Melanocyte development provides an excellent model for studying more complex developmental processes. Melanocytes have an apparently simple aetiology, differentiating from the neural crest and ...migrating through the developing embryo to specific locations within the skin and hair follicles, and to other sites in the body. The study of pigmentation mutations in the mouse provided the initial key to identifying the genes and proteins involved in melanocyte development. In addition, work on chicken has provided important embryological and molecular insights, whereas studies in zebrafish have allowed live imaging as well as genetic and transgenic approaches. This cross-species approach is powerful and, as we review here, has resulted in a detailed understanding of melanocyte development and differentiation, melanocyte stem cells and the role of the melanocyte lineage in diseases such as melanoma.
Information on crop pedigrees can be used to help maximise genetic gain in crop breeding and allow efficient management of genetic resources. We present a pedigree resource of 2,657 wheat (Triticum ...aestivum L.) genotypes originating from 38 countries, representing more than a century of breeding and variety development. Visualisation of the pedigree enables illustration of the key developments in United Kingdom wheat breeding, highlights the wide genetic background of the UK wheat gene pool, and facilitates tracing the origin of beneficial alleles. A relatively high correlation between pedigree- and marker-based kinship coefficients was found, which validated the pedigree and enabled identification of errors in the pedigree or marker data. Using simulations with a combination of pedigree and genotype data, we found evidence for significant effects of selection by breeders. Within crosses, genotypes are often more closely related than expected by simulations to one of the parents, which indicates selection for favourable alleles during the breeding process. Selection across the pedigree was demonstrated on a subset of the pedigree in which 110 genotyped varieties released before the year 2000 were used to simulate the distribution of marker alleles of 45 genotyped varieties released after the year 2000, in the absence of selection. Allelic diversity in the 45 varieties was found to deviate significantly from the simulated distributions at a number of loci, indicating regions under selection over this period. The identification of one of these regions as coinciding with a strong yield component quantitative trait locus (QTL) highlights both the potential of the remaining loci as wheat breeding targets for further investigation, as well as the utility of this pedigree-based methodology to identify important breeding targets in other crops. Further evidence for selection was found as greater linkage disequilibrium (LD) for observed versus simulated genotypes within all chromosomes. This difference was greater at shorter genetic distances, indicating that breeder selections have conserved beneficial linkage blocks. Collectively, this work highlights the benefits of generating detailed pedigree resources for crop species. The wheat pedigree database developed here represents a valuable community resource and will be updated as new varieties are released at https://www.niab.com/pages/id/501/UK_Wheat_varieties_Pedigree.
The presence of ribonucleotides in genomic DNA is undesirable given their increased susceptibility to hydrolysis. Ribonuclease (RNase) H enzymes that recognize and process such embedded ...ribonucleotides are present in all domains of life. However, in unicellular organisms such as budding yeast, they are not required for viability or even efficient cellular proliferation, while in humans, RNase H2 hypomorphic mutations cause the neuroinflammatory disorder Aicardi-Goutières syndrome. Here, we report that RNase H2 is an essential enzyme in mice, required for embryonic growth from gastrulation onward. RNase H2 null embryos accumulate large numbers of single (or di-) ribonucleotides embedded in their genomic DNA (>1,000,000 per cell), resulting in genome instability and a p53-dependent DNA-damage response. Our findings establish RNase H2 as a key mammalian genome surveillance enzyme required for ribonucleotide removal and demonstrate that ribonucleotides are the most commonly occurring endogenous nucleotide base lesion in replicating cells.
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► Ribonucleotides are the most common nucleotide base lesion in the mouse genome ► RNase H2 is a key genome surveillance enzyme required for removal of nucleotides ► RNase H2 is essential for mammalian development ► Without RNase H2, cells exhibit genome instability and p53 pathway activation
DNA polymerases can incorporate more than a million ribonucleotides into replicating mouse DNA in each cell, making ribonucleotides the most abundant kind of DNA lesion. RNase H2, which removes this “damage,” has an essential role in genome surveillance and is required for embryonic development.
