gametes (FUNI), on the genomic relationship matrix (FGRM), on excess homozygosity (FHET), or on homozygous-by-descent (HBD) segments (FHBD). Results: FUNI and FGRM were sensitive to used allele frequencies, whereas FHET and FHBD were more robust. We detected significant ID for four traits related to height and length; FHBD and FUNI presenting the strongest associations. Then, we took advantage of the classification of HBD segments in different age-related classes (the length of an HBD segment being inversely related to the number of generations to the common ancestors) to determine that recent HBD classes (common ancestors present approximately up to 15 generations in the past) presented stronger ID than more ancient HBD classes. We performed additional analyses to check whether these observations could result from a lower level of variation in ancient HBD classes, or from a reduced precision to identify these shorter segments. Conclusions: Overall, our results suggest that mutational load decreases with haplotype age, and that mating plans should consider mainly the levels of recent inbreeding. [ABSTRACT FROM AUTHOR]

Background: Viral vectors are attractive gene delivery vehicles because of their broad tropism, high transduction efficiency, and durable expression. With no risk of integration into the host genome, the vectors developed from RNA viruses such as Sendai virus (SeV) are especially promising. However, RNA-based vectors have limited applicability because they lack a convenient method to control transgene expression by an external inducer. Results: We engineered a Csy4 switch in Sendai virus-based vectors by combining Csy4 endoribonuclease with mutant FKBP12 (DD: destabilizing domain) that becomes stabilized when a small chemical Shield1 is supplied. In this Shield1-responsive Csy4 (SrC) switch, Shield1 increases Csy4 fused with DD (DD-Csy4), which then cleaves and downregulates the transgene mRNA containing the Csy4 recognition sequence (Csy4RS). Moreover, when Csy4RS is inserted in the viral L gene, the SrC switch suppresses replication and transcription of the SeV vector in infected cells in a Shield1-dependent manner, thus enabling complete elimination of the vector from the cells. By temporally controlling BRN4 expression, a BRN4-expressing SeV vector equipped with the SrC switch achieves efficient, stepwise differentiation of embryonic stem cells into neural stem cells, and then into astrocytes. Conclusion: SeV-based vectors with the SrC switch should find wide applications in stem cell research, regenerative medicine, and gene therapy, especially when precise control of reprogramming factor expression is desirable. [ABSTRACT FROM AUTHOR]

Background: The influence of genetics and environment on the association of the plasma proteome with body mass index (BMI) and changes in BMI remains underexplored, and the links to other omics in these associations remain to be investigated. We characterized protein–BMI trajectory associations in adolescents and adults and how these connect to other omics layers. Methods: Our study included two cohorts of longitudinally followed twins: FinnTwin12 (N = 651) and the Netherlands Twin Register (NTR) (N = 665). Follow-up comprised 4 BMI measurements over approximately 6 (NTR: 23–27 years old) to 10 years (FinnTwin12: 12–22 years old), with omics data collected at the last BMI measurement. BMI changes were calculated in latent growth curve models. Mixed-effects models were used to quantify the associations between the abundance of 439 plasma proteins with BMI at blood sampling and changes in BMI. In FinnTwin12, the sources of genetic and environmental variation underlying the protein abundances were quantified by twin models, as were the associations of proteins with BMI and BMI changes. In NTR, we investigated the association of gene expression of genes encoding proteins identified in FinnTwin12 with BMI and changes in BMI. We linked identified proteins and their coding genes to plasma metabolites and polygenic risk scores (PRS) applying mixed-effects models and correlation networks. Results: We identified 66 and 14 proteins associated with BMI at blood sampling and changes in BMI, respectively. The average heritability of these proteins was 35%. Of the 66 BMI-protein associations, 43 and 12 showed genetic and environmental correlations, respectively, including 8 proteins showing both. Similarly, we observed 7 and 3 genetic and environmental correlations between changes in BMI and protein abundance, respectively. S100A8 gene expression was associated with BMI at blood sampling, and the PRG4 and CFI genes were associated with BMI changes. Proteins showed strong connections with metabolites and PRSs, but we observed no multi-omics connections among gene expression and other omics layers. Conclusions: Associations between the proteome and BMI trajectories are characterized by shared genetic, environmental, and metabolic etiologies. We observed few gene-protein pairs associated with BMI or changes in BMI at the proteome and transcriptome levels. [ABSTRACT FROM AUTHOR]

