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PNAS Studies on Common LoF Genes, Testis Development Determinants, Coral Interactions

Editor's Note: Some of the articles described below are not yet available at the PNAS site, but they are scheduled to be posted some time this week.

In a paper appearing in the Proceedings of the National Academy of Sciences, researchers from France, the US, and the UK characterize autosomal genes that appear to be affected by loss-of-function (LoF) variants in more than 1 percent of the population. Starting with a set of more than 200 predicted LoF variants that reached this frequency in more than 120,000 individuals from five ancestry groups included in the ExAC and gnomAD databases, the team focused in on 166 genes affected by 179 LoF variants — a set that included 41 olfactory receptor genes that appear to be subject to relaxed selection. "Overall, the identification of 166 genes for which a sizable proportion of humans are homozygous for predicted LoF alleles reveals both redundancies and advantages of such deficiencies for human survival," the authors report.

An international team led by investigators at the Pasteur Institute takes a look at contributors to testis formation in individuals who have two copies of the X chromosome and the so-called 46,XX karyotype. Using exome sequencing, the researchers searched for contributors to testicular disorders/differences of sex development (TDSD) or ovotesticular disorders/differences of sex development (OTDSD) in 78 individuals with 46,XX, uncovering seven heterozygous variants in the same zinc finger domain-coding portion of the WT1 gene. In follow-up mouse model experiments, they found that the introduction of pathogenic variants affecting this zinc finger region led to fetal gonad masculinization in animals carrying two copies of the X chromosome. "The phenotype could be explained by the ability of the mutated proteins to physically interact with and sequester a key pro-ovary factor beta-CATENIN," the authors propose, "which may lead to up-regulation of testis-specific pathway."

Researchers from the University of Hawaii, San Diego State University, and elsewhere share findings from a metagenomic sequence-, metabolomic-, and fluorescence microscopy-based analysis of the holobiont collection of organisms associated with coral. Based on microbial abundance, metabolite profiles, genetic, and other data generated through multiomic analyses on dozens of coral-turf algae reef tissue and water samples collected near the Caribbean island of Curaçao, the team concludes that "there are specific functional genes, microbial taxa, and metabolites which distinguish coral, turf algae, and interface communities, and that these functions, taxa, and metabolites are also linked to the competitive outcomes of these interactions."