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Resolving the relationships between the major lineages in the animal tree of life is necessary to understand the origin and evolution of key animal traits. Sponges, characterized by their simple body plan, were traditionally considered the sister group of all other animal lineages, implying a gradual increase in animal complexity from unicellularity to complex multicellularity. However, the availability of genomic data has sparked tremendous controversy as some phylogenomic studies support comb jellies taking this position, requiring secondary loss or independent origins of complex traits. Here we show that incorporating site-heterogeneous mixture models and recoding into partitioned phylogenomics alleviates systematic errors that hamper commonly-applied phylogenetic models. Testing on real datasets, we show a great improvement in model-fit that attenuates branching artefacts induced by systematic error. We reanalyse key datasets and show that partitioned phylogenomics does not support comb jellies as sister to other animals at either the supermatrix or partition-specific level. Branching artefacts can confound the reconstruction of deep evolutionary relationships. Here, the authors show improvement in partitioned phylogenomic analyses when using site-heterogeneous models and amino acid recoding, including in resolving the debated phylogenetic placement of comb jellies.

Mendel, a genius experimentalist, meticulously uncovered the genetic basis of heredity in work that transformed the science of biology. But does the alluring simplicity of Mendel's laws sometimes obscure the true complexity of genetics?

The origin of novel protein-coding genes de novo was once considered so improbable as to be impossible. In less than a decade, and especially in the last five years, this view has been overturned by extensive evidence from diverse eukaryotic lineages. There is now evidence that this mechanism has contributed a significant number of genes to genomes of organisms as diverse as Saccharomyces, Drosophila, Plasmodium, Arabidopisis and human. From simple beginnings, these genes have in some instances acquired complex structure, regulated expression and important functional roles. New genes are often thought of as dispensable late additions; however, some recent de novo genes in human can play a role in disease. Rather than an extremely rare occurrence, it is now evident that there is a relatively constant trickle of proto-genes released into the testing ground of natural selection. It is currently unknown whether de novo genes arise primarily through an ‘RNA-first’ or ‘ORF-first’ pathway. Either way, evolutionary tinkering with this pool of genetic potential may have been a significant player in the origins of lineage-specific traits and adaptations.

The origin of ‘orphan’ genes, species-specific sequences that lack detectable homologues, has remained mysterious since the dawn of the genomic era. There are two dominant explanations for orphan genes: complete sequence divergence from ancestral genes, such that homologues are not readily detectable; and de novo emergence from ancestral non-genic sequences, such that homologues genuinely do not exist. The relative contribution of the two processes remains unknown. Here, we harness the special circumstance of conserved synteny to estimate the contribution of complete divergence to the pool of orphan genes. By separately comparing yeast, fly and human genes to related taxa using conservative criteria, we find that complete divergence accounts, on average, for at most a third of eukaryotic orphan and taxonomically restricted genes. We observe that complete divergence occurs at a stable rate within a phylum but at different rates between phyla, and is frequently associated with gene shortening akin to pseudogenization.

In this Opinion article, the authors discuss important questions relating to the study of de novo genes. They discuss the challenges of identifying de novo genes, understanding how they originate and why they spread, and propose that antagonistic evolution may have a key role in their evolution. The study of de novo protein-coding genes is maturing from the ad hoc reporting of individual cases to the systematic analysis of extensive genomic data from several species. We identify three key challenges for this emerging field: understanding how best to identify de novo genes, how they arise and why they spread. We highlight the intellectual challenges of understanding how a de novo gene becomes integrated into pre-existing functions and becomes essential. We suggest that, as with protein sequence evolution, antagonistic co-evolution may be key to de novo gene evolution, particularly for new essential genes and new cancer-associated genes.

