ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: Nature 2020; 581, 434–443

The Genome Aggregation Database (gnomAD) Consortium https://gnomad.broadinstitute.org compiled data on ˜125,000 exomes and ~15,000 whole genomes from populations around the world. This is one of seven articles (also see Refs 1–6) describing their initial discoveries, showing the power of this vast dataset, and presenting a more complete catalog of loss-of-function variants, which disrupt the encoded proteins. This is an important tool to help inform the diagnosis of rare genetic diseases in our patients. It also provides fundamental insights into which of our genes appear to be essential, by quantifying how many loss-of-function variants are present in each gene in humans.

This is an expansion of the 1000 Genomes Project. The many partners of the Consortium identified more than 443,000 loss-of-function variants, while classifying all protein-coding genes and identifying many duplications, deletions, inversions, and other changes involving larger DNA segments (> 50-100 bases long). At least 25% of all rare loss-of-function variants are structural variants; many people carry these deleterious structural alterations without the expected phenotypes or clinical outcomes.

The physiological function of most genes in the human genome remains unknown. For the discovery of gene function, a common approach is to introduce disruptive mutations into genes in cell or animal models to determine their effects on cellular and physiological phenotypes. Such studies have yielded valuable insight into eukaryotic physiology and have guided the design of therapeutic agents. However, while such model organisms have been crucial in deciphering the function of many human genes, they remain imperfect proxies for human physiology. Using natural loss-of-function variants is supposed to give us a more direct approach to the study of gene function.

Loss-of-function variants are mostly deleterious for health and development and are thus typically maintained at very low frequencies in human populations, but there is wide variation between genes in the numbers of such deleterious variants that we humans carry. These new data describe which genes we can survive without (e.g. loss-of-function variants are frequent in the olfactory genes) and which genes are more essential (e.g. genes that are also associated with embryonic lethality). The latter ‘constrained’ genes are more ubiquitously expressed throughout body tissues and interact with more other proteins – they can be associated with human disease but are more likely de novo mutations than inherited.

The authors suggest the near-future feasibility and considerable value of a human ‘knockout’ project—a systematic attempt to discover the phenotypic consequences of functionally disruptive mutations, in either the heterozygous or homozygous state, for all human protein-coding genes.

References:

1. RL Collins et al A structural variation reference for medical and population genetics. Nature, 2020; 581 (7809): 444.

2. BB Cummings et al, Transcript expression-aware annotation improves rare variant interpretation. Nature, 2020; 581 (7809): 452.

3. Q Wang, et al. Landscape of multi-nucleotide variants in 125,748 human exomes and 15,708 genomes. Nature Communications, 2020; 11 (1).

4. N Whiffin, et al. Characterising the loss-of-function impact of 5’ untranslated region variants in 15,708 individuals. Nature Communications, 2020; 11 (1).

5. EB Minikel, et al. Evaluating drug targets through human loss-of-function genetic variation. Nature, 2020; 581 (7809): 459.6. N Whiffin, et al The effect of LRRK2 loss-of-function variants in humans. Nature Medicine, 2020.