The advent of iPSCs has brought about a significant transformation in stem cell research, opening up promising avenues for advancing cancer treatment. The formation of cancer is a multifaceted ...process influenced by genetic, epigenetic, and environmental factors. iPSCs offer a distinctive platform for investigating the origin of cancer, paving the way for novel approaches to cancer treatment, drug testing, and tailored medical interventions. This review article will provide an overview of the science behind iPSCs, the current limitations and challenges in iPSC-based cancer therapy, the ethical and social implications, and the comparative analysis with other stem cell types for cancer treatment. The article will also discuss the applications of iPSCs in tumorigenesis, the future of iPSCs in tumorigenesis research, and highlight successful case studies utilizing iPSCs in tumorigenesis research. The conclusion will summarize the advancements made in iPSC-based tumorigenesis research and the importance of continued investment in iPSC research to unlock the full potential of these cells.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Understanding the genetic changes underlying phenotypic variation in sheep (Ovis aries) may facilitate our efforts towards further improvement. Here, we report the deep resequencing of 248 sheep ...including the wild ancestor (O. orientalis), landraces, and improved breeds. We explored the sheep variome and selection signatures. We detected genomic regions harboring genes associated with distinct morphological and agronomic traits, which may be past and potential future targets of domestication, breeding, and selection. Furthermore, we found non-synonymous mutations in a set of plausible candidate genes and significant differences in their allele frequency distributions across breeds. We identified PDGFD as a likely causal gene for fat deposition in the tails of sheep through transcriptome, RT-PCR, qPCR, and Western blot analyses. Our results provide insights into the demographic history of sheep and a valuable genomic resource for future genetic studies and improved genome-assisted breeding of sheep and other domestic animals.
In theoretical biology, a prevailing hypothesis posits a profound interconnection between effective population size (Ne), genetic diversity, inbreeding, and genetic load. The domestication and ...improvement processes are believed to be pivotal in diminishing genetic diversity while elevating levels of inbreeding and increasing genetic load. In this study, we performed a whole genome analysis to quantity genetic diversity, inbreeding, and genetic load across seven wild Ovis species and five domesticated sheep breeds. Our research demonstrates that the genetic load and diversity of species in the genus Ovis have no discernible impact on recent Ne, and three species within the subgenus Pachyceros tend to carry a higher genetic load and lower genetic diversity patterns. The results coincide with these species’ dramatic decline in population sizes within the subgenus Pachyceros ~80–250 thousand years ago. European mouflon presented with the lowest Ne, lower genetic diversity, and higher individual inbreeding coefficient but a lower genetic load (missense and LoF). This suggests that the small Ne of European mouflon could reduce harmful mutations compared to other species within the genus Ovis. We showed lower genetic diversity in domesticated sheep than in Asiatic mouflon, but counterintuitive patterns of genetic load, i.e., lower weak genetic load (missense mutation) and no significant difference in strong genetic load (LoF mutation) between domestic sheep and Asiatic mouflon. These findings reveal that the “cost of domestication” during domestication and improvement processes reduced genetic diversity and purified weak genetic load more efficiently than wild species.
BackgroundSheep and goats have undergone domestication and improvement to produce similar phenotypes, which have been greatly impacted by structural variants (SVs). Here, we report a high-quality ...chromosome-level reference genome of Asiatic mouflon, and implement a comprehensive analysis of SVs in 897 genomes of worldwide wild and domestic populations of sheep and goats to reveal genetic signatures underlying convergent evolution.ResultsWe characterize the SV landscapes in terms of genetic diversity, chromosomal distribution and their links with genes, QTLs and transposable elements, and examine their impacts on regulatory elements. We identify several novel SVs and annotate corresponding genes (e.g., BMPR1B, BMPR2, RALYL, COL21A1, and LRP1B) associated with important production traits such as fertility, meat and milk production, and wool/hair fineness. We detect signatures of selection involving the parallel evolution of orthologous SV-associated genes during domestication, local environmental adaptation, and improvement. In particular, we find that fecundity traits experienced convergent selection targeting the gene BMPR1B, with the DEL00067921 deletion explaining ~10.4% of the phenotypic variation observed in goats.ConclusionsOur results provide new insights into the convergent evolution of SVs and serve as a rich resource for the future improvement of sheep, goats, and related livestock.
