EMBL Keynote Lecture - The Role of Essential Genes in Human Disease, Maja Bucan

Presenter: Maja Bucan, Perelman School of Medicine, University of Pennsylvania, USA
From the EMBL Conference: Mammalian Genetics and Genomics: From Molecular Mechanisms to Translational Applications
EMBL Advanced Training Centre Heidelberg, Germany
24 - 27 October 2017
Large-scale genome-wide association studies (GWAS) have identified thousands of single nucleotide polymorphisms (SNPs) associated with hundreds of traits and diseases. However, risk SNPs explain a small fraction of trait variance and only occasionally pinpoint biological mechanisms underlying these associations. Application of several recently developed methods that aggregate the effects of all SNPs regardless of their significance (but weighted based on their effect size) revealed that common variants explain a large fraction of heritability for many
complex disease and traits. Therefore, the main challenge in the current understanding of the genetic architecture of complex neurodevelopmental diseases, such as Autism Spectrum
Disorder, comes from a need to study the interplay between rare variants with a high-effect (for example de novo variants or recurrent mutations) and a background of common variants with
an intermediate effect, but nevertheless still disrupt proper neuronal development. Essential genes, or genes that are necessary for successful completion of pre- and postnatal
development, are prime candidates for the source of this background. Essential genes are highly enriched for human disease genes and are under strong purifying selection. In addition
to intolerance to loss-of-function and deleterious mutations, the functional impact of essential genes is reflected by the relatively high frequency of haploinsufficiency in this group of genes.
We compiled a comprehensive list of essential genes in humans, and determined the allele frequencies of both de novo and inherited damaging variants in these genes in 1,781 ASD
subjects and their parents. Expression analysis in the developing human brain identified clusters of co-expressed essential genes that contribute to ASD risk, and which suggest prime candidates for several neurodevelopmental diseases.

[@SadhuBiochemist]

Maja should spend the rest of her life not avoiding the psychiatric problems that she caused in her employees, former students, and even family members. It's a disgrace that she avoids facing the music by engaging in trivial research.

[@SadhuBiochemist]

She is a complete hypocrite.

[@SadhuBiochemist]

What about sonic hedgehog? Published too quickly, because she was scooped by Joe Takahashi.

[@SadhuBiochemist]

Scott didn't tell you to do a balancer screen. I did; it was a key part of my prelim exam. Shame on both of you!

[@SadhuBiochemist]

Did Luke turn out to be autistic?