Human homologue protein domains aid in interpreting genetic variants

What is it about?

Protein domains are vastly present in the human genome. These protein domains are especially interesting as they can have homologous relationships spanning many different proteins. We have made use of these homologous relationships to develop a framework that maps population variation and known pathogenic mutations onto “meta-domains”. We find that genetic tolerance is consistent across domain homologues in different genes, and that patterns of genetic tolerance faithfully mimic patterns of evolutionary conservation. Secondly, we find that population variation re-occurs at the same positions across domain homologues. Additionally, we observe that the presence of pathogenic variants at an aligned homologous domain position is often paired with the absence of population variation and vice versa. These meta-domains aid in interpreting genetic variants in protein domains.

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Why is it important?

Whole exomes of patients with a genetic disorder are nowadays routinely sequenced. Interpretation of the identified genetic variants remains a major challenge. The continuous growth of catalogues of human genetic variation has made it feasible to design methods that are able to investigate genetic tolerance at much finer scale than previously possible. These measures have been used, for example, to predict disease-causing genes in neurodevelopmental disorders.

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