Background: Cystinuria is an autosomal recessive disorder characterized by a cystine transport deficiency in the renal tubules due to mutations in two genes: SLC3A1 and SLC7A9. Cystinuria can be classified into three forms based on the genotype: type A, due to mutations in the SLC3A1 gene; type B, due to mutations in the SLC7A9 gene; and type AB, due to mutations in both genes. Methods: We report a 12-year-old boy from central China with cystine stones. He was from a non-consanguineous family that had no known history of genetic disease. A physical examination showed normal development and neurological behaviors. Whole-exome and Sanger sequencing were used to identify and verify the suspected pathogenic variants. Results: The compound heterozygous variants c.898_905del (p.Arg301AlafsTer6) is located in exon5 and c.1898_1899insAT (p.Asp634LeufsTer46) is located in exon10 of SLC3A1 (NM_000341.4) were deemed responsible for type A cystinuria family. The variant c.898_905del was reported in a Japanese patient in 2000, and the variant c.1898_1899insAT is novel. Conclusion: A novel pathogenic heterozygous variant pair of the SLC3A1 gene was identified in a Chinese boy with type A cystinuria, enriching the mutational spectrum of the SLC3A1 gene. We attempted to find a pattern for the association between the genotype of SLC3A1 variants and the manifestations of cystinuria in patients with different onset ages. Our findings have important implications for genetic counseling and the early clinical diagnosis of cystinuria. [ABSTRACT FROM AUTHOR]

Background: In China, ~1,072,100 small for gestational age (SGA) births occur annually. These SGA newborns are a high-risk population of developmental delay. Our study aimed to evaluate the genetic profile of SGA newborns in the newborn intensive care unit (NICU) and establish a prognosis prediction model by combining clinical and genetic factors. Methods: A cohort of 723 SGA and 1317 appropriate for gestational age (AGA) newborns were recruited between June 2018 and June 2020. Clinical exome sequencing was performed for each newborn. The gene-based rare-variant collapsing analyses and the gene burden test were applied to identify the risk genes for SGA and SGA with poor prognosis. The Gradient Boosting Machine framework was used to generate two models to predict the prognosis of SGA. The performance of two models were validated with an independent cohort of 115 SGA newborns without genetic diagnosis from July 2020 to April 2022. All newborns in this study were recruited through the China Neonatal Genomes Project (CNGP) and were hospitalized in NICU, Children's Hospital of Fudan University, Shanghai, China. Results: Among the 723 SGA newborns, 88(12.2%) received genetic diagnosis, including 42(47.7%) with monogenic diseases and 46(52.3%) with chromosomal abnormalities. SGA with genetic diagnosis showed higher rates in severe SGA(54.5% vs. 41.9%, P=0.0025) than SGA without genetic diagnosis. SGA with chromosomal abnormalities showed higher incidences of physical and neurodevelopmental delay compared to those with monogenic diseases (45.7% vs. 19.0%, P=0.012). We filtered out 3 genes (ITGB4, TXNRD2, RRM2B) as potential causative genes for SGA and 1 gene (ADIPOQ) as potential causative gene for SGA with poor prognosis. The model integrating clinical and genetic factors demonstrated a higher area under the receiver operating characteristic curve (AUC) over the model based solely on clinical factors in both the SGA-model generation dataset (AUC=0.9[95% confidence interval 0.84–0.96] vs. AUC=0.74 [0.64–0.84]; P=0.00196) and the independent SGA-validation dataset (AUC=0.76 [0.6–0.93] vs. AUC=0.53[0.29–0.76]; P=0.0117). Conclusion: SGA newborns in NICU presented with roughly equal proportions of monogenic and chromosomal abnormalities. Chromosomal disorders were associated with poorer prognosis. The rare-variant collapsing analyses studies have the ability to identify potential causative factors associated with growth and development. The SGA prognosis prediction model integrating genetic and clinical factors outperformed that relying solely on clinical factors. The application of genetic sequencing in hospitalized SGA newborns may improve early genetic diagnosis and prognosis prediction. [ABSTRACT FROM AUTHOR]

Background: In this study, we present a NGS-based panel designed for sequencing 1993 SNP loci for forensic DNA investigation. This panel addresses unique challenges encountered in forensic practice and allows for a comprehensive population genetic study of the Chinese Korean ethnic group. To achieve this, we combine our results with datasets from the 1000 Genomes Project and the Human Genome Diversity Panel. Results: We demonstrate that this panel is a reliable tool for individual identification and parentage testing, even when dealing with degraded DNA samples featuring exceedingly low SNP detection rates. The performance of this panel for complex kinship determinations, such as half-sibling and grandparent-grandchild scenarios, is also validated by various kinship simulations. Population genetic studies indicate that this panel can uncover population substructures on both global and regional scales. Notably, the Han population can be distinguished from the ethnic minorities in the northern and southern regions of East Asia, suggesting its potential for regional ancestry inference. Furthermore, we highlight that the Chinese Korean ethnic group, along with various Han populations from different regional areas and certain northern ethnic minorities (Daur, Tujia, Japanese, Mongolian, Xibo), exhibit a higher degree of genetic affinities when examined from a genomic perspective. Conclusion: This study provides convincing evidence that the NGS-based panel can serve as a reliable tool for various forensic applications. Moreover, it has helped to enhance our knowledge about the genetic landscape of the Chinese Korean ethnic group. [ABSTRACT FROM AUTHOR]