MosaicBase:A Knowledgebase of Postzygotic Mosaic Variants in Noncancer Disease-related and Healthy Human Individuals

Mosaic variants resulting from postzygotic mutations are prevalent in the human genome and play important roles in human diseases.However,except for cancer-related variants,there is no collection of postzygotic mosaic variants in noncancer disease-related and healthy individuals.Here,we present MosaicBase,a comprehensive database that includes 6698 mosaic variants related to 266 noncancer diseases and 27,991 mosaic variants identified in 422 healthy individuals.Genomic and phenotypic information of each variant was manually extracted and curated from 383 publications.MosaicBase supports the query of variants with Online Mendelian Inheritance in Man(OMIM)entries,genomic coordinates,gene symbols,or Entrez IDs.We also provide an integrated genome browser for users to easily access mosaic variants and their related annotations for any genomic region.By analyzing the variants collected in MosaicBase,we find that mosaic variants that directly contribute to disease phenotype show features distinct from those of variants in individuals with mild or no phenotypes,in terms of their genomic distribution,mutation signatures,and fraction of mutant cells.MosaicBase will not only assist clinicians in genetic counseling and diagnosis but also provide a useful resource to understand the genomic baseline of postzygotic mutations in the general human population.MosaicBase is publicly available at http://mosaicbase.com/or http://49.4.21.8:8000.

Common Postzygotic Mutational Signatures in Healthy Adult Tissues Related to Embryonic Hypoxia

Postzygotic mutations are acquired in normal tissues throughout an individual’s lifetime and hold clues for identifying mutagenic factors.Here,we investigated postzygotic mutation spectra of healthy individuals using optimized ultra-deep exome sequencing of the time-series samples from the same volunteer as well as the samples from different individuals.In blood,sperm,and muscle cells,we resolved three common types of mutational signatures.Signatures A and B represent clocklike mutational processes,and the polymorphisms of epigenetic regulation genes influence the proportion of signature B in mutation profiles.Notably,signature C,characterized by C>T transitions at GpCpN sites,tends to be a feature of diverse normal tissues.Mutations of this type are likely to occur early during embryonic development,supported by their relatively high allelic frequencies,presence in multiple tissues,and decrease in occurrence with age.Almost none of the public datasets for tumors feature this signature,except for 19.6%of samples of clear cell renal cell carcinoma with increased activation of the hypoxia-inducible factor 1(HIF-1)signaling pathway.Moreover,the accumulation of signature C in the mutation profile was accelerated in a human embryonic stem cell line with drug-induced activation of HIF-1α.Thus,embryonic hypoxia may explain this novel signature across multiple normal tissues.Our study suggests that hypoxic condition in an early stage of embryonic development is a crucial factor inducing C>T transitions at GpCpN sites;and individuals’genetic background may also influence their postzygotic mutation profiles.

Postzygotic mosaic mutations in autism spectrum disorder and other neuropsychiatric disorders

Autism, or autism spectrum disorder （ASD）, refers to a range of neurodevelopmental disorders characterized by： （1） impaired social interaction, （2） impaired verbal and non-verbal communication, and （3） restricted and repetitive behavior. Although Wpically not diagnosed until the age of 3, symptoms can present during infancy. Early intervention with behavioral therapies has been shown to improve learning, communication, and social skills. This means it is essential to find a method for evaluating characteristics associated with ASD as early as possible .

Sex-specific life-history trait expression in hybrids of a cave- and surface-dwelling fish (Poecilia mexicana, Poecilidae)

Evaluating the fitness of hybrids can provide important insights into genetic differences between species or diverging populations.We focused on surface-and cave-ecotypes of the widespread Atlantic molly Poecilia mexicana and raised F1 hybrids of reciprocal crosses to sexual maturity in a common-garden experiment.Hybrids were reared in a fully factorial 2 x 2 design consisting of lighting(light vs.darkness)and resource availability(high vs.low food).We quantified survival,ability to realize their full reproductive potential(i.e.,completed maturation for males and 3 consecutive births for females)and essential life-history traits.Compared to the performance of pure cave and surface fish from a previous experiment,F1s had the highest death rate and the lowest proportion of fish that reached their full reproductive potential.We also uncovered an intriguing pattern of sex-specific phenotype expression,because male hybrids expressed cave molly life histories,while female hybrids expressed surface molly life histories.Our results provide evidence for strong selection against hybrids in the cave molly system,but also sug-gest a complex pattern of sex-specific(opposing)dominance,with certain surface molly genes being dominant in female hybrids and certain cavemollygenes beingdominant in malehybrids.

Experimental hybridization and reproductive isolation between two sympatric species of tephritid fruit flies in the Anastrepha fraterculus species group

Among tephritid fruit flies,hybridization has been found to produce local adaptation and speciation,and in the case of pest species,induce behavioral and ecological alterations that can adversely impact efficient pest management.Thefraterculus species group within Anastrepha (Diptera:Tephritidae),is a rapidly radiating aggregate,which includes cryptic species complexes,numerous sister species,and several pest species. Molecular studies have highlighted the possibility of introgression between A.fraterculus and A.obliqua.Reproductive isolation has been studied among morphotypes of the A. fraterculus species complex as a tool for species delimitation.Here we examined the exis- tence and strength of prezygotic and postzygotic isolation between sympatric populations of two closely related species within the highly derivedfraterculus group (A.fraterculus and A.obliqua),coexisting in nature.Although adults of both species showed a strong tendency for assortative mating,a small proportion of hybrid pairings in both directions were observed.We also observed asymmetric postzygotic isolation,with one hybrid cross displaying a strong reduction in fecundity and F1 egg fertility.Survival was greater for the progeny of homotypic and hybrid crosses in the maternal host.There was a marked female biased sex ratio distortion for both F1 hybrid adults.Hybridization between A.fraterculus and A.obliqua in nature may be difficult but possible;these two species display stronger reproductive isolation than all pairs of species previously examined in the A.fraterculus species complex.Asymmetric postzygotie isolation is suggestive of Wolbachia mediated cytoplasmic incompatibilities that may be exploited in area-wide pest management.