DNA replication follows a strict spatiotemporal program that intersects with chromatin structure but has a poorly understood genetic basis. To systematically identify genetic regulators of ...replication timing, we exploited inter-individual variation in human pluripotent stem cells from 349 individuals. We show that the human genome's replication program is broadly encoded in DNA and identify 1,617 cis-acting replication timing quantitative trait loci (rtQTLs) - sequence determinants of replication initiation. rtQTLs function individually, or in combinations of proximal and distal regulators, and are enriched at sites of histone H3 trimethylation of lysines 4, 9, and 36 together with histone hyperacetylation. H3 trimethylation marks are individually repressive yet synergistically associate with early replication. We identify pluripotency-related transcription factors and boundary elements as positive and negative regulators of replication timing, respectively. Taken together, human replication timing is controlled by a multi-layered mechanism with dozens of effectors working combinatorially and following principles analogous to transcription regulation.
The origin of Tibetans remains one of the most contentious puzzles in history, anthropology, and genetics. Analyses of deeply sequenced (30×–60×) genomes of 38 Tibetan highlanders and 39 Han Chinese ...lowlanders, together with available data on archaic and modern humans, allow us to comprehensively characterize the ancestral makeup of Tibetans and uncover their origins. Non-modern human sequences compose ∼6% of the Tibetan gene pool and form unique haplotypes in some genomic regions, where Denisovan-like, Neanderthal-like, ancient-Siberian-like, and unknown ancestries are entangled and elevated. The shared ancestry of Tibetan-enriched sequences dates back to ∼62,000–38,000 years ago, predating the Last Glacial Maximum (LGM) and representing early colonization of the plateau. Nonetheless, most of the Tibetan gene pool is of modern human origin and diverged from that of Han Chinese ∼15,000 to ∼9,000 years ago, which can be largely attributed to post-LGM arrivals. Analysis of ∼200 contemporary populations showed that Tibetans share ancestry with populations from East Asia (∼82%), Central Asia and Siberia (∼11%), South Asia (∼6%), and western Eurasia and Oceania (∼1%). Our results support that Tibetans arose from a mixture of multiple ancestral gene pools but that their origins are much more complicated and ancient than previously suspected. We provide compelling evidence of the co-existence of Paleolithic and Neolithic ancestries in the Tibetan gene pool, indicating a genetic continuity between pre-historical highland-foragers and present-day Tibetans. In particular, highly differentiated sequences harbored in highlanders’ genomes were most likely inherited from pre-LGM settlers of multiple ancestral origins (SUNDer) and maintained in high frequency by natural selection.
Studies of the Neanderthal and Denisovan genomes demonstrate archaic hominin introgression in Eurasians. Here, we present evidence of Neanderthal introgression within the chromosome 3p21.31 region, ...occurring with a high frequency in East Asians (ranging from 49.4% to 66.5%) and at a low frequency in Europeans. We also detected a signal of strong positive selection in this region only in East Asians. Our data indicate that likely candidate targets of selection include rs12488302-T and its associated alleles--among which four are nonsynonymous, including rs35455589-G in HYAL2, a gene related to the cellular response to ultraviolet-B irradiation. Furthermore, suggestive evidence supports latitude-dependent selection, implicating a role of ultraviolet-B. Interestingly, the distribution of rs35455589-G suggests that this allele was lost during the exodus of ancestors of modern Eurasians from Africa and reintroduced to Eurasians from Neanderthals.
This experiment was conducted to evaluate the combined effects of organic acid and phytase on the digestibility coefficients, growth performance, body composition, vertebral and serum mineral ...contents, and liver and serum antioxidant properties in juvenile yellow catfish. This experiment was conducted using 900 juvenile yellow catfish in a completely randomized design with a 3×2 factorial arrangement (0, 2, and 4gkg−1 feed organic acid and 0 and 0.2gkg−1 feed (1000IUkg−1 feed) phytase). Triplicate groups of 50 fish per tank were fed dietary treatments for eight weeks. Phytase addition increased the apparent digestibilities of dry matter, protein, and P; final body weight; specific growth rate; body crude ash; body crude protein; body P and Ca contents; and vertebral P and Ca contents; but decreased the fecal P content and feed conversion ratio. However, organic acid did not affect these parameters. Both dietary phytase and organic acid significantly reduced the blood reactive oxygen species (ROS) level, serum superoxide dismutase (SOD) activity, and catalase (CAT) activity. The addition of 4gkg−1 organic acid to the diet supplemented with 1000IUkg−1 phytase caused a significant interaction on the increments of blood ROS content and serum SOD and CAT activities, which indicated increasing oxidative stress (P<0.05). Phytase and organic acid showed no significant interaction on growth performance, body composition, and utilization of efficiency of plant-protein-source P in juvenile yellow catfish (P>0.05).
•Single supplement of phytase increased phosphorus utilization, calcium deposition.•Single supplement of phytase enhanced the antioxidant capacity.•Single organic acid enhanced the antioxidant capacity of juvenile yellow catfish.•High amount of organic acid together with phytase will increase oxidative stress.