The domestication and subsequent global dispersal of livestock are crucial events in human history, but the migratory episodes during the history of livestock remain poorly documented 1–3. Here, we ...first developed a set of 493 novel ovine SNPs of the male-specific region of Y chromosome (MSY) by genome mapping. We then conducted a comprehensive genomic analysis of Y chromosome, mitochondrial DNA, and whole-genome sequence variations in a large number of 595 rams representing 118 domestic populations across the world. We detected four different paternal lineages of domestic sheep and resolved, at the global level, their paternal origins and differentiation. In Northern European breeds, several of which have retained primitive traits (e.g., a small body size and short or thin tails), and fat-tailed sheep, we found an overrepresentation of MSY lineages y-HC and y-HB, respectively. Using an approximate Bayesian computation approach, we reconstruct the demographic expansions associated with the segregation of primitive and fat-tailed phenotypes. These results together with archaeological evidence and historical data suggested the first expansion of early domestic hair sheep and the later expansion of fat-tailed sheep occurred ∼11,800–9,000 years BP and ∼5,300–1,700 years BP, respectively. These findings provide important insights into the history of migration and pastoralism of sheep across the Old World, which was associated with different breeding goals during the Neolithic agricultural revolution.
•Novel ovine SNPs of the male-specific region of Y chromosome were developed•Y chromosome of domestic sheep contains four different paternal lineages•Lineages C and B predominate in breeds of primitive traits and fat tail, respectively•Expansions of sheep correlate with various phenotypic traits and breeding goals
Deng et al. show that domestic sheep harbor four Y chromosome lineages and early expansions of sheep were associated with the segregation of primitive and fat-tailed phenotypes as well as traits selected for different purposes.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Sheep show characteristics of phenotypic diversity and adaptation to diverse climatic regions. Previous studies indicated associations between copy number variations (CNVs) and climate-driven ...adaptive evolution in humans and other domestic animals. Here, we constructed a genomic landscape of CNVs (
= 39,145) in 47 old autochthonous populations genotyped at a set of high-density (600 K) SNPs to detect environment-driven signatures of CNVs using a multivariate regression model. We found 136 deletions and 52 duplications that were significantly (
< 0.05) associated with climatic variables. These climate-mediated selective CNVs are involved in functional candidate genes for heat stress and cold climate adaptation (e.g.,
,
, and
), coat and wool-related traits (e.g.,
,
,
, and
), repairing damaged DNA (e.g.,
), GTPase activity (e.g.,
), fast metabolism (e.g.,
and
), fertility and reproduction (e.g.,
and
), growth-related traits (e.g.,
and
), and immune response (e.g.,
and
) in sheep. In particular, we identified significant (
< 0.05) associations between probes in deleted/duplicated CNVs and solar radiation. Enrichment analysis of the gene sets among all the CNVs revealed significant (
< 0.05) enriched gene ontology terms and pathways related to functions such as nucleotide, protein complex, and GTPase activity. Additionally, we observed overlapping between the CNVs and 140 known sheep QTLs. Our findings imply that CNVs can serve as genomic markers for the selection of sheep adapted to specific climatic conditions.
Copy number variations (CNVs) are a major source of structural variation in mammalian genomes. Here, we characterized the genome-wide CNV in 2059 sheep from 67 populations all over the world using ...the Ovine Infinium HD (600K) SNP BeadChip. We tested their associations with distinct phenotypic traits by conducting multiple independent genome-wide tests. In total, we detected 7547 unique CNVs and 18,152 CNV events in 1217 non-redundant CNV regions (CNVRs), covering 245 Mb (∼10%) of the whole sheep genome. We identified seven CNVRs with frequencies correlating to geographical origins and 107 CNVRs overlapping 53 known quantitative trait loci (QTLs). Gene ontology and pathway enrichment analyses of CNV-overlapping genes revealed their common involvement in energy metabolism, endocrine regulation, nervous system development, cell proliferation, immune, and reproduction. For the phenotypic traits, we detected significantly associated (adjusted
P
< 0.05) CNVRs harboring functional candidate genes, such as
SBNO2
for polycerate;
PPP1R11
and
GABBR1
for tail weight;
AKT1
for supernumerary nipple;
CSRP1
,
WNT7B
,
HMX1
, and
FGFR3
for ear size; and
NOS3
and
FILIP1
in Wadi sheep;
SNRPD3
,
KHDRBS2
, and
SDCCAG3
in Hu sheep;
NOS3
,
BMP1
, and
SLC19A1
in Icelandic;
CDK2
in Finnsheep;
MICA
in Romanov; and
REEP4
in Texel sheep for litter size. These CNVs and associated genes are important markers for molecular breeding of sheep and other livestock species.