Defects in cilium and centrosome function result in a spectrum of clinically-related disorders, known as ciliopathies. However, the complex molecular composition of these structures confounds ...functional dissection of what any individual gene product is doing under normal and disease conditions. As part of an siRNA screen for genes involved in mammalian ciliogenesis, we and others have identified the conserved centrosomal protein Azi1/Cep131 as required for cilia formation, supporting previous Danio rerio and Drosophila melanogaster mutant studies. Acute loss of Azi1 by knock-down in mouse fibroblasts leads to a robust reduction in ciliogenesis, which we rescue by expressing siRNA-resistant Azi1-GFP. Localisation studies show Azi1 localises to centriolar satellites, and traffics along microtubules becoming enriched around the basal body. Azi1 also localises to the transition zone, a structure important for regulating traffic into the ciliary compartment. To study the requirement of Azi1 during development and tissue homeostasis, Azi1 null mice were generated (Azi1(Gt/Gt)). Surprisingly, Azi1(Gt/Gt) MEFs have no discernible ciliary phenotype and moreover are resistant to Azi1 siRNA knock-down, demonstrating that a compensation mechanism exists to allow ciliogenesis to proceed despite the lack of Azi1. Cilia throughout Azi1 null mice are functionally normal, as embryonic patterning and adult homeostasis are grossly unaffected. However, in the highly specialised sperm flagella, the loss of Azi1 is not compensated, leading to striking microtubule-based trafficking defects in both the manchette and the flagella, resulting in male infertility. Our analysis of Azi1 knock-down (acute loss) versus gene deletion (chronic loss) suggests that Azi1 plays a conserved, but non-essential trafficking role in ciliogenesis. Importantly, our in vivo analysis reveals Azi1 mediates novel trafficking functions necessary for flagellogenesis. Our study highlights the importance of both acute removal of a protein, in addition to mouse knock-out studies, when functionally characterising candidates for human disease.
Natural hair colour within European populations is a complex genetic trait. Previous work has established that MC1R variants are the principal genetic cause of red hair colour, but with variable ...penetrance. Here, we have extensively mapped the genes responsible for hair colour in the white, British ancestry, participants in UK Biobank. MC1R only explains 73% of the SNP heritability for red hair in UK Biobank, and in fact most individuals with two MC1R variants have blonde or light brown hair. We identify other genes contributing to red hair, the combined effect of which accounts for ~90% of the SNP heritability. Blonde hair is associated with over 200 genetic variants and we find a continuum from black through dark and light brown to blonde and account for 73% of the SNP heritability of blonde hair. Many of the associated genes are involved in hair growth or texture, emphasising the cellular connections between keratinocytes and melanocytes in the determination of hair colour.
We report genome sequences of 17 inbred strains of laboratory mice and identify almost ten times more variants than previously known. We use these genomes to explore the phylogenetic history of the ...laboratory mouse and to examine the functional consequences of allele-specific variation on transcript abundance, revealing that at least 12% of transcripts show a significant tissue-specific expression bias. By identifying candidate functional variants at 718 quantitative trait loci we show that the molecular nature of functional variants and their position relative to genes vary according to the effect size of the locus. These sequences provide a starting point for a new era in the functional analysis of a key model organism.
Following domestication, livestock breeds have experienced intense selection pressures for the development of desirable traits. This has resulted in a large diversity of breeds that display variation ...in many phenotypic traits, such as coat colour, muscle composition, early maturity, growth rate, body size, reproduction, and behaviour. To better understand the relationship between genomic composition and phenotypic diversity arising from breed development, the genomes of 13 traditional and commercial European pig breeds were scanned for signatures of diversifying selection using the Porcine60K SNP chip, applying a between-population (differentiation) approach. Signatures of diversifying selection between breeds were found in genomic regions associated with traits related to breed standard criteria, such as coat colour and ear morphology. Amino acid differences in the EDNRB gene appear to be associated with one of these signatures, and variation in the KITLG gene may be associated with another. Other selection signals were found in genomic regions including QTLs and genes associated with production traits such as reproduction, growth, and fat deposition. Some selection signatures were associated with regions showing evidence of introgression from Asian breeds. When the European breeds were compared with wild boar, genomic regions with high levels of differentiation harboured genes related to bone formation, growth, and fat deposition.
