De novo genes are very important for evolutionary innovation. However, how these genes originate and spread remains largely unknown. To better understand this, we rigorously searched for de novo genes in Saccharomyces cerevisiae S288C and examined their spread and fixation in the population. Here, we identified 84 de novo genes in S. cerevisiae S288C since the divergence with their sister groups. Transcriptome and ribosome profiling data revealed at least 8 (10%) and 28 (33%) de novo genes being expressed and translated only under specific conditions, respectively. DNA microarray data, based on 2-fold change, showed that 87% of the de novo genes are regulated during various biological processes, such as nutrient utilization and sporulation. Our comparative and evolutionary analyses further revealed that some factors, including single nucleotide polymorphism (SNP)/indel mutation, high GC content, and DNA shuffling, contribute to the birth of de novo genes, while domestication and natural selection drive the spread and fixation of these genes. Finally, we also provide evidence suggesting the possible parallel origin of a de novo gene between S. cerevisiae and Saccharomyces paradoxus . Together, our study provides several new insights into the origin and spread of de novo genes. IMPORTANCE Emergence of de novo genes has occurred in many lineages during evolution, but the birth, spread, and function of these genes remain unresolved. Here we have searched for de novo genes from Saccharomyces cerevisiae S288C using rigorous methods, which reduced the effects of bad annotation and genomic gaps on the identification of de novo genes. Through this analysis, we have found 84 new genes originating de novo from previously noncoding regions, 87% of which are very likely involved in various biological processes. We noticed that 10% and 33% of de novo genes were only expressed and translated under specific conditions, therefore, verification of de novo genes through transcriptome and ribosome profiling, especially from limited expression data, may underestimate the number of bona fide new genes. We further show that SNP/indel mutation, high GC content, and DNA shuffling could be involved in the birth of de novo genes, while domestication and natural selection drive the spread and fixation of these genes. Finally, we provide evidence suggesting the possible parallel origin of a new gene.

Background: Fungi exhibit astonishing diversity with multiple major phenotypic transitions over the kingdom’s evolutionary history. As part of this process, fungi developed hyphae, adapted to land environments (terrestrialization), and innovated their sexual structures. These changes also helped fungi establish ecological relationships with other organisms (animals and plants), but the genomic basis of these changes remains largely unknown. Results: By systematically analyzing 304 genomes from all major fungal groups, together with a broad range of eukaryotic outgroups, we have identified 188 novel orthogroups associated with major changes during the evolution of fungi. Functional annotations suggest that many of these orthogroups were involved in the formation of key trait innovations in extant fungi and are functionally connected. These innovations include components for cell wall formation, functioning of the spindle pole body, polarisome formation, hyphal growth, and mating group signaling. Innovation of mitochondria-localized proteins occurred widely during fungal transitions, indicating their previously unrecognized importance. We also find that prokaryote-derived horizontal gene transfer provided a small source of evolutionary novelty with such genes involved in key metabolic pathways. Conclusions: The overall picture is one of a relatively small number of novel genes appearing at major evolutionary transitions in the phylogeny of fungi, with most arising de novo and horizontal gene transfer providing only a small additional source of evolutionary novelty. Our findings contribute to an increasingly detailed portrait of the gene families that define fungal phyla and underpin core features of extant fungi.

Genome-wide nucleotide composition varies widely among species. Despite extensive research, the source of genome-wide nucleotide composition diversity remains elusive. Yeast mitochondrial genomes (mitogenomes) are highly A + T rich, and they provide a unique opportunity to study the evolution of AT-biased landscape. In this study, we sequenced ten complete mitogenomes of the Saccharomycodes ludwigii yeast with 8% G + C content, the lowest genome-wide %(G + C) in all published genomes to date. The S. ludwigii mitogenomes have high densities of short tandem repeats but severely underrepresented mononucleotide repeats. Comparative population genomics of these record-setting A + T-rich genomes shows dynamic indel mutations and strong mutation bias toward A/T. Indel mutations play a greater role in genomic variation among very closely related strains than nucleotide substitutions. Indels have resulted in presence–absence polymorphism of tRNA^Arg (ACG) among S. ludwigii mitogenomes. Interestingly, these mitogenomes have undergone recombination, a genetic process that can increase G + C content by GC-biased gene conversion. Finally, the expected equilibrium G + C content under mutation pressure alone is higher than observed G + C content, suggesting existence of mechanisms other than AT-biased mutation operating to increase A/T. Together, our findings shed new lights on mechanisms driving extremely AT-rich genomes.

OBJECTIVE: Metformin is the most common treatment for type 2 diabetes (T2D). However, there have been no pharmacogenomic studies for T2D in which a population of color was used in the discovery analysis. This study sought to identify genomic variants associated with metformin response in African American patients with diabetes. RESEARCH DESIGN AND METHODS: Patients in the discovery set were adult, African American participants from the Diabetes Multi-omic Investigation of Drug Response (DIAMOND), a cohort study of patients with T2D from a health system serving southeast Michigan. DIAMOND participants had genome-wide genotype data and longitudinal electronic records of laboratory results and medication fills. The genome-wide discovery analysis identified polymorphisms correlated to changes in glycated hemoglobin (HbA1c) levels among individuals on metformin monotherapy. Lead associations were assessed for replication in an independent cohort of African American participants from Kaiser Permanente Northern California (KPNC) and in European American participants from DIAMOND. RESULTS: The discovery set consisted of 447 African American participants, whereas the replication sets included 353 African American KPNC participants and 466 European American DIAMOND participants. The primary analysis identified a variant, rs143276236, in the gene ARFGEF3, which met the threshold for genome-wide significance, replicated in KPNC African Americans, and was still significant in the meta-analysis (P = 1.17 × 10−9). None of the significant discovery variants replicated in European Americans DIAMOND participants. CONCLUSIONS: We identified a novel and biologically plausible genetic variant associated with a change in HbA1c levels among African American patients on metformin monotherapy. These results highlight the importance of diversity in pharmacogenomic studies.