In theoretical biology, a prevailing hypothesis posits a profound interconnection between effective population size (Nsub.e), genetic diversity, inbreeding, and genetic load. The domestication and ...improvement processes are believed to be pivotal in diminishing genetic diversity while elevating levels of inbreeding and increasing genetic load. In this study, we performed a whole genome analysis to quantity genetic diversity, inbreeding, and genetic load across seven wild Ovis species and five domesticated sheep breeds. Our research demonstrates that the genetic load and diversity of species in the genus Ovis have no discernible impact on recent Nsub.e, and three species within the subgenus Pachyceros tend to carry a higher genetic load and lower genetic diversity patterns. The results coincide with these species’ dramatic decline in population sizes within the subgenus Pachyceros ~80–250 thousand years ago. European mouflon presented with the lowest Nsub.e, lower genetic diversity, and higher individual inbreeding coefficient but a lower genetic load (missense and LoF). This suggests that the small Nsub.e of European mouflon could reduce harmful mutations compared to other species within the genus Ovis. We showed lower genetic diversity in domesticated sheep than in Asiatic mouflon, but counterintuitive patterns of genetic load, i.e., lower weak genetic load (missense mutation) and no significant difference in strong genetic load (LoF mutation) between domestic sheep and Asiatic mouflon. These findings reveal that the “cost of domestication” during domestication and improvement processes reduced genetic diversity and purified weak genetic load more efficiently than wild species.
Abstract
Domestic sheep and their wild relatives harbor substantial genetic variants that can form the backbone of molecular breeding, but their genome landscapes remain understudied. Here, we ...present a comprehensive genome resource for wild ovine species, landraces and improved breeds of domestic sheep, comprising high-coverage (∼16.10×) whole genomes of 810 samples from 7 wild species and 158 diverse domestic populations. We detected, in total, ∼121.2 million single nucleotide polymorphisms, ∼61 million of which are novel. Some display significant (P < 0.001) differences in frequency between wild and domestic species, or are private to continent-wide or individual sheep populations. Retained or introgressed wild gene variants in domestic populations have contributed to local adaptation, such as the variation in the HBB associated with plateau adaptation. We identified novel and previously reported targets of selection on morphological and agronomic traits such as stature, horn, tail configuration, and wool fineness. We explored the genetic basis of wool fineness and unveiled a novel mutation (chr25: T7,068,586C) in the 3′-UTR of IRF2BP2 as plausible causal variant for fleece fiber diameter. We reconstructed prehistorical migrations from the Near Eastern domestication center to South-and-Southeast Asia and found two main waves of migrations across the Eurasian Steppe and the Iranian Plateau in the Early and Late Bronze Ages. Our findings refine our understanding of genome variation as shaped by continental migrations, introgression, adaptation, and selection of sheep.
Abstract
How animals, particularly livestock, adapt to various climates and environments over short evolutionary time is of fundamental biological interest. Further, understanding the genetic ...mechanisms of adaptation in indigenous livestock populations is important for designing appropriate breeding programs to cope with the impacts of changing climate. Here, we conducted a comprehensive genomic analysis of diversity, interspecies introgression, and climate-mediated selective signatures in a global sample of sheep and their wild relatives. By examining 600K and 50K genome-wide single nucleotide polymorphism data from 3,447 samples representing 111 domestic sheep populations and 403 samples from all their seven wild relatives (argali, Asiatic mouflon, European mouflon, urial, snow sheep, bighorn, and thinhorn sheep), coupled with 88 whole-genome sequences, we detected clear signals of common introgression from wild relatives into sympatric domestic populations, thereby increasing their genomic diversities. The introgressions provided beneficial genetic variants in native populations, which were significantly associated with local climatic adaptation. We observed common introgression signals of alleles in olfactory-related genes (e.g., ADCY3 and TRPV1) and the PADI gene family including in particular PADI2, which is associated with antibacterial innate immunity. Further analyses of whole-genome sequences showed that the introgressed alleles in a specific region of PADI2 (chr2: 248,302,667–248,306,614) correlate with resistance to pneumonia. We conclude that wild introgression enhanced climatic adaptation and resistance to pneumonia in sheep. This has enabled them to adapt to varying climatic and environmental conditions after domestication.
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