Defects in cilia formation and function result in a range of human skeletal and visceral abnormalities. Mutations in several genes have been identified to cause a proportion of these disorders, some ...of which display genetic (locus) heterogeneity. Mouse models are valuable for dissecting the function of these genes, as well as for more detailed analysis of the underlying developmental defects. The short-rib polydactyly (SRP) group of disorders are among the most severe human phenotypes caused by cilia dysfunction. We mapped the disease locus from two siblings affected by a severe form of SRP to 2p24, where we identified an in-frame homozygous deletion of exon 5 in WDR35. We subsequently found compound heterozygous missense and nonsense mutations in WDR35 in an independent second case with a similar, severe SRP phenotype. In a mouse mutation screen for developmental phenotypes, we identified a mutation in Wdr35 as the cause of midgestation lethality, with abnormalities characteristic of defects in the Hedgehog signaling pathway. We show that endogenous WDR35 localizes to cilia and centrosomes throughout the developing embryo and that human and mouse fibroblasts lacking the protein fail to produce cilia. Through structural modeling, we show that WDR35 has strong homology to the COPI coatamers involved in vesicular trafficking and that human SRP mutations affect key structural elements in WDR35. Our report expands, and sheds new light on, the pathogenesis of the SRP spectrum of ciliopathies.
GS:SFHS is a family-based genetic epidemiology study with DNA and socio-demographic and clinical data from about 24 000 volunteers across Scotland aged 18-98 years, from February 2006 to March 2011. ...Biological samples and anonymized data form a resource for research on the genetics of health, disease and quantitative traits of current and projected public health importance. Specific and important features of GS:SFHS include the family-based recruitment, with the intent of obtaining family groups; the breadth and depth of phenotype information, including detailed data on cognitive function, personality traits and mental health; consent and mechanisms for linkage of all data to comprehensive routine health-care records; and 'broad' consent from participants to use their data and samples for a wide range of medical research, including commercial research, and for re-contact for the potential collection of other data or samples, or for participation in related studies and the design and review of the protocol in parallel with in-depth sociological research on (potential) participants and users of the research outcomes. These features were designed to maximize the power of the resource to identify, replicate or control for genetic factors associated with a wide spectrum of illnesses and risk factors, both now and in the future.
AIM: Recent meta‐analyses have revealed that plant traits and their phylogenetic history influence decay rates of dead wood and leaf litter, but it remains unknown if decay rates of wood and litter ...covary over a wide range of tree species and across ecosystems. We evaluated the relationships between species‐specific wood and leaf litter decomposability, as well as between wood and leaf traits that control their respective decomposability. LOCATION: Global. METHODS: We compiled data on rates of wood and leaf litter decomposition for 324 and 635 tree species, respectively, and data on six functional traits for both organs. We used hierarchical Bayesian meta‐analysis to estimate, for the first time, species‐specific values for wood and leaf litter decomposability standardized to reference conditions (k*wₒₒd and k*ₗₑₐf) across the globe. With these data, we evaluated the relationships: (1) between wood and leaf traits, (2) between each k* and the selected traits within and across organs, and (3) between wood and leaf k*. RESULTS: Across all species k*wₒₒd and k*ₗₑₐf were positively correlated, phylogenetically clustered and correlated with plant functional traits within and across organs. k* of both organs was usually better described as a function of within‐ and cross‐organ traits, than of within‐organ traits alone. When analysed for angiosperms and gymnosperms separately, wood and leaf k* were no longer significantly correlated, but each k* was still significantly correlated to the functional traits. MAIN CONCLUSIONS: We demonstrate important relationships among wood and leaf litter decomposability as after‐life effects of traits from the living plants. These functional traits influence the decomposability of senesced tissue which could potentially lead to alterations in the rates of biogeochemical cycling, depending on the phylogenetic structure of the species pool. These results provide crucial information for a better representation of decomposition rates in dynamic global vegetation models.
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