Ancient polyploidization events have had a lasting impact on vertebrate genome structure, organization and function. Some key questions regarding the number of ancient polyploidization events and their timing in relation to the cyclostome-gnathostome divergence have remained contentious. Here we generate de novo long-read-based chromosome-scale genome assemblies for the Japanese lamprey and elephant shark. Using these and other representative genomes and developing algorithms for the probabilistic macrosynteny model, we reconstruct high-resolution proto-vertebrate, proto-cyclostome and proto-gnathostome genomes. Our reconstructions resolve key questions regarding the early evolutionary history of vertebrates. First, cyclostomes diverged from the lineage leading to gnathostomes after a shared tetraploidization (1R) but before a gnathostome-specific tetraploidization (2R). Second, the cyclostome lineage experienced an additional hexaploidization. Third, 2R in the gnathostome lineage was an allotetraploidization event, and biased gene loss from one of the subgenomes shaped the gnathostome genome by giving rise to remarkably conserved microchromosomes. Thus, our reconstructions reveal the major evolutionary events and offer new insights into the origin and evolution of vertebrate genomes. Early vertebrate genomes were shaped by multiple whole-genome duplication (WGD) events of debated timings. Here the authors’ reconstruction of ancestral genomes using the probabilistic macrosynteny model supports a WGD shared by all vertebrates and a gnathostome-specific WGD, and reveals evidence of a cyclostome-specific genome triplication.

Human copy number variants (CNVs) account for genome variation an order of magnitude larger than single-nucleotide polymorphisms. Although much of this variation has no phenotypic consequences, some variants have been associated with disease, in particular neurodevelopmental disorders. Pathogenic CNVs are typically very large and contain multiple genes, and understanding the cause of the pathogenicity remains a major challenge. Here we show that pathogenic CNVs are significantly enriched for genes involved in development and genes that have greater evolutionary copy number conservation across mammals, indicative of functional constraints. Conversely, genes found in benign CNV regions have more variable copy number. These evolutionary constraints are characteristic of genes in pathogenic CNVs and can only be explained by dosage sensitivity of those genes. These results implicate dosage sensitivity of individual genes as a common cause of CNV pathogenicity. These evolutionary metrics suggest a path to identifying disease genes in pathogenic CNVs. Copy number variants (CNVs) cause significant genomic variation in humans and may be benign or may cause disease. Here, the authors show that pathogenic CNVs are evolutionarily constrained compared with benign, pointing to dosage sensitivity as a potential cause of disease.

For a subset of genes in our genome a change in gene dosage, by duplication or deletion, causes a phenotypic effect. These dosage-sensitive genes may confer an advantage upon copy number change, but more typically they are associated with disease, including heart disease, cancers and neuropsychiatric disorders. This gene copy number sensitivity creates characteristic evolutionary constraints that can serve as a diagnostic to identify dosage-sensitive genes. Though the link between copy number change and disease is well-established, the mechanism of pathogenicity is usually opaque. We propose that gene expression level may provide a common basis for the pathogenic effects of many copy number variants.

About 30% of protein-coding genes in the human genome are related through two whole genome duplication (WGD) events. Although WGD is often credited with great evolutionary importance, the processes governing the retention of these genes and their biological significance remain unclear. One increasingly popular hypothesis is that dosage balance constraints are a major determinant of duplicate gene retention. We test this hypothesis and show that WGD-duplicated genes (ohnologs) have rarely experienced subsequent small-scale duplication (SSD) and are also refractory to copy number variation (CNV) in human populations and are thus likely to be sensitive to relative quantities (i.e., they are dosage-balanced). By contrast, genes that have experienced SSD in the vertebrate lineage are more likely to also display CNV. This supports the hypothesis of biased retention of dosage-balanced genes after WGD. We also show that ohnologs have a strong association with human disease. In particular, Down Syndrome (DS) caused by trisomy 21 is widely assumed to be caused by dosage effects, and 75% of previously reported candidate genes for this syndrome are ohnologs that experienced no other copy number changes. We propose the remaining dosage-balanced ohnologs on chromosome 21 as candidate DS genes. These observations clearly show a persistent resistance to dose changes in genes duplicated by WGD. Dosage balance constraints simultaneously explain duplicate gene retention and essentiality after WGD.