Genomic DNA is replicated every cell cycle by the programmed activation of replication origins at specific times and chromosomal locations. The factors that define the locations of replication ...origins and their typical activation times in eukaryotic cells are poorly understood. Previous studies highlighted the role of activating factors and epigenetic modifications in regulating replication initiation. Here, we review the role that repressive pathways – and their alleviation – play in establishing the genomic landscape of replication initiation. Several factors mediate this repression, in particular, factors associated with inactive chromatin. Repression can support organized, yet stochastic, replication initiation, and its absence could explain instances of rapid and random replication or re-replication.
DNA replication initiation in eukaryotic cells is mediated by a complex system, but its spatiotemporal regulation remains poorly understood.While factors that promote replication are typically invoked to explain initiation patterns, evidence is accumulating for the involvement of a variety of repressive factors as well.Combinations of repressive histone modifications may function in synergistic ways to promote site-specific replication initiation, possibly through the activity of histone mark erasers.Considering both activation and repression as central to replication initiation could have important implications for the interpretation of DNA replication biology.
DNA is replicated according to a defined spatiotemporal program that is linked to both gene regulation and genome stability. The evolutionary forces that have shaped replication timing programs in ...eukaryotic species are largely unknown. Here, we studied the molecular causes and consequences of replication timing evolution across 94 humans, 95 chimpanzees, and 23 rhesus macaques. Replication timing differences recapitulated the species' phylogenetic tree, suggesting continuous evolution of the DNA replication timing program in primates. Hundreds of genomic regions had significant replication timing variation between humans and chimpanzees, of which 66 showed advances in replication origin firing in humans, while 57 were delayed. Genes overlapping these regions displayed correlated changes in expression levels and chromatin structure. Many human-chimpanzee variants also exhibited interindividual replication timing variation, pointing to ongoing evolution of replication timing at these loci. Association of replication timing variation with genetic variation revealed that DNA sequence evolution can explain replication timing variation between species. Taken together, DNA replication timing shows substantial and ongoing evolution in the human lineage that is driven by sequence alterations and could impact regulatory evolution at specific genomic sites.
This experiment was conducted to evaluate the combined effects of phytase, citric acid and vitamin D3 on the digestibility coefficients, growth performance, body composition, and vertebral and serum ...mineral contents in juvenile yellow catfish (Pelteobagrus fulvidraco). The study used 1200 juvenile yellow catfish in a completely randomized design with a 2×2×2 factorial arrangement (0 and 500IUphytasekg−1 feed, 0 and 2g citric acidkg−1 feed, and 2000 and 4000IU vitamin D3kg−1 feed). Triplicate groups of 50 fish with an initial single body weight of 3g±0.0g per tank were fed to satiety for eight weeks. 500IU phytasekg−1 feed addition significantly increased (P<0.05) the apparent digestibilities of dry matter and phosphorous (P), whole body sodium (Na), P, calcium (Ca), magnesium (Mg) and zinc (Zn) retention, and vertebral P, Ca and Zn deposition. However, phytase did not enhance the growth response of juvenile yellow catfish. The addition of 2g citric acidkg−1 feed significantly increased (P<0.05) weight gain (WG) and specific growth rate (SGR), and significantly decreased (P<0.05) feed conversion ratio (FCR). High levels of vitamin D3 significantly increased (P<0.05) whole body Na, K, P, Ca, Mg and Zn retention while no difference in vertebral mineral deposition, the apparent digestibility of dry matter, P and protein, or growth performance between low and high levels of vitamin D3 supplementation was observed. In addition, no significant interactions were observed among or between phytase, citric acid and vitamin D3 on the growth or mineral utilization of juvenile yellow catfish.
•500IUkg−1 phytase was enough to increase mineral utilization.•Citric acid improved growth performance even at low amount of 2gkg−1 diet.•No different effects of two doses of vitamin D3 on growth performance•No interactions among or between phytase, citric acid and vitamin D3 in growth and mineral utilization
Abstract
A common assumption in dating patrilineal events using Y-chromosome sequencing data is that the Y-chromosome mutation rate is invariant across haplogroups. Previous studies revealed ...interhaplogroup heterogeneity in phylogenetic branch length. Whether this heterogeneity is caused by interhaplogroup mutation rate variation or nongenetic confounders remains unknown. Here, we analyzed whole-genome sequences from cultured cells derived from >1,700 males. We confirmed the presence of branch length heterogeneity. We demonstrate that sex-chromosome mutations that appear within cell lines, which likely occurred somatically or in vitro (and are thus not influenced by nongenetic confounders) are informative for germline mutational processes. Using within-cell-line mutations, we computed a relative Y-chromosome somatic mutation rate, and uncovered substantial variation (up to 83.3%) in this proxy for germline mutation rate among haplogroups. This rate positively correlates with phylogenetic branch length, indicating that interhaplogroup mutation rate variation is a likely cause of branch length heterogeneity.
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