Skortur á arfhreinum arfgerðum meðal 1,52 milljóna einstaklinga og erfðafræðilegar orsakir víkjandi fósturdauða

Abstract

Arfgerðir sem valda fósturdauða eru vandfundnar í lifandi einstaklingum. Til að kanna erfðafræðilegar orsakir víkjandi fósturdauða þróuðum við aðferð til að greina skort á arfhreinum arfgerðum (homozygous deficit) meðal 1,52 milljóna einstaklinga frá sex Evrópulöndum. Í þessari rannsókn auðkenndum við 25 gen með erfðabreytileika sem valda próteinbreytingum (protein altering variants) og skorti á arfhreinum arfgerðum (10% eða minna af áætluðum arfgerðum). Erfðabreytileikar í 12 genum valda víkjandi Mendelískum erfðasjúkdómi og tvö ríkjandi, en ekki hefur verið greint frá sjúkdómsvaldandi erfðabreytileika hinna 11 genanna. Gen með erfðabreytileika fyrir skorti af arfhreinum arfgerðum eru líklegri til að flokkast með genum sem nauðsynleg eru fyrir vöxt frumulína úr mönnum og lífvænleika músa. Virkni þessara gena gefur innsýn í erfðafræðilegar orsakir fósturdauða.

It is valuable to study the physiological and pathological consequences of naturally occurring gene knockouts. In a previous study[80], we identified 1,151 genes with homozygous loss-of-function genotypes in 104,220 Icelanders. However, our previous study had limited power to detect deficit of homozygosity for individual sequence variants. Our current study has vastly increased power to detect variants with deficit of homozygosity, as it is based on 1.52 million individuals from six European countries, amounting to a 15-fold increase in sample size from our previous study. To estimate a false discovery rate, we divided the fraction of intergenic sequence variants with strong deficits of homozygosity by that of protein-altering sequence variants. Using this method, we identified specific genes with protein-altering variants thatexhibited a strong deficit of homozygosity. Most importantly, we identified 25 genes with protein-altering variants exhibiting a deficit of homozygosity. Of these, 14 harbor variants reported to cause Mendelian disease. However, 11 of the genes were never previously implicated in human diseases. This is most likely becauseindividuals homozygous for these variants die before birth and are therefore unlikelyto be sampled in disease mutation discovery, which is typically based on livingindividuals with pathological conditions. As a key novelty of our study, we identifygenes that have an essential function for successful early development through theabsence of sampled individuals carrying homozygous genotypes.