The impact of ancestral, genetic, and environmental influences on germline de novo mutation rates and spectra.

De novo germline mutation is an important factor in the evolution of allelic diversity and disease predisposition in a population. Here, we study the influence of genetically-inferred ancestry and environmental factors on de novo mutation rates and spectra. Using a genetically diverse sample of ~10 K whole-genome sequenced trios, one of the largest de novo mutation catalogues to date, we found that genetically-inferred ancestry is associated with modest but significant changes in both germline mutation rate and spectra across continental populations.

Clonal diversification and histogenesis of malignant germ cell tumours.

Germ cell tumours (GCTs) are a collection of benign and malignant neoplasms derived from primordial germ cells. They are uniquely able to recapitulate embryonic and extraembryonic tissues, which carries prognostic and therapeutic significance. The developmental pathways underpinning GCT initiation and histogenesis are incompletely understood.

Reduced reproductive success is associated with selective constraint on human genes.

Genome-wide sequencing of human populations has revealed substantial variation among genes in the intensity of purifying selection acting on damaging genetic variants. Although genes under the strongest selective constraint are highly enriched for associations with Mendelian disorders, most of these genes are not associated with disease and therefore the nature of the selection acting on them is not known. Here we show that genetic variants that damage these genes are associated with markedly reduced reproductive success, primarily owing to increased childlessness, with a stronger effect in males than in females.

Extensive phylogenies of human development inferred from somatic mutations.

Starting from the zygote, all cells in the human body continuously acquire mutations. Mutations shared between different cells imply a common progenitor and are thus naturally occurring markers for lineage tracing. Here we reconstruct extensive phylogenies of normal tissues from three adult individuals using whole-genome sequencing of 511 laser capture microdissections.

The mutational landscape of human somatic and germline cells.

Over the course of an individual's lifetime, normal human cells accumulate mutations. Here we compare the mutational landscape in 29 cell types from the soma and germline using multiple samples from the same individuals. Two ubiquitous mutational signatures, SBS1 and SBS5/40, accounted for the majority of acquired mutations in most cell types, but their absolute and relative contributions varied substantially.

The contribution of X-linked coding variation to severe developmental disorders.

Over 130 X-linked genes have been robustly associated with developmental disorders, and X-linked causes have been hypothesised to underlie the higher developmental disorder rates in males. Here, we evaluate the burden of X-linked coding variation in 11,044 developmental disorder patients, and find a similar rate of X-linked causes in males and females (6.0% and 6.

A platform for curated products from novel open reading frames prompts reinterpretation of disease variants.

Recent evidence from proteomics and deep massively parallel sequencing studies have revealed that eukaryotic genomes contain substantial numbers of as-yet-uncharacterized open reading frames (ORFs). We define these uncharacterized ORFs as novel ORFs (nORFs). nORFs in humans are mostly under 100 codons and are found in diverse regions of the genome, including in long noncoding RNAs, pseudogenes, 3' UTRs, 5' UTRs, and alternative reading frames of canonical protein coding exons.

Identification of deleterious and regulatory genomic variations in known asthma loci.

Background: Candidate gene and genome-wide association studies have identified hundreds of asthma risk loci. The majority of associated variants, however, are not known to have any biological function and are believed to represent markers rather than true causative mutations. We hypothesized that many of these associated markers are in linkage disequilibrium (LD) with the elusive causative variants.